Compound and pharmaceutical composition

Abstract

This compound is represented by general formula (A), where: R1 is a hydrogen atom, a halogen atom, a hydroxy group, or an optionally substituted C1-10 hydrocarbon group; R2 is a hydrogen atom, a halogen atom, a hydroxy group, or an optionally substituted C1-10 hydrocarbon group; X is a nitrogen atom or a hydrogen-bonded carbon atom; Y is a carbonyl group or an optionally substituted methylene group; and n is an integer of 1-3.

Description

Compounds and pharmaceutical compositions

[0001] The present invention relates to a compound having neutrophil elastase inhibitory activity, and a pharmaceutical composition containing the compound as an active ingredient. This application claims priority under Japanese Patent Application No. 2024-230881, filed in Japan on December 26, 2024, the contents of which are incorporated herein by reference.

[0002] Neutrophil elastase, a serine protease with a molecular weight of approximately 30,000, is released from neutrophils that accumulate in the lungs. Released neutrophil elastase is known to induce acute lung injury by degrading pulmonary connective tissue and increasing pulmonary vascular permeability.

[0003] Furthermore, neutrophil elastase is attracting attention as an important contributing factor in acute lung injury associated with systemic inflammatory response syndrome (SIRS) because it promotes the production of neutrophil chemotactic factors and amplifies the inflammatory response.

[0004] Sivelestat sodium (sivelestat) is marketed as a neutrophil elastase inhibitor and is used to treat acute lung injury associated with SIRS (Non-Patent Documents 1, 2).

[0005] Package insert for "Elaspol (registered trademark) 100 for injection," Shigeki Nakamura et al., "Examination of the usefulness of siberestat sodium (Elaspol (registered trademark)) for acute lung injury associated with severe pneumonia," Journal of the Japanese Respiratory Society, 2008, Vol. 46, No. 10, pp. 793-797. Katsuhiro Imaki et al., Bioorganic & Medicinal Chemistry, 1996, vol. 4, No. 12, p. 2115-2134.

[0006] As treatment and preventive technologies for neutrophil elastase-related diseases advance, there is a growing need for new compounds with neutrophil elastase inhibitory activity.

[0007] This invention has been made in view of the above circumstances, and aims to provide a novel compound having neutrophil elastase inhibitory activity, and a pharmaceutical composition containing the compound as an active ingredient.

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

[0009] [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 carbon atom to which a nitrogen atom or 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 aR form and R １ is an alkyl group having 1 to 6 carbon atoms which may have a substituent. (6) A pharmaceutical composition comprising the compound according to any one of (1) to (5) as an active ingredient. (7) The pharmaceutical composition according to (6), wherein the pharmaceutical composition is a pharmaceutical composition for treating or preventing neutrophil elastase-related diseases. (8) The pharmaceutical composition according to (7), wherein the neutrophil elastase-related disease is acute lung injury associated with systemic inflammatory response syndrome.

[0011] According to the present invention, a novel compound having neutrophil elastase inhibitory activity and a pharmaceutical composition containing the compound as an active ingredient can be provided.

[0012] An image diagram of the axial asymmetry in the compound of this embodiment. (A) shows the measurement result of the circular dichroism spectrum (CD spectrum) of the enantiomer (aS form) of Compound 2 in the examples. (B) shows the measurement result of the CD spectrum of the enantiomer (aR form) of Compound 2 in the examples. (A) shows the measurement result of the CD spectrum of the enantiomer (aS form) of Compound 3 in the examples. (B) shows the measurement result of the CD spectrum of the enantiomer (aR form) of Compound 3 in the examples. The X-ray crystal structure analysis result of the enantiomer (aR form) of Compound 3 in the examples.

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

[0014] [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. Y is a carbonyl group or a methylene group which may have a substituent. n is an integer of 1 to 3. ]

[0015] The compound of this embodiment has a ring structure in which a benzene ring and a heterocyclic ring having 1 or 2 nitrogen atoms are condensed, and as shown in the examples described later, it exhibits neutrophil elastase inhibitory activity equal to or higher than that of the existing drug, sivelestat.

[0016] That is, the compound of the present invention is useful in the treatment or prevention of diseases in which an association with neutrophil elastase is suggested.

[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] Furthermore, the compounds of this embodiment have a planar structure between the nitrogen atom and sulfur atom of the sulfonamide, similar to the amide structure. There is chirality between the benzene ring and the sulfonamide bond in the compounds of this embodiment due to axial rotation. Therefore, axially chiral isomers (enantiomers) exist in the compounds of this embodiment (see Figure 1). That is, the compounds of this embodiment may include enantiomers (aS and aR forms) and racemates which are equimolar mixtures of the enantiomers.

[0019] In living organisms, enzymes and receptors recognize the three-dimensional structure of target substances. Therefore, when a drug has asymmetry, different enantiomers may exhibit different biological effects. In the compound of this 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 １The hydrocarbon group in [it] may be linear, branched, or cyclic. The above hydrocarbon group may be an alkyl group, an alkenyl group, or an aryl group. The number of carbon atoms of the above 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 [it] include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group, a 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 １ Examples of the substituent that the hydrocarbon group in [it] may have include an oxygen atom, a hydroxy group, a carboxy group, a halogen atom, an alkoxy group (such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, etc.), an alkyloxycarbonyl group, etc.

[0023] R １ Preferably, [it] is a hydrogen atom, a halogen atom, a hydroxy group, or a hydrocarbon group having 1 to 6 carbon atoms that may have a substituent. More preferably, it is a hydrogen atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an n-propyl group, or an i-propyl group. Even more preferably, it is a hydrogen atom or a methyl group.

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

[0025] R ２As 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 of substituents similar to those that the hydrocarbon group in the above may have include.

[0027] R ２ The 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 of substituents similar to those that the hydrocarbon group in the above may have include.

[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), from the viewpoint of making the chirality associated with the rotation of the axis more stable and forming a stable ring structure more easily, n is preferably 1 or 2, and more preferably 1. When n is 1 or 2, X is preferably a nitrogen atom.

[0032] Specific examples of the compounds of this embodiment are listed below, but the invention is not limited to these.

[0033]

[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, it is preferable that the compound of this embodiment be the aR form from the viewpoint of higher neutrophil elastase inhibitory activity. In particular, if the compound is the aR form, the R １ It is more preferably a C1-C6 hydrocarbon group which may have substituents, even more preferably an C1-C6 alkyl group which may have substituents, 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 aR form 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 an aS 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 the forms of their salts (in particular pharmaceutically acceptable salts), hydrates, solvates, and polymorphs.

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

[0040] If the compound of this embodiment is a racemate, known methods can be used to isolate the enantiomer from the racemate by appropriately adjusting them. 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 Corporation). Alternatively, the racemate 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 diastereomer to its corresponding enantiomer. Due to steric hindrance caused by its structure, the enantiomer of the compound of this embodiment can be stably isolated even at room temperature.

[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 analysis 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 and drugs. (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] (Pharmaceuticals) Examples of pharmaceuticals 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 / microbial extracts, cooling agents, enzymes, nucleic acids, anti-inflammatory analgesics, antifungal agents, antihistamines, hypnotics / sedatives, tranquilizers, antihypertensive agents, antihypertensive diuretics, antibiotics, anesthetics, antimicrobial substances, antiepileptic agents, coronary vasodilators, herbal medicines, antipruritics, UV blocking agents, antiseptics / bactericidal agents, antioxidants, etc. Pharmaceuticals 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] (Method of 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 recipient, 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 the target recipient's weight. 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 a subject. 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 the compound of this embodiment for treating or preventing neutrophil elastase-related diseases. In one embodiment, the present invention provides the use of the compound of this embodiment for treating or preventing neutrophil elastase-related diseases.

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

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

[0056] １３ The C-NMR spectrum was measured under the following conditions: Measurement device: JNM-ECA600 (manufactured by JEOL Ltd.) Static magnetic field strength: 14.1 T (resonance frequency: 150 MHz) Spinning: 15 Hz Measurement temperature: 23°C 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 Number of integrations: 32 Measurement range: 800-4000 cm －１

[0058] The fragment ion mass spectrum was measured under the following conditions: Measurement device: LCMS-IT-TOF (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: CH ３ OH measurement temperature: 20℃

[0061] The circular dichroism spectrum (CD spectrum) was measured under the following conditions: Measuring instrument: J-1500-450 (manufactured by JASCO Corporation) Solvent: CH ３ OH measurement temperature: 20℃

[0062] ​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°C 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 (racemates) obtained in this example were isolated using a chiral column under the following conditions: (Compound 2) Column: CHIRAL ART Amylose-SA (1 cmφ × 250 mm) (manufactured by YMC Corporation) Detector: SPD-20A (manufactured by Shimadzu Corporation) Column temperature: 23°C Mobile phase: Ethanol / n-hexane (1 / 4) mixed solution Flow rate: 2.1 mL / min (Compound 3) Column and detector: Same conditions as Compound 2 Mobile phase: Ethanol / n-hexane (1 / 1) mixed solution Flow rate: 0.3 mL / min

[0064] <Manufacturing of Compounds>

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

[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)) Compound (S8) was synthesized as described below. (f) 1.3 g of sodium 4-hydroxybenzenesulfonate was mixed with 745 mg of pivalic acid, 4.0 mL of trifluoroacetic acid, and 3.6 mL of trifluoroacetic anhydride, 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]

[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). 13 C 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]

[0081] Next, the enantiomers (aS and aR) 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, CH ３ OH) aR body: +147.9 (c=0.11, CH ３ OH)

[0084] [Example 3: Compound 3] Compound 3 was prepared as shown below. (a) to (b) Compound (S3b) was obtained in the same manner as the method 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. 51 μL of methyl bromoacetate was added again while cooling in an ice bath, and 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. 1H 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]

[0089] Next, the enantiomers (aS and aR) 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, CH ３ OH) aR body: +213.7 (c=0.11, CH ３ OH)

[0092] Molecular formula: C ２４ H ２８ N ２ O ７ S Molecular weight: 488.55 Crystal (appearance): colorless, block crystal size: 0.200 x 0.150 x 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: P2 １ (#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) to (b) Compound (S3b) was obtained in the same manner as the method for the synthesis of Compound 2.

[0094] (c) 226 mg of compound (S3b) obtained in (b) 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. 1 H 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 27N2O7S 475.1533; found, 475.1535. mp; 252-255℃.

[0098]

[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] [Methods] 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. In terms of inhibition rate, IC is the concentration of the compound required to inhibit NE activity by 50%. ５０ The calculation was performed in (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 This corresponds to [the above]. 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]

[0102] [Results] As shown in Table 1, compounds 1 to 4 are equivalent to the existing drug siberestat (IC ５０It showed inhibitory activity equivalent to or greater than that of (42.0 nmol / L). Furthermore, the aR enantiomer of one of compounds 2 and 3 showed even stronger activity, and in particular, the aR enantiomer of compound 3 showed inhibitory activity approximately 10 times higher than that of siberestat. From these results, it became clear that the compounds of this embodiment exhibit neutrophil elastase inhibitory activity. In particular, it became clear that the compounds of this embodiment exhibit higher neutrophil elastase inhibitory activity when they exist in the form of the aR enantiomer.

[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). [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 aR form, and the R １ The compound according to claim 1 or 2, wherein the alkyl group having 1 to 6 carbon atoms 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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