Novel compounds containing an N-methylpiperazineethanolcarbamate structure and their applications

Abstract

This invention relates to a novel compound containing an N-methylpiperazine ethanol carbamate structure and its uses.

Description

Technical Field

[0001] The present invention relates to a novel compound containing an N-methylpiperazine ethanol carbamate structure and its uses.

Background Art

[0002] Pulmonary fibrosis means a state in which fibrous connective tissue proliferates in the lungs, destroying the normal lung structure and causing the lung tissue to harden and deteriorate.

[0003] In particular, idiopathic pulmonary fibrosis is a disease in which chronic inflammatory cells invade the alveolar wall, causing various changes and hardening the lungs, resulting in profound structural changes in the lung tissue and sequentially deteriorating lung function. There is no effective treatment method yet.

[0004] In addition, radiotherapy is frequently used for NSCLC tumor patients who cannot undergo resection, but it often causes radiation-induced pulmonary fibrosis (RIPF).

[0005] To date, as a compound with a certain degree of effect, Ofev of Boehringer Ingelheim containing nintedanib as an active ingredient is known to delay the decline of lung function, but there is an increasing need to develop a more effective drug.

Summary of the Invention

Problems to be Solved by the Invention

[0006] As a result of intensive efforts to develop a more effective drug for the prevention or treatment of pulmonary fibrosis, the present inventors confirmed the preventive or therapeutic effect of pulmonary fibrosis of a novel compound containing an N-methylpiperazine ethanol carbamate structure, and completed this application.

Means for Solving the Problems

[0007] The present invention aims to provide a compound represented by chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof.

[0008] [ka]

[0009] In chemical formula (1), Ar is trifluoromethyl (CF3) or a halogen-substituted aryl or heteroaryl group, and R is represented by chemical formula (2) or (3).

[0010] [ka]

[0011] [ka]

[0012] In one embodiment, Ar in chemical formula (1) is represented by chemical formula (6) or (7).

[0013] [ka]

[0014] [ka]

[0015] In any of the above-described examples, the compound represented by chemical formula (1) is the compound represented by chemical formula (4) or (5).

[0016] [ka]

[0017] [Chemical formula]

[0018] Furthermore, an object of the present invention is to provide a composition comprising a compound represented by chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0019] Furthermore, an object of the present invention is to provide a pharmaceutical composition for preventing or treating pulmonary fibrosis, comprising a compound represented by chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof.

[0020] Furthermore, an object of the present invention is to provide a method for preventing or treating pulmonary fibrosis, comprising the step of administering the pharmaceutical composition to an individual.

[0021] Furthermore, an object of the present invention is to provide a food composition for preventing or treating pulmonary fibrosis, comprising a compound represented by chemical formula (1), or a food-grade acceptable salt or solvate thereof. [Advantages of the Invention]

[0022] The novel compound of the present invention is useful for preventing or treating pulmonary fibrosis. [Brief Description of the Drawings]

[0023] [Figure 1a] It is a diagram showing the MS analysis results of synthesized DCTP. [Figure 1b] It is a diagram showing the 1H-NMR analysis results of synthesized DCTP. [Figure 1c] It is a diagram showing the 1H-NMR analysis results of synthesized DCTP. [Figure 1d] It is a diagram showing the 1H-NMR analysis results of synthesized DCTP. [Figure 2]This figure shows the effect of administering nintedanib and / or DCTP to mice that had been given bleomycin to induce idiopathic pulmonary fibrosis, and then confirming the inhibitory effect on idiopathic pulmonary fibrosis by micro-CT imaging. [Figure 3] This graph shows the degree of inflammation and fibrosis observed in mice that were administered bleomycin to induce idiopathic pulmonary fibrosis, then nintedanib and / or DCTP, followed by H&E and Masson's Trichrome staining. [Figure 4] This figure shows the effect of administering nintedanib and / or DCTP to mice in which pulmonary fibrosis was induced by radiation, and then confirming the suppression of radiation-induced pulmonary fibrosis by micro-CT imaging. [Figure 5] This graph shows the degree of inflammation and fibrosis observed in mice in which pulmonary fibrosis was induced by radiation, followed by administration of nintedanib and / or DCTP, and then confirmed by H&E and Masson's Trichrome staining. [Figure 6a] This figure shows the MS analysis results of the synthesized PXDP. [Figure 6b] This figure shows the results of the H-NMR analysis of the synthesized PXDP. [Figure 7] This figure shows the effect of administering nintedanib and / or PXDP to mice that had been given bleomycin to induce idiopathic pulmonary fibrosis, and then confirming the inhibitory effect on idiopathic pulmonary fibrosis by micro-CT imaging. [Figure 8] This graph shows the degree of inflammation and fibrosis observed by H&E and Masson's Trichrome staining after administering nintedanib and / or PXDP to mice that had been given bleomycin to induce idiopathic pulmonary fibrosis. [Figure 9] This figure shows the results of administering bleomycin to mice to induce idiopathic pulmonary fibrosis, followed by administration of nintedanib and / or PXDP, and then checking the survival rate of the mice. [Figure 10] This figure shows the effect of administering nintedanib and / or PXDP to mice in which pulmonary fibrosis was induced by radiation, and then confirming the suppression of radiation-induced pulmonary fibrosis by micro-CT imaging. [Figure 11] This graph shows the degree of inflammation and fibrosis observed in mice in which pulmonary fibrosis was induced by radiation, followed by administration of nintedanib and / or PXDP, and then confirmed by H&E and Masson's Trichrome staining. [Modes for carrying out the invention]

[0024] These will be explained in detail below. Note that each description and embodiment disclosed in this invention applies to other descriptions and embodiments. That is, any combination of the various elements disclosed in this invention is included. Furthermore, this invention is not limited to the following specific descriptions.

[0025] Furthermore, a person with ordinary skill in the art would be able to recognize and confirm many equivalents of the specific embodiments of the present invention described herein using only ordinary experiments. Moreover, these equivalents are also intended to be included in the present invention.

[0026] Furthermore, numerous papers and patent documents are referenced throughout this specification, and their citations are indicated. The disclosures of the cited papers and patent documents are incorporated in their entirety as references within this specification, thereby more clearly explaining the level of the art to which the present invention belongs and the content of the present invention.

[0027] One aspect of the present invention provides a compound comprising an N-methylpiperazine ethanol carbamate structure represented by chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof.

[0028] [ka]

[0029] In chemical formula (1), Ar is trifluoromethyl (CF3) or a halogen-substituted aryl or heteroaryl group, and R is represented by chemical formula (2) or (3).

[0030] [ka]

[0031] [ka]

[0032] For example, the halogen may be Cl or F.

[0033] For example, the Ar in chemical formula (1) may be represented by chemical formula (6) or (7).

[0034] [ka]

[0035] [ka]

[0036] For example, the compound of chemical formula (1) of the present invention may have the structure of chemical formula (4).

[0037] [ka]

[0038] The compound of chemical formula (4) is named 2-(4-methylpiperazin-1-yl)ethyl(E)-(3-chloro-4-fluorophenyl)(7-methoxy-6-(4-(piperidin-1-yl)but-2-enamido)quinazolin-4-yl)carbamate, and in this invention it is also called "DCTP".

[0039] For example, the compound of chemical formula (1) of the present invention may have the structure of chemical formula (5).

[0040] [ka]

[0041] The compound of chemical formula (5) is named 2-(4-methylpiperazin-1-yl)ethyl(5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamate, and in this invention it is also called "PXDP".

[0042] The compounds provided in this invention include not only compounds represented by specific chemical formulas, but also their clathrates, hydrates, solvates, or polymorphs. Furthermore, "compounds of the present invention" includes pharmaceutically acceptable salts of the compounds of the present invention unless otherwise specified. In one example, the compounds of the present invention exist as stereoisomerically pure compounds (for example, those substantially free of other stereoisomers (e.g., 85% ee or higher, 90% ee or higher, 95% ee or higher, 97% ee or higher, or 99% ee or higher)), but are not limited thereto.

[0043] "Hydrate" means a compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces.

[0044] "Clathrate" refers to the compound or salt thereof of the present invention in the form of a crystal lattice containing spaces (e.g., channels) that confine guest molecules (e.g., solvent or water).

[0045] "Pharmaceutically acceptable" means that a compound, substance, composition, and / or dosage form is suitable for use as a pharmaceutical preparation and can be used in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of sound medical judgment, and is used to indicate a reasonable benefit / risk ratio.

[0046] In this invention, "pharmaceutically acceptable salt" means a derivative of a compound obtained by the parent compound being modified to produce an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts of the present invention include, but are not limited to, salts commonly used in the pharmaceutical field, such as hydrochloride, hydrobromide, hydroiodide, hydrofluoride, sulfate, sulfonate, citrate, camphorate, maleate, acetate, lactate, nicotinate, nitrate, succinate, phosphate, malonate, malate, salicylate, phenylacetate, stearate, formate, fumarate, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamate, methylamino acid, methanesulfonate, picrate, p-toluenesulfonate, naphthalenesulfonate, tartrate, triethylamino acid, dimethylamino acid, and tri(hydroxymethyl)aminomethane.

[0047] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the compound in the form of a free acid or base with a sufficient amount of a suitable base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile, or a mixture thereof.

[0048] A "solvate" or "pharmaceutically acceptable solvate" means a solvate formed by the bonding of at least one solvent molecule with a compound. Solvates include hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, etc.).

[0049] Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis comprising a compound represented by chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof.

[0050] Pulmonary fibrosis refers to a respiratory disease in which lung tissue hardens, causing severe respiratory impairment. Pulmonary fibrosis can be caused by various factors, including radiation, tuberculosis, syphilis, pneumoconiosis, and viral infections, but it can also be caused by unknown factors. All of these types of pulmonary fibrosis are included in the definition of pulmonary fibrosis in this invention.

[0051] In one embodiment of the present invention, pulmonary fibrosis may be selected from pulmonary fibrosis caused by radiation exposure, acute pulmonary fibrosis, and idiopathic pulmonary fibrosis.

[0052] In this invention, "idiopathic pulmonary fibrosis" or "idiopathic pulmonary fibrosis" (IPF) refers to an interstitial lung disease of unknown cause in which recurrent inflammation due to alveolar damage leads to fibrosis and respiratory failure in the patient.

[0053] In one embodiment of the present invention, pulmonary fibrosis may be a side effect of radiation therapy caused by exposure of normal tissue to radiation during radiation therapy for cancer, or it may be a side effect of drug therapy for anti-cancer treatment.

[0054] Radiation therapy or drug therapy for cancer that causes pulmonary fibrosis includes, but is not limited to, the treatment of breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer, liver cancer, colorectal cancer, or brain tumors.

[0055] In one embodiment, the pharmaceutical composition of the present invention may be administered before or after radiation exposure.

[0056] "Treatment" means any action that improves or favorably alters the symptoms of fibrosis by administering the pharmaceutical composition, and "prevention" means any action that suppresses or delays the onset of fibrosis by administering the pharmaceutical composition.

[0057] The pharmaceutical composition according to the present invention can be manufactured by conventional methods in the pharmaceutical field. The pharmaceutical composition may be compounded with a suitable pharmaceutically acceptable carrier depending on the dosage form, and may further contain, as necessary, excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc. The suitable carrier, etc., does not inhibit the activity and properties of the compound according to the present invention, and different carriers may be selected depending on the administration form and dosage form.

[0058] The pharmaceutical compositions of the present invention may further contain suitable carriers, excipients, or diluents commonly used in the manufacture of pharmaceutical compositions. Compositions containing pharmaceutically acceptable carriers are in various oral or parenteral dosage forms. When formulated, they are prepared using commonly used fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, or other diluents or excipients. Examples of oral solid formulations include tablets, pills, powders, granules, and capsules, which are prepared by mixing at least one compound with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to common excipients, lubricants such as magnesium stearate and talc are also used. Examples of oral liquid formulations include suspensions, oral solutions, emulsions, and syrups, and in addition to commonly used diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives are used. Parenteral formulations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, tween 61, cocoa butter, lauric acid butter, and glycerol gelatin.

[0059] Furthermore, although not limited to these, the pharmaceutical compositions of the present invention have any dosage form selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, lyophilized preparations, and suppositories.

[0060] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount.

[0061] "Pharmacologically effective dose" means an amount sufficient to suppress or mitigate the increase in vascular permeability with a reasonable benefit / risk ratio applicable to medical use. The effective dose level is determined by factors including the individual's species and severity, age, sex, drug activity, sensitivity to the drug, administration time, route of administration and elimination rate, duration of treatment, any drugs used concurrently, and other factors known in the medical field.

[0062] The effective dose level of the pharmaceutical composition is determined by the intended use, the patient's age, sex, weight and health status, the type and severity of the disease, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the elimination rate, the duration of treatment, the elements of the drugs included in the formulation or used simultaneously, and other elements known in the medical field. For example, although not constant, it is generally 0.001 to 100 mg / kg, and as an example, 0.01 to 10 mg / kg may be administered once a day or in several divided doses. The above dosage does not limit the present invention in any way.

[0063] The pharmaceutical composition can be appropriately administered to an individual by target or, if necessary, by conventional methods, routes of administration, and dosages used in the art. Examples of routes of administration include oral, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal administration, while parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. Furthermore, an appropriate dosage and number of administrations can be selected by methods known in the art, and the actual amount and number of administrations of the pharmaceutical composition of the present invention can be appropriately determined based on various factors such as the type of symptom to be treated, route of administration, sex, health status, diet, age and weight of the individual, and severity of the disease.

[0064] "Administration" means introducing the pharmaceutical composition of the present invention into a subject by any appropriate method, and the route of administration can be any route, whether oral or parenteral, as long as it can be delivered to the target tissue.

[0065] The pharmaceutical composition can be administered to any animal in which pulmonary fibrosis may occur, and such animals include, for example, humans and primates, as well as livestock such as cattle, pigs, horses, and dogs. In one embodiment, the animal may be any animal other than a human.

[0066] The pharmaceutical composition can be administered via an appropriate route of administration depending on the formulation, and can be administered orally or parenterally via various routes, as long as it can be delivered to the target tissue. The method of administration is not particularly limited, and can be administered by conventional methods such as oral, rectal, intravenous, intramuscular, topical application, intrarespiratory inhalation, intradural, or intraventricular injection.

[0067] In addition to compositions containing the compound represented by chemical formula (1) according to the present invention, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient, the pharmaceutical compositions of the present invention may be administered in combination with other compositions for the prevention or treatment of pulmonary fibrosis.

[0068] Examples of compositions to be administered in combination with the pharmaceutical composition of the present invention include compositions containing at least one component selected from pirfenidone, nintedanib, steroids, azathioprine, cyclophosphamide, and pharmaceutically acceptable salts or solvates thereof as an active ingredient.

[0069] In one embodiment, the pharmaceutical composition of the present invention is administered in combination with a pharmaceutical composition containing nintedanib as an active ingredient.

[0070] In the present invention, "combined administration," "being used in combination," and "using in combination" mean administering a composition containing the compound represented by chemical formula (1) according to the present invention, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient, to an individual together with another pulmonary fibrosis inhibitor. This is not limited to simply the simultaneous administration of the drugs used in combination, but may also be an administration form in which the compound of the present invention and the other pulmonary fibrosis inhibitor act together on the individual, and each substance performs at a level equivalent to or greater than its original function. Therefore, in the present invention, "combined administration" should be understood to mean simultaneous, individual, sequential, or reversed administration, and the order may be any. When the administration is sequential, reversed, or individual, the order of administration is not particularly limited, but the interval between administrations of the secondary component must not lose the advantageous effect of the combination.

[0071] In the present invention, (i) a composition comprising the compound represented by chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and (ii) a composition comprising nintedanib, or a pharmaceutically acceptable salt or solvate thereof, are administered in the following forms, but are not limited thereto.

[0072] a) (i) a compound represented by chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and (ii) nintedanib or a pharmaceutically acceptable salt or solvate thereof, administered as a single mixture, or b) (i) the compound represented by chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and (ii) nintedanib or a pharmaceutically acceptable salt or solvate thereof, administered in a separated form, but not limited to these.

[0073] (i) a compound represented by chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and (ii) nintedanib or a pharmaceutically acceptable salt or solvate thereof, in which case (i) and (ii) may be formulated into separate formulations and administered simultaneously, individually, sequentially, or in reverse order.

[0074] The therapeutically effective dose of each active ingredient used in combination administration varies depending on the specific compound or pharmaceutical composition used, the mode of administration, the symptoms being treated, the severity of the symptoms, the species, body weight, sex, diet, and age of the warm-blooded animal. Therefore, the dosage regimen using the compounds of the present invention is selected according to the route of administration and various factors, including the patient's renal and hepatic function. Surgeons, clinicians, or veterinarians in the art can easily determine and prescribe the effective amount of drug required to prevent, manage, or halt the progression of symptoms. Optimal accuracy in obtaining drug concentrations within an efficient range without toxicity requires dosage regimens based on the dynamics of drug usability targeting specific sites. This includes considering the distribution, balance, and removal of the drug. Therefore, dosage regimens, i.e., the administration levels and frequencies of any individual components of the formulations of the present invention described below, are adjusted to provide an optimal therapeutic response.

[0075] A further aspect of the present invention is a combination of the compound of chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and nintedanib, or a pharmaceutically acceptable salt or solvate thereof.

[0076] In this invention, "combination" means having a use for co-administration of the compound of chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, with nintedanib or a pharmaceutically acceptable salt or solvate thereof, and is used in the same sense as "combined used." This includes, but is not limited to, the form of pharmaceutical compositions and pharmaceutical kits characterized by the co-administration of the compound of chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, with nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0077] The “kit” in the present invention may include a combination or composition according to the present invention for co-administration of the compound of chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and nintedanib or a pharmaceutically acceptable salt or solvate thereof. Specifically, the kit of the present invention may include the compound of chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and nintedanib or a pharmaceutically acceptable salt or solvate thereof, formulated into a single formulation, or it may include individual formulations of the compound of chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and nintedanib or a pharmaceutically acceptable salt or solvate thereof. The kit may further include substances necessary for the co-administration of the two substances, but is not necessarily limited thereto.

[0078] A further aspect of the present invention is a method for preventing or treating pulmonary fibrosis, comprising the step of administering to an individual a pharmaceutical composition comprising a compound represented by chemical formula (1), or a food-acceptable salt or solvate thereof.

[0079] A further aspect of the present invention provides the use of a compound represented by chemical formula (1), or a food-grade salt or solvate thereof, in a composition for the prevention or treatment of pulmonary fibrosis.

[0080] The compounds represented by chemical formula (1), or their food-grade salts or solvates, and their use in preventing and treating pulmonary fibrosis are as previously described.

[0081] A further aspect of the present invention is a food composition for preventing or improving pulmonary fibrosis, comprising a compound represented by chemical formula (1), or a food-safe salt or solvate thereof.

[0082] In the present invention, "improvement" means any action by which the administration of the composition of the present invention reduces, at least, parameters related to pulmonary fibrosis, such as the severity of symptoms.

[0083] The compounds represented by chemical formula (1), or their food-grade salts or solvates, pulmonary fibrosis, and prevention are as described above.

[0084] "Food-grade salt" refers to salt in a form that can be used in food science, and a concrete example of this type is the aforementioned "pharmaceutically acceptable salt."

[0085] The food composition of the present invention may be used as a functional food.

[0086] "Functional foods" refer to foods manufactured and processed using raw materials or ingredients that possess beneficial functional properties for the human body. "Functionality" means that nutrients are regulated in relation to the structure and function of the human body, or that they provide beneficial effects for health purposes, such as physiological effects.

[0087] The food composition of the present invention may contain additional components that are commonly used to improve aroma, taste, appearance, etc. For example, it may contain vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, etc. It may also contain minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), and copper (Cu). Furthermore, it may contain amino acids such as lysine, tryptophan, cysteine, and valine. Furthermore, the product may contain food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleaching powder and high-grade bleaching powder, sodium hypochlorite, etc.), antioxidants (butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc.), colorants (tar dyes, etc.), color fixatives (sodium nitrite, sodium acetate, etc.), bleaching agents (sodium sulfite), seasonings (monosodium glutamate (MSG), etc.), sweeteners (dulcin, cyclamate, saccharin, sodium, etc.), flavorings (vanillin, lactones, etc.), leavening agents (alum, potassium bitartrate, etc.), fortifiers, emulsifiers, thickeners, coating agents, gum bases, foam inhibitors, solvents, and improvers. The aforementioned additives are selected and used in appropriate amounts according to the type of food.

[0088] When the food composition of the present invention is used as a food additive, it may be added as is, or used together with other foods or food components, and may be used appropriately in the usual manner. [Examples]

[0089] The present invention will be described in more detail below with reference to examples and experimental cases. However, these examples and experimental cases are merely illustrative of the present invention, and the present invention is not limited to these examples and experimental cases. [Examples]

[0090] Synthesis of DCTP(2-(4-methylpiperazin-1-yl)ethyl(5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamate) Example 1-1. Synthesis of the intermediate (E)-(3-chloro-4-fluorophenyl)(7-methoxy-6-(4-(piperidin-1-yl)but-2-enamido)quinazolin-4-yl)carbamic chloride. (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidine-1-yl)buta-2-enamide (500 mg, 1.06 mmol) was suspended in anhydrous dichloromethane (10 ml), and then pyridine (126.2 mg, 1.59 mmol) was added and the mixture was stirred at 0-5°C under a nitrogen stream. Triphosgene (189.4 mg, 0.63 mmol) was added and the mixture was stirred at room temperature for more than 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was separated by silica column chromatography (10% MC: MeOH) to obtain 178.4 mg (31.5%) of a pale yellow solid compound.

[0091] Example 1-2. Synthesis of 2-(4-methylpiperazin-1-yl)ethyl(E)-(3-chloro-4-fluorophenyl)(7-methoxy-6-(4-(piperidin-1-yl)but-2-enamido)quinazolin-4-yl)carbamate 2-(4-methylpiperazine-1-yl)ethane-1-ol (44.6 mg, 0.31 mmol) was added to anhydrous dichloromethane (3.0 ml), and then 60% sodium hydride (16.9 mg, 0.42 mmol) was added under a nitrogen stream at 0-5°C and the mixture was stirred. (E)-(3-chloro-4-fluorophenyl)(7-methoxy-6-(4-(piperidine-1-yl)buta-2-enamide)quinazolin-4-yl)carbamine chloride (150 mg, 0.28 mmol) obtained in Example 1-1 was added and the mixture was stirred at room temperature for more than 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was separated by silica column chromatography (20% MC:MeOH) to obtain 41.8 mg (23.2%) of a yellow solid compound. Chemical Formula: C 32 H 39 ClFN7O4 Exact Mass: 639.27 LC / MS: [M+H] 640.28 1 H-NMR(DMSO-d6): δ 9.78(1H), 9.03(1H), 9.00(1H), 7.72-7.70(1H), 7.54(1H), 7.45-7.41(1H), 7.32-7.28(1H), 6.83-6.77(1H), 6.68-6.64(1H), 4.22-4.19(2H), 4.11(3H), 3.18-3.17(2H), 3.09-3.08(2H), 2.38-2.33(8H), 2.14-2.10(4H), 2.08(3H), 1.55-1.49(4H), 1.40-1.39(2H)

[0092] MS and NMR information are shown in Figure 1. The obtained compound 2-(4-methylpiperazine-1-yl)ethyl(E)-(3-chloro-4-fluorophenyl)(7-methoxy-6-(4-(piperidine-1-yl)buta-2-enamide)quinazolin-4-yl)carbamate (hereinafter referred to as "DCTP") was used in the following Examples 2 and 3. [Examples]

[0093] Confirmation of the effect of bleomycin on suppressing idiopathic pulmonary fibrosis. Six-week-old male C57BL / 6 mice were administered bleomycin sulfate at a concentration of 1.5 U / kg, and pulmonary fibrosis was observed (10 mice in each group). Each drug was administered starting 14 days after bleomycin administration. The drugs were administered orally at a dose of 20 mg / kg daily for a total of 13 times over two weeks. The control group received nintedanib at a dose of 60 mg / kg, and the combination therapy group received nintedanib at 60 mg / kg and DCTP at 20 mg / kg daily for a total of 13 times over two weeks.

[0094] Figure 2 shows the results of a micro-CT scan performed 4 weeks after bleomycin administration.

[0095] In the group without drug treatment, the degree of fibrosis worsened after 4 weeks of bleomycin administration. In the group treated with nintedanib, a known pulmonary fibrosis inhibitor, the degree of fibrosis was mitigated based on micro-CT imaging results. Furthermore, the combination therapy of nintedanib and DCTP showed an even greater effect on pulmonary fibrosis.

[0096] Figure 3 shows the results of H&E and Masson's Trichrome staining to confirm the degree of inflammation and fibrosis.

[0097] Compared to the untreated group, pulmonary fibrosis and inflammation were reduced in the nintedanib-treated group. In particular, the combination therapy of nintedanib and DCTP showed an even greater reduction in the degree of fibrosis and inflammation. [Examples]

[0098] Confirmation of the effect of suppressing radiation-induced pulmonary fibrosis. Seven-week-old male mice from C57BL / 6 were orally administered a DCTP drug and nintedanib, an FDA-approved pulmonary fibrosis inhibitor, one hour before stereotactic body radiation therapy (SBRT, 90 Gy, 4 mm collimator). Two weeks after radiation exposure, the degree of pulmonary fibrosis and the effect of suppressing radiation-induced lung damage were observed.

[0099] DCTP was administered at a concentration of 30 mg / kg, and nintedanib was administered daily at a concentration of 60 mg / kg.

[0100] Figure 4 shows the results of a Micro-CT scan taken two weeks after radiation therapy.

[0101] In the group that did not receive any drugs, the degree of fibrosis worsened two weeks after radiation exposure. In the groups treated with DCTP and nintedanib, a known pulmonary fibrosis inhibitor, the degree of fibrosis was reduced, as confirmed by micro-CT imaging results.

[0102] Furthermore, Figure 5 shows the results of H&E staining and Masson's Trichrome staining performed two weeks after radiation exposure to analyze the degree of inflammatory response and fibrosis.

[0103] To assess the degree of inflammation and fibrosis, H&E and Masson's Trichrome staining were performed. The results showed that fibrosis and inflammation were reduced in the nintedanib-treated group and the DCTP-treated group compared to the lungs of the untreated group (Figure 5). [Examples]

[0104] Synthesis of PXDP((2-(4-methylpiperazin-1-yl)ethyl(5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamate) Example 4-1. Synthesis of the intermediate (5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamic chloride (5-((5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)methyl)-N-((6-(trifluoromethyl)pyridine-3-yl)methyl)pyridine-2-amine (500 mg, 1.19 mmol) was suspended in anhydrous dichloromethane (10 ml), and then pyridine (141.9 mg, 1.79 mmol) was added and the mixture was stirred at 0-5°C under a nitrogen stream. Triphosgene (213.0 mg, 0.71 mmol) was added and the mixture was stirred at room temperature for more than 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was separated by silica column chromatography (5% MC: MeOH) to obtain 235.6 mg (41.0%) of a pale yellow solid compound.

[0105] Example 4-2. Synthesis of 2-(4-methylpiperazin-1-yl)ethyl (5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl) ((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamate 2-(4-methylpiperazine-1-yl)ethane-1-ol (66.0 mg, 0.45 mmol) was added to anhydrous dichloromethane (4.0 ml), and then 60% sodium hydride (24.9 mg, 0.62 mmol) was added under a nitrogen stream at 0-5°C and the mixture was stirred. (5-((5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)methyl)pyridine-2-yl)((6-(trifluoromethyl)pyridine-3-yl)methyl)carbamine chloride (200 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for more than 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was separated by silica column chromatography (15% MC: MeOH) to obtain 76.4 mg (31.2%) of a yellow solid compound. Chemical Formula: C 28 H 29 ClF3N7O2 Exact Mass: 587.20 LC / MS: [M+H] 588.21 1 H-NMR(DMSO-d6): δ 11.74(1H), 8.73(1H), 8.38(1H), 8.17(1H), 8.04(1H), 7.98-7.96(1H), 7.83-7.81(1H), 7.71-7.47(2H), 7.47(1H), 5.19(2H), 4.20-4.17(2H), 4.03(2H), 2.47-2.44(2H), 2.27-2.16(8H), 2.07(3H)

[0106] MS and NMR information are shown in Figure 6. The obtained compound 2-(4-methylpiperazine-1-yl)ethyl(5-((5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)methyl)pyridine-2-yl)((6-(trifluoromethyl)pyridine-3-yl)methyl)carbamate (hereinafter referred to as "PXDP") was used in the following Examples 4 and 5. [Examples]

[0107] Confirmation of the effect of bleomycin on suppressing idiopathic pulmonary fibrosis. Six-week-old male C57BL / 6 mice were administered bleomycin sulfate at a concentration of 1.5 U / kg, and pulmonary fibrosis was observed (10 mice per group). Each drug was administered starting 14 days after bleomycin administration. Nintedanib and PXDP were each administered orally at a dose of 60 mg / kg daily for 13 doses over 2 weeks. In the combination therapy group, nintedanib was administered orally at a dose of 60 mg / kg and PXDP at a dose of 60 mg / kg daily for 13 doses over 2 weeks.

[0108] Figure 7 shows the results of a micro-CT scan performed 4 weeks after bleomycin administration.

[0109] In the group that did not receive any drugs, the degree of fibrosis worsened after 4 weeks of bleomycin administration. Furthermore, in the groups treated with nintedanib, a known pulmonary fibrosis inhibitor, and PXDP, the degree of fibrosis was mitigated. In particular, the combination therapy of nintedanib and PXDP showed an even greater effect on pulmonary fibrosis.

[0110] Figure 8 shows the results of H&E and Masson's Trichrome staining to confirm the degree of inflammation and fibrosis.

[0111] Compared to the untreated group, fibrosis and inflammation were reduced in the nintedanib-treated group and the PXDP-treated group. In particular, the combination therapy of nintedanib and PXDP showed an even greater reduction in the degree of fibrosis and inflammation.

[0112] Furthermore, the mouse survival rates are compared and shown in Figure 9.

[0113] The survival rates of each drug treatment group were examined, and it was confirmed that the survival rates were improved in the nintedanib-treated group and the PXDP-treated group compared to the untreated group. In particular, the survival rate was significantly improved in the group receiving nintedanib and PXDP in combination. [Examples]

[0114] Confirmation of the effect of suppressing radiation-induced pulmonary fibrosis. Seven-week-old male mice from C57BL / 6 were orally administered PXDP and nintedanib, an FDA-approved pulmonary fibrosis inhibitor, one hour before stereotactic body radiation therapy (SBRT, 90 Gy, 4 mm collimator). Two weeks after radiation therapy, the degree of pulmonary fibrosis and the effect of suppressing radiation-induced lung damage were observed. Figure 10 shows the results of micro-CT scans taken two weeks after radiation therapy.

[0115] PXDP was administered at a concentration of 100 mg / kg, and nintedanib was administered daily at a concentration of 60 mg / kg. Two weeks after radiation exposure, H&E staining and Masson's Trichrome staining were performed to analyze the degree of inflammation and fibrosis. The results are shown in Figure 11.

[0116] In the group without drug treatment, the degree of fibrosis worsened two weeks after radiation exposure. In the PXDP-treated group and the nintedanib-treated group (a known pulmonary fibrosis inhibitor), the degree of fibrosis was reduced, as confirmed by micro-CT imaging. In particular, the effect of PXPD was found to be superior to that of nintedanib.

[0117] Furthermore, to confirm the degree of inflammation and fibrosis, H&E and Masson's Trichrome staining were performed. The results showed that fibrosis and inflammation were reduced in the PXPD-treated group and the nintedanib-treated group compared to the lungs of the untreated group.

[0118] From the above description, those skilled in the art in the field to which the present invention pertains will understand that the present invention can be implemented in other specific forms without altering its technical idea or essential features. It should be understood that the above embodiments are merely illustrative and not limiting. The present invention should be interpreted as encompassing all modified or altered forms derived from the meaning and scope of the claims and their equivalent concepts, rather than the specification.

Claims

1. Compounds represented by the following chemical formula (1), or pharmaceutically acceptable salts or solvates thereof: 【Chemistry 1】 In the above chemical formula (1), Ar is a trifluoromethyl (CF3) or halogen-substituted aryl or heteroaryl group. R is represented by the following chemical formula (2) or (3). 【Chemistry 2】 【Transformation 3】

2. The Ar in the aforementioned chemical formula (1) is represented by chemical formula (6) or (7). The compound according to claim 1. 【Chemistry 4】 【Transformation 5】

3. The aforementioned compound is represented by chemical formula (4) or (5). The compound according to claim 1. 【Transformation 6】 【Transformation 7】

4. A composition comprising a compound represented by the following chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier: 【Transformation 8】 In the above chemical formula (1), Ar is a trifluoromethyl (CF3) or halogen-substituted aryl or heteroaryl group. R is represented by the following chemical formula (2) or (3). 【Chemistry 9】 【Chemistry 10】

5. A pharmaceutical composition for the prevention or treatment of pulmonary fibrosis comprising a compound represented by the following chemical formula (1), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 11】 In the above chemical formula (1), Ar is a trifluoromethyl (CF3) or halogen-substituted aryl or heteroaryl group. R is represented by the following chemical formula (2) or (3). 【Chemistry 12】 【Chemistry 13】

6. The pulmonary fibrosis described above is selected from pulmonary fibrosis caused by radiation exposure and idiopathic pulmonary fibrosis. The pharmaceutical composition for the prevention or treatment of pulmonary fibrosis according to claim 5.

7. The aforementioned pharmaceutical composition is administered in combination with a pharmaceutical composition containing nintedanib as an active ingredient. The pharmaceutical composition for the prevention or treatment of pulmonary fibrosis according to claim 5.

8. A method for preventing or treating pulmonary fibrosis, comprising the step of administering a pharmaceutical composition according to any one of claims 5 to 7 to an individual.

9. Food compositions for the prevention or improvement of pulmonary fibrosis, comprising a compound represented by the following chemical formula (1), or a food-grade salt or solvate thereof: 【Chemistry 14】 In the above chemical formula (1), Ar is a trifluoromethyl (CF3) or halogen-substituted aryl or heteroaryl group. R is represented by the following chemical formula (2) or (3). 【Chemistry 15】 【Chemistry 16】

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