Lipopeptide compounds and their use in modulating eosinophilia

Abstract

Provided herein are compounds of Formula (I-A), or salts thereof, including any isomer of the above, wherein the variables are as defined herein. Such compounds can be useful in methods of treating an eosinophilic condition, disease, or disorder. Such compounds can be administered orally. Compositions described herein can be used to reduce eosinophil effector function.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 596,380, filed November 6, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure relates generally to lipopeptides, and more specifically to the use of lipopeptide compounds suitable for treating eosinophilic disorders, diseases, or conditions. Background Technology

[0003] Inflammation is an immunological puzzle. On the one hand, the physiological changes that accompany inflammation enable us to respond acutely to external threats that would otherwise have wiped out the human species. On the other hand, chronic inflammation, in which age or external stressors overactivate our immune system, can lead to a range of debilitating diseases, from Alzheimer's to diabetes and bronchial asthma.

[0004] Eosinophils are a type of white blood cell that are stored in tissues throughout the body and are constantly replenished from the bone marrow. Eosinophils typically live for two days in the blood, but inflammatory conditions (such as infections and allergic diseases) can extend their lifespan by activating eosinophil cytokines, up to two weeks. See Park YM & Bochner BS. Allergy Asthma Immunol Res 2010, 2:87-101. Eosinophil count is a blood test used to measure the amount of eosinophils in a person's body. Elevated levels, usually measured during a routine complete blood count, indicate the presence of infection or allergy.

[0005] Under inflammatory conditions, eosinophils, activated by cytokines that activate them, are a major source of reactive oxygen species, cytotoxic proteins, and pro-inflammatory cytokines. They signal for the activation of tissue-resident cells, such as epithelial cells, endothelial cells, and fibroblasts, leading to the progression of inflammation and mucus secretion. Therefore, eosinophils are potent activators and modulators of diseases such as bronchial asthma, atopic dermatitis, and ulcerative colitis. See Hogan SP, Int Arch Allergy Immunol . 2007, 143(Supplement 1):3-14; Simon D et al., Allergy . 2004,59:561-570; Wedemeyer J&Vosskuhle K., Best Pract Res Clin Gastroenterol 2008, 22:537-549. Furthermore, in asthmatic patients, the levels of eosinophil granule proteins (such as eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO)) are closely related to asthma severity. See Parra A, et al. J Investig Allergol Clin Immunol 1999; 9:27–34. Eosinophilic inflammation of the upper respiratory tract can also occur independently of allergies, as observed in subjects with chronic sinusitis (CRS). See Hutcheson PS, et al. J Rhinol Allergy 2010, 24:405-408. These individuals represent a unique subgroup with a high degree of tolerance to medical and surgical interventions, while therapies targeting eosinophilic amplification and effector function can show direct benefits. Summary of the Invention

[0006] In some respects, compounds of formula (I) are provided: (I), Or its salts, including any isomer of the above substances, wherein: R 1 It is at least one optionally substituted amino acid; R 2x It is an alkyl or alkenyl group, optionally substituted with -OH or -COOH; R 2y It is H or alkyl; or R 2x and R 2y Together with the atoms they are attached to, they form arbitrarily substituted 5-membered heterocycles; R 3 It is alkyl or alkenyl; and Z can be -OH, -OC(O)alkyl, -NH2, -NH(alkyl) or -N(alkyl)2.

[0007] In some respects, compounds of formula (IA) are provided: (IA), Or its salts, including any isomer of the above substances, wherein: R 2x and R 2y Together with the atoms they are attached to, they form arbitrarily substituted 5-membered heterocycles; R 3 It is alkyl or alkenyl; and R 4 It is H or alkyl; R 5 It is a hydrophobic side chain of Ala, Val, Ile, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 8It is a hydrophobic side chain of Ala, Val, Ile, Leu, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 6 It is H or alkyl; and R 7 It can be –OH, –O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, –SH, or –S(C=O)alkyl; and Z can be -OH, -OC(O)alkyl, -NH2, -NH(alkyl) or -N(alkyl)2.

[0008] In some implementations, compounds of formula (IB) are provided: (IB), Or its salts, including any isomer of the above substances, wherein: R 3 It is alkyl or alkenyl; R 7a It is an H or -C(O) alkyl group; R b It is H or -OH; and Z can be -OH, -OC(O)alkyl, -NH2, -NH(alkyl) or -N(alkyl)2.

[0009] On the one hand, a compound selected from Table A or Table A' of this document, or a salt thereof, including any isomer of the above-mentioned compound, is provided.

[0010] In some respects, a pharmaceutical composition comprising any one of the compounds described herein, and at least one pharmaceutically acceptable excipient is also provided.

[0011] In other respects, this document provides eosinophilic modulation therapy using any of the compounds described herein, such as for the treatment of eosinophilic esophagitis and asthma. In some embodiments, the asthma is bronchial asthma. In some embodiments, the treatment provided is targeted at a subgroup of patients (e.g., patients with eosinophilic esophagitis and asthma) who have a high degree of tolerance to medical and surgical interventions, including steroid therapy.

[0012] In some respects, a method is provided for treating an inflammatory condition, symptom, or disease in a person in need, comprising: orally administering an effective dose of any of the compounds described herein to a person for the treatment of the inflammatory condition, symptom, or disease.

[0013] In some respects, a method is provided for treating eosinophilic disorders, conditions, or diseases in persons in need, comprising: orally administering to a person an effective dose of any of the compounds described herein to treat eosinophilic disorders, conditions, or diseases.

[0014] In some respects, a method is provided for reducing eosinophil effector function in a person in need, comprising administering to a person any of the compounds described herein to reduce eosinophil effector function.

[0015] In other respects, an article of manufacture is provided, comprising: a container containing any of the compounds described herein; and a label containing instructions for use of such compounds.

[0016] In other aspects, a medicine box is provided, comprising: a dosage form of any of the compounds described herein; and a package insert containing instructions for use of the composition. In some variations of the foregoing aspects, the dosage form is a syrup, chewable tablet, capsule, or soft gelatin capsule. In other variations, the compositions provided herein are formulated for aerosol delivery. Detailed Implementation

[0017] The following description illustrates exemplary methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is instead provided as a description of exemplary embodiments.

[0018] In some respects, compounds of formula (I) are provided: (I), Or its salts, including any isomer of the above substances, wherein: R 1 It is at least one optionally substituted amino acid; R 2x It is an alkyl or alkenyl group, optionally substituted with -OH or -COOH; R 2y It is H or alkyl; or R 2x and R 2y Together with the atoms they are attached to, they form arbitrarily substituted 5-membered heterocycles; R 3 It is alkyl or alkenyl; and Z can be -OH, -OC(O)alkyl, -NH2, -NH(alkyl) or -N(alkyl)2.

[0019] In some variants of the above, the compound is not: 1-(N-(O-acetyl-N-(N-(2,4-dimethyloctanoyl)-N-methylleucyl)threonyl)-N-methylvaline)-4-hydroxypyrrolidine-2-carboxylic acid; or (12-Isopropyl-8,11-dimethyl-9-(4-methyl-2-(N-methyloctamido)pentamido)-10-oxo-2,5,7-trioxa-11-azatridecane-13-acyl)proline; Or its salts, including any isomers of the above substances.

[0020] In other variations of the aforementioned aspects, when R 3 When R is an alkyl group and Z is OH, then R 1 No – optional substitution Leu – optional substitution Thr – optional substitution Val –.

[0021] In some implementation schemes, R 1 It is the sequence of three optionally substituted amino acid motifs.

[0022] In some implementations, R 1 For –R 1a -R 1b -R 1c -,in: R 1a It is an optional substituted amino acid moiety with a hydrophobic side chain; R 1b It is an optionally substituted amino acid moiety with a polar, uncharged side chain; and R 1c It is an optional substituted amino acid moiety with a hydrophobic side chain; In some variants, R 1a It is an optional substituted amino acid moiety selected from Leu, Val, and Gly; R 1b It is an optional substituted amino acid moiety selected from Thr, Ser, and Cys; R 1c It is an optional substituted amino acid moiety selected from Val, Leu, and Gly.

[0023] In some implementations, R 1 For –R 1a -R 1b -R 1c -,in: R 1a Phe is an optional substitute; R 1b Thr is an optional replacement; and R 1c Val is an optional replacement.

[0024] In some implementations, R 1 for: Phe-OAcThr-Val, wherein each Phe and Val is N-methylated; or Phe-Thr-Val, where each Phe and Val is N-methylated.

[0025] It should be understood that in the aforementioned variants, "OAc-amino acid moiety" refers to an amino acid moiety in which the oxygen atom (as the case may be) of the amino acid moiety is replaced by an acetyl group. For example, "OAcThr" or "OAcSer" refers to threonine or serine, respectively, in which the oxygen atom of the amino acid side chain is replaced by an acetyl group.

[0026] In some implementation schemes, R 2x and R 2y Together with the atoms they are attached to, they form optionally substituted 5-membered heterocycles. In some variants, the heterocycle is a pyrrolidine. In some variants, the heterocycle is a pyrrolidine substituted with one or more -OH groups. In some variants, the heterocycle is a 4-hydroxypyrrolidine.

[0027] In some variants, R 3 It is a branched alkyl group. In other variants, R 3 C 1-20 Alkyl, C 1-10 Alkyl, or C 5-10 Alkyl, or C 7-9 Alkyl group. In some of the variants described above, the alkyl group is either unbranched or branched. In some variants, R... 3 for: , or In one variant, the alkyl group is branched at the 1- and / or 3-positions of the alkyl chain, referring to the following positions on the exemplary alkyl chain depicted below: .

[0028] In some variants, R 3 It is an alkenyl group. In some variants, R 3 For C2-C 30 Alkenyl. In some variants, R 3 for ,or This includes any cis and / or trans configurations of such portions.

[0029] In yet another few other variations, R 3 It is an ω-3 fatty acid or its derivative. In some variants, R 3 It is the eicosapentaenoic acid (EPA) portion, or the docosahexaenoic acid (DHA) portion, or a derivative of any of the above.

[0030] In some respects, compounds of formula (IA) are provided: (IA), Or its salts, including any isomer of the above substances, wherein: R 2x and R 2y Together with the atoms they are attached to, they form arbitrarily substituted 5-membered heterocycles; R 3 It is alkyl or alkenyl; and R 4 It is H or alkyl; R 5 It is a hydrophobic side chain of Ala, Val, Ile, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 8 It is a hydrophobic side chain of Ala, Val, Ile, Leu, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 6 It is H or alkyl; and R 7 It can be –OH, –O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, –SH, or –S(C=O)alkyl; and Z can be -OH, -OC(O)alkyl, -NH2, -NH(alkyl) or -N(alkyl)2.

[0031] In some variants, R 5 For the hydrophobic side chain of Leu. In some variants, R 5 It is a hydrophobic side chain of Phe.

[0032] In some variants, R 6 It is an alkyl group. In some variants, R 6 C 1-10 Alkyl, or C 1-5 Alkyl, or C 1-3 alkyl.

[0033] In some variants, R 7 For –OH. In other variants, R 7 It is an –O (C=O) alkyl group. In one variant mentioned above, the alkyl group is methyl. In other variants, R 7 It is either -O-alkyl-O-alkyl-O-alkyl. In one variant, R 7a It is -O-methyl-O-ethyl-O-methyl.

[0034] In some variants, R 6 It is methyl, and R 7 It is OH.

[0035] The following abbreviations are used in the descriptions in this article: "Ala" refers to alanine; "Val" refers to valine; "Ile" refers to isoleucine; "Leu" refers to leucine; "Met" refers to methionine; "Phe" refers to phenylalanine; "Tyr" refers to tyrosine; "Trp" refers to tryptophan; and "Gly" refers to glycine.

[0036] In some respects, compounds of formula (IB) are provided: (IB), Or its salts, including any isomer of the above substances, wherein: R 3 It is alkyl or alkenyl; R 7a It can be H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl; R b It is H or -OH; and Z can be -OH, -OC(O)alkyl, -NH2, -NH(alkyl) or -N(alkyl)2.

[0037] In some variants, the alkyl group is C10. 1-20 Alkyl, C 1-15 Alkyl, C 1-10 Alkyl, or C 1-5 Alkyl, or C 1-3 alkyl.

[0038] In some variants, R 7a It is H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl. In some variants, R 7a It can be H, -C(O)CH3 or -methyl-O-ethyl-O-methyl.

[0039] In some variants, R b For H. In other variants, R b It is -OH.

[0040] In some respects, a compound selected from Table A or Table A' below, or a salt thereof, including any isomer of the above compounds, is provided: Table A.

[0041] Table A'.

[0042] In some embodiments, the compound of formula (I) is selected from compounds 1-6, 8-10, 12, 13 and 15 of Table A and compounds 1a-6a, 8a-10a, 12a, 13a and 15a of Table A'.

[0043] In some variations, the compositions described herein may include one or more isomers of the compounds described herein, including compounds of formulas (I), (IA), and (IB), and compounds of Tables A and A'. Compounds having the same molecular formula but differing in the bonding properties or sequence of their atoms or in the spatial arrangement of their atoms are called "isomers." Isomers having the same atomic bonding sequence but different atomic spatial arrangements are called "stereoisomers." A diastereomer is a stereoisomer with opposite configurations at one or more chiral centers, and is not an enantiomer. A stereoisomer with one or more asymmetric centers is called an "enantiomer," where the asymmetric centers are mirror images that cannot be superimposed on each other. When a compound has an asymmetric center, for example, if the carbon atom is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of one or more asymmetric centers and described by the R- and S-sorting rules of Cahn, Ingold, and Prelog, or by the way the molecule rotates in the plane of polarized light and is named dextrorotatory or levorotatory. The prefixes d and l, or (+) and (-), are used to indicate the rotational notation of the plane-polarized light of a compound, where (-) or 1 indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. Chiral compounds can exist as single enantiomers or mixtures thereof. Mixtures containing equal proportions of enantiomers are called "racemic mixtures" or "racemates".

[0044] In some embodiments, the compositions described herein comprise a racemic mixture of compounds of formulas (I), (IA), and (IB), as well as compounds from Tables A and A'. In some embodiments, the compounds are enriched in at least about 90% by weight of a single diastereomer or enantiomer. In other embodiments, the compounds are enriched in at least about 95%, 98%, or 99% by weight of a single diastereomer or enantiomer.

[0045] In some variations, the compositions described herein may include one or more salts of the compounds described herein, including compounds of formulas (I), (IA), and (IB), as well as compounds in Tables A and A'. In some variations, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effects and properties of a free base or free acid, which are not biological or undesirable.

[0046] General Synthesis of Compounds The compounds provided herein, including those of formulas (I), (IA), and (IB), as well as the exemplary compounds in Tables A and A', can all be synthesized according to the following general scheme 1. The general scheme and the reactions described in the Examples section below can be readily adapted to prepare the compounds disclosed herein. For example, non-exemplary compounds according to this disclosure can be successfully synthesized by modifications obvious to those skilled in the art, such as by utilizing other suitable reagents known in the art besides those described, or by conventional modifications to the reaction conditions, reagents, and starting materials.

[0047] General Plan The compounds provided herein, including those of formulas (I), (IA), and (IB), as well as the exemplary compounds in Tables A and A', can all be synthesized according to the following general scheme 1. The general scheme and the reactions described in the Examples section below can be readily adapted to prepare the compounds disclosed herein. For example, non-exemplary compounds according to this disclosure can be successfully synthesized by modifications obvious to those skilled in the art, such as by utilizing other suitable reagents known in the art besides those described, or by conventional modifications to the reaction conditions, reagents, and starting materials.

[0048] Option 1 The exemplary compounds in Tables A and A' can be synthesized according to general scheme 1, wherein: R 2x and R 2y Together with the atoms they are attached to, they form arbitrarily substituted 5-membered heterocycles; R 3 It is alkyl or alkenyl; and R 4 It is H or alkyl; R 5 It is a hydrophobic side chain of Ala, Val, Ile, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 8 Independently, it is a hydrophobic side chain of Ala, Val, Ile, Leu, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 6 It is H or alkyl; and R 7 It can be –OH, –O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, –SH, or –S(C=O)alkyl.

[0049] The following is an example procedure applicable to general scheme 1: Step 1 (R) 3 (Condensation of COOH). A coupling agent (e.g., N,N'-carbonyldiimidazole (CDI)) is combined with a suitable solvent such as dichloromethane. The solution is cooled. Separately, R1 is also combined with a suitable solvent (e.g., dichloromethane) and a suitable base (e.g., diisopropylethylamine (DIPEA)) is added. Once the suspension becomes clear, it is added to a cooled CDI suspension. When the resulting second suspension becomes clear, the reaction continues under drying conditions (e.g., in a CaCl2 drying tube) until the reaction is complete. After completion, the reaction mixture is post-treated, involving extraction with a suitable organic solvent such as ethyl acetate, drying the organic layer (e.g., through MgSO4), filtration, and removal of the solvent to obtain a crude product (e.g., a viscous oil).

[0050] Add an additional solvent, such as dichloromethane, to the crude product. Add R to it. 3 COOH, coupling agents (such as 1-hydroxybenzotriazole hydrate (HOBt hydrate)) and catalysts (such as CuBr) 2) After the reaction is complete, the reaction mixture is post-treated, which involves quenching (e.g., with an aqueous HCl solution) and extraction with a suitable organic solvent such as dichloromethane. The organic layer is washed with an aqueous solution (e.g., NaHCO3), dried (e.g., by passing through MgSO4), filtered, and the solvent is removed to give a crude product (e.g., an oil) (P1).

[0051] Step 2 (Condensation of P1 with R2). P1 is added to an organic solvent (e.g., methanol) and a catalyst (e.g., Pd / C). The reaction is stirred under H2, then filtered and the solvent is removed to give the crude product (e.g., oil) (P1 acid).

[0052] The coupling agent (e.g., N,N'-carbonyldiimidazole (CDI)) is combined with a suitable solvent such as dichloromethane. The solution is cooled. Separately, R2 is also combined with a suitable solvent (e.g., dichloromethane) and a suitable base (e.g., diisopropylethylamine (DIPEA)) is added. Once the suspension becomes clear, it is added to the cooled CDI suspension. After the resulting second suspension becomes clear, the reaction continues under drying conditions (e.g., in a CaCl2 drying tube) until the reaction is complete. Upon completion, the reaction mixture is post-treated by extraction with a suitable organic solvent such as ethyl acetate, drying the organic layer (e.g., through MgSO4), filtering, and removing the solvent to obtain a crude product (e.g., a viscous oil).

[0053] Add additional solvents, such as dichloromethane, to the crude product. Add a PI acid (from above), a coupling agent (such as 1-hydroxybenzotriazole hydrate (HOBt hydrate)), and a catalyst (such as CuBr) to it. 2) After the reaction is complete, the reaction mixture is post-treated, which involves quenching (e.g., with an aqueous HCl solution) and extraction with a suitable organic solvent such as dichloromethane. The organic layer is washed with an aqueous solution (e.g., NaHCO3), dried (e.g., by passing through MgSO4), filtered, and the solvent is removed to give a crude product (e.g., an oil) (P2).

[0054] Step 3 (Condensation of P2 with R3). P2 is added to a suitable organic solvent (such as methanol) and a suitable catalyst (such as Pd / C). The reaction is stirred under H2, then filtered and the solvent is removed to give the crude product (e.g., oil) (P2 acid).

[0055] The coupling agent (e.g., N,N'-carbonyldiimidazole (CDI)) is combined with a suitable solvent such as dichloromethane. The solution is cooled. Separately, R3 is also combined with a suitable solvent (e.g., dichloromethane) and a suitable base (e.g., diisopropylethylamine (DIPEA)) is added. Once the suspension becomes clear, it is added to the cooled CDI suspension. After the resulting second suspension becomes clear, the reaction continues under drying conditions (e.g., in a CaCl2 drying tube) until the reaction is complete. Upon completion, the reaction mixture is post-treated by extraction with a suitable organic solvent such as ethyl acetate, drying the organic layer (e.g., through MgSO4), filtering, and removing the solvent to obtain a crude product (e.g., a viscous oil).

[0056] Add an additional solvent, such as dichloromethane, to the crude product. Add a P2 acid (from above), a suitable coupling agent (such as 1-hydroxybenzotriazole hydrate (HOBt hydrate)), and a suitable catalyst (such as CuBr2). After the reaction is complete, the reaction mixture is post-treated involving quenching (e.g., with aqueous HCl) and extraction with a suitable organic solvent such as dichloromethane. The organic layer is washed with an aqueous solution (e.g., NaHCO3), dried (e.g., through MgSO4), filtered, and the solvent is removed to give the crude product (such as an oil) (P3).

[0057] Step 4 (Condensation of P3 with R4). P3 is added to an organic solvent (e.g., methanol) and a catalyst (e.g., Pd / C). The reaction is stirred under H2, then filtered and the solvent is removed to give the crude product (e.g., oil) (P3 acid).

[0058] The coupling agent (e.g., N,N'-carbonyldiimidazole (CDI)) is combined with a suitable solvent such as dichloromethane. The solution is cooled. Separately, R4 is also combined with a suitable solvent (e.g., dichloromethane) and a suitable base (e.g., diisopropylethylamine (DIPEA)) is added. Once the suspension becomes clear, it is added to the cooled CDI suspension. After the resulting second suspension becomes clear, the reaction continues under drying conditions (e.g., in a CaCl2 drying tube) until the reaction is complete. Upon completion, the reaction mixture is post-treated by extraction with a suitable organic solvent such as ethyl acetate, drying the organic layer (e.g., through MgSO4), filtering, and removing the solvent to obtain a crude product (e.g., a viscous oil).

[0059] Add an additional solvent, such as dichloromethane, to the crude product. Add a P3 acid (from above), a coupling agent (such as 1-hydroxybenzotriazole hydrate (HOBt hydrate)), and a catalyst (such as CuBr2). After the reaction is complete, the reaction mixture is post-treated involving quenching (e.g., with aqueous HCl) and extraction with a suitable organic solvent such as dichloromethane. The organic layer is washed with an aqueous solution (e.g., NaHCO3), dried (e.g., through MgSO4), filtered, and the solvent is removed to give the crude product (such as an oil) (P4).

[0060] Step 5 (Deprotection of P4). P4 is added to an organic solvent (e.g., methanol) and a catalyst (e.g., Pd / C). The reaction is stirred under H2, then filtered and the solvent is removed to give a crude product (e.g., oil) (formula (P)).

[0061] Option 2 The exemplary compounds in Tables A and A' can be synthesized according to the general scheme 2 described above, wherein: X is -OC(O)alkyl, -NH2, -NH(alkyl) or -N(alkyl)2; and LG is H or a suitable leaving group.

[0062] The following is an example procedure applicable to general scheme 2: (Condensation of compound P). In some embodiments, an exemplary compound of formula P is reacted with reagent R5, wherein LG is H or a suitable leaving group (e.g., a halogen, pTsOH, or Fmoc), to undergo a condensation reaction to form compound Q.

[0063] Option 3 The reagents in Scheme 1 and / or Scheme 2 can be synthesized according to the general Scheme 3 above, wherein: R 6 It is H or alkyl; R 7b It is -O-alkyl-O-alkyl-O-alkyl; and LG a A suitable leaving group.

[0064] The following is an example procedure applicable to general scheme 3: In some embodiments, carboxylic acid of formula R2-1a reacts with a suitable protecting agent (such as BnBr) in the presence of K2CO3 at 0°C. o The reaction was carried out at room temperature to give compound R2-1b. The hydroxyl group of compound R2-1b was selectively deprotected, for example, by using an acid such as TFA when the protecting group was tBu. The resulting alcohol of formula R2-1c was reacted with LG... a -R 7b The reaction, in which LG a A suitable leaving group (e.g., a halogen), such as Cl-MEM, is used to carry out a condensation reaction to form a reagent of formula R2-1d.

[0065] The general scheme and any reactions described in the Examples section below can be readily adapted to prepare the compounds disclosed herein. For example, in some variants, reagent R1 can be N-methyl-L-leucine benzyl ester p-toluenesulfonate, or can be substituted with other suitable compounds to produce the variable R in formula (IV-A). 4 and R 5 The corresponding other parts.

[0066] Disease, illness or ailment In some aspects, the compositions provided herein, including compositions comprising compounds of formulas (I), (IA), and (IB), and exemplary compounds of Tables A and A', can be used to treat inflammatory disorders, conditions, or diseases, including respiratory disorders, conditions, or diseases. In some embodiments, these disorders, conditions, or diseases are inflammation of the respiratory tract. In some aspects, a method of treating an inflammatory disorder, condition, or disease in a person in need is provided, comprising applying the compositions provided herein to a person.

[0067] In some aspects, the compositions provided herein, including compositions comprising compounds of formulas (I), (IA), and (IB), and exemplary compounds of Tables A and A', can be used to treat inflammatory disorders, conditions, or diseases, including eosinophilic disorders, conditions, or diseases. In some embodiments, these disorders, conditions, or diseases are inflammation of the respiratory tract. In some aspects, a method of treating an inflammatory disorder, condition, or disease in a person in need is provided, comprising applying the compositions provided herein to a person.

[0068] In some embodiments, the compositions provided herein comprise compounds selected from compounds 1-6, 8-10, 12, 13 and 15 of Table A and compounds 1a-6a, 8a-10a, 12a, 13a and 15a of Table A'.

[0069] In some variations, "treatment" or "treating" refers to a method used to obtain a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include one or more of the following: (i) Reduce one or more symptoms caused by the aforementioned disease, illness, or condition; (ii) To reduce the severity of a disease and / or stabilize a disease, illness, or condition (e.g., to delay the worsening of a disease, illness, or condition); (iii) To delay the spread of disease, illness, or ailment; (iv) To delay or slow the recurrence and / or progression of a disease, illness, or condition; (v) To improve the state of disease and / or provide relief (whether partial or complete) from the disease, ailment or condition and / or reduce the dosage of one or more other medicines required to treat the disease, ailment or condition; (vi) Improve quality of life; and / or (vii) Extend lifespan.

[0070] In some embodiments, the compositions provided herein, including compositions comprising compounds of formulas (I), (IA), and (IB), can be used to treat asthma, pneumonia, bronchiectasis, emphysema, tuberculosis, lung collapse, pulmonary fibrosis, fibrotic alveolitis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, chronic sinusitis (CRS), and acute respiratory syndrome.

[0071] In some embodiments, the compositions provided herein, including compositions comprising compounds of formulas (I), (IA), and (IB), are indicated for the treatment of eosinophilic respiratory disorders, diseases, or conditions. In some variations, the disorders, diseases, or conditions may include allergic rhinitis, asthma, atopic dermatitis (or eczema), allergic gastroenteritis, eosinophilic esophagitis, eosinophilic folliculitis, eosinophilic gastritis, eosinophilic colitis, eosinophilic cellulitis, eosinophilic syndrome, eosinophilic leukemia, eosinophilic granulomatosis, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, and hyperIgE syndrome.

[0072] In some implementations, the disorder, disease, or condition is a chronic inflammatory condition. In some implementations, the chronic inflammatory condition is a chronic inflammatory condition of the airways. In some variations, the disorder, disease, or condition is an inflammatory lung disease. In some variations, the disorder, disease, or condition involves narrowing and / or swelling of the airways, resulting in dyspnea and triggering cough, wheezing, and / or shortness of breath. In some variations, the disorder, disease, or condition is asthma. In some variations, asthma is bronchial asthma. In one variation, the disorder, disease, or condition involves steroid-treated resistant asthma and airway narrowing.

[0073] In some implementations, the ailment, disease, or condition is a chronic inflammatory condition. In some implementations, the chronic inflammatory condition is a chronic inflammatory condition of the esophagus. In some variations, the ailment, disease, or condition is an inflammatory gastrointestinal disease. In some variations, the ailment, disease, or condition involves esophageal stricture and / or swelling, resulting in dysphagia and triggering cough and pain. In some variations, the ailment, disease, or condition is eosinophilic esophagitis. In one variation, the ailment, disease, or condition involves both eosinophilic esophagitis and esophageal stricture.

[0074] In other implementations, the disease, ailment, or condition is an allergy or allergic inflammation.

[0075] In other implementations, the illness, disease, or condition is a viral respiratory illness. In some variants, the illness, disease, or condition is severe acute respiratory syndrome (SACS). In some variants, SACS is caused by a coronavirus.

[0076] In some variants, the person in need is an individual with impaired lung function. In some variants, fluid accumulates in the alveoli of the lungs of an individual with impaired lung function. This fluid can leak into the alveoli from the smallest blood vessels in the lungs due to the disruption of the protective membrane within the alveoli. The membrane that normally holds this fluid within the blood vessels can be damaged due to a disruption of the immune response caused by severe illness or injury. The fluid enters the alveoli, preventing the lungs from filling with enough air, meaning less oxygen reaches the bloodstream. This deprives organs of the oxygen they need to function, which can trigger multiple organ failure and lead to death.

[0077] In one embodiment, a method of treating a hospitalized person with lung damage in need is provided, comprising administering to the person a composition provided herein, including a composition comprising compounds of formulas (I), (IA), and (IB), to reduce or delay the need for assisted breathing to the person.

[0078] In some embodiments, the method herein includes applying a composition comprising a compound selected from compounds 1-6, 8-10, 12, 13 and 15 of Table A and compounds 1a-6a, 8a-10a, 12a, 13a and 15a of Table A'.

[0079] In some variations, “delaying” the development of a disease, ailment, or condition refers to postponing, hindering, slowing, delaying, stabilizing, and / or postponing its progression. This delay may vary in length depending on the individual’s history of the disease, ailment, or condition and / or the treatment they receive.

[0080] In other respects, the compositions provided herein, including compositions comprising compounds of formulas (I), (IA), and (IB), enhance anti-inflammatory efficacy by reducing eosinophil effector function. Therefore, in some embodiments, a method for reducing eosinophil effector function in a person of need is provided, comprising administering to said person the compositions provided herein, including compositions comprising compounds of formulas (I), (IA), and (IB), to reduce eosinophil effector function.

[0081] patient subgroups In some embodiments, the methods provided herein involve treating a person in need. In some embodiments, the person has a high degree of tolerance to medical and surgical interventions for treating the inflammatory ailment, condition, or disease described herein. In one embodiment, the person exhibits or has tolerance to steroid therapy. For example, in one variant, the person suffers from steroid-resistant asthma. In another instance, the person suffers from eosinophilic esophagitis.

[0082] In some of the above variations, the person is a child. In some variations, the person is less than 18 years old, less than 12 years old, less than 10 years old, less than 5 years old, less than 2 years old, or less than 1 year old; or between 2 and 12 years old.

[0083] preparation In some embodiments, the compositions provided herein, including compositions comprising compounds of formulas (I), (IA), and (IB), are formulated for oral administration. Suitable forms for oral administration may include, for example, tablets, pills, capsules, sachets, lozenges, tablets, liquids, gels, syrups, liquids, elixirs, suspensions, aerosols, or powders.

[0084] In some embodiments, the pharmaceutical compositions described herein are in the form of syrups, capsules, and soft gelatin capsules (including, for example, chewable gummies).

[0085] In some embodiments, the pharmaceutical compositions provided herein comprise compounds selected from compounds 1-6, 8-10, 12, 13 and 15 of Table A and compounds 1a-6a, 8a-10a, 12a, 13a and 15a of Table A'.

[0086] Techniques for the formulation and application of the composition can be found in Remington's Pharmaceutical Sciences 18th edition, Mack Publishing Co., Easton, Pa., 1990. The pharmaceutical compositions described herein can be prepared using any conventional method, such as mixing, dissolving, granulating, sugar coating, grinding, emulsifying, encapsulating, melt-spinning, spray drying, or lyophilizing. Those skilled in the art can determine the optimal pharmaceutical formulation based on the route of administration and the desired dosage. Such formulations can affect the physical state, stability, rate of release, and rate of clearance of the administered drug.

[0087] In some variations, the compositions provided herein are administered to humans in unit doses, for example, in the form of syrups, capsules, and soft gelatin capsules (including, for example, chewable gummies) as described herein. In one variation, "unit dosage form" means a physically discrete unit suitable as a unit dose, each unit representing a predetermined amount of the compositions provided herein or a composition containing a bioactive substance isolated from the compositions provided herein, which may be in a pharmaceutically acceptable carrier.

[0088] As used herein, "pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable; for example, the material can be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects or interacting in a harmful manner with any other component of the composition containing it. Therefore, in some embodiments, pharmaceutically acceptable carriers or excipients preferably meet the required standards for toxicological and manufacturing testing and / or are included according to the inactive ingredient guidelines prepared by the U.S. Food and Drug Administration.

[0089] In other variations, the compositions provided herein are formulated for aerosol delivery.

[0090] dose In some embodiments, the provided method includes administering an effective amount of the composition provided herein, including compositions comprising compounds of formulas (I), (IA), and (IB), to a person in need. In some variations, "effective amount" means an amount that the composition or bioactive substance of the present invention should be effective in a given therapeutic form. In some variations, an effective amount of the composition provided herein is an amount sufficient to reduce eosinophil effector function in a person, thereby treating a person suffering from the disease, ailment, or condition described herein, or alleviating existing symptoms of such disease, ailment, or condition.

[0091] In some variations, exemplary human dose levels may range from 0.01 mg / kg to 100 mg / kg of body weight.

[0092] The final dosage regimen is determined by the attending physician based on good pharmaceutical practice, taking into account various factors that affect the efficacy of the salmon oil compositions described herein or compositions containing bioactive substances isolated from salmon oil compositions, the nature and severity of the disease state, the subject's responsiveness, the subject's age, condition, weight, sex, and diet, and the severity of any infection. Other factors that may be considered include the timing and frequency of administration, drug combinations, sensitivity to response, and tolerability / response to treatment. Skilled practitioners routinely refine the dosage appropriately for treatment involving any of the formulations mentioned herein, without excessive experimentation, particularly based on publicly available dosage information and assays, and pharmacokinetic data observed in human clinical trials.

[0093] An effective amount may be within one or more doses; that is, a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. In some embodiments, the salmon oil composition provided herein, or a composition comprising a bioactive substance isolated from the salmon oil composition, is administered once, twice, or three times daily. In some embodiments, the composition provided herein is administered once or twice daily. In some embodiments, the composition provided herein is administered once daily.

[0094] Products and medicine boxes The compositions provided herein, including compositions comprising compounds of formulas (I), (IA), and (IB), and exemplary compounds of Tables A and A', can be formulated in one or more pharmaceutically acceptable carriers, excipients, or other ingredients, prepared, placed in suitable containers, and labeled for the treatment of specified diseases, ailments, or conditions. Accordingly, in some aspects, an article is also provided, such as a container for a dosage form comprising a salmon oil composition, or a composition comprising a bioactive substance isolated from the compositions provided herein, and a label containing instructions for use of such compositions.

[0095] In some embodiments, the article is a container containing a dosage form of the composition provided herein, and one or more pharmaceutically acceptable carriers, excipients, or other ingredients. In one embodiment of the article described herein, the dosage form is a syrup, capsule, or soft gelatin capsule (including, for example, chewable gummies).

[0096] In some aspects, a medicine box is also provided. For example, in some embodiments, the medicine box may include a dosage form of the composition provided herein, and a package insert containing instructions for use of the composition / active ingredient to treat a disease, ailment, or condition. The instructions for use in the medicine box may be for treating respiratory inflammation or inflammation of the respiratory tract, including, for example, asthma. In one variation, the instructions for use in the medicine box may be for treating bronchial asthma. In another variation, the instructions for use in the medicine box may be for treating severe acute respiratory syndrome. In other variations, the instructions for use in the medicine box may be for treating gastrointestinal inflammation or inflammation of the gastrointestinal tract, including, for example, eosinophilic esophagitis or asthma. In one variation, the instructions for use in the medicine box may be for treating eosinophilic esophagitis. In another variation, the instructions for use in the medicine box may be for treating asthma.

[0097] The labels and packaging instructions for the products and medicine boxes contain instructions for treating any of the diseases, conditions, or ailments described herein. In some embodiments, the label contains instructions for treating inflammatory diseases, conditions, or ailments (including respiratory diseases, conditions, or ailments). In some variations, the label contains instructions for treating chronic inflammatory conditions of the airways. In one variation, the label contains instructions for treating asthma (such as bronchial asthma and / or steroid-resistant asthma). In other embodiments, the label contains instructions for treating viral respiratory diseases (such as severe acute respiratory syndrome, including, for example, severe acute respiratory syndrome caused by coronaviruses). In some embodiments, the label contains instructions for treating inflammatory diseases, conditions, or ailments (including eosinophilic diseases, conditions, or ailments). In some variations, the label contains instructions for treating chronic inflammatory conditions of the esophagus. In one variation, the label contains instructions for treating eosinophilic esophagitis and asthma (such as bronchial asthma, steroid-resistant asthma, and / or eosinophilic esophagitis). In other implementations, the label includes instructions for treating viral eosinophilic disease.

[0098] Unless otherwise explicitly stated, the terms “an”, “a kind”, etc., refer to one (kind) or more (kinds).

[0099] In some variations, "about" refers to a common range of error for the corresponding value that is readily known to those skilled in the art. References herein to "about" a value or parameter include (and describe) an embodiment for said value or parameter itself. For example, "about x" includes and describes x itself. In some embodiments, the term "about" when used in relation to a measurement or to modify a value, unit, constant, or range of values ​​refers to a variation of + / - 2%.

[0100] In some variations, the phrase "between" two values ​​or parameters in this document includes (and describes) the implementation that includes both values ​​or parameters themselves. For example, a description referring to "between x and y" includes a description of "x" and "y" themselves.

[0101] List of implementation plans The following embodiments represent some aspects of the present invention.

[0102] Implementation Scheme 1. A compound of formula (IA): (IA) Or its salts, including any isomer of the above substances, wherein: R 2x and R 2y Together with the atoms they are attached to, they form arbitrarily substituted 5-membered heterocycles; R 3It is alkyl or alkenyl; and R 4 It is H or alkyl; R 5 It is a hydrophobic side chain of Ala, Val, Ile, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 8 Independently, it is a hydrophobic side chain of Ala, Val, Ile, Leu, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 6 It is H or alkyl; and R 7 It can be –OH, –O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, –SH, or –S(C=O)alkyl; and Z can be -OH, -OC(O)alkyl, -NH2, -NH(alkyl) or -N(alkyl)2.

[0103] Implementation Scheme 2. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (IB): (IB) Or its salts, including any isomer of the above substances, wherein: R 7a It is H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl; and R b It can be H or -OH.

[0104] Implementation Scheme 3. A compound selected from:

[0105] Or its salts, including any isomers of the above substances.

[0106] Implementation Scheme 4. The compound as described in Implementation Scheme 3, wherein the compound is:

[0107] Or its salts, including any isomers of the above substances.

[0108] Implementation Scheme 5. A pharmaceutical composition comprising: at least one compound as described in any one of Implementation Schemes 1 to 4, and at least one pharmaceutically acceptable excipient.

[0109] Implementation Scheme 6. A method for treating eosinophilic inflammatory disorders, conditions, or diseases in persons in need, comprising: The person is given an effective dose of at least one compound as described in any one of embodiments 1 to 4, or a pharmaceutical composition as described in embodiment 5, to treat eosinophilic inflammatory disease, condition, or illness.

[0110] Implementation Scheme 7. The method as described in Implementation Scheme 6, wherein the eosinophilic inflammatory disorder, disease, or condition is an inflammatory gastrointestinal disease.

[0111] Implementation Scheme 8. The method as described in Implementation Scheme 6 or 7, wherein the eosinophilic inflammatory disorder, condition or disease is a chronic inflammatory condition of the esophagus.

[0112] Implementation Scheme 9. The method of any one of Implementation Schemes 6 to 8, wherein the eosinophilic inflammatory disorder, condition or disease is eosinophilic esophagitis.

[0113] Implementation Scheme 10. The method as described in Implementation Scheme 6, wherein the eosinophilic inflammatory disorder, condition, or disease is a chronic inflammatory condition of the airway.

[0114] Implementation Scheme 11. The method as described in Implementation Scheme 6 or 10, wherein the eosinophilic inflammatory disorder, disease, or condition is asthma.

[0115] Implementation Scheme 12. The method of any one of Implementation Schemes 6 to 11, wherein the eosinophilic inflammatory disorder, condition or disease is bronchial asthma.

[0116] Implementation Scheme 13. A method for treating eosinophilic respiratory disorders, symptoms, or diseases in persons in need, comprising: The person is given an effective dose of at least one compound as described in any one of embodiments 1 to 4, or a pharmaceutical composition as described in embodiment 5, to treat eosinophilic respiratory disorders, symptoms, or diseases.

[0117] Implementation Scheme 14. The method as described in Implementation Scheme 13, wherein the eosinophilic respiratory disorder, condition, or disease is a viral respiratory disease.

[0118] Implementation Scheme 15. The method as described in Implementation Scheme 13, wherein the eosinophilic respiratory disorder, condition, or disease is severe acute respiratory syndrome.

[0119] Implementation Scheme 16. The method as described in Implementation Scheme 13, wherein the severe acute respiratory syndrome is caused by a coronavirus.

[0120] Implementation Scheme 17. The method as described in Implementation Scheme 13, wherein the eosinophilic respiratory disorder, condition, or disease is allergic rhinitis, asthma, atopic dermatitis (or eczema), allergic gastroenteritis, eosinophilic esophagitis, eosinophilic folliculitis, eosinophilic gastritis, eosinophilic colitis, eosinophilic cellulitis, eosinophilic syndrome, eosinophilic leukemia, eosinophilic granulomatosis, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, and hyper-IgE syndrome.

[0121] Implementation Scheme 18. The method of any one of Implementation Schemes 13 to 17, wherein the person has a high degree of tolerance to medical and surgical interventions for treating the disease, ailment, or illness.

[0122] Implementation Scheme 19. The method of any one of Implementation Schemes 13 to 17, wherein the person exhibits or has tolerance to steroid treatment.

[0123] Implementation Scheme 20. The method of any one of Implementation Schemes 13 to 17, wherein the person suffers from steroid-resistant asthma.

[0124] Implementation Scheme 21. The method of any one of Implementation Schemes 13 to 17, wherein the person suffers from eosinophilic esophagitis.

[0125] Implementation Scheme 22. The method of any one of Implementation Schemes 13 to 21, wherein administering the composition to the person reduces or delays the need to provide assisted breathing to the person.

[0126] Implementation Scheme 23. A method for reducing the function of eosinophil effectors in a person in need, comprising: The person is given at least one compound as described in any one of embodiments 1 to 4, or a pharmaceutical composition as described in embodiment 5, to reduce eosinophil effector function.

[0127] Implementation Scheme 24. The method of any one of Implementation Schemes 6 to 23, wherein the composition is administered as a syrup, chewable tablet, capsule or soft gelatin capsule, or the composition is formulated for aerosol administration.

[0128] Implementation Scheme 25. An article comprising: A container comprising at least one compound as described in any one of embodiments 1 to 4, or a pharmaceutical composition as described in embodiment 5; and The label contains instructions for use of this composition.

[0129] Implementation Scheme 26. The article of manufacture as described in Implementation Scheme 25, wherein the composition is provided in a dosage form.

[0130] Implementation Scheme 27. The article of embodiment 25 or 26, wherein the dosage form is a syrup, chewable tablet, capsule or soft gelatin capsule.

[0131] Implementation Scheme 28. The article of embodiment 25 or 26, wherein the container is an aerosol container.

[0132] Implementation Scheme 29. A medicine box, comprising: At least one compound as described in any one of embodiments 1 to 4, or a dosage form of the pharmaceutical composition as described in embodiment 5; and Packaging instructions, which contain instructions for use of this composition.

[0133] Implementation Scheme 30. The medicine box as described in Implementation Scheme 29, wherein the dosage form is a syrup, chewable tablet, capsule or soft gelatin capsule, or the dosage form is an aerosol.

[0134] Example The following examples are merely illustrative and are not intended to limit any aspect of this disclosure in any way.

[0135] Synthesis Examples By obtaining the expected M of all synthesized final analogues + Ions were used for structural verification. The purity of the compound was determined by LCMS and HPLC. Mass spectrometry was performed using a Shimadzu LCMS 2020 system (equipped with N-series DUIS) with positive-to-negative conversion. HPLC spectra were determined using an Agilent 1200 series system.

[0136] The abbreviations used are those conventional in the art. The following examples are illustrative only and are not intended to be limiting in any way.

[0137] Example A1 Synthesis and characterization of compound 1a This embodiment describes the synthesis and characterization of compound 1a. These compounds were prepared according to the scheme provided below. The synthesis of compound 1a was carried out using a solid-phase peptide synthesis method. The following methods, steps, and resins were used in the synthesis.

[0138] Structure verification was performed by obtaining the expected M+ ions from all synthesized final analogs. All mass-resolution LC / MS data were obtained.

[0139] Procedure: In a glass sintering vessel containing glass frit, 4.5 g of 2-chlorotriphenylmethyl chloride resin was swollen in dry DCM (45 mL) for 1 h. The dried DCM solution was filtered. Fmoc-Pro-OH (3.2 g, 3.0 equivalent) was dissolved in DCM (50 mL) in the presence of DIPEA (2.2 mL, 6.0 equivalent) and added to the resin. The reaction mixture was shaken on a fixed-track shaker at room temperature for 3 h. The solution was drained, and the resin was washed with DMF:DCM (3 times each). The Fmoc-Pro-OH coupling resin was treated with a 20% piperidine DMF solution for 20 min. The mixture was filtered, and the peptide resin was washed with DMF:DCM:DMF (3 x 45 mL). Coupling was then performed using the coupling reagent in DMF with amino acids (3 equivalents), Fmoc-NMeVal-OH, Fmoc-NMeVal-OH, Fmoc-NMePhe-OH, EPA acid, and HATU / DIPEA (3 equivalents). The beads were subjected to a Kaiser test to confirm the presence of free amines.

[0140] End capping: End capping is performed using MeOH / DIPEA / DCM (24 / 2 / 24).

[0141] Table A1.

[0142] Finally, each of the above peptide resins was washed with DMF:DCM (3 x 40 mL), followed by washing with methanol (40 mL) and diethyl ether (2 x 40 mL). The resins were then dried under vacuum overnight.

[0143] Whole-body deprotection: Peptide lysis from the solid support was achieved by treating the peptide-based resin (6.0 g) with a reagent mixture (95% TFA / 2.5% TIPS / 2.5% H2O) at a cooling temperature of 0–5 °C for 1 hour, followed by treatment at room temperature for 1 hour. The precipitated peptide was centrifuged (4000 rpm), and the supernatant was removed with diethyl ether. Fresh diethyl ether was added to the peptide, and centrifugation was repeated. This method was repeated three times. The precipitated peptide (compound 1a) was lyophilized under high vacuum for 16 hours to obtain a white solid product. HPLC and LCMS analysis were used to confirm the quality and identify the desired peptide.

[0144] Purification: The crude product was dissolved in acetonitrile and methanol. The dissolved crude product was purified using an Agilent preparative HPLC 1200 series (equipped with a diode array detector, capable of monitoring at 210 nm). Method:

[0145] Product (compound 1a): Total crude product weight: 3.5 g, total recovery: 400 mg. M + = 773.5.

[0146] Biological Examples Example B1 Percentage of eosinophil apoptosis in purified peripheral blood eosinophils from allergic individuals Triple aliquots of allergic human eosinophils were placed in RPMI 1640 medium supplemented with IL-5 (50 pM), 1% FBS, and PenStrep in the presence of 5 nM Fevipiprant (positive control), 10 nM test compound, and formulation mediator (negative control). The test compound included compound 1a, which was obtained according to the synthesis procedure described in Example A1 above. After 18 hours of incubation, aliquots were removed, washed twice in PBS, and resuspended in binding buffer. Eosinophils were stained using the Annexin V-FITC Apoptosis Detection Kit I (Sigma Aldrich) and analyzed immediately by flow cytometry. Each sample was collected for 1 minute, and the total number of eosinophils and the percentage of viable cells (annexin Vneg) and apoptotic cells (annexin Vpos) on forward / lateral scatter plots were recorded. (Standard deviation of the determination is + / - 2.3%). Results are shown in Table 1 below.

[0147] Table 1.

[0148] Triple copies were used, employing allergic human eosinophils as before, but with fevipiprant as a control to match the in vivo assay control. (SD in the assay was ±2.1%) Example B2 Changes in CD11b on the PMNL surface stimulated with 2.5 nm CCL11 (baseline 100%) PMNL cells were pretreated for 30 min with 5 nM Fevipiprant (positive control), 10 nM test compound, and formulation mediator (negative control), and incubated at 37°C with serial dilutions of CCL11 for 30 min. Samples were stained with anti-CD16-PE-Cy5 and anti-CD11b-PE (ICRF44) antibodies. Eosinophils were identified as CD16-negative cells. CD11b upregulation was analyzed by flow cytometry and reported above. (Standard deviation in assays is + / - 2%). Results are shown in Table 2 below.

[0149] Table 2.

[0150] Three copies were prepared, using normal polymorphonuclear leukocytes (PMNL) as before. (SD in the measurement is + / - 3%) Example B3 Regulatory properties of exemplary compounds on eosinophils and other leukocytes and cytokines in a mouse asthma model induced by house dust mite (HDM) extract. This embodiment was implemented to determine the regulatory properties of low and high doses of the exemplary compounds described herein on eosinophils and other leukocytes and cytokines in a house dust mite (HDM) extract-induced mouse asthma model (30 and 150 µg / animal / day). For the same purpose, no treatment was used as an eosinophilia control, and fevipiprant (5 µg / animal / day) was used as a positive control.

[0151] The experimental design included inducing asthma in mice using house dust mite (HDM) extract, while evaluating the effects of compound 1a (30 and 150 µg / animal / day) and fevipiprant (5 µg / animal / day) as positive controls on eosinophil regulation in mice.

[0152] On day 1 of the experiment, all 40 mice were anesthetized with isoflurane and sensitized intranasally with 1 µg of HDM protein in 40 µL PBS. Then, from day 7 to day 11, all mice were challenged daily with 10 µg of HDM protein (dissolved in 40 µL PBS) administered intranasally. From day 7 to day 14, mice received the appropriate mediator, test compound, or fevipiprant daily, according to their respective groups. On day 15 of the experiment, all mice were anesthetized, bronchoalveolar lavage (BAL) fluid was collected, centrifuged, and the cell pellet was stored at -20°C and sent to an external laboratory for eosinophil analysis. In addition, spleen samples were collected from all these animals, frozen, and sent for eosinophil analysis.

[0153] Animal observation included monitoring mortality / morbidity, the appearance of any clinical signs / symptoms, and body weight. Eosinophilia analysis of BAL fluid and spleen was performed by an approved external laboratory.

[0154] No clinical signs or symptoms were observed in any of the animals in any of the groups.

[0155] Throughout the experiment, there were no statistically significant differences in the body weight or percentage change in body weight among the animals in all groups.

[0156] in conclusion Observations revealed that compound 1a has regulatory properties on eosinophils and other leukocytes and cytokines (markers of asthma), indicating its therapeutic efficacy in a mouse asthma model induced by house dust mite (HDM) extract.

[0157] Example C Regulatory properties of exemplary compounds on eosinophils and other leukocytes and cytokines in a mouse asthma model induced by house dust mite (HDM) extract. The aim of this embodiment was to determine the effects of an intermediate dose of compound 1a (90 μg / animal / day) during an 8-week treatment period in a house dust mite (HOM) extract-induced mouse asthma model on the regulation of eosinophils, other leukocytes, and cytokines, and consequently on lung tissue pathology. For the same purpose, no treatment (saline / carrier) was used as an eosinophilic control, and montelukast (60 µg / animal / day) was used as a positive control.

[0158] The experimental design involved inducing asthma in mice using house dust mite (HOM) extract, while simultaneously evaluating the effects of compound 1a (90 µg / animal / day) and montelukast (60 µg / animal / day) as positive controls on eosinophil regulation in mice. On day 1, all 30 mice were anesthetized with isoflurane and sensitized intranasally with 1 µg of HOM protein in 40 µL PBS. From day 7 to day 15, all mice were challenged by intranasal administration of 10 µg of HOM protein (dissolved in 40 µL PBS) once daily. Mice also received the causative agent, compound 1a, and montelukast once daily from day 7 to day 56, according to their respective groups. On day 57, all mice were anesthetized, and bronchoalveolar lavage (BAL) fluid was collected from the right lung (with the left bronchus ligated). The collected fluid was centrifuged, and the cell pellet was stored at -20°C and sent to an external laboratory for eosinophilic analysis. In addition, spleen samples were collected from all these animals, frozen, and sent for eosinophil analysis. The left lung was fixed in neutral buffered formalin for subsequent sectioning, staining, and assessment of the extent of asthma changes, including airway inflammation and obstruction.

[0159] Animal observation included monitoring mortality / morbidity, the appearance of any clinical signs / symptoms, and body weight. Eosinophilia was analyzed in BAL fluid and spleen.

[0160] Mortality / morbidity Throughout the adaptation and experimental periods, observe all animals twice daily (morning and evening) for any morbidity or mortality.

[0161] Clinical signs or symptomsThroughout the adaptation and treatment periods, observations should be conducted once daily to check for any clinical signs or symptoms. These cageside observations include (but are not limited to) changes in skin and hair, eyes and mucous membranes, as well as changes in the respiratory, circulatory, autonomic and central nervous systems, somatic motor activities, and behavioral patterns.

[0162] weight Animals were weighed during randomization, on day 1, day 7, and day 15 of the experiment.

[0163] Collection of BAL (bronchoalveolar lavage) fluid, serum, lungs, and spleen. On day 57, animals were anesthetized. Their trachea were exposed, and one side of the lung (left lung) was ligated. A total of 3 ml of BAL buffer (PBS containing 1 mM EDTA) was divided into three fractions and perfused into the lung. BAL fluid and spleen were collected and stored on ice. The left lung was collected and fixed in 10% neutral buffered formalin (NBF). After BAL fluid collection, the liquid was centrifuged (400 g, 4°C, 7 min), and the collected cell pellets were frozen (-20°C) until sent for airway eosinophil assay. All pellets were collected from BALF and spleen samples from all animals and stored at -20°C until the samples were sent for systemic eosinophil assay. Serum was separated from the blood and stored at -80°C until the levels of IL4, IL5, IL6, IL10, IL13, IL17, IgE, and IgG1 were estimated using an ELISA kit. Lung tissue was processed, and one set of slides from all animals was stained with hematoxylin and eosin for histopathological evaluation, while another set of slides was stained with PAS to detect the presence of mucus in asthma.

[0164] BAL fluid and spleen sample analysis Eosinophil counts were analyzed in the collected cell pellet and spleen tissue. Total cell counts were performed using a hematology counter. To analyze differential eosinophil counts, 80 µl of resuspended cell pellet was stained using methods and techniques known in the art.

[0165] result Results Evaluation / Statistical Analysis The raw data were processed using commercial statistical software. The software was used to calculate the mean and standard deviation, and all data were summarized into a table. The Shapiro-Wilk test was used to check the homogeneity of all continuous data. All homogeneous data were analyzed using ANOVA, and data showing significant variance were analyzed using Dunnett's t-test. A p-value less than or equal to 0.05 was considered statistically significant.

[0166] Mortality / morbidityNo mortality / morbidity was observed in any of the four groups of animals throughout the entire experiment.

[0167] Clinical signs of toxicity No treatment-related clinical signs were observed in any group.

[0168] Weight and weight change % Throughout the experiment, no statistically significant difference in mean body weight was observed between the treatment group and the vehicle control group. Similarly, no statistically significant difference was observed in the percentage change in body weight relative to day 1 between any two groups throughout the experiment.

[0169] Estimates of CXCL-1, IL4, ILG, IL10 and IL17 Compared with the disease control group (G1), the serum CXCL-1 concentration of compound 1a (G2) and the positive control group (G3) was significantly reduced.

[0170] In compound 1a (G2) and the positive control group (G3), a decreasing trend in serum IL6 levels was observed.

[0171] In compound 1a (G2) and the positive control group (G3), serum IL10 levels were reduced.

[0172] Compared with the disease control group, serum IL-17 levels were reduced in the compound 1a treatment group and the positive control group.

[0173] No statistically significant changes were observed in serum IL4 levels.

[0174] IL-5 was significantly reduced in compound 1a (G2) and the positive control group (G3), consistent with the reduced eosinophilia observed in histopathological evaluation.

[0175] Serum IL-13 levels were found to be comparable among disease controls (G1, untreated), compound 1a (G2, treated), and montelukast (G3, positive control), indicating that treatment with compound 1a and montelukast had no effect on IL-13 expression.

[0176] No significant differences were found in IgE levels among disease controls (G1, untreated), compound 1a (G2, treated), and montelukast (G3, positive control).

[0177] No significant differences were found in lgG1 levels among disease controls (G1, untreated), compound 1a (G2, treated), and montelukast (G3, positive control).

[0178] The BAL (bronchoalveolar lavage) fluid and spleen cellularity were evaluated, and the results are as follows. Compared with G1 (disease control), the total cell count, eosinophil count in BAL fluid, and percentage of eosinophils in spleen tissue were significantly reduced in all treatment groups.

[0179] Hematoxylin and eosin staining: Lung histology stained with hematoxylin and eosin clearly showed the typical lesions of G1 group asthma: goblet cell hypertrophy, smooth muscle hyperplasia, and airway obstruction, which exacerbated pulmonary congestion during G1 disease. The severity of these lesions was mildly to moderately reduced after treatment with compound 1a (G2) and montelukast (G3).

[0180] PAS staining revealed varying degrees of inflammatory infiltration, epithelial shedding, basement membrane thickening, mucus production, and goblet cell enlargement—significant asthmatic changes observed in G1, accompanied by marked inflammation, impaired barrier function, airway remodeling, and airway obstruction. The severity subsequently decreased in G2 and to some extent in G3.

[0181] Immunohistochemical staining revealed that IL13 markers were significantly expressed in groups G1, G2, and G3.

[0182] In summary, no adverse clinical signs or symptoms were observed in any animal across all groups, and all animals remained healthy. Throughout the experiment, there were no statistically significant differences in body weight or percentage change in body weight among the groups.

[0183] in conclusion The reduction in IL-5, IL-10, CXCL-1, IL-6, IL-17, and eosinophils suggests a potential role for compound 1a in inhibiting asthma pathogenicity, which was also confirmed in lung histopathology. The unchanged levels of IL-4, IL-13, IgG1, and IgE suggest that compound 1a may not trigger the IL-4 and IL-13 pathways, but rather the IL-5 pathway, thus contributing to the counteracting of the inflammatory response.

Claims

1. A compound of formula (IA): (IA) Or its salts, including any isomer of the above substances, wherein: R 2x and R 2y Together with the atoms they are attached to, they form arbitrarily substituted 5-membered heterocycles; R 3 It is alkyl or alkenyl; and R 4 It is H or alkyl; R 5 It is a hydrophobic side chain of Ala, Val, Ile, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 8 Independently, it is a hydrophobic side chain of Ala, Val, Ile, Leu, Met, Phe, Tyr, Trp or Gly, wherein the hydrophobic side chain is optionally replaced; R 6 It is H or alkyl; and R 7 It can be –OH, –O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, –SH, or –S(C=O)alkyl; and Z can be -OH, -OC(O)alkyl, -NH2, -NH(alkyl) or -N(alkyl)2.

2. The compound of claim 1, wherein the compound is a compound of formula (IB): (IB) Or its salts, including any isomer of the above substances, wherein: R 7a It is H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl; and R b It can be H or -OH.

3. A compound selected from: Or its salts, including any isomers of the above substances.

4. The compound of claim 3, wherein the compound is: Or its salts, including any isomers of the above substances.

5. A pharmaceutical composition comprising: at least one compound as claimed in any one of claims 1 to 4, and at least one pharmaceutically acceptable excipient.

6. A method for treating eosinophilic inflammatory disorders, diseases, or conditions in persons in need, or for treating eosinophilic respiratory disorders, diseases, or conditions in persons in need, or for reducing the function of eosinophil effectors in persons in need, comprising: Administer to the person an effective dose of at least one compound as described in any one of claims 1 to 4, or a pharmaceutical composition as described in claim 5.

7. The method of claim 6, wherein the eosinophilic inflammatory disorder, disease, or condition is: Inflammatory gastrointestinal disease; or Chronic inflammatory conditions of the esophagus; or Eosinophilic esophagitis; or Chronic inflammatory conditions of the airways; or Asthma; or Bronchial asthma.

8. The method of claim 6, wherein the eosinophilic respiratory disorder, disease, or symptom is: Viral respiratory illness; or Severe acute respiratory syndrome, optionally wherein the severe acute respiratory syndrome is caused by a coronavirus; or Allergic rhinitis, asthma, atopic dermatitis (or eczema), allergic gastroenteritis, eosinophilic esophagitis, eosinophilic folliculitis, eosinophilic gastritis, eosinophilic colitis, eosinophilic cellulitis, eosinophilic syndrome, eosinophilic leukemia, eosinophilic granulomatosis, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, and hyper-IgE syndrome.

9. The method of any one of claims 6 to 8, wherein the person: (i) Has a high degree of tolerance to medical and surgical interventions for treating the aforementioned ailment, condition, or disease. (ii) Showing or tolerating steroid treatment (iii) Patients with steroid-resistant asthma (iv) Having eosinophilic esophagitis Or any combination of (i)-(iv).

10. The method of any one of claims 6 to 9, wherein administering the composition to the person reduces or delays the need to provide assisted breathing to the person.

11. The method of any one of claims 6 to 10, wherein the composition is administered as a syrup, chewable tablet, capsule, or soft gelatin capsule, or the composition is formulated for aerosol administration.

12. An article comprising: A container comprising at least one compound as claimed in any one of claims 1 to 4, or a pharmaceutical composition as claimed in claim 5; as well as The label contains instructions for use of this composition.

13. The article of claim 12, wherein the composition is provided in a dosage form.

14. The article of claim 12 or 13, wherein the dosage form is a syrup, chewable tablet, capsule or soft gelatin capsule.

15. The article of manufacture according to any one of claims 12 to 14, wherein the container is an aerosol container.

16. A medicine box, comprising: At least one compound as described in any one of claims 1 to 4, or a dosage form of the pharmaceutical composition as described in claim 5; as well as Packaging instructions, which contain instructions for use of this composition. Optionally, the dosage form is a syrup, chewable tablet, capsule, or soft gelatin capsule, or the dosage form is an aerosol.

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