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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

• the present invention relates to a novel use of pyrrolopyridine derivative compounds for preventing and/or treating inflammatory diseases.
• Pyrrolopyridine derivatives are bicyclic compounds wherein pyridine and pyrrole are bonded and used for various pharmaceutical purposes. Accordingly, various pyrrolopyridine derivatives have been synthesized.
• Patent literature which discloses pyrrolopyridine derivatives include Korean Laid-open Patent Nos. 10-2018-0015142, 10-2017-0106452, and 10-2017-0058465.
• Inflammation is the mechanism by which living tissue that has been damaged by physical action, chemical substance, or bacterial infection is restored.
• vasoactive substances such as histamine, serotonin, and prostaglandin are released, increasing vascular permeability and causing inflammation.
• nonsteroidal anti-inflammatory drugs including bradykinin antagonists and TNF-a inhibitors having anti-inflammatory, analgesic, and antipyretic actions are commonly used as anti-inflammatory drugs.
• NSAIDs nonsteroidal anti-inflammatory drugs
• long-term use of non-steroidal anti-inflammatory drugs may cause gastrointestinal disorders, and serious side effects such as secondary anemia, asthma, suppression of labor induction, adverse effects on the kidneys, liver damage, and hypersensitivity have been reported.
• an anti-inflammatory agent which minimizes the usual and often seen side effects of currently known anti-inflammatory agents, does not harm the human body especially for maintenance use, and can be administered over an extended period of time.
• pyrrolopyridine derivatives inhibit the expression of inflammation-related factors including inflammatory cytokines such as NO, IL-6, IL-1J3, TNF-a and the like, and by confirming in-vivo stability and safety of the same, have identified potential for the use of pyrrolopyridine derivatives as pharmaceutical agents for the prevention and/or treatment of inflammatory diseases.
• inflammation-related factors including inflammatory cytokines such as NO, IL-6, IL-1J3, TNF-a and the like
• a purpose of the present invention is to provide a pharmaceutical composition for prevention and/or treatment of inflammatory diseases, the composition comprising a pyrrolopyridine -derivative compound as an active ingredient.
• Another purpose of the present invention is to provide a method for preventing and/or treating inflammatory diseases by administering an effective dose of a pyrrolopyridine-derivative compound to a subject.
• Yet another purpose of the present invention is to provide a pyrrolopyridine-derivative composition for prevention and/or treatment of inflammatory disease, and a use for a pharmaceutical composition comprising the same as an active ingredient.
• the present invention provides a method of preventing and/or treating an inflammatory disease in a patient in need thereof, the method comprising administering to the patient a compound represented by Chemical Formula 1:
• R 1 is C1-C3 alkoxy
• R 2 and R 3 are each independently hydrogen, straight-chain or branched C1-C10 alkyl, or C3-C6 cycloalkyl;
• R 4 is haloalkyl
• the present invention provides a method for preventing and/or treating inflammatory diseases, the method comprising a step of administering an effective dose of a pharmaceutical composition comprising a compound represented by Chemical Formula 1, or an isomer or pharmaceutically acceptable salt thereof.
• the present invention provides a use of a compound represented by Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same as an active ingredient, for preventing and/or treating inflammatory diseases.
• a compound represented by Chemical Formula 1 according to the present invention has excellent inhibitory activity with regard to various protein kinases including DYRK1A, CLK and the like, and/or excellent inhibitory activity against inflammation-related factors, while having excellent in-vivo stability, and a pharmaceutical composition comprising the same as an active ingredient can be useful in treating and/or preventing inflammatory diseases.
• a compound of Chemical Formula 1 can be used for the prevention, treatment, and/or improvement of inflammatory bowel disease, psoriasis, rheumatoid arthritis, and lupus.
• FIG. la and FIG. lb show inhibitory activity against expression of the pro-inflammatory cytokines TNF-a and IL-6 when LPS-stimulated THP-1 cells are treated with Compound 1 (FIG. la) and inhibitory activity against intranuclear mobility of p50 and p65 involved in the NF-Kb signaling pathway (FIG. lb).
• FIG. 2 shows the results of assessing regulation activity against regulatory T cell and Th 17 cell differentiation.
• FIG. 3 shows the results of treating a collagen-induced arthritis mouse model with Compound 1 to evaluate the therapeutic effects against arthritis, showing results of arthritis index evaluation (a), joint weight measurement (b), and histologic analysis results (c) through (e) observed under a microscope after dyeing with H&E and T-blue.
• FIG. 4 shows the results of evaluating the inhibitory activity of Compound 1 on the secretion of inflammatory cytokines (TNF-a, IL-6 and IL-17A) when peripheral blood mononuclear cells in the blood of inflammatory bowel disease patients have been treated with various concentrations.
• FIG. 5 is a drawing of the result of optical microscope observation after H/E dyeing the colon tissue of a TNBS-induced inflammatory bowel disease mouse model treated with Compound 1 and Enbrel and Cyclosporin A as comparative compounds.
• FIG. 6 shows the degree of expression of myeloperoxidase (MPO), as well as the weight and histological analysis results of colon tissue after treatment of a 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis model with Compound 1.
• MPO myeloperoxidase
• TNBS 2,4,6-trinitrobenzenesulfonic acid
• FIG. 7 shows the results of evaluating the efficacy after treating a DSS (dextran sodium sulfate)- induced inflammatory bowel disease mouse model, showing the results of evaluation weight loss suppression effect and disease activity index (DAI).
• DSS distal sodium sulfate
• FIG. 8a through FIG. 8c show the expression of inflammatory cytokines in colon tissue of a DSS- induced inflammatory bowel disease mouse model treated with Compound 1 and comparative compounds Cyclosporin A and Tofacitinib (FIG. 8a), an optical microscope photograph of colon tissue after H/E dyeing (FIG. 8b), and the results of scoring the weight to length ratio and Goblet cell depletion of colon tissue (FIG. 8c).
• FIG. 9 shows the results of scoring the skin state of a house dust mite-induced atopic dermatitis model to analyze the therapeutic effects of treating a house dust mite-induced atopic dermatitis model with Compound 1.
• FIG. 10 shows the results of evaluating the inhibitory activity of Compound 1 of IL-4, IL-6, MIP- 1b, KC and IL-33 expression in skin tissue and IgE expression in blood serum when a house dust mite- induced atopic dermatitis model is administered with Compound 1 at varying concentrations.
• FIG. 1 la and FIG. 1 lb show the results of the topical anti-inflammatory activity of Compound 1 in the imiquimod (IMQ)-induced psoriasis-like skin inflammation model.
• FIG. 12a and FIG. 12b show the results of the oral anti-inflammatory activity of Compound 1 in the imiquimod (IMQ)-induced psoriasis-like skin inflammation model.
• Examples of the present invention may be modified into various different forms, and the scope of the present invention is not limited to the examples described in the following. Furthermore, the examples of the present invention are provided to more completely describe the present invention to a person having ordinary skill in the art. Additionally, in the entirety of the specification, “comprising” an element, unless specifically stated otherwise, does not exclude other elements and means that other elements may be further comprised.
• the term “administration” refers to using a suitable method to introduce the pharmaceutical composition of the present invention to a subject suspected to have inflammatory disease, and administration may be performed through various pathways so long as the target tissue can be reached.
• alkyl may mean a straight-chain or branched acyclic saturated hydrocarbon consisting of carbon atoms.
• Representative -(Ci-xalkyl) may include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl; and branched chain saturated alkyls may include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 2,3- dimethylbutyl, and the like.
• the Ci-s alkyl may be substituted or unsubstituted.
• a Ci-s alkyl group may be substituted with a phenyl to form a benzyl group.
• the phrase “conjointly administering” refers herein to any form of administration of two or more different therapeutic compounds such that the second administered compound is administered while the first administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include additive or synergistic effects of the two compounds).
• cycloalkyl may refer to a nonaromatic saturated or unsaturated carbon ring.
• Representative cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3 -cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1 ,3- cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl and cyclooctadienyl.
• the cycloalkyl group may be substituted or unsubstituted.
• the cycloalkyl group may be a C3-8 cycloalkyl group.
• a cycloalkyl group of C7 or greater may have two or more cyclic structures, and a specific example thereof may be a bicycloalkyl group, and more specifically, bicycloheptane may be used in the present invention.
• At least one of the homogenous or heterogeneous substituents mentioned in the above may be substituted in like positions or different positions, and may also be sequentially substituted.
• the term “sequentially” in the above refers to one substituent being substituted in a chemical formula followed by the consecutive substitution of another substituent, and, for example, in a case wherein an alkyl group is substituted, and then a cycloalkyl is substituted at the alkyl group, and a carbonyl group is sequentially substituted at the cycloalkyl group, the compound may be named carbonylcycloalkylalkyl to indicate it has been sequentially substituted.
• halogen may be F, Cl, Br or I.
• haloalkyl may refer to a straight chain or branched chain alkyl (hydrocarbon) having a carbon atom substituted by at least one halogen atom.
• haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and A-Zu/tyl independently substituted by at least one halogen atom, for example, F, Cl, Br or I.
• the term “hydrate” refers to a compound of the present invention or a salt thereof, comprising a stoichiometric or non-stoichiometric amount of water bonded by a non-covalent intermolecular force.
• the hydrate of the compound represented by Formula 1 of the present invention may include a stoichiometric or non-stoichiometric amount of water that is bound by non-covalent intermolecular forces.
• Such hydrates may comprise at least one equivalent, and preferably 1 to 5 equivalents, of water.
• Such hydrates may be prepared by crystallizing, from water or a solvent comprising water, a compound represented by Chemical Formula 1 of the present invention, an isomer thereof, or pharmaceutically acceptable salts thereof.
• the term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but differs structurally or sterically. Included in such isomers are all structural isomers such as tautomers, R or S isomers, stereoisomers such as geometrical isomers (trans, cis), and enantiomers. All such isomers and compounds thereof are too included in the scope of the present invention. Unless otherwise specified, a solid line bond (-) connected to an asymmetric carbon atom may include a solid wedge bond ; or dashed wedge bond : ; representing the absolute arrangement of a stereogenic center.
• the term “inflammatory disease” is a term generally referring to diseases whose principal condition is inflammation, and specifically, but not limited to, may be one selected from asthma, acute lung injury, GvHD Graft versus Host Disease), chronic obstructive pulmonary disease, allergy, systemic lupus erythematosus, scleroderma, inflammatory bowel disease (for example ulcerative colitis and Crohn’s disease), atopic dermatitis, psoriasis, anaphylaxis, dermatitis, diabetic retinosis, retinitis, macular degeneration, uveitis, conjunctivitis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, osteoporosis, diabetes, diabetic kidney disease, nephritis, Sjogren’s syndrome, Crohn’s disease, autoimmune pancreatitis, periodontal disease, alopecia areata, graft versus Host Disease
• the term “pharmaceutically effective dose” refers to a dose sufficient to treat disease with a reasonable benefit/risk ratio applicable to medical treatment, and the level of the effective dose may be determined depending on factors including the type of subject, severity of disease, age, sex, type of disease, activity of the drug, drug sensitivity, duration of administration, administration pathway and excretion rate, duration of therapy and concomitantly used drugs, and other factors known well to the medical art.
• the compounds or compositions of the present invention may be administered as a single drug or concomitantly with other drugs, such as by conjoint administration, and may be administered sequentially or simultaneously with commercially marketed therapeutic agents. Furthermore, it may be administered as a single dose or multiple doses.
• the administration dose of the compound or composition of the present invention may be determined by an expert according to various factors such as patient status, age, sex and complications. As the compound or composition of the present invention has excellent safety, it may be used at above the decided administration dose.
• the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C i-4alkyl ) salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
• the provided compounds are purified in salt form for convenience and/or ease of purification, e.g., using an acidic or basic mobile phase during chromatography.
• Salts forms of the provided compounds formed during chromotagraphic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.
• solvate refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of solvent bonded by a non-covalent intermolecular force.
• Preferable solvents therefore, include volatile or non-toxic solvents, and/or solvents suitable for human administration.
• treatment includes the suppression, delay, identification, alleviation, weakening, limiting, reduction, inhibition, avoidance or healing of illnesses, conditions, disabilities, damage or health problems, or the occurrence or progression/improvement of such statuses and/or symptoms of such statuses.
• prevention refers to avoidance or reduction of risk of contracting, experiencing, suffering or having illnesses, conditions, disabilities, damage or health problems, or the occurrence or progression of such statuses and/or symptoms of such statuses.
• Treatment or prevention of a disease, condition, disorder, injury or health problem may be partial or complete.
• the present invention provides a compound for the prevention and/or treatment of inflammatory diseases, the compound represented by Chemical Formula 1:
• R 1 is C1-C3 alkoxy
• R 2 and R 3 are each independently hydrogen, straight-chain or branched C1-C10 alkyl, or C3-C6 cycloalkyl;
• R 4 is haloalkyl
• R 1 is C1-C3 alkoxy.
• R 1 is C1-C3 alkoxy. In some embodiments, R 1 is methoxy.
• R 1 is as found in the compounds of Table 1, below.
• R 2 and R 3 are each independently hydrogen, straight-chain or branched C1-C10 alkyl, or C3-C6 cycloalkyl.
• R 2 is hydrogen. In some embodiments, R 2 is a straight-chain C1-C10 alkyl. In some embodiments, R 2 is a branched C1-C10 alkyl. In some embodiments, R 2 is a C3-C6 cycloalkyl. In some embodiments, R 2 is straight chain or branched chain C1-C5 alkyl or C3-C4 cycloalkyl.
• R 3 is hydrogen. In some embodiments, R 3 is a straight-chain C1-C10 alkyl. In some embodiments, R 3 is a branched C1-C10 alkyl. In some embodiments, R 3 is a C3-C6 cycloalkyl.
• R 2 and R 3 are as found in the compounds of Table 1, below.
• R 4 is haloalkyl
• R 4 is haloalkyl. In some embodiments, R 4 is trifluoromethyl.
• R 1 is methoxy;
• R 2 is straight chain or branched chain C1-C5 alkyl or C3- C4 cycloalkyl;
• R 3 is hydrogen;
• R 4 is trifluoromethyl.
• a compound represented by Chemical Formula 1 is (4-((-4-ethylamino)- 3-(trifluoromethyl)-lH-pyrrolo[2,3-b]pyridine-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidine-l- yl)methanone.
• a pharmaceutically acceptable salt of a compound represented by Chemical Formula 1 may be interpreted as existing in any form selected from a group comprising any crystalline or amorphous form, or hydrates, solvates or co-crystals thereof.
• a compound of present invention may act as an inhibitor for protein kinase.
• the compounds mentioned herein may act as inhibitors against inflammation-related factors (e.g., cytokines).
• the protein kinase may be one or more of ALK, ALK (Cl 156Y), ALK (L1196M), CLK1, CLK2, CLK3, CLK4, CSNK1D, DYRK1A, DYRK1B, DYRK2, GAK, JNK1, LRRK2 (G2019S), LTK, MYLK, PAK2, PHKG1, PHKG2, STK33, ABL1 -nonphosphorylated, CAMK2D, CAMKK2, CHEK2, CSNK1A1, CSNK1E, ERK5, HUNK, INSR, JAK1 (JH2domain- pseudokinase), JNK2, JNK3, LRRK2, MAPKAPK2, PLK4, and STK39.
• ALK ALK
• ALK Cl 156Y
• ALK L1196M
• CLK1, CLK2, CLK3, CLK4, CSNK1D DYRK1A, DYRK1B, DYRK2,
• inflammation-related factors may refer to all factors known to be directly or indirectly associated with inflammatory reaction.
• inflammation-related factors may include pro-inflammatory cytokines, and inflammation-related factors whose activity is inhibited by the compound of the present invention and thereby exhibit preventive and/or therapeutic effects against inflammation may be, for example, selected from one or more of NO, IFN-y, IL-la, IL-ip, IL-4, IL-6, IL- 10, IL-12, IL-13, IL-17, IL-17A, IL-22, IL-23, IL-33, KC, MIP-la, MIP-lb, GM-CSF, and TNF-a.
• the present invention provides a method of reducing pro-inflammatory cytokines in a patient in need thereof, the method comprising administering an effective dose of a compound represented by Chemical Formula 1 or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a patient.
• the method of reducing pro- inflammatory cytokines reduces one or more of NO, IFN-y, IL-la, IL-ip, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, IL-17A, IL-22, IL-23, IL-33, KC, MIP-la, MIP-lb, GM-CSF, and TNF-a.
• the method of reducing pro-inflammatory cytokines reduces one or more of IL-6, IL-17A, and TNR-a. In certain embodiments, the method of reducing pro-inflammatory cytokines reduces one or more of IL-4, IL-6, MIP-lb, KC and IL-33. In some embodiments, the disclosed methods reduce IL-4. In some embodiments, the disclosed methods reduce IL-6. In some embodiments, the disclosed methods reduce IL-17A. In some embodiments, the disclosed methods reduce TNR-a. In some embodiments, the disclosed methods reduce MIP-lb. In some embodiments, the disclosed methods reduce KC. In some embodiments, the disclosed methods reduce IL-33. In some embodiments, the method of decreasing pro- inflammatory cytokines in a patient comprises preventing and/or treating inflammatory diseases, such as, but not limited to, inflammatory bowel disease or colitis.
• inflammatory diseases such as, but not limited to, inflammatory bowel disease or colitis.
• the present invention provides a method of reducing IgE in a patient in need thereof, the method comprising administering an effective dose of a compound represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof to the patient.
• the present invention provides a method of increasing differentiation of regulatory T cells (T reg ) in a patient in need thereof, the method comprising administering an effective dose of a compound represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a patient.
• the method of increasing differentiation of regulatory T cells (T reg ) in a patient comprises preventing and/or treating inflammatory diseases, such as, but not limited to, an autoimmune disease.
• the present invention provides a method of decreasing pro-inflammatory T cells (e.g., Thl7) in a patient in need thereof, the method comprising administering an effective dose of a compound represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a patient.
• the method of decreasing pro- inflammatory T cells (e.g., Thl7) in a patient comprises preventing and/or treating inflammatory diseases, such as, but not limited to, an autoimmune disease.
• the present invention provides a method of increasing differentiation of regulatory T cells (T reg ) and decreasing pro-inflammatory T cells (e.g., Th 17) in a patient in need thereof, the method comprising administering an effective dose of a compound represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a patient.
• the method of increasing differentiation of regulatory T cells (T reg ) and decreasing pro-inflammatory T cells (e.g., Th 17) in a patient comprises preventing and/or treating inflammatory diseases, such as, but not limited to, an autoimmune disease.
• the inflammatory disease which can be treated according to the methods of this invention is a Thl7-mediated disease, but is not limited to that disease.
• the Thl7-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and/or an inflammatory bowel disease, such as, but not limited to, Crohn's disease or ulcerative colitis.
• the present invention provides a method for preventing and/or treating inflammatory diseases for a patient in need thereof, the method comprising administering an effective dose of a compound represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof to the patient.
• a compound of the present invention represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof are useful in the prevention and/or treatment of inflammatory or obstructive airway diseases, resulting, for example, but not limited to, in reduction of tissue damage, airway inflammation, bronchial hyperreactivity, remodeling, or disease progression.
• obstructive airway diseases include obstructive airway diseases having an inflammatory component.
• Inflammatory or obstructive airway diseases to which the present invention is applicable include but are not limited to: asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
• Treatment of asthma also is to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as “whez infants”, an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.
• a compound of the present invention represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof are useful in the prevention and/or treatment of heteroimmune diseases.
• heteroimmune diseases include, but are not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, cockroach calyx, or other sources), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
• Prophylactic efficacy in the treatment of asthma will be evidenced for this invention by reduced frequency or severity of symptomatic attack, but not limited to this, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function, and/or improved airway hyperreactivity. Such efficacy may further be evidenced by reduced requirement for other symptomatic therapy, such as, but not limited to, therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to “morning dipping”.
• Morning dipping is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4 to 6 AM, i.e., at a time normally substantially distant from any previously administered symptomatic asthma therapy.
• a compound of the present invention represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof are useful in the prevention and/or treatment of other inflammatory or obstructive airway diseases and conditions to which the present invention is applicable and include but are not limited to acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airway hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
• ALI acute lung injury
• ARDS adult/acute respiratory distress syndrome
• COAD or COLD chronic obstructive pulmonary, airways or lung disease
• COAD chronic obstructive pulmonary, airways or lung disease
• COAD chronic obstructive pulmonary, airways or lung disease
• the invention also is applicable to the prevention and/or treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupous, chronic, or phthinoid bronchitis.
• inflammatory or obstructive airway diseases to which the present invention is applicable include but are not limited to pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airway obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptosis, siderosis, silicosis, tabacosis, and/or byssinosis.
• a compound of the present invention represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof are also useful in the prevention and/or treatment of eosinophil-related disorders, e.g.
• eosinophilia in particular eosinophil-related disorders of the airways (e.g., involving morbid eosinophilic infdtration of pulmonary tissues) including but not limited to hypereosinophilia as it affects the airways and/or lungs as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, and/or eosinophil-related disorders affecting the airways occasioned by drug reaction.
• hypereosinophilia e.g., involving morbid eosinophilic infdtration of pulmonary tissues
• a compound of the present invention represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof are useful in the prevention and/or treatment of inflammatory or allergic conditions of the skin; for example, but not limited to, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, hidradenitis suppurativa, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita (EBA), acne vulgaris, and/or other inflammatory or allergic conditions of the skin.
• EBA epidermolysis bullosa
• a compound of the present invention represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or a pharmaceutical composition thereof are useful for the prevention and/or treatment of inflammatory diseases or conditions, including but not limited to diseases or conditions having an inflammatory component; for example, graft versus host disease (GvHD), chronic obstructive airway disease, obstructive pulmonary disease, allergy, systemic lupus erythematosus, scleroderma, inflammatory bowel disease (e.g., ulcerative colitis and Crohn’s disease), atopic dermatitis, psoriasis, anaphylaxis, dermatitis, diabetic retinosis, retinitis, macular degeneration, uveitis, conjunctivitis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, osteoporosis, diabetes, diabetic kidney disease, nephritis, Sjogren
• Becker’ s/Duchenne muscular dystrophy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g.
• idiopathic nephrotic syndrome or minimal change nephropathy including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, leptospirosis renal disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bron
• the inflammatory disease is, but not limited to, asthma, acute lung injury, GvHD Graft versus Host Disease), chronic obstructive pulmonary disease, allergy, systemic lupus erythematosus, scleroderma, inflammatory bowel disease (for example ulcerative colitis and Crohn’s disease), atopic dermatitis, psoriasis, anaphylaxis, dermatitis, diabetic retinosis, retinitis, macular degeneration, uveitis, conjunctivitis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, osteoporosis, diabetes, diabetic kidney disease, nephritis, Sjogren’s syndrome, Crohn’s disease, autoimmune pancreatitis, periodontal disease, alopecia areata, graft versus host disease, chronic pelvic inflammatory disease, endometriosis, rhinit
• the inflammatory disease which can be prevented and/or treated according to the methods of this invention is but is not limited to a disease of the skin.
• the inflammatory disease of the skin is but is not limited to being selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita (EBA), and/or other inflammatory or allergic conditions of the skin.
• EBA epidermolysis bullosa acquisita
• the inflammatory disease which can be prevented and/or treated according to the methods of this invention is but is not limited to being selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin associated periodic syndrome (CAPS), and osteoarthritis.
• the inflammatory disease which can be prevented and/or treated according to the methods of this invention is but is not limited to being selected from Sjogren's syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and/or diseases affecting the nose, such as allergic rhinitis.
• the present invention provides a method for improving, preventing, treating and/or alleviating inflammation occurring on the skin and/or mucous membranes, the method comprising applying, on a patient requiring improvement and/or alleviation of inflammation occurring on the skin and/or mucous membranes, a compound represented by Chemical Formula 1, or an isomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
• the present invention provides a use of a compound represented by Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preventing and/or treating inflammatory diseases.
• the present invention provides a use of a compound represented by Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the production of medicaments for use in preventing and/or treating inflammatory diseases.
• composition of the present invention by further comprising excipients, disintegrating agents, sweetening agents, lubricants, flavoring agents and the like, may be formulated using ordinary methods into tablets, capsules, powders, granules, suspensions, emulsions, syrups, topicals, or other liquid or semi -liquid or solid formulations.
• the pharmaceutical composition of the present invention may act systemically and/or locally, and may be administered to subjects orally or non-orally, that is, through various pathways such as but not limited to pulmonary route administration, intranasal administration, sublingual administration, lingual administration, buccolingual administration, rectal administration, dermal administration, transdermal administration, or conjunctival administration, the pharmaceutical composition may be formulated into a form suitable for the administration pathway.
• dosage forms suitable for oral administration are but not limited to formulations comprising a compound of the present invention in crystalline and/or amorphous and/or dissolved form, and may be, for example, tablets (coated or non-coated tablets, for example, using gastric fluid-resistant, delayed-dissolution or insoluble coatings), tablets or films/oblates which rapidly disintegrate in the oral cavity, films/freeze-dried preparations, capsules (for example, hard or soft gelatin capsules), sugar-coated tablets, chewables (for example, soft chewables), granules, pellets, powders, emulsions, suspensions, aerosols and/or solutions.
• tablets coated or non-coated tablets, for example, using gastric fluid-resistant, delayed-dissolution or insoluble coatings
• tablets or films/oblates which rapidly disintegrate in the oral cavity
• films/freeze-dried preparations for example, hard or soft gelatin capsules
• sugar-coated tablets for example, chewables (for example, soft
• Parenteral administration may be achieved by avoiding the absorption stage (for example, through intravenous, intraarterial, intra cardiac, intrathecal or intra lumbar administration) or including absorption (for example, through intramuscular, dermal, intradermal, subdermal, percutaneous or intraperitoneal pathways).
• Dosage forms suitable for parenteral administration may include but are not limited to solutions, suspensions, emulsions, freeze-dried preparations, or preparations in the form of sterilized powders for injection.
• the present invention provides a method for preventing and/or treating inflammatory diseases for a patient in need thereof, the method comprising conjointly administering an effective dose of a compound represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or pharmaceutical composition thereof and at least one additional active ingredient.
• the pharmaceutical composition of the present invention may, for more effective treatment and/or prevention of inflammatory disease, comprise, in addition to a compound of the present invention, at least one additional active ingredient.
• Active ingredients that may be suitable for combination include but are not limited to gamma globulin, immunomodulatory and immunosuppressive compounds (for example, cyclosporine, Methotrexate®), TNF antagonists (for example, Humira®, etanercept, infliximab), IL-1 inhibitors (for example, anakinra, canakinumab, rilonacept), phosphodiesterase inhibitors (for example, apremilast), JAK/STAT inhibitors (for example, tofacitinib, baricitinib, GLPG0634), IRAK4 inhibitors, leflunomide, cyclophosphamide, rituximab, belimumab, tacrolimus, rapamycin, mycophenolate mo
• Additional active agents that may be used in combination with a compound represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or pharmaceutical composition thereof, may be but are not limited to small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®),
• the present invention provides a method of preventing and/or treating gout comprising administering to a patient in need thereof a compound of formula I and one or more additional active agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and/or the like, probenecid, allopurinol and febuxostat (Uloric®).
• NSAIDS non-steroidal anti-inflammatory drugs
• ibuprofen such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib
• colchicine Colderrys®
• corticosteroids such as prednisone, prednisolone,
• the present invention provides a method of preventing and/or treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as but not limited to aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ri
• NSAIDS non-ster
• the present invention provides a method of preventing and/or treating osteoarthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and/or monoclonal antibodies such as tanezumab.
• NSAIDS non-steroidal anti-inflammatory drugs
• the present invention provides a method of preventing and/or treating lupus comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and/or anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Co
• NSAIDS non-ster
• the present invention provides a method of preventing and/or treating inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and/or antibiotics such as Flagyl or ciprofloxacin.
• the present invention provides a method of preventing and/or treating asthma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HF A), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone
• Singulair® beta-2
• the present invention provides a method of preventing and/or treating COPD comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as
• Embodiment 1 A pharmaceutical composition for preventing and/or treating inflammatory diseases, the composition comprising, as an active substance, a compound represented by Chemical Formula 1, or an isomer or pharmaceutically acceptable salt thereof:
• R 1 is C1-C3 alkoxy
• R 2 and R 3 are each independently hydrogen, straight chain or branched chain C1-C10 alkyl, or C3-C6 cycloalkyl;
• R 4 is haloalkyl
• Embodiment 2 The pharmaceutical composition for preventing and/or treating inflammatory disease of embodiment 1, the composition comprising, as an active substance, a compound wherein, R 1 is methoxy; R 2 is straight chain or branched chain C1-C5 alkyl, or C3-C4 cycloalkyl; R 3 is hydrogen; and R 4 may be trifluoromethyl, or an isomer or pharmaceutically acceptable salt thereof.
• Embodiment 3 The pharmaceutical composition for preventing and/or treating inflammatory disease of embodiment 1, the composition comprising, as an active substance, a compound, or an isomer or pharmaceutically acceptable salt thereof, where the compound represented by Chemical Formula 1 may be (4-((-4-ethylamino)-3-(trifhioromethyl)-lH-pyrrolo[2,3-b]pyridine-6-yl)amino)-3- methoxyphenyl)(4-morpholinopiperidine- 1 -yl) methanone .
• the compound represented by Chemical Formula 1 may be (4-((-4-ethylamino)-3-(trifhioromethyl)-lH-pyrrolo[2,3-b]pyridine-6-yl)amino)-3- methoxyphenyl)(4-morpholinopiperidine- 1 -yl) methanone .
• Embodiment 4 The pharmaceutical composition for preventing and/or treating inflammatory disease of any one of embodiment 1 through embodiment 3, the composition comprising, as an active substance, a compound, or an isomer or pharmaceutically acceptable salt thereof, where the inflammatory disease is at least one selected from a group comprising asthma, acute lung injury, graft versus host disease (GvHD), chronic obstructive pulmonary disease, allergy, systemic lupus erythematosus, scleroderma, inflammatory bowel disease (for example, ulcerative colitis and Crohn’s disease), atopic dermatitis, psoriasis, anaphylaxis, dermatitis, diabetic retinosis, retinitis, macular degeneration, uveitis, conjunctivitis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, osteoporosis, diabetes, diabetic kidney disease, nephritis, Sjogren’s syndrome
• Embodiment 5 The pharmaceutical composition for preventing and/or treating inflammatory disease of any one of embodiment 1 through embodiment 3, the composition comprising, as an active substance, a compound, or an isomer or pharmaceutically acceptable salt thereof, where the inflammatory disease is at least one selected from a group comprising inflammatory bowel disease, rheumatoid arthritis, lupus, psoriasis, atopic dermatitis, graft versus host disease (GvHD), acute lung injury, alopecia areata, and osteoarthritis.
• a group comprising inflammatory bowel disease, rheumatoid arthritis, lupus, psoriasis, atopic dermatitis, graft versus host disease (GvHD), acute lung injury, alopecia areata, and osteoarthritis.
• Embodiment 6 The pharmaceutical composition for preventing and/or treating inflammatory disease of any one of embodiment 1 through embodiment 3, the composition comprising, as an active substance, a compound, or an isomer or pharmaceutically acceptable salt thereof, which inhibits protein kinase activity.
• Embodiment 7 The pharmaceutical composition for preventing and/or treating inflammatory disease of any one of embodiment 1 through embodiment 3, the composition comprising, as an active substance, a compound, or an isomer or pharmaceutically acceptable salt thereof, which inhibits inflammation-related factors.
• the positive control refers to a compound showing a percentage control of 0%
• the negative control indicates a percentage control of 100% with DMSO.
• the enzyme selectivity of the present invention if the percentage control for each enzyme was ⁇ 41% (that is, less than 41%), the compound was judged to have activity with regard to such enzyme.
• THP-1 cells were pre-treated with Compound 1 for 1 hour, and then treated with lipopolysaccharides (Lipopolysaccharides, LPS, 0.5 pg/ml), an inflammatory substance, for 24 hours to confirm the expression of the pro-inflammatory cytokines TNF-a and IL-6 by the THP-1 cells and the NF-Kb signaling pathway associated with their expression.
• lipopolysaccharides Lipopolysaccharides, LPS, 0.5 pg/ml
• an inflammatory substance for 24 hours to confirm the expression of the pro-inflammatory cytokines TNF-a and IL-6 by the THP-1 cells and the NF-Kb signaling pathway associated with their expression.
• Example 4 Evaluation of the efficacy of the compound of the present invention using a collagen- induced arthritis mouse model
• Compound 1 was sufficiently dissolved in a solvent (1% citric acid + 20% HP-beta-CD) and then orally administered at 30 mg/kg twice a day for 2 weeks starting on day 29.
• Enbrel (anti-TNF-a) 10 mg/kg was subcutaneously administered once every 2 days, then dexamethasone (0.15 mg/kg), Baricitinib (5 mg/kg), Filgotinib (50 mg/kg), and Tofacitinib (10 mg/kg) were orally administered twice a day; as for arthritis assessment, the scores assessed at the four feet of the mouse were added and divided by 4 to give a mean, based on the mean arthritic index by Rosloniec et al (Reference Literature 1: Brand DD, et al. Nat Protoc. 2007;2(5): 1269-75).
• Score 1 Mild edema and erythema limited to the foot or ankle joint
• Score 3 Moderate edema and erythema from the ankle joint to the metatarsals.
• Score 4 Severe edema and skin flaring from the ankle to the entire leg, or stiffness in the leg
• FIG. 3 The results of evaluating the arthritis index after inducing inflammation with collagen are shown in FIG. 3. It was determined in the results that the increased arthritic index was reduced when the compound of the present invention was administered, and the weight of the joint, which had increased due to induction of arthritis, was reduced (FIG. 3a to 3b). Furthermore, based on photography of the joint area for histological analysis, it can be seen that treatment with Compound 1 reduced the area of cells were collagen-induced inflammation had occurred, and also reduced the area of the damaged joint (FIG. 3c to 3e). This confirms that the above compound inhibits inflammatory reaction and has the potential to treat and suppress the progression of arthritis.
• Example 5 Evaluation of inflammatory cytokine expression inhibition activity in peripheral blood mononuclear cells (PBMC) of inflammatory bowel disease patients
• peripheral blood mononuclear cells of inflammatory bowel disease patients are already activated and express inflammatory cytokines. It was confirmed by treating the peripheral blood mononuclear cells of patients with inflammatory bowel disease with Compound 1 effectively inhibiting expression of the inflammatory cytokines TNF-a, IL-6 and IL-17A, and this result can be interpreted as indicating potential of the compound for use in treatment of inflammatory bowel disease (FIG. 4).
• Compound 1 effectively inhibiting expression of the inflammatory cytokines TNF-a, IL-6 and IL-17A
• Compound 1 was sufficiently dissolved in a solvent (5% DMSO, 5% PEG400, 90% DDW within 1% Tween 80) and then orally administered once daily at the prescribed concentration (60 mpk).
• the comparative compound, cyclosporine A, was orally administered once daily, and the TNF-a blocker (Enbrel®) was administered intraperitoneally once daily.
• MPO levels were lower than the MPO levels of the control not treated with the compound. Furthermore, weighing the bowel tissue showed a weight reduction in the experimental group treated with Compound 1, and this can be interpreted as being due to the reduction of the edema, etc. caused by inflammation. Additionally, the inflammation sites on the collected bowel tissue were dyed with H&E and photographed with an optical microscope, and the results showed that the lamina intestinal, whose thickness had increased due to induction of inflammation, decreased in thickness due to treatment with the compound of the present invention (FIG. 5).
• Example 7 Evaluation of the efficacy of the compounds using a DSS-induced inflammatory bowel disease mouse model
• mice used for the present experiment was male C57BL/6 mice (aged 6 to 8 weeks) weighting 20 to 24 g, purchased from Charles River Laboratories. All the mice except the normal control were made to drink 3% DSS water for 5 days to induce enteritis.
• Compound 1 was sufficiently dissolved in solvent (0.5% citric acid in clH 2 0) then orally administered twice a day at a prescribed concentration (20 mg/kg).
• the comparative compound cyclosporine A was dissolved in 0.5% methylcellulose solvent and orally administered once a day at a prescribed concentration (20 mg/kg), and Tofacitinib was dissolved in 0.5% methylcellulose solvent and orally administered twice a day at a prescribed concentration (10 mg/kg).
• Example 8 Evaluation of the efficacy of the compounds using a house dust mite-induced atopic dermatitis model
• dermatitis on the back and ears was alleviated in a concentration-dependent manner for administration of Compound 1, and administration at 30 mpk was most effective at alleviating dermatitis; it was confirmed that Compound 1 was more effective at alleviating atopic dermatitis than the upadacitinib control group.
• Aggravation of atopic dermatitis leads to increased inflammatory cytokines that induce inflammation in the lesion area, and comparing the degree of inflammatory cytokine expression in the back tissue in the group administered Compound 1 at 30 mpk against the control group, a statistically significant reduction was confirmed.
• a luminescence assay was used to measure and evaluate inhibition activity against 1A2, 2C9, 2C19, 2D6 and 3A4, which are important Phase 1 drug metabolism CYP450 enzymes involved in drug metabolism. Whereas the CYP 3A4 index is normally suppressed, almost no enzyme inhibition activity was exhibited by the compound of the present invention.
• the hERG analysis is used as an indicator of cardiac toxicity, and generally a value of 5 pM indicates safety; the compound of the present invention was confirmed to have excellent safety in terms of cardiac toxicity.
• Caco-2 permeability observes the cell membrane permeability of a drug, and can be considered an index associated with drug absorption and excretion. An ER ratio value close to “1” indicates almost equivalent drug absorption and excretion, and the compound of the present invention, exhibiting a value of 1.08, was confirmed to have excellent cell membrane permeability.
• Hydrolysis in plasma is a factor which, together with metabolic reactions, impacts fast in-vivo decomposition of a drug and short half-life thereof; plasma stability is a test which assesses these.
• the compound at a certain concentration was added to plasma and reacted for a certain period, then collected, and LC-MS/MS was used to measure the percentage of compound remaining relative to the amount prior to the reaction.
• Example 10 Evaluation of topical anti-inflammatory activity of Compound 1 in the imiquimod (IMQ)-induced psoriasis-like skin inflammation
• Ear swelling was measured on Day 0 and thereafter 30 min before dosing on Days 2, 4, 6 and 8. On Day 10, ear swelling was measured 24 hours after the last dosing.
• FIG. 1 la and FIG. 1 lb The results are shown in FIG. 1 la and FIG. 1 lb.
• topical administration of vehicle control 5% DMSO/ 75% PEG400/ 20% EtOH
• Compound 1 (0.3, 1% and 3%) had moderate to significant (/? 0.05 ) inhibition on IMQ-induced ear swelling from Day 6 to Day 10 in a dose-dependent manner, relative to the no treatment and vehicle control groups.
• Example 11 Evaluation of oral anti-inflammatory activity of the compounds in the imiquimod (IMQ)-induced psoriasis-like skin inflammation
• Compound 1 at 45 and 60 mg/kg and the vehicle (0.5% citric acid + 20% HP-b-CD in DDW) at 5 mL/kg were given by oral gavage twice (BID) daily for 9 consecutive days.
• the positive control, methotrexate at 2 mg/kg and tofacitinib at 5 mg/kg were administered by oral gavage twice (BID) daily during the same study period.
• FIG. 12a and FIG. 12b The results are shown in FIG. 12a and FIG. 12b.
• Compound 1 given at 45 and 60 mg/kg had a statistically (/? 0.05 ) significant inhibition on IMQ- induced ear swelling from Day 8 to Day 10, when compared to the vehicle group.
• methotrexate at 2 mg/kg showed a significant (/? .05 ) effect on the IMQ- induced ear swelling on Day 8, when compared to the vehicle group.
• Tofacitinib given at 5 mg/kg also showed a significant (/? 0.05 ) inhibition on IMQ-induced ear swelling from Day 8 to Day 10 in the study.

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