Compounds and pharmaceutical compositions

Abstract

The present invention provides a novel compound having neutrophil elastase inhibitory activity, and a pharmaceutical composition containing the compound as an active ingredient. [Solution] It is represented by the following general formula (A), where R 1 R is a hydrogen atom, a halogen atom, a hydroxyl group, or a hydrocarbon group having 1 to 10 carbon atoms which may have substituents. 2 A compound in which is a hydrogen atom, a halogen atom, a hydroxyl group, or a C1-C10 hydrocarbon group which may have substituents, X is a nitrogen atom, or a carbon atom to which a hydrogen atom is bonded, Y is a carbonyl group or a methylene group which may have substituents, and n is an integer from 1 to 3. TIFF2026114507000011.tif58170

Description

Technical Field

[0001] The present invention relates to a compound having neutrophil elastase inhibitory activity and a pharmaceutical composition containing the compound as an active ingredient.

Background Art

[0002] Neutrophil elastase, a serine protease with a molecular weight of about 30,000, is released from neutrophils accumulated in the lung. The released neutrophil elastase is known to induce acute lung injury by decomposing lung connective tissue and enhancing lung vascular permeability.

[0003] In addition, neutrophil elastase promotes the production of neutrophil chemotactic factors and amplifies the inflammatory response, and thus has attracted attention as an important causative factor in acute lung injury associated with systemic inflammatory response syndrome (SIRS).

[0004] Sivelestat sodium (sivelestat) is commercially available as a neutrophil elastase inhibitor and is used for the treatment of acute lung injury associated with SIRS (Non-Patent Documents 1 and 2).

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

[0006] As the technology for treating or preventing neutrophil elastase-related diseases is making increasing progress, new compounds having neutrophil elastase inhibitory activity are desired.

[0007] The present invention has been made in view of the above circumstances, and an object thereof is to provide a novel compound having neutrophil elastase inhibitory activity and a pharmaceutical composition containing the compound as an active ingredient. [Means for Solving the Problems]

[0008] The present invention includes the following aspects. (1) A compound represented by the following general formula (A).

[0009] [Chemical formula] [In the formula, R 1 is a hydrogen atom, a halogen atom, a hydroxy group, or a hydrocarbon group having 1 to 10 carbon atoms which may have a substituent. R 2 is a hydrogen atom, a halogen atom, a hydroxy group, or a hydrocarbon group having 1 to 10 carbon atoms which may have a substituent. X is a nitrogen atom or a carbon atom to which a hydrogen atom is bonded. Y is a carbonyl group or a methylene group which may have a substituent. n is an integer of 1 to 3.]

[0010] (2) The compound according to (1), wherein n is 1 or 2. (3) The compound according to (1) or (2), wherein R 1 is a hydrogen atom, a halogen atom, a hydroxy group, or a hydrocarbon group having 1 to 6 carbon atoms which may have a substituent. (4) The compound according to any one of (1) to (3), which is a racemate. (5) The compound according to (1) or (2), which is an R form and R 1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent. (6) A pharmaceutical composition containing any one of the compounds described in (1) to (5) as an active ingredient. (7) The pharmaceutical composition according to (6), wherein the pharmaceutical composition is a pharmaceutical composition for the treatment or prevention of neutrophil elastase-related disease. (8) The pharmaceutical composition according to (7), wherein the neutrophil elastase-related disorder is acute lung injury associated with systemic inflammatory response syndrome. [Effects of the Invention]

[0011] According to the present invention, it is possible to provide a novel compound having neutrophil elastase inhibitory activity, and a pharmaceutical composition containing the compound as an active ingredient. [Brief explanation of the drawing]

[0012] [Figure 1] This is an illustrative diagram of the axial chirality in the compound of this embodiment. [Figure 2] (A) shows the measurement results of the circular dichroism spectrum (CD spectrum) of the enantiomer (aS) of compound 2 in the example. (B) shows the measurement results of the CD spectrum of the enantiomer (aR) of compound 2 in the example. [Figure 3] (A) shows the CD spectrum measurement results for the enantiomer (aS) of compound 3 in the example. (B) shows the CD spectrum measurement results for the enantiomer (aR) of compound 3 in the example. [Figure 4] This shows the X-ray crystal structure analysis results of the enantiomer (aR) of compound 3 in the example. [Modes for carrying out the invention]

[0013] <Compound> The compound of this embodiment is represented by the following general formula (A).

[0014] [ka] [In the formula, R 1R is a hydrogen atom, a halogen atom, a hydroxyl group, or a hydrocarbon group having 1 to 10 carbon atoms, which may have substituents. 2 X is a hydrogen atom, a halogen atom, a hydroxyl group, or a C1-C10 hydrocarbon group which may have substituents. X is a nitrogen atom or a carbon atom. Y is a carbonyl group or a methylene group which may have substituents. n is an integer from 1 to 3.

[0015] The compound of this embodiment has a ring structure in which a benzene ring and a heterocycle having one or two nitrogen atoms are fused, and as shown in the examples described later, it exhibits neutrophil elastase inhibitory activity equivalent to or greater than that of the existing drug sivelestat.

[0016] In other words, the compounds of the present invention are useful in the treatment or prevention of diseases that are suggested to be associated with neutrophil elastase.

[0017] Diseases associated with neutrophil elastase include, for example, acute lung injury associated with systemic inflammatory response syndrome (SIRS), chronic obstructive pulmonary disease (COPD), cystic pulmonary fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic pulmonary fibrosis (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic respiratory tract infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, rheumatoid arthritis, and arthritis sclerosis. These include osteoarthritis, psoriasis, periodontitis, atherosclerosis, organ transplant rejection, premature rupture of membranes, bullous diseases, shock, sepsis, systemic lupus erythematosus (SLE), Crohn's disease, disseminated intravascular coagulation (DIC), tissue damage during ischemia-reperfusion, formation of corneal scar tissue, myelitis, lung cancers such as squamous cell carcinoma, adenocarcinoma, and non-small cell lung cancer, breast cancer, liver cancer, bladder cancer, colorectal cancer, skin cancer, pancreatic cancer, and glioma. Among these, it is particularly useful in the treatment or prevention of acute lung injury associated with SIRS.

[0018] In addition, in the compound of the present embodiment, between the nitrogen atom and the sulfur atom of the sulfonamide, it has a planar structure similar to an amide structure. Between the benzene ring and the sulfonamide bond in the compound of the present embodiment, there is asymmetry associated with the rotation of the axis. From these facts, in the compound of the present embodiment, axial chiral isomers (enantiomers) exist (see Figure 1). That is, the compound of the present embodiment may include enantiomers (S-form, R-form), and a racemic form that is an equimolar mixture of enantiomers.

[0019] In vivo, enzymes, receptors, etc. recognize the three-dimensional structure of the target substance. Therefore, when a pharmaceutical product has asymmetry, different biological actions may be exhibited between enantiomers. In the compound of the present embodiment, as shown in the examples described later, one of the enantiomers exhibits higher neutrophil elastase inhibitory activity.

[0020] In the above general formula (A), R 1 The hydrocarbon group in may be linear, branched, or cyclic. The hydrocarbon group may be an alkyl group, an alkenyl group, or an aryl group. The number of carbon atoms of the hydrocarbon group is preferably 1 to 8, more preferably 1 to 6, and even more preferably 1 to 3.

[0021] R 1 Examples of the hydrocarbon group in include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, and linear and branched pentyl groups, hexyl groups, heptyl groups, octyl groups, methylene groups, vinyl groups, n-butenyl groups, sec-butenyl groups, pentenyl groups, heptenyl groups, octenyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, phenyl groups, etc.

[0022] R 1Examples of substituents that the hydrocarbon group in the compound may have include oxygen atoms, hydroxyl groups, carboxyl groups, halogen atoms, alkoxy groups (such as methoxy groups, ethoxy groups, propoxy groups, butoxy groups, etc.), and alkyloxycarbonyl groups.

[0023] R 1 The hydrogen atom is preferably a hydrogen atom, a halogen atom, a hydroxyl group, or a C1-C6 hydrocarbon group which may have substituents. A hydrogen atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an n-propyl group, or an i-propyl group is more preferably used, and a hydrogen atom or a methyl group is even more preferably used.

[0024] In the above general formula (A), R 2 The hydrocarbon group in this compound may be linear, branched, or cyclic, but it is preferably linear or branched. The above hydrocarbon group may be an alkyl group or an alkenyl group, but it is preferably an alkyl group. The number of carbon atoms in the hydrocarbon group is preferably 1 to 8, more preferably 1 to 6, and even more preferably 1 to 4.

[0025] R 2 As for hydrocarbon groups in R, 1 Examples include hydrocarbon groups similar to those in [the relevant context].

[0026] R 2 The substituents that the hydrocarbon group in the region may have include R 1 Examples include substituents similar to those that the hydrocarbon group in the above may have.

[0027] R 2The hydrogen atom, halogen atom, hydroxyl group, or C1-C6 hydrocarbon group which may have substituents is preferred, more preferably a hydrogen atom, chlorine atom, bromine atom, hydroxyl group, methyl group, carboxymethyl group, carboxymethyl methyl ester group, ethyl group, carboxymethyl ethyl ester group, n-propyl group, or isopropyl group, and even more preferably a methyl group, carboxymethyl group, or carboxymethyl methyl ester group.

[0028] In the above general formula (A), X is preferably a nitrogen atom.

[0029] In the above general formula (A), the substituents that the methylene group in Y may have are R 1 Examples include substituents similar to those that the hydrocarbon group in the above may have.

[0030] Y is preferably a carbonyl group or an unsubstituted methylene group, and more preferably a carbonyl group.

[0031] In the above general formula (A), n is preferably 1 or 2, and more preferably 1, from the viewpoint of making the chirality associated with the rotation of the axis more stable and making it easier to form a stable ring structure. When n is 1 or 2, it is preferable that X is a nitrogen atom.

[0032] The following are specific examples of the compounds of this embodiment, but the invention is not limited to these.

[0033] [ka]

[0034] As for the compounds of this embodiment, as shown in the examples described later, from the viewpoint of higher neutrophil elastase inhibitory activity, the compounds represented by formulas 1 to 4 above are preferred, compounds 1 to 3 are more preferred, and compound 2 or 3 is even more preferred.

[0035] Furthermore, from the viewpoint of achieving higher neutrophil elastase inhibitory activity, the compound of this embodiment is preferably a racemic mixture, and more preferably one of the enantiomers.

[0036] The R in the compound of this embodiment 1 However, if the compound is a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms which may have substituents, the compound of this embodiment is preferably the R-isomer from the viewpoint of higher neutrophil elastase inhibitory activity. In particular, the R 1 It is more preferably a hydrogen atom or a C1-C6 hydrocarbon group which may have substituents, even more preferably a hydrogen atom or a C1-C6 alkyl group which may have substituents, a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an i-propyl group which is particularly preferred, and a methyl group which is most preferred. More specifically, the R-isomer of the compound represented by formula 2 or 3 above is preferred.

[0037] The R in the compound of this embodiment 1 However, in the case of a halogen atom or a hydroxyl group, the compound of this embodiment is preferably the S-isomer from the viewpoint of higher neutrophil elastase inhibitory activity. In particular, the R 1 It is more preferably a halogen atom or a hydroxyl group, and even more preferably a chlorine atom, a bromine atom, or a hydroxyl group.

[0038] The compounds of this embodiment include salts (in particular pharmaceutically acceptable salts), hydrates, solvates, and polymorphs thereof.

[0039] (Manufacturing method) The compounds of this embodiment can be produced by appropriately combining known methods. Specifically, the production methods described in the examples below can be used.

[0040] If the compound of this embodiment is a racemic mixture, known methods can be used to isolate the enantiomer from the racemic mixture, with appropriate modifications. For example, it can be isolated by chromatography using a chiral column. An example of a chiral column is CHIRAL ART Amylose-SA (manufactured by YMC Co., Ltd.). Alternatively, the racemic mixture can be reacted with a suitable optically active compound to convert it into a diastereomer mixture, and after separating each diastereomer, it can be isolated by converting each individual diastereomer to its corresponding enantiomer. The compounds of this embodiment can be stably isolated as enantiomers even at room temperature due to steric hindrance caused by their structure.

[0041] The structure of the compound in this embodiment is 1 H-nuclear magnetic resonance (NMR) spectroscopy, 13 It can be identified by common organic analysis methods such as 13C-NMR spectroscopy, infrared absorption (IR) spectroscopy, mass spectrometry (MS), liquid chromatography / mass spectrometry, elemental analysis, X-ray crystal structure analysis, optical rotation, and melting point measurement. The raw materials and reagents used in each analytical method may be commercially available or synthesized.

[0042] <Pharmaceutical composition> The pharmaceutical composition of this embodiment contains the above compound as an active ingredient.

[0043] The compound of this embodiment may contain various additives, drugs, etc. (Additives) As additives, various substances commonly used as pharmaceutical additives can be used, as long as they do not impair the effects of the invention. Examples of additives include, but are not limited to, solvents, diluents, vehicles, excipients, flow promoters, binders, granulators, dispersants, suspending agents, wetting agents, lubricants, disintegrants, solubilizers, stabilizers, emulsifiers, fillers, preservatives (e.g., antioxidants), chelating agents, surfactants, thickeners, gelling agents, buffering agents, water, inorganic acids, organic acids, inorganic bases, organic bases, alcohols, inorganic salts, polymer additives, metal-containing compounds, polymeric carboxylic acids, fragrances, dyes, colorants, dyes, pigments, pH adjusters, metal soaps, flavoring and deodorizing agents, and sweeteners. Additives may be used individually or in combination of two or more.

[0044] (Medicine) Examples of drugs include, but are not limited to, preservatives, antibacterial agents, vitamins and their derivatives, anti-inflammatory agents, blood circulation promoters, stimulants, hormones, cooling agents, warming agents, wound healing promoters, irritation relievers, analgesics, cell activators, plant, animal, and microbial extracts, cooling agents, enzymes, nucleic acids, anti-inflammatory and analgesic agents, antifungal agents, antihistamines, hypnotics and sedatives, tranquilizers, antihypertensive agents, antihypertensive diuretics, antibiotics, anesthetics, antimicrobial substances, antiepileptic agents, coronary vasodilators, herbal medicines, antipruritics, UV blocking agents, antiseptics and disinfectants, and antioxidants. Drugs may be used individually or in combination of two or more.

[0045] The pharmaceutical composition of this embodiment can be manufactured by mixing the compound of this embodiment with various drugs, additives, etc., as appropriate.

[0046] The dosage form of the pharmaceutical composition in this embodiment is not particularly limited, and any dosage form commonly used in pharmaceutical preparations can be used as appropriate. Examples of dosage forms of the pharmaceutical composition according to this embodiment include tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, liquid propellants, and emulsions, eye drops, injections, and topical skin preparations. Pharmaceutical compositions of these dosage forms can be formulated as appropriate according to known methods.

[0047] (How to use) The pharmaceutical composition of this embodiment can be used as a pharmaceutical composition for the treatment or prevention of neutrophil elastase-related diseases.

[0048] Examples of neutrophil elastase-related diseases include those similar to those described above. Among these, acute lung injury associated with SIRS is preferred.

[0049] The target animals for administration of the pharmaceutical composition of this embodiment are not particularly limited as long as they possess neutrophil elastase. For example, they may be humans or other mammals. Examples of other mammals include pets such as dogs and cats, livestock such as cattle, pigs and horses, and laboratory animals such as mice and rats.

[0050] The method of administering the pharmaceutical composition of this embodiment is not particularly limited as long as it does not impair the effects of the present invention, but examples include oral administration, pulmonary administration, nasal administration, rectal administration, intravenous administration, intramuscular administration, intradermal administration, subcutaneous administration, transdermal administration, and ocular administration.

[0051] The dosage and administration interval of the pharmaceutical composition of this embodiment can be appropriately selected depending on, for example, the target of administration, the target disease, the patient's condition, weight, age, sex, and method of administration. The dosage can be, for example, 0.01 to 3000 mg per kg of body weight of the recipient. The administration interval can be, for example, every few hours, once a day, once every two to three days, or once a week.

[0052] [Other embodiments] In one embodiment, the present invention provides a method for treating or preventing neutrophil elastase-related diseases, comprising administering the compound of this embodiment or the pharmaceutical composition of this embodiment to the target. In one embodiment, the present invention provides the use of the compound of this embodiment in the manufacture of a pharmaceutical composition for treating or preventing neutrophil elastase-related diseases. In one embodiment, the present invention provides a compound of this embodiment for treating or preventing neutrophil elastase-related diseases. In one embodiment, the present invention provides the use of the compounds of this embodiment for the treatment or prevention of neutrophil elastase-related diseases. [Examples]

[0053] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0054] <Method for identifying compounds> The structure of the compound in this example is: 1 H-NMR spectrum and 13 It was identified by measuring 13C-NMR spectra, IR spectra, fragment ion mass spectra, melting points, optical rotation, X-ray crystal structure, and circular dichroism spectra (CD spectra).

[0055] 1 The H-NMR spectra were measured under the following conditions. Measuring device: JNM-ECA600 (manufactured by JEOL Ltd.) Static magnetic field strength: 14.1 T (resonance frequency: 600 MHz) Spinning: 15 Hz Measurement temperature: 23℃ Internal standard: Tetramethylsilane

[0056] 13 The 1C-NMR spectrum was measured under the following conditions. Measuring device: JNM-ECA600 (manufactured by JEOL Ltd.) Static magnetic field strength: 14.1 T (resonance frequency: 150 MHz) Spinning: 15 Hz Measurement temperature: 23℃ Internal standard: Tetramethylsilane

[0057] The IR spectrum was measured under the following conditions. Measurement device: JASCO FT / IR-4200 (manufactured by JASCO Corporation) Detector: DLATGS Total number of times: 32 Measurement range: 800-4000cm -1

[0058] The fragment ion mass spectra were measured under the following conditions. Measurement device: LCMS-IT-TOF (manufactured by Shimadzu Corporation) Ionization mode: ESI

[0059] The melting point was measured under the following conditions. Measuring device: MP-J3 (manufactured by Yanako Instruments Development Laboratory Co., Ltd.)

[0060] Optical rotation was measured under the following conditions. Measuring device: JASCO P-2200 (manufactured by JASCO Corporation) Solvent: CH3OH Measurement temperature: 20℃

[0061] The circular dichroism spectrum (CD spectrum) was measured under the following conditions. Measuring device: J-1500-450 (manufactured by JASCO Corporation) Solvent: CH3OH Measurement temperature: 20℃

[0062] The X-ray crystal structure analysis was performed under the following conditions. Measurement device: Rigaku Raxis Rapid-2 imaging plate area detector with graphite monochromated Cu-Ka radiation (manufactured by Rigaku Corporation) Measurement temperature: -100℃ Analysis software: Crystal Structure (Crystal Structure 4.3.3), SHELXL Crystallization solvent: Dichloromethane / hexane mixed solvent

[0063] <Method for isolating enantiomers> The enantiomers from compounds 2 and 3 (racemic mixtures) obtained in this example were isolated using a chiral column under the following conditions. (Compound 2) Column: CHIRAL ART Amylose-SA (1cmφ x 250mm) (Manufactured by YMC Co., Ltd.) Detector: SPD-20A (manufactured by Shimadzu Corporation) Column temperature: 23℃ Mobile phase: Ethanol / n-hexane (1 / 4) mixed solution Flow rate: 2.1mL / min (Compound 3) Column and detector: Same conditions as for compound 2. Mobile phase: Ethanol / n-hexane (1 / 1) mixed solution Flow rate: 0.3mL / min

[0064] <Manufacturing of compounds>

[0065] Compounds 1 to 4 used in this example were prepared by the following synthesis route. [ka]

[0066] The details of the manufacturing methods for each compound will be explained based on the synthesis routes described above.

[0067] [Example 1: Compound 1] Compound 1 was prepared as shown below. (a) Compound (S2a) was obtained by adding 3.0 mL of acrylic acid and 1.5 mL of sulfuric acid to 2.0 g of 2-nitroaniline (S1a in the above synthesis route) and stirring at 80°C for 30 minutes.

[0068] (b) 1.48 g of the compound (S2a) obtained in (a) was dissolved in 23 mL of 1,4-dioxane, and 2.76 g of zinc and 3.0 mL of phosphoric acid were added. The mixture was then stirred at 110°C for 4 hours to obtain the compound (S3a in the above formula).

[0069] (c) 0.5 g of compound (S3a) obtained in (b) was dissolved in 25 mL of N,N-dimethylformamide, and 159 mg of sodium hydride was added while cooling in an ice bath, and the mixture was stirred at room temperature for 30 minutes. After adding 0.29 mL of iodomethane while cooling again in an ice bath, the mixture was stirred at room temperature for 6 hours to obtain compound (S4a).

[0070] (d) Dissolve 67 mg of the compound obtained in (c) (S4a in the above formula) in 4.2 mL of dichloromethane, add 0.77 mL of pyridine dropwise, then add 126 mg of the above compound (S8) and stir at room temperature for 24 hours to obtain 1:157 mg of the achiral compound.

[0071] (Synthesis of compound (S8)) The aforementioned compound (S8) was synthesized as described below. (f) To 1.3 g of sodium 4-hydroxybenzenesulfonate, 745 mg of pivalic acid, 4.0 mL of trifluoroacetic acid, and 3.6 mL of trifluoroacetic anhydride were added, and the mixture was stirred at room temperature for 1.5 hours to obtain compound (S7 in the above formula).

[0072] (g) The compound (S7) obtained in (f) was dissolved in 4.0 mL of dichloromethane, and 0.12 mL of N,N-dimethylformamide was added. While cooling in an ice bath, 0.49 mL of oxalyl chloride dissolved in 2.6 mL of dichloromethane was slowly added, and the mixture was reacted at room temperature for 24 hours to obtain the target compound (S8) at a dose of 584 mg.

[0073] The structure of the obtained compound 1 was identified based on the following analysis results. 1H NMR; (600 MHz, CDCl3) δ 7.63 (dd, J = 1.3, 7.5 Hz, 1H), 7.58 (d, J = 8.9 Hz, 2H), 7.39 (ddd, J = 1.3, 7.5, 7.5 Hz, 1H), 7.29, (ddd, J = 1.3, 7.5, 8.2 Hz, 1H), 7.11 (d, J = 8.9 Hz, 2H), 7.07 (dd, J = 1.3, 8.2 Hz, 1H), 4.71 (br, 1H), 3.94 (br, 1H), 2.43 (s, 3H), 2.52 (br, 2H), 1.33 (s, 9H). 13 C NMR; (150 MHz, CDCl3) δ 176.4, 154.4, 142.8, 137.1, 133.0, 130.0, 129.7, 128.4, 126.6, 122.8, 122.3, 52.0, 39.1, 34.3, 33.9, 27.0. IR; (ATR) 2937, 2031, 1663, 1347, 1084 cm -1 . MS; HRMS (ESI) m / z: [M+H] + calcd for: C 21 H 25 N2O5S 417.1479; found, 417.1480. mp; 137-139℃

[0074] [ka]

[0075] [Example 2: Compound 2] Compound 2 was prepared as shown below. (a) 5.0 g of 2-methyl-6-nitroaniline (S1b in the above synthesis route) was mixed with 6.8 mL of acrylic acid and 3.5 mL of sulfuric acid, and stirred at 80°C for 30 minutes to obtain compound (S2b).

[0076] (b) Compound (S3b) was obtained by adding 2.0 g of compound (S2b) obtained in (a) to 22 mL of 1,4-dioxane, 4.4 g of zinc, and 5.6 mL of phosphoric acid, and then stirring at 110°C for 4 hours.

[0077] (c) 1.04 g of compound (S3b) obtained in (b) was dissolved in 40 mL of N,N-dimethylformamide, and 306 mg of sodium hydride was added while cooling in an ice bath, and the mixture was stirred at room temperature for 30 minutes. After adding 0.55 mL of iodomethane while cooling again in an ice bath, the mixture was stirred at room temperature for 6 hours to obtain compound (s4b).

[0078] (d) 53 mg of compound (s4b) obtained in (c) was dissolved in 3.5 mL of dichloromethane, and 43 μL of pyridine was added dropwise. Then, 100 mg of the above compound (S8) was added and the mixture was stirred at room temperature for 24 hours to obtain 25 mg of racemic compound 2 (a 1:1 mixture of enantiomers).

[0079] The structure of the obtained compound 2 was identified based on the following analysis results. 1 H NMR; (600 MHz, CDCl3) δ 7.67 (d, J = 8.7 Hz, 2H), 7.29 (dd, J = 7.7, 7.9 Hz, 1H), 7.21, (dd, J = 0.8, 7.7 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 6.92 (dd, J = 0.8, 7.9 Hz, 1H), 4.65 (ddd, J = 5.2, 13.4, 13.7 Hz, 1H), 3.87 (ddd, J = 0.8, 7.0, 13.4 Hz, 1H), 2.60 (s, 3H), 2.52 (s, 3H), 2.45 (ddd, J = 7.0, 13.7, 13.8 Hz, 1H), 2.34 (ddd, J = 0.8, 5.2, 13.8 Hz, 1H), 1.35 (s, 9H). 13C NMR; (150 MHz, CDCl3) δ 176.4, 169.9, 154.4, 143.7, 142.4, 137.6, 129.3, 129.2, 128.9, 128.6, 122.4, 120.2, 51.1, 39.1, 34.2, 34.1, 27.0, 19.2. IR; (ATR) 2973, 1973, 1666, 1344, 1101 cm -1 . MS; (ESI) m / z: [M+Na] + calcd for: C 22 H 26 N2O5SNa 453.1455; found, 453.1455. mp; 72-74℃

[0080] [ka]

[0081] Next, the enantiomers (aS and aR forms) of compound 2 were isolated from the resulting racemic compound 2 by HPLC using the chiral column described above.

[0082] The structures of the obtained enantiomers were identified based on the optical rotation measurements (aS and aR isomers) shown below, the CD spectrum measurements (aS and aR isomers) shown in Figure 2, and the results of the X-ray crystal structure analysis of compound 3 (aR isomer), which will be described later.

[0083] [αD]aS body: -146.6 (c=0.11, CH3OH) aR isomer: +147.9 (c=0.11, CH3OH)

[0084] [Example 3: Compound 3] Compound 3 was prepared as shown below. (a)~(b) Compound (S3b) was obtained in the same manner as the method used for the synthesis of compound 2.

[0085] (c) 53 mg of compound (S3b) obtained in (b) was dissolved in 3.0 mL of N,N-dimethylformamide, and 18 mg of sodium hydride was added while cooling in an ice bath, and the mixture was stirred at room temperature for 30 minutes. After adding 51 μL of methyl bromoacetate while cooling again in an ice bath, the mixture was stirred at room temperature for 5 hours to obtain compound (S4c).

[0086] (d) 82 mg of compound (s4c) obtained in (c) was dissolved in 4.3 mL of dichloromethane, and 43 μL of pyridine was added dropwise. Then, 143 mg of the above compound (S8) was added and the mixture was stirred at room temperature for 24 hours to obtain 45 mg of racemic compound 3 (a 1:1 mixture of enantiomers).

[0087] The structure of the obtained compound 3 was identified based on the following analysis results. 1 H NMR; (600 MHz, CDCl3) δ 7.66 (d, J = 8.7 Hz, 2H), 7.27 (dd, J = 7.7, 7.8 Hz, 1H), 7.23 (dd, J = 0.9, 7.7 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 6.92, (dd, J = 0.9, 7.8 Hz, 1H), 4.66 (ddd, J = 5.2, 13.4, 13.7 Hz, 1H), 3.92 (d, J = 17.6 Hz, 1H), 3.87 (ddd, J = 0.7, 7.2, 13.4 Hz, 1H), 3.73 (s, 3H), 3.17 (d, J = 17.6 Hz, 1H), 2.57 (ddd, J = 7.2, 13.5, 13.7 Hz, 1H), 2.49 (s, 3H), 2.40 (ddd, J = 0.7, 5.2, 13.5 Hz, 1H), 1.37 (s, 9H). 13 C NMR; (150 MHz, CDCl3) δ 170.2, 169.7, 154.5, 143.0, 142.2, 137.6, 129.6, 129.5, 128.6, 122.5, 120.1, 52.4 50.8, 49.6, 33.9, 27.0, 19.1. IR; (ATR) 2959, 2030, 1661, 1347, 1092 cm -1 . MS; (ESI) m / z: [M+H]+ calcd for: C 24 H 29 N2O7S 489.1690; found, 489.1692. mp; 186-188℃.

[0088] [ka]

[0089] Next, the enantiomers (aS and aR forms) of compound 3 were isolated from the resulting racemic compound 3 by HPLC using the chiral column described above.

[0090] The structures of the obtained enantiomers were identified based on the optical rotation measurements (aS and aR isomers) shown below, the CD spectrum measurements (aS and aR isomers) shown in Figure 3, and the results of the X-ray crystal structure analysis (aR isomer) shown below and in Figure 4.

[0091] [αD]aS body: -208.9 (c=0.11, CH3OH) aR isomer: +213.7 (c=0.11, CH3OH)

[0092] Molecular formula:C 24 H 28 N2O7S Molecular weight: 488.55 Crystal (appearance): Colorless, blocky Crystal size: 0.200 × 0.150 × 0.030 mm Crystal system: monoclinic Lattice constant: a=8.2604(4)Å,b=9.4759(5)Å,c=15.5250(8)Å, :β=91.749(7)° :V=1214.65(10)Å 3 Space group: P21 (#4) Z value: 2 Measured density: 1.336 g / cm³ 3 F000:516.00 Absorption coefficient μ(CuKα): 15.853 cm⁻¹ R1:0.0526 wR2:0.0665 Goodness of Fit (GOF): 1.025 Flack parameter: 0.038(19)

[0093] [Example 4: Compound 4] Compound 4 was prepared as shown below. (a)~(b) Compound (S3b) was obtained in the same manner as the method used for the synthesis of compound 2.

[0094] (c) Compound (S3b) obtained in (b): 226 mg was dissolved in 12 mL of N,N-dimethylformamide, and 77 mg of sodium hydride was added while cooling in an ice bath, and the mixture was stirred at room temperature for 30 minutes. After adding 0.36 mL of benzyl bromoacetate while cooling again in an ice bath, the mixture was stirred at room temperature for 6 hours to obtain compound (S4d).

[0095] (d) 76 mg of compound (S4d) obtained in (c) was dissolved in 3.4 mL of dichloromethane, and 48 μL of pyridine was added dropwise. Then, 78 mg of the above compound (S8) was added and the mixture was stirred at room temperature for 24 hours to obtain racemic compound 4 (a 1:1 mixture of enantiomers).

[0096] (e) Compound (S4e) was obtained by adding 1.5 mL of ethanol and 2.3 mg of 10% palladium to 24 mg of compound (S4d) obtained in (d), and then stirring at room temperature under a hydrogen atmosphere for 9 hours.

[0097] The structure of the obtained compound 4 was identified based on the following analysis results. 1H NMR; (600 MHz, CD3OD) δ 7.72 (d, J = 8.2 Hz, 2H), 7.30 (dd, J = 6.8, 7.5 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 6.8 Hz, 1H), 7.17, (d, J = 7.5 Hz, 1H), 4.53 (ddd, J = 5.1, 13.1, 13.7 Hz, 1H), 3.96 (d, J = 17.2 Hz, 1H), 3.85 (dd, J = 7.4, 13.1 Hz, 1H), 3.24 (d, J = 17.2 Hz, 1H), 2.58 (ddd, J = 7.4, 13.4, 13.7 Hz, 1H), 2.41 (s, 3H), 2.28 (dd, J = 5.1, 13.1 Hz, 1H), 1.35 (s, 9H). 13 C NMR; (150 MHz, CD3OD) δ 177.6, 172.8, 156.0, 145.1, 143.0, 139.2, 130.9, 130.5, 130.1, 130.0, 123.8, 121.9, 53.5, 51.7, 40.2, 35.1, 27.3, 19.2. IR; IR (ATR) 2923, 1974, 1583, 1339, 1098 cm -1 . MS; (ESI) m / z: [M+H] + calcd for: C 23 H 27 N2O7S 475.1533; found, 475.1535. mp; 252-255℃.

[0098] [ka]

[0099] <Measurement of neutrophil elastase inhibitory activity> The inhibitory activity against neutrophil elastase was evaluated using compounds 1-4 and the enantiomers of compounds 2 and 3.

[0100] [method] Neutrophil elastase (NE) inhibitory activity was measured using a commercially available Neutrophil Elastase Inhibitor Screening Kit (Abcam). Specifically, 50 μL of the NE solution included in the kit and 25 μL of the compound solution of this example (concentrations: 1000, 250, 62.5, 15.625, 3.906 nmol / L), serially diluted with the NE Assay Buffer included in the kit, were mixed and pre-incubated at 37°C for 5 minutes. After pre-incubation, 25 μL of the NE substrate solution included in the kit was added to the mixed solution to initiate the reaction. Immediately, the fluorescence intensity of the fluorescent product was measured at an excitation wavelength of 400 nm and an emission wavelength of 505 nm to determine the inhibition rate. The inhibition rate was defined as the IC50 concentration of the compound required to inhibit NE activity by 50%. 50 The calculation was performed using (nmol / L). The results are shown in Table 1 below. In Table 1, R 1 and R 2 R in the above general formula (A) is 1 and R 2 It corresponds to this. For comparison, the existing drug sivelestat was used. According to Non-Patent Document 3, the inhibitory activity of sivelestat was 44.0 nmol / L.

[0101] [Table 1]

[0102] [result] As shown in Table 1, compounds 1-4 are similar to the existing drug sivelestat (IC). 50 It showed equivalent or superior inhibitory activity compared to (42.0 nmol / L). Furthermore, the aR enantiomer of compound 2 and 3 was even more potent, with the aR enantiomer of compound 3 showing approximately 10 times higher inhibitory activity compared to siberestat. These findings reveal that the compound of this embodiment exhibits neutrophil elastase inhibitory activity. In particular, it was found that the compound of this embodiment exhibits higher neutrophil elastase inhibitory activity when it exists in the R-isomer form. [Industrial applicability]

[0103] According to the present invention, it is possible to provide a novel compound having neutrophil elastase inhibitory activity, and a pharmaceutical composition containing the compound as an active ingredient.

Claims

1. A compound represented by the following general formula (A). 【Chemistry 1】 [In the formula, R １ R is a hydrogen atom, a halogen atom, a hydroxyl group, or a hydrocarbon group having 1 to 10 carbon atoms, which may have substituents. ２ X is a hydrogen atom, a halogen atom, a hydroxyl group, or a C1-C10 hydrocarbon group which may have substituents. X is a nitrogen atom, or a carbon atom to which a hydrogen atom is bonded. Y is a carbonyl group or a methylene group which may have substituents. n is an integer from 1 to 3.

2. The compound according to claim 1, wherein n is 1 or 2.

3. The aforementioned R １ The compound according to claim 1 or 2, wherein the compound is a hydrogen atom, a halogen atom, a hydroxyl group, or a hydrocarbon group having 1 to 6 carbon atoms which may have substituents.

4. The compound according to claim 1 or 2, which is a racemic mixture.

5. It is an R body, and the R １ The compound according to claim 1 or 2, wherein the compound is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, which may have substituents.

6. A pharmaceutical composition comprising the compound described in claim 1 or 2 as an active ingredient.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a pharmaceutical composition for the treatment or prevention of neutrophil elastase-related diseases.

8. The pharmaceutical composition according to claim 7, wherein the neutrophil elastase-related disorder is acute lung injury associated with systemic inflammatory response syndrome.

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