WO2025101524A1 - Composés lipopeptidiques et leur utilisation dans la modulation de l'éosinophilie - Google Patents

Composés lipopeptidiques et leur utilisation dans la modulation de l'éosinophilie Download PDF

Info

Publication number
WO2025101524A1
WO2025101524A1 PCT/US2024/054584 US2024054584W WO2025101524A1 WO 2025101524 A1 WO2025101524 A1 WO 2025101524A1 US 2024054584 W US2024054584 W US 2024054584W WO 2025101524 A1 WO2025101524 A1 WO 2025101524A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
eosinophilic
compound
disease
disorder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/054584
Other languages
English (en)
Inventor
Bomi Patel Framroze
Crawford Linden Alexander CURRIE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hbc Immunology Inc
Original Assignee
Hbc Immunology Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hbc Immunology Inc filed Critical Hbc Immunology Inc
Publication of WO2025101524A1 publication Critical patent/WO2025101524A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present disclosure related generally to lipopeptides, and more specifically to the use of lipopeptide compounds suitable for treating eosinophilic conditions, diseases or disorders.
  • Inflammation is an immunological conundrum.
  • the physiological changes that accompany inflammation allow us to mount an acute response to external threats that would otherwise have wiped out the human species.
  • chronic inflammation where age or external stressors keep our immune system in overdrive, can contribute to many debilitating diseases ranging from Alzheimer’s to diabetes and bronchial asthma.
  • An eosinophil is a type of white blood cell stored in tissues throughout the body and continually replenished from the bone marrow. Eosinophils typically have a two-day lifespan in blood, but inflammatory conditions such as infections and allergic diseases will extend the lifespan up to two weeks by eosinophil-activating cytokines. See Park YM & Bochner BS, Allergy Asthma Immunol Res. 2010, 2:87-101.
  • An eosinophil count is a blood test that measures the quantity of eosinophils in the human body. Elevated levels, usually measured during routine complete blood count testing, indicate an infection or allergy.
  • eosinophils which are promoted by eosinophil-activating cytokines under inflammatory conditions, are a major source of reactive oxygen species, cytotoxic proteins and proinflammatory cytokines. They signal the activation of resident tissue cells such as epithelial, endothelial and fibroblast cells, leading to the progression of inflammation and mucus secretion. Eosinophils are therefore potent activators and modulators of diseases such as bronchial asthma, atopic dermatitis 5 and colitis ulcerosa. See Hogan SP, IntArch Allergy Immunol. 2007, 143(Suppl 1):3-14; Simon D et al., Allergy.
  • ECP eosinophil cationic protein
  • EPO eosinophil peroxidase
  • R 1 is at least one optionally substituted amino acid
  • R 2x is alkyl or alkenyl, optionally substituted with -OH, or -COOH;
  • R 2y is H or alkyl
  • R 2x and R 2y are taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle
  • R 3 is alkyl or alkenyl
  • Z is -OH, -OC(O)alkyl, -NH 2 , -NH(alkyl), or -N(alkyl) 2.
  • R 2x and R 2y are taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle
  • R 3 is alkyl or alkenyl
  • R 4 is H or alkyl
  • R 5 is a hydrophobic side chain of Ala, Vai, lie, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;
  • R 8 is a hydrophobic side chain of Ala, Vai, lie, Leu, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;
  • Z is -OH, -OC(O)alkyl, -NH2, -NH(alkyl), or -N(alkyl)2.
  • R 3 is alkyl or alkenyl
  • R 7a is H or -C(O)alkyl
  • R b is H or -OH
  • Z is -OH, -OC(O)alkyl, -NH 2 , -NH(alkyl), or -N(alkyl) 2 ,
  • composition comprising: any of the compounds described herein; and at least one pharmaceutically acceptable excipient.
  • eosinophilia modulating treatments such as eosinophilic esophagitis and asthma treatments, using any of the compounds described herein.
  • the asthma is bronchial asthma.
  • the treatments provided target a subgroup of patients (e.g., eosinophilic esophagitis and asthma patients) that are largely resistant to medical and surgical interventions, including steroid therapies,
  • a method for treating an inflammatory condition, disorder or disease in a human in need thereof comprising: orally administering to the human an effective dose of any of the compounds described herein to treat the inflammatory condition, disorder or disease.
  • a method for reducing eosinophil effector function in a human in need thereof comprising administering to the human any of the compounds described herein to reduce eosinophil effector function.
  • an article of manufacture comprising: a container comprising any of the compounds described herein; and a label containing instructions for use of such compounds.
  • a kit comprising: a dosage form of any of the compounds described herein; and a package insert containing instructions for use of such composition.
  • die dosage form is a syrup, chewable, capsule or soft gel.
  • the compositions provided herein Eire formulated for aerosol delivery.
  • R ! is at least one optionally substituted amino acid
  • R 3 is aikyl or alkenyl
  • Z is -OH, -OC(O)alkyl, -NH2, -NH(alkyl), or -N(alkyl)2.
  • R ! is -R ,a -R 1! ’-R k -, wherein:
  • R la is an optionally substituted amino acid moiety with a hydrophobic side chain
  • R ,b is an optionally substituted amino acid moiety with a polar uncharged side chain
  • R k is an optionally substituted amino acid moiety with a hydrophobic side chain.
  • R ia is an optionally substituted amino acid moiety selected from the group consisting of Leu, Vai, and Gly
  • R ib is an optionally substituted amino acid moiety selected from the group consisting of Thr, Ser, and Cys
  • R ,c is an optionally substituted amino acid moiety selected from the group consisting of Vai, Leu, and Gly.
  • R ! is -R la -R lt ‘-R lc -, wherein:
  • R la is an optionally substituted Phe
  • R ,b is optionally substituted Thr; and R k; is is optionally substituted Vai.
  • R ! is:
  • OAc-amino acid moiety refers to the amino acid moiety substituted with an acetyl group via the oxygen atom of the amino acid moiety (as the case may be).
  • OAcThr or “OAcSer” refers to threonine or serine, respectively, substituted with an acetyl group through the oxygen atom of the amino acid side chain.
  • R 2x and R 2y are taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle.
  • the heterocycle is pyrrolidine.
  • the heterocycle is pyrrolidine substituted with one or more -OH.
  • the heterocycle is 4-hydroxy-pyrrolidine.
  • R 3 is a branched alkyl.
  • R 3 is C1-20 alkyl, Ci-io alkyl, or C5-10 alkyl, or C7-9 alkyl.
  • the alkyl is unbranched or branched.
  • R 3 is: or - ⁇ r ⁇ XyA .
  • the alkyl is branched at the 1- and/or 3-position of the alkyl chain, referring to the following positions on the exemplary alkyl chain depicted below':
  • R 3 is alkenyl. In certain variations, R 3 is C2-C30 alkenyl. In certain variations including any cis- and/or trans- configurations of such moieties.
  • R 3 is an omega-3 fatty acid, or a derivative thereof.
  • R 3 is an eicosapentaenoic acid (EP A) moiety, or a docosahexaenoic acid (DHA) moiety, or a derivative of any of the foregoing.
  • EP A eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • R 2X and R 2y are taken together with the atoms to which they are attached to form an optionally substituted 5 -membered heterocycle
  • R 3 is alkyl or alkenyl; and R“ is H or alkyl;
  • R 5 is a hydrophobic side chain of Ala, Vai, He, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;
  • R 8 is a hydrophobic side chain of Ala, Vai, He, Leu, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;
  • R 6 is H or alkyl
  • Z is -OH, -OC(O)alkyl, -XH . -NH(alkyl), or -N( alkyl) 2 .
  • R 5 is the hydrophobic side chain of Leu. In certain variations, R 5 is the hydrophobic side chain of Phe.
  • R 6 is alkyl. In certain variations, R 6 is Ci-io alkyl, or Chs alkyl, or C us alky 1.
  • R 7 is -OH. In other variations, R 7 is -O(C-O)alkyl. In one variation of the foregoing, the alkyl is methyl. In other variations, R ? is or -O-alkyl-O-alkyl-O- alkyl. In one variation, R ?a is -O-methyl-O-ethyl-O-methyl.
  • R 6 is methyl
  • R 7 is OH
  • Al refers to alanine
  • valine refers to valine
  • He refers to isoleucine
  • Leu refers to leucine
  • Met refers to methionine
  • Phe refers to phenylalanine
  • Teyr refers to tyrosine
  • Trp refers to tryptophan
  • Gly refers to glycine
  • R 3 is alkyl or alkenyl
  • R 7a is H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl;
  • R b is H or -OH
  • Z is -OH, -OC(O)alkyi, -NH2, -NH(alkyl), or -N(alkyl)2.
  • the alkyl is C1-20 alkyl, Ci-15 alkyl, Ci-10 alkyl, or C1.5 alkyl, or C1-3 alkyl.
  • R 7a is H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl. In certain variations, R 7a is H, -C(O)CHs, or -methyl-O-ethyl-O-methyl.
  • R b is H. In other variations, R b is -OH.
  • the compound of formula (I) is a compound selected from compounds 1-6, 8-10, 12, 13, and 15 of Table A and compounds la-6a, 8a-10a, 12a, 13a, and 15a of Table A’.
  • compositions described herein may include one or more isomers of the compounds described herein, including compounds of formulae (I), (I- A), and (I- B), as well as compounds of Tables A and A’.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.”
  • isomers Compounds that have the same sequence of bonding of their atoms but differ in the arrangement of their atoms in space are termed “stereoisomers.”
  • Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers.
  • enantiomers bearing one or more asymmetric centers that are non-superimposable mirror images of each other are termed “enantiomers.”
  • a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory.
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning tha t the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is referred to as a “racemic mixture” or “racemate”.
  • compositions described herein comprise a racemic mixture of a compound of formulae (I), (I- A), and (I-B), as well as compounds of Tables A and A’.
  • the compound is enriched by at least about 90% by weight with a single diastereomer or enantiomer. In other embodiments, the compound is enriched by at least about 95%', 98%, or 99%' by weight with a single diastereomer or enantiomer.
  • compositions described herein may include one or more salts of the compounds described herein, including compounds of formulae (I), (I-A), and (I-B), as well as compounds of Tables A and A’.
  • the salts are pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to those salts which retain the biological effectiveness and properties of the tree bases or free acids, which are not biologically or otherwise undesirable.
  • the compounds provided herein including compounds of formulae (I), (I-A), and (I- B), and the exemplary compounds of Tables A and A’, may be synthesized according to General Scheme 1 below.
  • the general scheme, as well as the reactions described in the Examples section below, can be readily adapted to prepare the compounds disclosed herein.
  • the synthesis of non-exemplified compounds according to the present disclosure can be successfully performed by modifications apparent to those skilled in the art, e.g., by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions, reagents, and starting materials.
  • R 2X and R 2y are taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle
  • R 3 is alkyl or alkenyl; and R 4 is H or alkyl;
  • R 5 is a hydrophobic side chain of Ala, Vai, He, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;
  • R 8 is independently a hydrophobic side chain of Ala, Vai, He, Leu, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;
  • R 6 is H or alkyl
  • Step 1 Condensation of R 3 COOH.
  • a coupling reagent e.g, N,N'- carbonyldiimidazole (CDI)
  • CDI N,N'- carbonyldiimidazole
  • R1 is also combined with a suitable solvent, such as dichloromethane, to which a suitable base, such as diisopropyl ethylamine (DIPEA), is added.
  • DIPEA diisopropyl ethylamine
  • reaction mixture Upon completion, the reaction mixture undergoes a workup, involving extraction with a suitable organic solvent, such as ethyl acetate, and the organic layer dried (e.g., over MgS(>4), filtered and solvent is removed to obtain a crude product (such as a viscous oil).
  • a suitable organic solvent such as ethyl acetate
  • reaction mixture undergoes a workup, involving quenching (e.g.with an aqueous solution of HO) and extraction with a suitable organic solvent, such as dichloromethane, and the organic layer is washed with an aqueous solution (e.g. NaHCOs), dried (e.g. over MgSCb), filtered and the solvent is removed to obtain a crude product (such as an oil) (Pl).
  • a coupling reagent such as 1 -hydroxybenzotri azole hydrate (HOBt hydrate)
  • a catalyst such as CuBr?.
  • Step 2 Condensation of Pl with R2.
  • Pl is added to an organic solvent (e.g. methanol) and a catalyst (e.g. Pd/C).
  • a catalyst e.g. Pd/C.
  • the reaction is stirred under H?, then filtered and the solvent is removed to obtain a crude product (e.g. an oil) (Pl acid).
  • a coupling reagent e.g. N,N' -carbonyldiimidazole (CDI)
  • a suitable solvent such as dichloromethane.
  • R2 is also combined with a suitable solvent, such as dichlorometh aneto which a suitable base, such as diisopropylethylamine (DIPEA), is added.
  • DIPEA diisopropylethylamine
  • reaction mixture Upon completion, the reaction mixture undergoes a workup, involving extraction with a suitable organic solvent, such as ethyl acetate, and the organic layer dried (e.g., over MgSO4), filtered and solvent is removed to obtain a crude product (such as a viscous oil).
  • a suitable organic solvent such as ethyl acetate
  • reaction mixture undergoes a workup, involving quenching (e.g. with an aqueous solution of HCI) and extraction with a suitable organic solvent, such as dichloromethane, and the organic layer is washed with an aqueous solution (e.g. NaHCCh), dried (e.g. over MgSCb), filtered and the solvent is removed to obtain a crude product (such as an oil) (P2).
  • a coupling reagent such as 1 -hydroxybenzo tri azole hydrate (HOBt hydrate)
  • a catalyst such as CuBi2.
  • 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.
  • a suitable organic solvent such as methanol
  • Pd/C a suitable catalyst
  • the reaction is stirred under H2, then filtered and the solvent is removed to obtain a crude product (e.g. an oil) (P2 acid).
  • a coupling reagent e.g. N,N'-carbonyldiimidazole (CDI)
  • CDI N,N'-carbonyldiimidazole
  • R3 is also combined with a suitable solvent, such as dichloromethane to which a suitable base, such as diisopropylethyl amine (DIPEA), is added.
  • DIPEA diisopropylethyl amine
  • reaction mixture Upon completion, the reaction mixture undergoes a workup, involving extraction with a suitable organic solvent, such as ethyl acetate, and the organic layer dried (e.g., over MgSO4), filtered and solvent is removed to obtain a crude product (such as a viscous oil).
  • a suitable organic solvent such as ethyl acetate
  • reaction mixture undergoes a workup, involving quenching (e.g.with an aqueous solution of HC1) and extraction with a suitable organic solvent, such as dichloromethane, and the organic layer is washed with an aqueous solution (e.g. NaHCCh), dried (e.g. over MgSC>4), filtered and the solvent is removed to obtain a crude product (such as an oil) (P3).
  • a suitable organic solvent such as dichloromethane
  • Step 4 Condensation of P3 with R4.
  • P3 is added to an organic solvent (e.g. methanol) and a catalyst (e.g. Pd/C).
  • organic solvent e.g. methanol
  • a catalyst e.g. Pd/C
  • the reaction is stirred under H2, then filtered and the solvent is removed to obtain a crude product (e.g. an oil) (P3 acid).
  • a coupling reagent e.g. N,N’-carbonyldiimidazole (GDI)
  • a suitable solvent such as dichloromethane
  • R4 is also combined with a suitable solvent, such as dichloromethane to which a suitable base, such as diisopropylethylamine (DIPEA), is added.
  • DIPEA diisopropylethylamine
  • reaction mixture Upon completion, the reaction mixture undergoes a workup, involving extraction with a suitable organic solvent, such as ethyl acetate, and the organic layer dried (e.g., over MgSO4), filtered and solvent is removed to obtain a crude product (such as a viscous oil).
  • a suitable organic solvent such as ethyl acetate
  • reaction mixture undergoes a workup, involving quenching (e.g. with an aqueous solution of HC1) and extraction with a suitable organic solvent, such as dichloromethane, and the organic layer is washed with an aqueous solution (e.g. NaHCCh), dried (e.g. over MgSCh), filtered and the solvent is removed to obtain a crude product (such as an oil) (P4).
  • a coupling reagent such as 1 -hydroxybenzotri azole hydrate (HOBt hydrate)
  • a catalyst such as CuBrj
  • Step 5 Deprotection of P4.
  • P4 is added to an organic solvent (e.g. methanol) and a catalyst (e.g. Pd/C).
  • organic solvent e.g. methanol
  • a catalyst e.g. Pd/C
  • the reaction is stirred under H2, then filtered and the solvent is removed to obtain a crude product (e.g. an oil) (Formula (P)).
  • exemplary compounds of Tables A and A’ may be synthesized according to General Scheme 2 above, wherein: X is -OC(O)alkyl, -NH 2 , -NH(alkyl), or -Nfalkyl ) 2; and LG is H or a suitable leaving group.
  • exemplary compounds of formula P are reacted with reagent R5, wherein LG is H or a suitable leaving group (e.g. halo, pTsOH, or Fmoc), in a condensation reaction, to form compounds of Formula
  • R 6 is H or alkyl
  • R 7b is -O-alkyl-O-alkyl-O-alkyl
  • LG a is a suitable leaving group.
  • carboxylic acids of formula R2-1& are reacted with a suitable protecting reagent, such as BnBr in the presence of K2CO3, 0° to room temperature, to provide compounds of formula R2-lb.
  • a suitable protecting reagent such as BnBr in the presence of K2CO3, 0° to room temperature
  • the hydroxyl group of compounds of formula R2-lb are selectively deprotected, for example where the protecting group is tBu the hydroxyl groups are deprotected using an acid such as TFA.
  • Resulting alcohols of formula R2-lc are reacted with LG a -R ?b , wherein LG a is a suitable leaving group (e.g. halo), such as Cl -MEM, in a condensation reaction, to form reagents of formula R2-ld.
  • LG a is a suitable leaving group (e.g. halo), such as Cl -MEM
  • reagent R1 may be N-Methyl-L-leucine benzyl ester p-toluenesulf onate or may be substituted with other appropriate compounds to produce other moieties corresponding to variables R 4 and R 5 in formula (IV-A).
  • compositions provided herein including compositions comprising compounds of formulae (I), (I-A), and (I-B), as well as the exemplary compounds of Tables A and A’, may be used to treat inflammatory conditions, disorders or diseases, including respiratory conditions, disorders or diseases.
  • the conditions, disorders or diseases are inflammations of the respiratory tract.
  • a method for treating inflammatory conditions, disorders or diseases in a human in need thereof comprising administering the compositions provided herein to the human.
  • compositions provided herein including compositions comprising compounds of formulae (I), (I-A), and (I-B), as well as the exemplary compounds of Tables A and A’, may be used to treat inflammatory conditions, disorders or diseases, including eosiniphilia conditions, disorders or diseases.
  • the conditions, disorders or diseases are inflammations of the respiratory tract.
  • provided is a method for treating inflammatory conditions, disorders or diseases in a human in need thereof, comprising administering the compositions provided herein to the human.
  • compositions provided herein comprise a compound selected from compounds 1-6, 8-10, 12, 13, and 15 of Table A and compounds la-6a, 8a- 10a, 12a, 13a, and 15a of Table A’.
  • treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following:
  • compositions provided herein including compositions comprising compounds of formulae (I), (I- A), and (I-B) may be used to treat asthma, pneumonia, bronchiectasis, emphysema, tuberculosis, lung collapse, lung fibrosis, fibrosing alveolitis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, chronic rhinosinusitis (CRS), and acute respiratory disease syndrome.
  • COPD chronic obstructive pulmonary disease
  • CRS chronic rhinosinusitis
  • compositions provided herein may be used to treat eosinophilic respiratory conditions, diseases or disorders.
  • conditions, diseases or disorders may include allergic rhinitis, asthma, atopic dermatitis (or eczema), allergic gastroenteritis, eosinophilic esophagitis, eosinophilic folliculitis, eosinophilic gastritis, eosinophilic colitis, eosinophilic cellulitis, hypereosinophilic syndrome, eosinophilic leukemia, eosinophilic granulomatosis, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, and hyper- IgE syndrome.
  • the condition, disease or disorder is a chronic inflammatory disorder.
  • the chronic inflammatory disorder is a chronic inflammatory disorder of the airways.
  • the condition, disease or disorder is an inflammatory lung disease.
  • the condition, disease or disorder involves narrowing and/or swelling of airways, thereby making breathing difficult and triggering coughing, wheezing and/or shortness of breath.
  • the condition, disease or disorder is asthma.
  • the asthma is bronchial asthma.
  • the condition, disease or disorder involves steroid treatment resistant asthma and airway constrictions.
  • the condition, disease or disorder is a chronic inflammatory disorder.
  • the chronic inflammatory disorder is a chronic inflammatory disorder of the esophagus.
  • the condition, disease or disorder is an inflammatory gastrointestinal disease.
  • the condition, disease or disorder involves narrowing and/or swelling of esophagus, thereby making swallowing difficult and triggering coughing and pain.
  • the condition, disease or disorder is eosinophilic esophagitis.
  • the condition, disease or disorder involves eosinophilic esophagitis and esophagus constrictions.
  • condition, disease or disorder is an allergy or an allergic inflammation.
  • condition, disease or disorder is a viral respiratory disease.
  • condition, disease or disorder is severe acute respiratory syndrome.
  • the severe acute respiratory syndrome is caused by a coronavirus.
  • the human in need thereof is a lung-compromised individual.
  • the lung-compromised individual has fluid build-up in the alveoli in the lungs.
  • This fluid can leak from the smallest blood vessels in the lungs into the alveoli due to the destruction of the protective membrane in the alveoli.
  • the membrane which normally keeps this fluid in the vessels may be destroyed because of a disruption in immune response due to severe disease or injury.
  • the fluid enters the alveoli and keeps the lungs from filling with enough air, which means less oxygen reaches the bloodstream. This deprives organs of the oxygen that is needed to function, which can cause multiple organ failure resulting in death.
  • compositions provided herein including compositions comprising compounds of formulae (I), (LA), and (LB) to the human to reduce or delay the need to provide the human with assisted respiration.
  • the methods described herein comprise administering a composition comprising a compound selected from compounds 1-6, 8-10, 12, 13, and 15 of Table A and compounds la-6a, 8a-10a, 12a, 13a, and 15a of Table A’.
  • “delaying” development of a condition, disease or disorder means to defer, hinder, slow, retard, stabilize and/or postpone development of the condition, disease or disorder. This delay can be of varying lengths of time, depending on the history of the condition, disease or disorder and/or individual being treated.
  • compositions provided herein including compositions comprising compounds of formulae (I), (LA), and (LB) improve anti-inflammatory efficacy via a reduction in eosinophil effector function.
  • a method for reducing eosinophil effector function in a human in need thereof comprising administering the compositions provided herein, including compositions comprising compounds of formulae (I), (LA), and (LB) to the human to reduce eosinophil effector function.
  • the methods provided herein involve treating a human in need thereof.
  • the human is largely resistant to medical and surgical interventions for treating the inflammatory conditions, disorders or diseases described herein.
  • the human exhibits or has resistance to steroid therapy.
  • the human has steroid treatment resistant asthma.
  • the human has eosinophilic esophagitis.
  • the human is a child. In certain variations, the human 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; or between 2 years old and 12 years old.
  • compositions provided herein including compositions comprising compounds of formulae (I), (I-A), and ( I B ) are formulated for oral administration.
  • Forms suitable for oral administration may include, for example, tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, aerosols, or powders.
  • the pharmaceutical compositions described herein are in the form of syrups, capsules, and soft gels (including, for example, chewable gummies).
  • the pharmaceutical compositions provided herein comprise a compound selected from compounds 1-6, 8-10, 12, 13, and 15 of Table A and compounds la-6a, 8a-10a, 12a, 13a, and 15a of Table A’.
  • compositions described herein can be manufactured using any conventional method, e.g., mixing, dissolving, granulating, dragee -making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes.
  • An optimal pharmaceutical formulation can be determined by one of skill in the art depending on the route of administration and the desired dosage. Such formulations can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent.
  • compositions provided herein are administered to the human as a unit dosage, for example, in the form of syrups, capsules, and soft gels (including, for example, chewable gummies) as described herein.
  • unit dosage form refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of the compositions provided herein, or compositions comprising biological active(s) isolated from the compositions provided herein, which may be in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably thus in some embodiments met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • compositions provided herein are formulated for aerosol delivery.
  • the methods provided comprise administering to the human in need thereof an effective amount of the compositions provided herein, including compositions comprising compounds of formulae (I), (I-A), and (I-B).
  • an “effective amount” intends such amount of a composition or biological active of the invention which should be effective in a given therapeutic form.
  • an effective amount of the composition provided herein is an amount sufficient to reduce eosinophil effector function in the human, and thereby treating the human suffering from the conditions, diseases or disorders described herein, or alleviating the existing symptoms of such conditions, diseases or disorders.
  • exemplary dosage levels for a human may be between 0.01 mg/kg to lOOmg/kg weight of the human.
  • the final dosage regimen is determined by the attending physician in view of good medical practice, considering various factors that modify the action of the salmonid oil composition, or composition comprising biological active(s) isolated from the salmonid oil compositions provided herein, the identity and severity of the disease state, the responsiveness of the subject, the age, condition, body weight, sex, and diet of the subject, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • the salmonid oil composition, or composition comprising biological active(s) isolated from the salmonid oil compositions provided herein are administered once, twice, or three times daily. In certain embodiments, the composition provided herein are administered once or twice daily. In certain embodiments, the composition provided herein are administered once daily.
  • compositions provided herein including compositions comprising compounds of formulae (I), (I- A), and (I-B), as well as the exemplary compounds of Tables A and A’, may be formulated in one or more pharmaceutically acceptable carriers, excipients or other ingredients can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, disease or disorder.
  • an article of manufacture such as a container comprising a dosage form of salmonid oil composition, or composition comprising biological active(s) isolated from the compositions provided herein, and a label containing instructions for use of such compositions.
  • the article of manufacture is a container comprising a dosage form of compositions provided herein, and one or more pharmaceutically acceptable carriers, excipients or other ingredients.
  • the dosage form is a syrup, capsule and soft gel (including, for example, chewable gummies).
  • kits also are provided.
  • a kit can comprise a dosage form of compositions provided herein, and a package insert containing instructions for use of the composition/active(s) in treatment of a condition, disease or disorder.
  • the instructions for use in the kit may be for treating a respiratory inflammation or inflammation of the respiratory tract, including, for example, asthma.
  • the instructions for use in the kit may be for treating bronchial asthma. In another variation, the instructions for use in the kit may be for treating severe acute respiratory syndrome. In other variations, the instructions for use in the kit may be for treating a gastrointestinal inflammation or inflammation of the gastrointestinal tract, including, for example, eosinophilic esophagitis or asthma. In one variation, the instructions for use in the kit may be for treating eosinophilic esophagitis. In another variation, the instructions for use in the kit may be for treating asthma.
  • the labels and package inserts of the articles of manufacture and kits contain instructions for treating any of the conditions, diseases or disorders described herein.
  • the label contain instructions for treatment of inflammatory conditions, disorders or diseases, including respiratory conditions, disorders or diseases.
  • the label contains instructions for treatment of a chronic inflammatory disorder of the airways.
  • the label contains instructions for treatment of asthma, such as bronchial asthma and/or steroid treatment resistant asthma.
  • the label contains instructions for treatment of a viral respiratory disease, such as severe acute respiratory syndrome (including, for example, severe acute respiratory syndrome caused by a coronavirus).
  • the label contains instructions for treatment of inflammatory conditions, disorders or diseases, including eosinophilic conditions, disorders or diseases.
  • the label contains instructions for treatment of a chronic inflammatory disorder of the esophagus.
  • the label contain instructions for treatment of eosinophilic esophagitis and asthma, such as bronchial asthma, steroid treatment resistant asthma, and/or eosinophilic esophagitis.
  • the label contains instructions for treatment of a viral eosinophilic condition.
  • the terms “a,” “an.” and the like, refer to one or more.
  • “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, “about x” includes and describes “x” per se.
  • the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values refers to variations of +/- 2%.
  • “between” two values or parameters herein includes (and describes) embodiments that include those two values or parameters per se.
  • description referring to “between x and y” includes description of “x” and “y” per se.
  • Embodiment 1 A compound of formula (I- A); or a salt thereof, including any isomers of the foregoing, wherein:
  • R 2X and R 2y are taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle
  • R 3 is alkyl or alkenyl
  • R 4 is H or alkyl
  • R 5 is a hydrophobic side chain of Ala, Vai, He, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;
  • R 8 is independently a hydrophobic side chain of Ala, Vai, He, Leu, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;
  • Z is -OH, -OC(O )aikyl, -NH 2 , -NH(alkyl), or -N(alkyi ) 2 .
  • Embodiment 2 The compound of Embodiment 1, wherein the compound is a compound of formula (I-B);
  • R 7a is H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl; and R b is H or -OH.
  • Embodiment 3 A compound selected from the group consisting of:
  • Embodiment 4 The compound of Embodiment 3, wherein the compound is:
  • Embodiment 5 A pharmaceutical composition, comprising: at least one compound of any one of Embodiments 1 to 4, and at least one pharmaceutically acceptable excipient.
  • Embodiment 6 A method for treating an eosinophilic inflammatory condition, disorder or disease in a human in need thereof, comprising: administering to the human an effective dose of at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5, to treat the eosinophilic inflammatory condition, disorder or disease.
  • Embodiment 7 The method of Embodiment 6, wherein the eosinophilic inflammatory condition, disorder or disease is an inflammatory gastrointestinal disease.
  • Embodiment 8 The method of Embodiment 6 or 7, wherein the eosinophilic inflammatory condition, disorder or disease is a chronic inflammatory disorder of the esophagus.
  • Embodiment 9. The method of any one of Embodiments 6 to 8, wherein the eosinophilic inflammatory condition, disorder or disease is eosinophilic esophagitis.
  • Embodiment 10 The method of Embodiment 6, wherein the eosinophilic inflammatory condition, disorder or disease is a chronic inflammatory disorder of the airways.
  • Embodiment 11 The method of Embodiment 6 or 10, wherein the eosinophilic inflammatory condition, disorder or disease is asthma.
  • Embodiment 12 The method of any one of Embodiments 6 to 11, wherein the eosinophilic inflammatory condition, disorder or disease is bronchial asthma.
  • Embodiment 13 A method for treating an eosinophilic respiratory condition, disorder or disease in a human in need thereof, comprising: administering to the human an effective dose of at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5, to treat the eosinophilic respiratory condition, disorder or disease.
  • Embodiment 14 The method of Embodiment 13, wherein the eosinophilic respiratory condition, disorder or disease is a viral respiratory disease.
  • Embodiment 15 The method of Embodiment 13, wherein the eosinophilic respiratory condition, disorder or disease is severe acute respiratory syndrome.
  • Embodiment 16 The method of Embodiment 13, wherein the severe acute respiratory syndrome is caused by a coronavirus.
  • Embodiment 17 The method of Embodiment 13, wherein the eosinophilic respiratory condition, disorder or disease is allergic rhinitis, asthma, atopic dermatitis (or eczema), allergic gastroenteritis, eosinophilic esophagitis, eosinophilic folliculitis, eosinophilic gastritis, eosinophilic colitis, eosinophilic cellulitis, hypereosinophilic syndrome, eosinophilic leukemia, eosinophilic granulomatosis, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, and hyper- IgE syndrome.
  • Embodiment 18 The method of any one of Embodiments 13 to 17, wherein the human is largely resistant to medical and surgical interventions for treating the condition, disorder or disease.
  • Embodiment 19 The method of any one of Embodiments 13 to 17, wherein the human exhibits or has resistance to steroid treatments.
  • Embodiment 20 The method of any one of Embodiments 13 to 17, wherein the human has steroid treatment resistant asthma.
  • Embodiment 21 The method of any one of Embodiments 13 to 17, wherein the human has eosinophilic esophagitis.
  • Embodiment 22 The method of any one of Embodiments 13 to 21, wherein the administration of the composition to the human reduces or delays the need to provide the human with assisted respiration.
  • Embodiment 23 A method for reducing eosinophil effector function in a human in need thereof, comprising: administering to the human at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5, to reduce eosinophil effector function.
  • Embodiment 24 The method of any one of Embodiments 6 to 23, wherein the composition is administered as a syrup, chewable, capsule or soft gel, or the composition is formulated for aerosol administration.
  • Embodiment 25 An article of manufacture, comprising: a container comprising at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5: and a label containing instructions for use of such composi tion.
  • Embodiment 26 The article of manufacture of Embodiment 25, wherein the composition is provided in a dosage form.
  • Embodiment 27 The article of manufacture of Embodiment 25 or 26, wherein the dosage form is a syrup, chewable, capsule or soft gel.
  • Embodiment 28 The article of manufacture of Embodiment 25 or 26, wherein the container is an aerosol container.
  • Embodiment 29 A kit, comprising: a dosage form of at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5; and a package insert containing instructions for use of such composition.
  • Embodiment 30 The kit of Embodiment 29, wherein the dosage form is a syrup, chewable, capsule or soft gel, or the dosage form is in aerosol form.
  • Fmoc-N-Me Phe-OH Fmoc-N Methyl Phenylalanine-OH HATH : (l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate
  • TIPS Triisopropylsilane
  • This example describes the synthesis and characterization of Compound la. These compounds were produced according to the scheme provided below. Synthesis of Compound la was performed on solid phase peptide synthesis. The below method, sequence and resins were used for the synthesis.
  • Capping is performed with MeOH/DIPEA/DCM (24/2, ''24). Table Al.
  • 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 compounds, and formulation vehicle (negative control).
  • the test compounds include Compound la, which was obtained in accordance with the synthesis procedures described in Example Al above. Aliquots were removed after 18 hr incubation, washed twice in PBS, and resuspended in binding buffer. The eosinophil cells were stained using the Annexin V-FITC Apoptosis Detection Kit I (Sigma Aldrich) and immediately analyzed by flow cytometry.
  • PMNL cells were pretreated with 5 nM Fevipiprant (positive control), 10 nM test compounds, and formulation vehicle (negative control) for 30 minutes and incubated with serial dilutions of CCL11 for 30 minutes at 37°C. Samples were stained with anti-CD16-PE-Cy5 and anti-CD 11 b ⁇ PE (ICRF44) antibodies. Eosinophils were identified as CD 16 negative cells. CD1 ib upregulation was analyzed by flow cytometry and reported above. (Standard deviation in the assay is +/- 2%). See results in Table 2 below.
  • This Example was performed to determine Eosinophil and other leucocyte and cytokine modulating properties of exemplary compounds described herein (30 and 150 pg/animal/day) at low and high doses in House Dust Mite (HDM) extract-induced murine asthma model. For the same purpose, no treatment as eosinophilia control and, fevipiprant (5 pg/animal/day) as a positive control.
  • HDM House Dust Mite
  • the experimental design involved induction of asthmatic condition in mice using House Dust Mite (HDM) extract and simultaneous evaluation of the effects Compound la (30 and 150 pg/animal/day), and Fevipiprant! 5 pg/animal/day) as a positive control on Eosinophil modulation in mice.
  • HDM House Dust Mite
  • mice were anesthetized with isoflurane and sensitized intranasally with 1 pg HDM protein in 40 pL PBS. All mice were then challenged by intranasal application of 10 pg HDM protein in 40 pL PBS once daily from days 7 to 11. Mice also received the vehicle, test compounds, or Fevipiprant as per the respective groups once daily from days 7 to 14.
  • mice were anesthetized and Broncho- Alveolar Lavage (BAL) fluid was collected, centrifuged and cell pellet was stored at -20°C and dispatched to an external laboratory for eosinophilia analyses. In addition, from all these animals, spleen samples were collected, frozen and dispatched for eosinophilia analysis.
  • BAL Broncho- Alveolar Lavage
  • Compound la was observed to have properties to modulate eosinophils and other leucocyte and cytokines which are markers for asthma, indicating its efficacy in House Dust Mite (HDM) extract-induced murine asthma model.
  • HDM House Dust Mite
  • the objective of this example was to determine the impact of Compound la at an intermediate dose of 90 pg/animal/day over 8 weeks of treatment on modulating eosinophils, other leucocytes, and cytokines and thereby lung histopathology in House Dust Mite (HOM) extract-induced murine asthma model.
  • HOM House Dust Mite
  • mice were anesthetized with isoflurane and sensitized intranasally with 1 pg HOM protein in 40 pL PBS. All mice were then challenged by intranasal application of 10 pg HOM protein in 40 pL PBS once daily from days 7 to 15. Mice also received the vehicle, Compound la and Montelukast as per the respective groups once daily from days 7 to 56.
  • HOM House Dust Mite
  • mice On day 57 of the experiment, all the mice were anesthetized and Broncho- Alveolar Lavage (BAL) fluid was collected from the right lung (the left bronchus was tied off), centrifuged and cell pellet was stored at -20°C and dispatched to an external laboratory for eosinophilia analyses.
  • BAL Broncho- Alveolar Lavage
  • spleen samples were collected, frozen and dispatched for eosinophilia analysis and the left lung was fixed in neutral buffered formalin to enable subsequent sectioning, staining and assessment of the extent of asthmatic changes including airway inflammation and obstruction.
  • Mortality/Morbidity All animals were observed twice daily (morning and evening) for any morbidity or mortality, throughout the acclimatization and the experimental period.
  • Clinical Signs or symptoms Observations were made once daily to check for any clinical signs or symptoms throughout the acclimatization and treatment periods. These cage-side observations included (but were not limited to) changes in skin and fur, eyes and mucous membranes, as well as respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behavior patterns.
  • Body weight Animals were weighed during randomization, on day 1, on day 7 and on day 15 of the experiment.
  • the fluid was centrifuged (400 g at 4°C for 7 min) and the collected cell-pellets were frozen (at - 20°C) till they were sent for assay for airway eosinophilia. All the pellets from the BALF and spleen samples were collected from all animals and stored at -20°C until samples were dispatched for assay of systemic eosinophilia. Serum was separated from blood and stored in - 80°C till the estimation of IL4, IL5, IL6, IL10, II..13, IL17, IgE and IGgl performed using ELISA kits. The lung tissues were processed and one set of sections from all the animals were stained with Hematoxylin and Eosin stain for histopathological evaluation and the other set with PAS stain for the presence of mucus in the condition of asthma.
  • BAL fluid and spleen sample analysis The cell pellets and spleen tissues collected were analyzed for eosinophilia. Total cell count was performed using hemocytometer. For the analysis of differential eosinophils count, 80p 1 of resuspended cell pellets were stained using methods and techniques known in the art.
  • the serum IL10 levels were found decreased in Compound la (G2), and positive control group (G3).
  • Serum IL 17 levels were found to be reduced in the treated groups of Compound la and positive control in comparison with the disease control group,
  • IL 5 showed a considerable reduction in Compound la (G2), and positive control group (G3) and can be corroborated with the reduction in eosinophilia observed in the histopathological evaluation.
  • Serum IL- 13 was found comparable in the disease control (Gl, untreated). Compound la (G2, treated) and Monteluekast (G3, positive control) showing no effect on the IL- 13 expression due to treatment with Compound la and Monteluekast.
  • IgE levels did not show any significant difference between the disease control (Gl, untreated). Compound la (G2, treated) and Monteluekast (G3, positive control).
  • IgGl levels did not show any significant difference between the disease control (Gl , untreated). Compound la (G2, treated) and Monteluekast (G3, positive control).
  • BAL, (Broncho Alveolar Lavage) fluid and spleen cellularity were evaluated and the results are as follows.
  • the total cell count, eosinophil count in BAL fluid and percent eosinophils in spleen tissues decreased significantly in all the treatment groups in comparison with Gl (disease control).
  • Hematoxylin and eosin staining the histology of lungs with Hematoxylin and eosin stain clearly showed lesions typical of asthma in the Gl group: hypertrophy of goblet cells. smooth muscle hyperplasia and airway obstruction thereby elevating the congestion in the lungs during the diseased condition in Gl. The severity of these lesions was mild to moderately reduced after the treatment with Compound la (G2) and Montelukast (G3).
  • PAS staining Inflammatory infiltration, epithelial desquamation, thickening of basement membrane, mucous production and enlargement of goblet cells was observed of various degrees of severity i.e. marked asthmatic changes in Gl with marked inflammation, impaired barrier function, airway remodeling and airways obstruction. The degree of severity was subsequently reduced in G2 and to some extent in G3.
  • IL13 marker with immunohistochemical staining technique was found to be markedly expressed in the Gl, G2 and G3 groups.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I-A) : ou un sel de ceux-ci, y compris n'importe quels isomères de ce qui précède, les variables étant telles que définies dans la description. De tels composés peuvent être appropriés pour être utilisés dans des méthodes de traitement d'états, de maladies ou de troubles éosinophiles. De tels composés peuvent être administrés par voie orale. Les compositions décrites ici peuvent être utiles pour réduire la fonction effectrice des éosinophiles.
PCT/US2024/054584 2023-11-06 2024-11-05 Composés lipopeptidiques et leur utilisation dans la modulation de l'éosinophilie Pending WO2025101524A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363596380P 2023-11-06 2023-11-06
US63/596,380 2023-11-06

Publications (1)

Publication Number Publication Date
WO2025101524A1 true WO2025101524A1 (fr) 2025-05-15

Family

ID=95696346

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/054584 Pending WO2025101524A1 (fr) 2023-11-06 2024-11-05 Composés lipopeptidiques et leur utilisation dans la modulation de l'éosinophilie

Country Status (1)

Country Link
WO (1) WO2025101524A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130065861A1 (en) * 2010-03-23 2013-03-14 Irm Llc Compounds (cystein based lipopeptides) and compositions as tlr2 agonists used for treating infections, inflammations, respiratory diseases etc.
US20200085961A1 (en) * 2018-09-14 2020-03-19 Cara Therapeutics, Inc. Oral Formulations of Kappa Opioid Receptor Agonists
WO2022108883A1 (fr) * 2020-11-17 2022-05-27 Hofseth Biocare Asa Traitements respiratoires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130065861A1 (en) * 2010-03-23 2013-03-14 Irm Llc Compounds (cystein based lipopeptides) and compositions as tlr2 agonists used for treating infections, inflammations, respiratory diseases etc.
US20200085961A1 (en) * 2018-09-14 2020-03-19 Cara Therapeutics, Inc. Oral Formulations of Kappa Opioid Receptor Agonists
WO2022108883A1 (fr) * 2020-11-17 2022-05-27 Hofseth Biocare Asa Traitements respiratoires

Similar Documents

Publication Publication Date Title
JP5065047B2 (ja) 肺表面活性物質の配合物
JP2024525732A (ja) インターロイキン－２３受容体の脂質化ペプチド阻害剤
CA3112420A1 (fr) Nouveaux conjugues de montelukast et de peptides
AU2021215772A1 (en) Compounds and pharmaceutical uses thereof
JP2026000993A (ja) 新ペプチド
WO2015161820A1 (fr) Peptide antimicrobien synthétique amphiphile, composition pharmaceutique et leur utilisation
US20240218016A1 (en) Peptides and their use in the treatment of inflammation
CN120731082A (zh) 新多功能寡肽
CN103200955A (zh) 包含肽和病毒神经氨酸酶抑制剂的组合物
CN101090977A (zh) 三肽和四肽硫醚
CA2727973C (fr) Peptidyl-diacylglycerides
WO2016192819A2 (fr) Peptides modifiés et leur utilisation pour le traitement de maladies inflammatoires chroniques
WO2011125930A1 (fr) Agent prophylactique ou thérapeutique pour les maladies intestinales inflammatoires ou la neuropathie périphérique autoimmune
WO2025101524A1 (fr) Composés lipopeptidiques et leur utilisation dans la modulation de l'éosinophilie
CA2949328A1 (fr) Polymyxines faiblement substituees et compositions les comprenant
JPH02270895A (ja) Ｔ―リンパ球の成熟及びマクロファージの活性を阻害する新規ペプチド、それらを含む医薬組成物及びそれらの調製方法
KR20230110295A (ko) 호흡기 치료
JP4541642B2 (ja) 肺感染症および肺腫瘍を治療するためのリポペプチド類およびリポプロテイン類の使用
JP2018517779A (ja) 薬物送達及びイメージング化学コンジュゲート、製剤及びその使用方法
HK40101414A (en) Conjugates of montelukast and peptides
CN121930316A (zh) 一种植物来源的活性多肽及其在预防或治疗帕金森综合征中的用途
HK40088963A (zh) 化合物和其药学用途
WO2015061412A1 (fr) Méthodes et compositions pour favoriser la dilatation des bronchioles
CN114377111A (zh) 一种化痰止咳的药物组合物
HK40033390B (en) Conjugates of montelukast and peptides

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24889453

Country of ref document: EP

Kind code of ref document: A1