Methods for treatment of psoriatic arthritis

Abstract

To provide pharmaceutical compositions for use in the treatment of psoriatic arthritis (PsA).SOLUTION: Provided are a compound according to Formula I, or a pharmaceutically acceptable salt thereof, or a solvate or the salt of a solvate thereof, and pharmaceutical compositions comprising the same.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to the medical use of the compounds of the invention according to formula I for the treatment of psoriatic arthritis (PsA). The present invention relates to the treatment of PsA and / or also offers a method of prevention. [Background technology]

[0002] (background) Psoriatic arthritis (PsA) is an inflammatory form of arthritis that affects up to 30 percent of people with psoriasis. Psoriatic arthritis causes swelling, stiffness, and pain in and around the joints. This can cause nail changes and overall fatigue. Research has shown that psoriatic arthritis can be treated with It has been shown that delaying treatment by as little as six months can result in permanent joint damage. Early recognition, diagnosis, and treatment of joint pain can reduce pain and inflammation and help prevent joint damage. Although several treatment options are available, most No current treatment effectively relieves enthesitis and symptoms of joints and skin.

[0003] Janus kinase (JAK) inhibitors have been developed to combat RA. JAKs are membrane receptors that bind to It is a cytoplasmic tyrosine kinase that converts cytokine signaling from STAT transcription factors. Four JAK family members have been described: JAK1, JAK2, JAK3, and TYK2. Upon cytokine binding to its receptor, JAK family members undergo autophosphorylation and / or or transphosphorylate each other, which then phosphorylates STAT, which then translocates to the nucleus. JAK-STAT intracellular signaling regulates transcription of interferons, most interferons, and Interleukins, and various cytokines and endocrine factors, e.g., EPO, TPO, GH, OS M, LIF, CNTF, GM-CSF, and PRL (Vainchenker et al., 2008).

[0004] JAK1 is a target in the field of immune inflammatory diseases. JAK1 heterodimerizes with other JAKs. and transduce cytokine-driven pro-inflammatory signaling. Inhibition of JAK1 inhibits JAK1 signaling, such as IL-6, IL-4, IL-9, IL-15, IL-21, or IFNγ. For immunoinflammatory diseases with pathology-associated cytokines and JAK-mediated signaling The compounds according to formula I, cycloproline, are of interest for other diseases driven by steroid hormone receptor agonists. Pancarboxylic acid {5-[4-(1,1-dioxo-thiomorpholin-4-ylmethyl)-phenyl]-[1,2,4] Triazolo[1,5-a]pyridin-2-yl}-amide (compound 1) was prepared as described in WO 2010 / 149769 (Menet and Smi ts, 2010) and has the chemical structure shown below: [ka] .

[0005] Compound I is a potent and selective JAK1 inhibitor for the treatment of inflammatory disorders. , for inhibition of JAK1 among 451 unique kinase gene products tested in vitro. Highly selective. Cytokine-induced STAT1 phosphorylation in a human whole blood assay. showed half-maximal values ​​of 629 nM and 17,453 nM for JAK1- and JAK2-mediated signaling, respectively. Inhibitory concentration (IC 50 ) value, and in this assay, Compound I also showed 27-fold selectivity for JAK1. Therefore, compound I is a selective inhibitor of JAK1. do.

[0006] In humans, Compound I is metabolized to one major active metabolite, a compound according to Formula II. Form: [ka] .

[0007] This molecule also inhibited JAK1 signaling, but with approximately 20-fold less potency than the parent compound, and Although this metabolite is less potent than the parent molecule, it is still present in approximately 10 times more abundant form overall in humans. The expected exposures and peak plasma concentrations were higher than those seen in all animal species tested. Therefore, specialized pharmacology and toxicology studies are being conducted with Compound II. The results of pharmacodynamic (PD) experiments in Australia indicate that the clinical activity of Compound I is due to the combination of the parent molecule and metabolites. It is suggested that the compound according to formula II may be produced from the .

[0008] JAK inhibitors are being evaluated for the treatment of PsA. Patients with active psoriatic arthritis who have had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs A Phase III study in patients showed a 50% and 10% mortality rate when administered at 5 mg compared with 33% in the placebo group. When administered at 1 mg, it demonstrated a 61% ACR20 response rate at 3 months (Mease P. et al., NEJM 377;16 1 537-1550).

[0009] However, while JAK inhibitors are useful and effective molecules in the treatment of inflammatory conditions, they are poorly tolerated. blood, thrombocytopenia and neutropenia, hypercholesterolemia, increased creatinine, There are reported obstacles to the use of these compounds, all of which lack selectivity, particularly against JAK2. This may be due to the lack of selectivity for the ATP synthesis (O'Shea, JJ et al., 2013. Back to the Few Back to the Future: Oral Targeted Therapies for RA and Other Autoimmune Diseases eted therapy for RA and other autoimmune diseases). Nat. Rev. Rheumatol. 9, 173- 182; O'Shea, JJ, Plenge, R., 2012. JAK and IgA in immune regulation and immune-mediated diseases. and STATs (JAKs and STATs in Immunoregulation and Immune-Mediated Disease). Immunity 36, 542-550). In contrast, selective JAK inhibition, particularly JAK1, has the potential to provide safe and effective therapeutic agents. (Yamaoka, K., 2016. Janus kinase inhibitors for rheumatoid arthritis) inase inhibitors for rheumatoid arthritis). Curr. Opin. Chem. Biol. 32, 29-33).

[0010] Therefore, it is expected to be a promising option for the treatment of PsA with a better risk-benefit profile. There remains a need in the art for additional agents that Summary of the Invention

[0011] (Summary of the Invention) The present invention provides compound I, which has a favorable benefit-risk profile in the treatment of psoriatic arthritis. The findings showed unexpectedly high potency with a pharmacokinetic profile. In a study (reported Example 1 herein), the efficacy of psoriatic arthritis in treating patients with psoriatic arthritis was demonstrated. Compound I has been shown to have an ACR20 of up to 80% after 16 weeks of use. , as will become apparent from the following description of the invention.

[0012] Therefore, the present invention provides a method for administering the compound at a dose selected from 100 to 200 mg once a day or 50 to 100 mg twice a day. Provided are compounds according to formula I for use in the treatment of psoriatic arthritis that are orally administered. [ka] .

[0013] In a specific embodiment, a compound according to Formula I is used as the sole active agent for the treatment of PsA. It is administered as follows.

[0014] In a further embodiment, the dose is selected from 100 or 200 mg once daily or 100 mg twice daily. The present invention provides a compound according to formula I for use in the treatment of psoriatic arthritis, the compound being administered orally at a dose of In this case, an ACR20 response is seen in at least 60, 70, or 80% of patients.

[0015] In a further embodiment, the dose is selected from 100 or 200 mg once daily or 100 mg twice daily. The present invention provides a compound according to formula I for use in the treatment of psoriatic arthritis, the compound being administered orally at a dose of where an ACR50 response is seen in at least 30, 35, or 40% of patients.

[0016] In a further embodiment, the dose is selected from 100 or 200 mg once daily or 100 mg twice daily. The present invention provides a compound according to formula I for use in the treatment of psoriatic arthritis, the compound being administered orally at a dose of In this case, a statistically significant ACR20 response is seen one week after treatment.

[0017] In a further embodiment, the dose is selected from 100 or 200 mg once daily or 100 mg twice daily. The present invention provides a compound according to formula I for use in the treatment of psoriatic arthritis, the compound being administered orally at a dose of In this case, a statistically significant ACR50 response is seen one week after treatment.

[0018] In a further embodiment, in the treatment of psoriatic arthritis in patients with enthesitis There is provided a compound according to Formula I for use in

[0019] In a further embodiment, the patient has not previously been exposed to a bDMARD, particularly an anti-TNF drug. Compounds according to Formula I for use in treating psoriatic arthritis in a patient are provided. .

[0020] In another embodiment, compound I according to any of the embodiments disclosed herein and Compositions, eg, pharmaceutical compositions, are provided that include a pharmaceutically acceptable vehicle.

[0021] In another embodiment, a person in need thereof is administered 100 or 200 mg once daily or 10 mg twice daily. 10. The method of claim 1, further comprising administering a compound according to formula I orally administered at a dose selected from 0 mg to 100 mg. Methods for treating arthritis are provided.

[0022] In certain embodiments, the treatment method reduces AC in at least 60, 70, or 80% of patients. In a further embodiment, the ACR20 response is statistically significant after one week of treatment. is meaningful.

[0023] In another embodiment, the treatment method reduces AC in at least 30, 35, or 40% of patients. In a further embodiment, the ACR50 response is measured after one week of treatment. is meaningful.

[0024] In a further embodiment, the patient receiving said treatment has previously received a bDMARD, in particular an anti-TNF therapy. I didn't receive treatment.

[0025] In a further embodiment, the patient receiving the treatment has signs and / or symptoms of enthesitis. Shows. DETAILED DESCRIPTION OF THE INVENTION

[0026] (Detailed Description of the Invention) The following terms shall have the meanings set out below and shall be used in conjunction with the description and use of the present invention. This information is useful in understanding the scope and intended scope of the

[0027] compounds, pharmaceutical compositions containing such compounds, and methods for using such compounds and compositions. When describing the present invention, which may include methods of using the present invention, the following terms, when present, are used unless otherwise indicated: Unless otherwise indicated, the moieties defined below have the following meanings: Each of these groups may be substituted with various substituents, and each definition defines the group that defines such a substituted moiety. It should also be understood that the following statements are intended to be included within their scope. Unless otherwise specified, the term "substituted" is defined as set forth below. As used herein, the terms "group" and "radical" are interchangeable. It should further be understood that the

[0028] The articles "a" and "an" refer to one or to more than one (i.e., , at least one). "n analogue" means one analog or multiple analogs.

[0029] The terms "compound I," "compound according to formula I," or "compound of formula I" refer to a compound having structural formula I. may be used interchangeably to refer to compounds that: [ka] .

[0030] "Pharmaceutically acceptable" means a substance that meets the requirements of the Federal Regulations for use in animals, and more specifically, in humans. has not been approved by any federal or state regulatory authority or the corresponding regulatory authority of a country outside the United States. that may be approved or recognized by the United States Pharmacopoeia or other generally recognized pharmacopeia; This means that

[0031] A "pharmaceutically acceptable salt" is a salt that is pharmaceutically acceptable and is a derivative of the parent compound. It refers to salts of the compounds of the present invention that possess the desired pharmacological activity. In particular, such salts are non-toxic. These salts may be inorganic or organic acid addition salts and base addition salts. : (1) Formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or vinegar Acid, Propionic Acid, Hexanoic Acid, Cyclopentane Propionic Acid, Glycolic Acid, Pyruvate Acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, Benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfone Acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluene Sulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carbo acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, Lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid (2) Acid addition salts formed with organic acids such as phosphoric acid and muconic acid; or (3) salts present in the parent compound The acidic protons are metal ions, such as alkali metal ions, alkaline earth ions, or substituted by aluminum ions; or e.g., ethanolamine , diethanolamine, triethanolamine, N-methylglucamine, and other organic bases. Salts include, by way of example only, sodium, potassium, sodium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and if the compound contains a basic functional group, a salt of a non-toxic organic or inorganic acid, e.g., hydrochloric acid Other examples include salts, hydrobromides, tartrates, mesylates, acetates, maleates, and oxalates. The term "pharmaceutically acceptable cation" refers to an acceptable cation of an acidic functional group. Such cations include sodium, potassium, calcium, For example, alkyl, magnesium, ammonium, and tetraalkylammonium cations. is shown.

[0032] A "pharmaceutically acceptable vehicle" is a liquid with which a compound of the present invention is administered. refers to an agent, adjuvant, excipient, or carrier.

[0033] "Solvate" refers to a form of a compound that is associated with a solvent, usually through solvation. This physical association involves hydrogen bonding. Traditional solvents include water, EtOH, and acetic acid. The compounds of the invention may, for example, be prepared in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates such as hydrates. In certain instances, both stoichiometric and non-stoichiometric solvates are further included. For example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvation The term "solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. do.

[0034] "Subject" includes a human. The terms "human," "patient," and "subject" are used herein. are used interchangeably in

[0035] An "effective amount" is an amount that, when administered to a subject for treating a disease, provides such an effective amount for that disease. "Effective amount" means the amount of a compound of the present invention that is sufficient to provide effective treatment. The treatment varies depending on the type, disease and its severity, as well as the age and weight of the patient to be treated. It could be.

[0036] "Prevent" or "prevention" refers to the prevention of a disease by preventing exposure to a disease-causing agent or by preventing the disease. The risk of acquiring or developing a disease or disorder in a subject who may be predisposed to the disease before the onset of the disease This refers to a reduction in risk, i.e., the absence of at least one of the clinical symptoms of the disease.

[0037] The term "prophylaxis" is related to "prevention" and has the purpose of: Refers to measures or treatments that are intended to prevent disease, rather than to treat or cure it. Non-limiting examples of preventive measures include administering vaccinations; administration of low molecular weight heparin to hospitalized patients at risk of thrombosis; and or taking antiviral drugs such as chloroquine prior to visiting geographic areas where there is a high risk of contracting malaria. Examples include administration of antimalarial drugs.

[0038] "Treating" any disease or disorder or "treatment" of any disease or disorder means In an embodiment, the disease or disorder is ameliorated (i.e., the disease is halted or refers to a reduction in the sign, extent, or severity of at least one of the clinical symptoms In another embodiment, "treating" or "treatment" refers to a small amount of damage that may not be discernible by the subject. In another embodiment, the improvement in at least one physical parameter is "Treating" or "treatment" refers to physically modulating (e.g., recognizing) a disease or disorder. stabilization of symptoms) or physiological regulation (e.g., stabilization of physical parameters); In a further embodiment, "treating" or "treatment" refers to the treatment of a disease. It relates to slowing progression.

[0039] For purposes of the present invention, "ACR20," "ACR50," and "ACR70" are used herein. The term "periarthritis" refers to the condition of a patient whose peripheral arthritis symptoms are associated with a condition that is not treated by the American College of Rheumatology. According to the criteria set by the American College of Rheumatology (ACR), The ACR score is expressed as a percentage. The ACR20 score is a score that indicates A 20% improvement in arthritis symptoms in people taking the drug is indicated, and an ACR50 score indicates a 50% improvement. An ACR70 score means a 70% improvement. To qualify for CORE, participants must have at least 20% fewer tender joints (at baseline tender joint count). At least 20% improvement from TJC68) and at least 20% fewer swollen joints (number of swollen joints) (at least a 20% improvement from the baseline SJC66). Patients are assessed in five areas: a person's overall (global) assessment of their disease activity; The score (using a visual analog scale (VAS) ranging from 0 to 100 mm) is a physician's overall assessment of a person's disease activity. Subjective assessment (using a visual analog scale of 0-100 mm), and a person's own assessment of PsA pain intensity (using a visual analog scale of 0-100 mm). a person's assessment of their own physical function, as measured by the HAQ-DI; and C-reactive protein (CRP) blood test results (units: mg / dL or mg / L) A 20% improvement in all three criteria must be demonstrated. ACR50 and ACR70 scores are based on the same criteria. are in use, but require improvements of 50% and 70%, respectively.

[0040] As used herein, the term "DAS28(CRP)" refers to a measure of disease activity in a patient. This refers to a clinical scoring system ranging from 2.0 to 10.0 to measure 28 tender and swollen joints. This includes blood analysis to measure CRP and a visual analog scale (VAS) to assess overall health. Further details are provided in Example 1. A DAS28(CRP) value of less than 2.6 indicates remission. A DAS28 (CRP) of 2.6 to 3.2 indicates low disease activity, and a DAS28 (CRP) of 3.2 to 5.1 indicates low disease activity. A DAS28(CRP) of 8 indicates moderate disease activity, whereas a DAS28(CRP) of more than 5.1 indicates high disease activity. It is associated with disease activity (Wells et al., 2009 Ann. Rheum. Dis. 68,954-960).

[0041] As used herein, the term "CRP" refers to serum C-reactive protein. In particular, guidelines for CRP are widely available and should be <0.5 mg / d Normal values ​​for L are recommended (Porter, 2011, The Merck Manual of Diagnosis and Therapy). ck Manual of Diagnosis and Therapy)(Wiley)).

[0042] As used herein, the term "enthesitis" refers to a condition that is a typical feature of PsA. and refers to the enthesitis that is one of the characteristics that distinguishes it from rheumatoid arthritis.

[0043] As used herein, the term "SPARCC Enthesitis Index" refers to the pressure exerted by palpation. Sixteen subjects were assessed for pain and scored as 0 (not tender) or 1 (tender). Refers to the clinical scoring of peripheral (enthesitis) tenderness after examination. is the sum of the scores for all sites, up to a maximum of 16. The higher the score, the more severe the tendon insertion. The inflammation burden is greater (Maksymowych WP et al., Canadian Spondyloarthritis Research Consortium ( Development and validation of the Spondyloar thritis Research Consortium of Canada (SPARCC) Enthesitis Index). Ann Rheum Dis 2 009;68:948-53).

[0044] As used herein, the term "Leeds Enthesitis Index" or "LEI" refers to six Locations: Two sites each at the lateral epicondyle of the humerus, the medial condyle of the femur, and the insertion of the Achilles tendon The LEI score ranges from 0 to 6. The higher the score, the greater the enthesitis burden.

[0045] As used herein, the term "HAQ-ID" refers to a measure of a patient's physical functioning. The HAQ-DI refers to the Health Assessment Questionnaire without Disability Index. This is a 20-question document that assesses the degree of difficulty people have in achieving their goals (B. Bruce and J. Frie s paper, "The Stanford Health Assessment Questionnaire: Scale and Practical Applications" ssessment Questionnaire: dimensions and practical applications)”, Health Qual L (Faife Outcomes, p. 1:20, 2003). The HAQ-DI total score ranges from 0 to 3, with higher scores being The core shows greater dysfunction.

[0046] As used herein, the term "MDA" refers to minimal disease activity, a measure of disease remission. For purposes of the present invention, patients must meet the seven following criteria: -TJC68≦1 -SJC66≦1 -PASI≦1 or BSA≦3% - Patient Global Assessment of PsA Pain Intensity score ≤ 15 (0-100mm VAS) - Patient Global Assessment of Disease Activity ≤ 20 (0-100mm VAS) -HAQ-DI≦0.5 -SPARCC Enthesitis Index ≤1 A person is classified as having achieved MDA when five of the following conditions are met:

[0047] As used herein, the term "PASI" refers to the Psoriasis Area and Severity Index score. It is an index used to express the severity of psoriasis. and desquamation) and the percentage of affected area. Details are provided in Example 1. PASI scores represent the change from baseline. "PASI50" refers to the percentage of patients who achieve a 50% improvement in PASI score when receiving study treatment. "PASI75" is the percentage of patients who achieved a 75% improvement in PASI score when receiving the study treatment. "PASI90" refers to patients who achieved a 90% improvement in their PASI score when receiving test treatment. Refers to a percentage.

[0048] As used herein, the term "BSA" refers to body surface area and is used to describe the area of ​​the body affected by psoriasis. A BSA of <3% is scored as mild psoriasis, and a BSA of 3% is scored as severe psoriasis. ~10% BSA is scored as moderate psoriasis, and >10% BSA is scored as severe psoriasis. It will be ringed.

[0049] As used herein, the term "cDMARD" refers to conventional disease-modifying antirheumatic drugs. cDMARDs are usually synthetic drugs also known as conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Specific examples of cDMARDs for the treatment of psoriatic arthritis include methotrexate, These include leflunomide, sulfasalazine, chloroquine, and hydroxychloroquine. .

[0050] As used herein, the term "bDMARD" refers to a biological disease-modifying antirheumatic drug. A specific class of bDMARDS is tumor necrosis factor (TNF) inhibitors, also known as anti-TNF drugs. , e.g., etanercept, adalimumab, infliximab, golimumab, certolizumab mab, or certolizumab pegol.

[0051] As used herein, the term "TNF-naive patient" refers to a patient receiving anti-TNF monoclonal antibody therapy. Patients who have not previously received anti-TNF medications such as antibody therapy or have been taking anti-TNF medications for at least 8 weeks to participate in the study Anti-TNF therapy at a dose registered for the treatment of an inflammatory condition that has been discontinued recently (e.g., limited Although not a common treatment, infliximab, golimumab, adalimumab, certolizumab, and This refers to subjects who have previously received rituximab and / or certolizumab pegol.

[0052] As used herein, the term "TNF-experienced patient" refers to a patient who is ≥ 18 years of age or older at the time of study entry. Anti-TNF monoclonal antibody therapy (e.g., but not limited to, infliximab) , golimumab, adalimumab, certolizumab, and / or certolizumab pegol) Patients who are currently receiving or have previously received any anti-TNF drug or patients who do not respond to such treatment.

[0053] As used herein, the term "anti-TNF drug" refers to a drug that is effective in treating inflammatory conditions, particularly arthritis. Uromatoid arthritis (RA), psoriatic arthritis, juvenile arthritis, inflammatory bowel disease (Crohn's disease and ulcerative colitis) TNF refers to a class of drugs used to treat psoriasis, ankylosing spondylitis, and psoriasis. It is a chemical produced by the immune system that causes inflammation in the body. Excess TNF in the blood is naturally blocked, but in inflammatory conditions, higher levels of TNF in the blood occur. Specific examples of anti-TNF drugs include insulin, insulin-like inhibitors, and insulin-like inhibitors. Fliximab, golimumab, adalimumab, certolizumab, and certolizumab pegol Therefore, the term "anti-TNF treatment" refers to the administration of anti-TNF drugs. This refers to treatment using

[0054] The term "compounds of the invention" and equivalent expressions refer to compounds of Formula I as described herein. and where the context permits, this expression includes pharmaceutically acceptable Salts and solvates, such as hydrates and solvates of pharmaceutically acceptable salts, are included. Similarly, references to intermediates, whether or not they themselves are claimed, Where the context so permits, salts and solvates thereof are also intended to be embraced.

[0055] The term "therapeutic effect" refers to a specific or directed effect, such as the treatment of psoriatic arthritis with Compound I. Refers to the effects resulting from a specific treatment.

[0056] Psoriatic arthritis (PsA) is a condition associated with psoriasis and affecting the peripheral joints, axial skeleton, tendon and ligament insertion sites (tendons). Characterized by a heterogeneous musculoskeletal phenotype involving multiple areas, including the musculoskeletal system (enthesis), the musculoskeletal system (enthesis), and the fingers and toes (dactylitis) PsA is an inflammatory joint disease that affects approximately 30% of people with psoriasis. The majority of cases (75%) In this study, psoriasis precedes joint disease, but in some cases (15%), the onset occurs simultaneously. In 10% of cases, arthritis precedes psoriasis. In the latter, unrecognized psoriasis may be found. There may also be a history of widespread guttate psoriasis in childhood or a strong family history. be.

[0057] PsA occurs equally frequently in men and women. PsA arthritis typically affects the joints of the fingers and toes. They tend to be distributed in a radial pattern, so that all the same joints of a single finger or toe may be affected. The degree of erythema over the affected joint, the presence of asymmetric spinal involvement, tendon attachment The presence of foot inflammation and lower levels of tenderness are also typical features of PsA. PsA affects up to 40% of Due to the presence of spondylitis in the patient, it belongs to the group of spondyloarthropathy. Extra-articular features observed in PsA are Similar to other spondyloarthropathies, these include mucosal lesions, iritis, urethritis, diarrhea, and ataxia. These include ventricle dilatation and association with HLA-B27.

[0058] First-line treatment has traditionally consisted of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying anti-inflammatory drugs (MODs). Rheumatic drugs (cDMARDs), such as sulfasalazine (SSZ), methotrexate (MTX), and These drugs are limited to those with limited access to biologic agents. With the advent of anti-tumor necrosis factor (anti-TNF) agents more than 10 years ago, This has dramatically increased the armamentarium for the treatment of PsA, resulting in significant improvements in outcomes for both skin and joint disease. Nevertheless, anti-TNF agents are not effective in all patients, in part due to immunogenicity. may not work and may lose response over time. Interleukin-1 receptors that promote inflammation of the skin and joints Drugs with different mechanisms of action that target the IL-23 / IL-17 pathway are now available. Many more are currently being evaluated in clinical trials. These agents include IL-12 / IL-23 inhibitors ustekinumab and tildrakizumab; IL-23 inhibitor guselkumab; IL-17 receptor Receptor A inhibitors, such as secukinumab and ixekizumab, and IL-17 receptor inhibitors, such as brodalumab the IL-17 receptor A / F inhibitor bimekizumab, and the phosphodiesterase E4 inhibitor a These newer agents include primilast. The therapeutic response to these newer agents is characterized by significant plaque clearance. The results of these agents in PsA are most evident in psoriasis, where the tumors are irritated; These results are similar to those reported in previous studies. IL-17 blockade is also effective in axial disease, preventing radiological progression. The oral drug apremilast showed minimal responses in the skin and joints and a safety profile It is not indicated in patients with few signals and radiological lesions or axial lesions.

[0059] Several key cytokines in the IL-23 / IL-17 pathway are members of the Janus kinase (JAK) family. Activated JAK promotes inflammatory signaling in the skin and joints through its receptor-associated TYK. recruits and activates signal transducers and activators of transcription (STATs), which in turn initiate gene transcription. Specific JAK-STAT activation is mediated by IFN and related cytokines, the common γ-chain cytokine. It is dependent on cytokine signaling, including cytokines of the IL-6 type. It has been demonstrated that phospho-STAT3 (pSTAT3) and pSTAT1 expression is increased in psoriatic skin, and IFNγ , IL-6, and IL-22 can induce pSTAT1 or pSTAT3 in keratinocytes. is shown.

[0060] (invention) The present invention provides a compound of the invention for use in the treatment of psoriatic arthritis, wherein the The compounds of the invention are according to Formula I: [ka] .

[0061] In one aspect, a compound of the invention according to any one of the embodiments described herein. exists as the free base.

[0062] In one aspect, a compound of the invention according to any one of the embodiments described herein. is a pharmaceutically acceptable salt. In certain embodiments, the compounds of the present invention are It exists as the maleate salt.

[0063] In one aspect, a compound of the invention according to any one of the embodiments described herein. is a solvate of the compound.

[0064] In one aspect, a compound of the invention according to any one of the embodiments described herein. is a solvate of a pharmaceutically acceptable salt of the compound. A solvate of a pharmaceutically acceptable salt is a [compound according to formula I:HCl:3H2O] adduct.

[0065] It will be understood that compounds of the present invention may be metabolized to produce biologically active metabolites. Active metabolites of compounds according to Formula I are described in WO 2013 / 189771. Alternative Embodiments wherein the compounds of the present invention are metabolites of compounds according to formula I, the metabolites being of formula II It is due to: [ka] .

[0066] In one embodiment, the present invention provides a method for the treatment of one or more rheumatoid arthritis, when administered orally at a daily dose of 100 mg to 250 mg. The present invention provides a method for treating psoriatic arthritis, the method comprising administering the compound of formula (I) in two doses. or a pharmaceutical composition comprising the compound of the present invention. In particular, the dosage is 50 mg twice daily. (bid), 100 mg once daily (qd), 100 mg bid, and 200 mg qd.

[0067] In one embodiment of the above uses and methods, the patient is receiving another treatment for psoriatic arthritis. or not being treated with medications at the same time.

[0068] In another embodiment of the above uses and methods, the patient is receiving methotrexate, refractory one or more conventional antihistamines, such as thiazolinone, ... had an inadequate response to or were not receiving a cDMARD; Intolerance to rheumatic drugs.

[0069] In an alternative embodiment of the above uses and methods, the patient is treated for psoriatic arthritis. another drug for steroid therapy, e.g., cDMARD therapy, e.g., methotrexate (e.g., oral or (e.g., parenteral, up to 25 mg / week), leflunomide (e.g., oral, up to 20 mg / day), sulfasalanobis quinidine (e.g., 3 g orally per day), hydrochloroquine (e.g., up to 400 mg per day), or chloroquine It is often treated with concurrent therapy with benzodiazepines (e.g., up to 250 mg / day).

[0070] In another embodiment of the above uses and methods, the patient is receiving a bDMARD, particularly an anti-TNF drug. Not receiving medical treatment.

[0071] In an alternative embodiment of the above uses and methods, the patient has previously received a bDMARD, in particular In particular, patients may have a history of using bDMARDs, e.g., anti-TNF drugs. had an insufficient or inadequate response to treatment.

[0072] In another embodiment, the compounds of the present invention are useful in treating psoriatic arthritis that exhibits signs and symptoms of enthesitis. In a further embodiment, such a compound is useful for treating patients with PsA. Patients have enthesitis as determined according to the SPARCC Enthesitis Index. In embodiments, such PsA patients are assessed by a Leeds Enthesitis Index (LEI score), e.g., Affected by enthesitis as determined according to an LEI score of greater than 0.5 or greater than 1.0.

[0073] In specific embodiments of the above uses and methods in patients with psoriatic arthritis, AC An R20 response is seen in at least 50% of the patient population after 4 weeks of treatment. In particular, an ACR20 response is seen in at least 55% and at least 60% of the patient population 4 weeks after treatment. CR20 responses are seen after 8 weeks of treatment, 12 weeks of treatment, or 16 weeks of treatment. In particular, ACR20 responses were observed in at least 75%, at least 76%, and At least 77%, at least 78%, at least 79%, at least 80%, at least 81%, At least 82% and at least 83% of cases are seen. In particular, at least 75%, at least 76%, At least 77%, at least 78%, at least 79%, at least 80%, at least 81%, ACR20 responses of at least 82% and at least 83% are seen after 16 weeks of treatment.

[0074] In specific embodiments of the above uses and methods in patients with psoriatic arthritis, AC An R50 response is seen in at least 30% of the patient population after 12 weeks of treatment. In particular, an ACR50 response at least 31%, at least 32%, at least 33%, of the patient population after 16 weeks of treatment At least 34%, at least 35%, at least 36%, at least 37%, at least 38%, At least 39%, at least 40%, at least 41%, at least 42%, at least 43%, It is seen in at least 44%, at least 45%.

[0075] In specific embodiments of the above uses and methods in patients with psoriatic arthritis, AC An ACR70 response is seen in at least 10% of the patient population after 12 weeks of treatment. In particular, an ACR70 response at least 11%, at least 12%, at least 13%, of the patient population after 16 weeks of treatment At least 14%, at least 15%, at least 16%, at least 17%, at least 18%, At least 19%, at least 20%, at least 21%, at least 22%, at least 23%, It is seen in at least 24%, at least 25%.

[0076] In a specific embodiment of the above uses and methods in patients with psoriatic arthritis, LE I scores are at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least At least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7 , or at least 1.8, or at least 1.9. In particular, the LEI score will be reduced by, more specifically: 16 weeks after treatment, 12 weeks after treatment, 8 weeks after treatment, or even more specifically, A decrease of at least 1.5 after 4 weeks of treatment.

[0077] In specific embodiments of the above uses and methods in patients with psoriatic arthritis, The HAQ-DI (regarding the patient's physical function) immediately after treatment with Compound I should be at least 0.35 and at least at least 0.40, at least 0.43, at least 0.44, at least 0.45, at least 0.46, at least 0.47, at least 0.48, at least 0.49, at least 0.50, at least 0.51, at least 0.52, at least 0.53, at least 0.54, at least 0.55, or less In particular, the HAQ-DI score decreased by at least 0.40 points 4 weeks after treatment. In particular, the HAQ-DI score will decrease by at least 0.45 points after 12 weeks of treatment. The HAQ-DI score decreased by at least 0.45 points after 8 weeks of treatment. A reduction of at least 0.50 points 16 weeks after treatment.

[0078] In another embodiment of the above uses and methods in patients with psoriatic arthritis, the compound I was effective in reducing psoriatic skin conditions, also known as psoriasis. Psoriasis is assessed and quantified by the Psoriasis Area and Severity Index (PASI) (see section 1.5.3). In particular, compounds according to Formula I may be administered to PsA patients with psoriasis, e.g., psoriasis affecting at least 3% of their body surface area. is for use in patients covered with psoriasis. In this study, Compound I was used to improve the itchy component of psoriasis.

[0079] In another embodiment of the above uses and methods in patients with psoriatic arthritis, the patient At least 15%, at least 17%, or at least 20% of patients were at least 16 weeks or more post-treatment More specifically, after 12 weeks of treatment, MDA status was achieved. [Example]

[0080] (Example) The compounds of the present invention according to formula I have been extensively profiled and the data are set out in WO 2010 The synthesis of salts and suitable formulations are disclosed in Menet and Smits, 2010, Vol. 149769. , WO2015 / 117980, WO2015 / 117981, and PCT / US2018 / 022027.

[0081] Similarly, compounds of the present invention according to Formula II have been extensively profiled and the data , as disclosed in WO 2013 / 189771 (Van't Klooster et al., 2013).

[0082] Example 1. Clinical Trial - Treatment of Subjects with Moderate to Severe Active Psoriatic Arthritis .Government identification number: NCT03101670)) (a. Purpose of the test) The primary objective of this study was to evaluate the efficacy and safety of EGFR-1000 compared with placebo, as assessed by ACR20 after 16 weeks of treatment. The objective of this study was to evaluate the effect of Compound I on psoriatic arthritis compared with placebo.

[0083] The secondary objectives of this study are: -Compared to placebo: Signs and symptoms of PsA assessed by MDA ACR50 and ACR70 response, DAS28 (CRP), SDAI, CDAI, EULAR, PsARC, by physician and patient Global assessment of disease activity, patient global assessment of PsA pain intensity, 66 / 68-joint count, and C Signs and Symptoms of Peripheral Arthritis Assessed by RP Measurement PASI, PASI50, PASI75, PASI90, and PASI100 (including body surface area [BSA]), physicians and patients Psoriasis assessed by the comprehensive assessment of psoriasis using the mNAPSI, mNAPSI, and pruritus NRS Enthesitis assessed by the SPARCC Enthesitis Index and Leeds Enthesitis Index Dactylitis assessed by LDI Physical function assessed by HAQ-DI Fatigue and overall quality of life assessed by FACIT-Fatigue, SF-36, and PsAID To evaluate the effect of Compound I on -To evaluate the safety and tolerability of Compound I is.

[0084] The exploratory objectives of this study are: -To evaluate the effect of Compound I on spinal cord symptoms assessed by BASDAI -To evaluate the effect of Compound I on all features of PsA as assessed by PASDAS - To characterize the population PK and PD of Compound I and its active metabolite in this population is.

[0085] (1.2. Study Design) This is due to the inadequate response to conventional disease-modifying therapy or the inability to tolerate conventional disease-modifying therapy. A multicenter, phase 2, double-blind study in subjects with moderately to severely active PsA who are intolerant to rituximab This is a blinded, placebo-controlled study. A total of approximately 124 subjects will be randomized to two treatment arms: 200 mg of Compound I qd or matching placebo qd in a 1:1 ratio to the treatment group Randomization of patients was based on current cDMARD use (yes or no) and past anti-TNF medication use (yes or no). stratified by (or none).

[0086] 1.3. Study Population (1.3.1. Sample size) Approximately 124 subjects with moderate to severe PsA will receive 200 mg of Compound I or a matching placebo. Screen a sufficient number of subjects to ensure that they are randomly assigned to .

[0087] (1.3.2. Inclusion criteria) Subjects who meet all of the following criteria are eligible to participate in this study: 1. Male or female subjects who are 18 years of age or older on the day they sign the informed consent form. 2. A diagnosis of PsA for at least 12 weeks prior to screening and a meeting of the classification criteria for psoriatic arthritis (CASP) AR) is currently met. 3. 5 or more swollen joints (out of 66 swollen joint counts [SJCs]) at screening and baseline and 5 or more tender joints (out of 68 tender joint counts [TJC]) (as a single swollen joint and when tender) Active P defined as the number of measurable dactylitis in the fingers and toes (if present, as well as in a single tender joint) Has sA. 4. Have a documented history of or currently active plaque psoriasis. 5. If using cDMARD therapy, subjects are only allowed to use one of the following medications: and that it was administered at a stable dose (including a stable route of administration) for at least 4 weeks prior to baseline. , which must be taken in the 12 weeks prior to screening: - Up to 25 mg / week of oral or parenteral methotrexate (with or without concomitant folic acid or folinic acid supplementation) local standard of care must be adhered to); -Oral leflunomide up to 20 mg / day; -Oral sulfasalazine up to 3 g / day; - Hydroxychloroquine up to 400 mg / day or chloroquine up to 250 mg / day 6. If non-pharmacological treatments (including physical therapy) are used, these must be stable during the screening period. should be maintained at 7. Heterosexual men and women of childbearing potential should use highly effective contraceptive methods. You must agree to use it. 8. Women of childbearing potential must have a negative serum pregnancy test at screening and baseline A urine pregnancy test at the time of administration must be negative. 9. Sign an Informed Consent Form (ICF) approved by an Independent Ethics Committee (IEC). A written agreement must be provided before the screening assessment begins. Subjects must read and understand the ICF and comply with the requirements of the study. You must fully understand the terms and conditions and be willing to attend all study visits and evaluations. It won't happen. (1.3.3. Exclusion criteria) Subjects who meet one or more of the following criteria will not be eligible for the study: 1. Use of any of the following treatments: - Strong opioid analgesics (e.g., methadone, hydromorphone, morphine, or oxalate) Current use of sycodon); Use of alkylating agents, e.g., chlorambucil or cyclophosphamide, at any time for; Use of any investigational or approved JAK inhibitor, including Compound I, at any time; - Multiple TNF inhibitors at any time (TNF inhibitors approved for efficacy in clinical trials) Prior use of TNF inhibitors (including proposed biosimilars with proven equivalence to existing anti-tumor agents). Prior use is permitted with the following minimum washout periods before screening: i. Etanercept: 4 weeks ii. Adalimumab, certolizumab pegol, golimumab: 8 weeks iii. Infliximab: 12 weeks; - At any time, including but not limited to: cell-depleting biological agents (e.g., anti-CD20, CAMPATH, anti-CD4 , anti-CD3), denosumab, anti-IL-6 (e.g., tocilizumab), anti-IL-17 (e.g., secukinumab , ixekizumab, brodalumab), anti-IL-12 / IL-23 (e.g., ustekinumab), anti-IL-23 ( For example, tildrakizumab, guselkumab), rituximab, and other agents listed above. No use of any other investigational or approved biologic immunomodulatory agents; - Any intramuscular or intravenous corticosteroid treatment within 4 weeks prior to screening; ->10 mg / day prednisone or prednisone equivalent at baseline Use of oral steroids at doses that have not been stable for at least the previous 4 weeks; - Any therapy by intra-articular injection (e.g., corticosteroids) within 4 weeks prior to screening ides, hyaluronate); - Use of multiple NSAIDs or cyclooxygenase-2 (COX-2) inhibitors. If harmful substances are used, they must be permitted by local labeling. The maximum dose administered should not be exceeded and the patient must have been on a stable dose for at least 2 weeks prior to baseline. In addition, subjects must be taking ≤325 mg qd for heart disease prevention. It is permitted to take acetylsalicylic acid in amounts; - Received any treatment (e.g., cholestyramine) within 12 weeks prior to baseline or washout leflunomide, if implemented, if discontinued within 4 weeks prior to baseline; Any of the following systemic immunomodulatory therapies within 4 weeks prior to screening, including but not limited to: Not limited to: 6-mercaptopurine, azathioprine, cyclosporine, or other Lucineurin inhibitors (e.g., sirolimus, tacrolimus), dapsone, fumaric acid derivatives , gold therapy, MTX if discontinued, mycophenolate, antimalarial drugs if discontinued steroids (e.g., hydroxychloroquine, chloroquine), SSZ if discontinued, and Remilast, or thioguanine; - Any prohibited drug within the specified minimum washout period prior to baseline, such as Current use of psoriasis treatments / medications: iv. Oral retinoids (including tazarotene) or vitamin D analogues: 4 weeks v. Phototherapy (UVA or UVB) with or without psoralens or sun exposure Self-treatment using a tanning bed: 4 weeks vi. Non-limiting examples include: alpha or beta hydroxy acids, anthralin, corticosteroids (Except for corticosteroids with low efficacy on the face, scalp, axillae and genital areas), >3% Any topical topical antiperspirant containing licylic acid, retinoids including tazarotene, tar preparations, or ureas Oral therapy: 2 weeks; - Any strong P-glycoprotein (P-gp) inducer (e.g., carbamazepine, clotrimazole, Rimazole, cyclosporine, dexamethasone, phenothiazine, phenytoin, retinoin Treatment with benzodiazepines (e.g., rifampin, St. John's wort, and venlafaxine). Potent P-gp inducers require a 3-week washout period before baseline; - Any previously unmentioned event within 4 weeks or 5 half-lives prior to screening, whichever is longer Use of any test drug and / or device 2. Known hypersensitivity to any component of the test drug 3. Synovectomy in 4 or more joints and / or within the last 12 weeks of screening and Have undergone surgical treatment for PsA, including arthroplasty 4. Major surgery (requiring local or general anesthesia) within the last 12 weeks prior to screening Previous or planned surgical procedures during the study period 5. Any systemic musculoskeletal disorder, e.g., systemic osteoarthritis or systemic inflammation other than PsA Disease states, including but not limited to RA, juvenile chronic arthritis, ankylosing spondylitis, reactive arthritis , IBD-related arthropathy, systemic lupus erythematosus, scleroderma, inflammatory myopathy, mixed connective tissue Patients with a diagnosis of uric acid-lowering therapy Well-controlled and with evidence of disease flare in the previous year and current uric acid level <7.0 mg / dL If not, gout is acceptable. 6. Very poor functional status or inability to care for oneself. 7. Active IBD requiring systemic or topical therapy, current presence of peptic ulcer disease, or severe ulcers History of ventriculitis (i.e., requiring hospitalization) or previous gastrointestinal perforation. 8. Serious medical conditions, including but not limited to: uncontrolled hypertension (≥ 16 0 / 95mmHg), congestive heart failure (New York Heart Association Class III or IV status), controlled Diabetes mellitus, cerebrovascular accident, myocardial infarction, unstable angina, unstable arrhythmia, or In the opinion of the study participants, the past 24 hours prior to screening puts the subjects at risk. Any other cardiovascular disease for a week. 9. History of malignant tumor or bone marrow or lymphoproliferative disorder within the past 5 years prior to screening ( 3 cases of adequately treated basal cell carcinoma of the skin or treated in situ cervical carcinoma without evidence of recurrence (excluding those occurring less than once in a lifetime). 10. Previous bone marrow or organ transplant. 11. Untreated or inadequately treated active or is latent TB infection (LTBI): - Positive QuantiFERON-TB Gold test result (Note: If the QuantiFERON-TB Gold test result is negative, If the test is definitive, repeat the process. If the retest is indeterminate or positive, Elephants are ineligible) or - Qualified radiologist with a scan taken within 12 weeks prior to screening or at the time of screening Current active or past inactive TB as determined by a radiologist or pulmonologist An anteroposterior chest radiograph with no evidence of sexually transmitted TB or - Clinically significant illness suggestive of TB within 12 weeks prior to first study drug administration Condition. Subjects receiving appropriate treatment for LTBI or active TB infection were included in the study This treatment must be documented and It is defined as follows: i. Subjects who have previously been treated for TB, i.e., subjects who have previously received an appropriate treatment course for latent TB. 36 weeks of isoniazid or other acceptable regimen, with early multidrug-resistant TB infection rates <5% % of people living in a place where TB is present) or an appropriate course of treatment for active TB (an acceptable multidrug regimen) If you have completed one of the following, you do not need to get the QuantiFERON-TB Gold test. If not done within 12 weeks prior to lean testing or if results are not available at the study site, A peripheral radiograph should be obtained. Subjects with newly identified LTBI, i.e., a newly confirmed positive diagnostic TB test have a positive result (any QuantiFERON-TB Gold test or two separate QuantiFERON-TB Gold tests) Subjects with an indeterminate test result (as defined by the Gold test) and a negative chest radiograph Subjects for whom the possibility of active TB has been ruled out, including those for whom appropriate treatment for LTBI has been initiated, , continued for at least 4 weeks prior to the first study drug dose and ongoing at screening If so, subjects are planned to continue for the duration of the study until completion. , as defined according to United States (US) Centers for Disease Control guidelines. 12. Human immunodeficiency virus (HIV) 1 or 2, Hepatitis B virus (i.e., Hepatitis B virus) Hepatitis B surface antigen [HBsAg] or core antibody [Ab] positive), or hepatitis C virus (HCV) (i.e., H Positive serology (CV Ab positive) or a history of infectious hepatitis from any cause except hepatitis A Past. 13. Invasive or opportunistic infections (e.g., listeriosis, pneumocystis, or histopathological conditions) History of pulmonary thrombocytopenia (PTD) or immunodeficiency syndrome. 14. Clinically significant active infection, or hospitalization or screening, as determined by the investigator. Any infection requiring treatment with intravenous anti-infectives within 30 days prior to screening, or screening Any infection requiring oral anti-infective therapy within 14 days of cleaning. 15. Currently have a chronic infection (e.g., Pneumocystis, cytomegalovirus, herpes simplex, receiving any treatment for herpes zoster, and atypical mycobacteria. 16. History of symptomatic varicella zoster or herpes simplex infection within 12 weeks prior to screening History of disseminated or combined herpes zoster infection (e.g., multiple skin, eye, or CNS lesions) at any time Has. 17. History of disseminated Staphylococcus aureus infection. 18. History of infection of the joint prosthesis with the prosthesis still in place. 19. Administration of live or attenuated vaccines within 12 weeks prior to baseline. 20. History or current drug or alcohol abuse within the past two years in the opinion of the investigator Evidence of drug or alcohol abuse. 21. Where applicable under national or local laws and regulations, those admitted to a facility by administrative or court order This is the history. 22. Pregnant, breastfeeding, or breastfeeding during study enrollment or within 35 days of the last dose of study drug. Or are planning a pregnancy. 23. The investigator's clinical assessment may be incomplete, as this may complicate the risk-benefit assessment. unstable concomitant medical conditions or active fiber that make the subject an inappropriate candidate for the study based on the Any condition involving muscle pain. 24. Any intervention that, in the opinion of the investigator or sponsor, makes it unlikely that the subject will complete the study. or the inability to complete the test or comply with the test procedures and requirements. may result in lower performance or inability to comply with testing procedures and requirements. The state or condition of. - Significant blood loss (>450 mL) or transfusion of any blood product within 12 weeks prior to baseline. - Results of the following laboratory tests performed in a central laboratory at screening meet the following criteria: - hemoglobin <8.5 g / dL (International System of Units [SI]: <85 g / L); -White blood cells <3.0×103 cells / mm3 (SI:<3.0×109 cells / L); - Neutrophils <1.5×103 cells / mm3 (SI:<1.5×109 cells / L); - lymphocytes <0.5 × 103 cells / mm3 (SI: <0.5 × 109 cells / L); - Platelets <100×103 cells / mm3 (SI:<100×109 cells / L); -Alanine aminotransferase (ALT) or aspartate aminotransferase ze (AST) ≥ 1.5 × ULN; - Total biliary tract infections unless the subject has been diagnosed with Gilbert's disease and this is clearly documented Lirubin level ≥ 2 × ULN; Creatinine clearance <40 mL / min by Cockcroft-Gault formula Satisfy one of the following.

[0088] (1.4. Effectiveness Evaluation) Unless otherwise specified, symptoms of PsA and peripheral arthritis, psoriasis, enthesitis, dactylitis, and spondylitis Efficacy assessments to estimate signs and symptoms, and physical function were performed at baseline (Day 1) and and Weeks 1, 2, 4, 8, 12, and 16, or at the Early Discontinuation Visit (EDV), if applicable. ACR Individual components of the response criteria are obtained at screening and throughout the study.

[0089] Additionally, at baseline (Day 1) and Weeks 4 and 16 (or at EDV, if applicable), The subjects were the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue) questionnaire and a 36-item simple health questionnaire. Patients will be asked to complete the SF-36 survey and the Psoriatic Arthritis Disease Impact (PsAID) questionnaire. .

[0090] (1.4.1. High-sensitivity serum C-reactive protein) Subjects' serum CRP will be measured using the hsCRP test at the time points indicated in the study flow chart. Post-baseline CRP results will be kept confidential by the investigator and trial participants until database lock. The study will be blinded to the participants.

[0091] (1.4.2. 66 / 68-number of joints) At the time points described in the protocol, each of the 66 joints was evaluated for swelling (SJC66). Each of the eight joints is assessed for tenderness (TJC68).

[0092] To perform all joint assessments, a qualified medical professional with appropriate training and experience in performing joint assessments must be present. A joint assessor will be designated at each trial site. This joint assessor will preferably be a rheumatologist. in the absence of a rheumatologist, this assessor is less knowledgeable in performing the joint assessment. This assessor should be a healthcare professional with at least one year of experience. This should remain the same for each elephant throughout the study. In the absence of a designated joint assessor , the designated joint assessor must identify an appropriate supporting assessor to provide compensation.

[0093] 68 Tender joint counts were based on the presence or absence of tenderness assessed by pressure and joint manipulation on physical examination. This should be done by scoring the simulation.

[0094] Synovial fluid and / or soft tissue swelling represented a positive result for the number of swollen joints assessed in 66 joints. Bone overgrowth does not represent it.

[0095] (1.4.3. Physician's Global Assessment of Disease Activity) A comprehensive assessment of the subject's arthritis disease activity will be performed by a physician with access to joint evaluation. (Section 1.4.2). A vertical line is drawn with a ruler on the visual assessment scale (VAS), measuring 10-cm in mm. Anchor and mark of "No disease activity" on the m line (the end indicates "Extreme disease activity"). The distance between them is a score from 0 to 100.

[0096] (1.4.4. Evaluation of Enthesitis) Enthesitis is assessed using the SPARCC Enthesitis Index. 16 body sites are assessed by palpation. The entire tendon attachment is assessed for tenderness and scored as 0 (not tender) or 1 (tender). The site inflammation score is the sum of all site scores, up to a maximum of 16. The higher the score, the more severe the pain. The burden of enthesitis is great.

[0097] When assessing the SPARCC enthesitis index, the 16 components used to assess enthesitis are: In addition to the position, the medial femoral condyles (left and right) were examined to allow for the assessment of the Leeds Enthesitis Index (LEI). will be assessed and evaluated in the same way as the other 16 sites.

[0098] (1.4.5. Evaluation of Dactylitis) Dactylitis was assessed by assessing the size and tenderness of all fingers and toes using the LDI. LDI is measured using a Leeds ductilometer to measure the circumference of the affected finger and toe and the circumference of the contralateral hand or foot. The ratio of the circumferences of the two digits is measured. A dactylitis digit is defined by a minimum difference of 10%. If the fingers and toes are also affected, a table of normative values ​​based on population means can be used to provide a comparison. The circumference ratio is used to calculate the two-component tenderness score (0 for no tenderness, 1 for tenderness). The results from each digit with dactylitis are then summed to arrive at a final score. vinegar.

[0099] (1.4.6. Psoriasis Area and Severity Index (PASI) Score Including Body Surface Area (BSA)) The PASI score is used to measure the severity and extent of psoriasis. A section is selected for each body region (head, arms, trunk, and legs). and the intensity of desquamation was rated as none (0), mild (1), moderate (2), severe (3), or very severe (4). will be done.

[0100] Numerical scores ranging from 0 to 100% represent the percentage of psoriasis-associated symptoms as assessed by the investigator. It is used to measure the proportion of total BSA in a subject that is

[0101] (1.4.7. Physician's comprehensive assessment of psoriasis) A physician's global assessment of psoriasis is used to determine a subject's overall psoriatic lesions at a given time point. The subject's psoriasis disease activity is measured on a 6-point scale ranging from 0 (resolved) to 5 (severe). The patient is assessed by a physician using the MRI scan (see 1.5.1 below).

[0102] 1.4.8. Modified Nail Psoriasis Area and Severity Index (mNAPSI) The mNAPSI assesses the severity of nail matrix psoriasis and nail bed psoriasis (Cassell S. et al., "Modified The improved nail psoriasis severity index: a tool to assess psoriatic nail lesions in patients with psoriatic arthritis The modified Nail Psoriasis Severity Index: validation of an instrument to assess psoriatic nail involvement in patients with psoriatic arthritis.) J Rheumatol., pp. 34(1):123-9, 2007). Nail matrix psoriasis is characterized by pitting, leukocytes, and nail plaques. The nail bed is characterized by crescentic red spots and destruction of the nail plate. These include oily pigmentation, onycholysis, nail bed hyperkeratosis, and splinter hemorrhages.

[0103] Each of the subject's nails will be evaluated for any of the characteristics of nail matrix and nail bed psoriasis, taking into account the following abnormalities and rules: It is evaluated for the presence of any of:

[0104] The following abnormalities are graded on a scale of 0 to 3: -Onycholysis and oily drop (salmon patch) pigmentation disorder (considered together) - Nail depression - Nail plate collapse.

[0105] The following four abnormalities are scored solely by their presence: a score of 1 indicates presence; A score of 0 indicates absence: -Nail plate vitiligo -Red spots on the nails -Nail bed hyperkeratosis -Striate hemorrhage.

[0106] Each toe has a score of 0 to 14, with the total mNAPSI score ranging from 0 to 140.

[0107] 1.4.9. Patient Global Assessment of Disease Activity Subjects' global assessment of their arthritis disease activity is recorded on a 0-100 mm VAS. , on the VAS, drawn using a ruler, the distance between the start of this line and the mark on the 10-cm line in mm is , a score from 0 to 100. "Consider all the ways that psoriatic arthritis affects you." For the question, "How are you feeling today?", a score of 0 indicates "very good." and 100 indicates "very poor."

[0108] 1.4.10. Patient Global Assessment of Psoriasis Patients' global assessment of their psoriasis ranged from "clear" (0 points - no psoriasis) to "severe" (4 points). Using a five-category scale, the overall severity of psoriasis-related skin disease at a specific point in time was assessed. It is a single-item patient-administered assessment used to assess the degree of

[0109] 1.4.11. Patient Assessment of PsA Pain Intensity Patient pain assessment was done on the scale "The worst pain you experienced today due to your psoriatic arthritis." After the question, "Please show the vertical symbol ( | ) between the two ends of the horizontal line," This is done using a 0-100 mm VAS, which ranges from "no pain" to "unbearable pain." The length of the line to the mark is recorded. This assessment should be completed before the joint examination. The pain scores are also used to obtain the ACR20 / 50 / 70.

[0110] (1.4.12. Health Assessment Questionnaire-Disability Index (HAQ-DI)) The HAQ-DI is used to monitor a subject's self-assessed physical function or disability. The 20 questionnaires are designed to assess a person's ability to function in eight areas: dressing, standing, eating, walking, and sleeping. The degree of difficulty a person has in completing tasks in areas such as: mobility, hygiene, reach, grip strength, and housework and chores. Responses are rated on a scale from 0, indicating no difficulty, to 1, indicating an inability to perform the task in that area. It is scored on a 4-point Likert scale with a maximum of 3. The need for medical attention is also recorded. The total score for the HAQ-DI ranges from 0 to 3, with higher scores indicating , indicating greater dysfunction.

[0111] (1.4.13.Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)) Patient-reported disease activity of interest is assessed using the BASDAI (Sieper J. et al. The International Society for the Assessment of Spondyloarthritis (ASAS) Handbook: Guidelines for assessing spondyloarthritis Needles (The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis.), Ann Rheum Dis., pp. 68 Suppl 2:ii1-44, 20 09). This is a six-item index (fatigue, spinal pain, peripheral arthritis) scored on a 0-10 NRS. The total score ranges from 0 to 10. A score of 4 or higher suggests suboptimal disease management.

[0112] (1.4.14. Pruritus Numerical Rating Scale (Pruritus NRS)) Subjects completed a visual rating scale with numbered intervals (whole numbers) at each study visit. Subjects are asked to complete an assessment of their itch using the itch-related questionnaire. The intensity of pruritus is assessed based on a 24-hour retrospective period of the most severe attack. Patients are asked to rate their itching on a scale of 0 (no itching) to 10 (worst itching imaginable).

[0113] (1.4.15. Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue)) The FACIT-Fatigue Scale (Version 4) measures an individual's fatigue during their usual daily activities over the past week. This measures the level of fatigue in a person, with 0 indicating "not tired at all" and 4 indicating "very tired." It consists of 13 questions with a 7-day retrospective period on a 5-point Likert scale indicating "I have a feeling that I am Scores range from 0 to 52. The higher the score, the better the quality of life. .

[0114] (1.4.16. 36-item Short-Form Health Survey (SF-36)) The subjects' health-related quality of life was assessed using the SF-36 (version 2, SF-36v2) with a 1-week retrospective period. It is assessed using the Health Survey (registered trademark), which covers eight areas in two components: It consists of 36 questions: -Physical well-being: 4 domains: physical function (10 items), daily role function (4 items), physical pain (2 items), and and general health (5 items). -Mental well-being: 4 domains: vitality (4 items), social functioning (2 items), mental role functioning (3 items) eyes), and mental health (5 items).

[0115] The remaining items (health transitions) are not part of the above domains and are kept separate.

[0116] These scores are scaled from 0 to 100 (0 being the lowest possible score, The highest possible score is converted to 100), with higher scores representing better quality of life. Show quality.

[0117] (1.4.17. Psoriatic Arthritis Disease Impact Questionnaire (PsAID)) The PsAID questionnaire assesses the impact of PsA on a person's life. The experimental EULAR PsAID questionnaire, PsAID9, is used. Each item is scored from 0 to 10. All items are rated according to the importance of the health domain they represent. The weight of each area is taken into account in the total PsAID score. A higher score indicates a greater impact of the disease. A score of less than 4 out of 10 is considered an acceptable situation for the patient. A change of 3 or more points indicates a relevant absolute This is considered a fundamental change.

[0118] (1.5. Efficacy Analysis) (1.5.1. ACR20 / 50 / 70) Signs and symptoms of peripheral arthritis are measured using ACR20 / 50 / 70. ACR response is measured in patients with multiple diseases. It is a measure of improvement in patient assessment criteria.

[0119] Positive ACR20 responses were observed in both baseline swollen joint counts (SJC66) and tender joint counts (TJC68). At least 20% improvement from the previous model, based on the following five criteria: -Patient Global Assessment of Disease Activity (0-100mm VAS) -Physician's global assessment of disease activity (0-100mm VAS) -Patient's global assessment of PsA pain intensity (0-100mm VAS) -Patient-assessed physical function measured by HAQ-DI -CRP in mg / dL or mg / L defined as at least a 20% improvement in three or more of the following:

[0120] Positive ACR50 and ACR70 responses are derived from the definition of ACR20, but require a response of at least 50 % and 70% improvements are required.

[0121] At week 16, statistically significant differences were observed in ACR20, ACR50, and ACR70 scores for Compound I versus placebo. ACR20 and ACR50 showed statistically significant differences from placebo from the first week. Reach. Table 1-ACR20 [Table 1] Table 2-ACR50 [Table 2] Table 3-ACR70 [Table 3]

[0122] Significant differences between anti-TNF drug-naive and previously anti-TNF treated patients is not observed.

[0123] (1.5.2. Minimal disease activity (MDA)) Disease activity in PsA is measured using the MDA, a measure used to indicate disease remission. The MDA is based on a composite score of seven domains. If five of the seven following criteria are met, A patient is classified as having achieved MDA if: -TJC68≦1 -SJC66≦1 -PASI≦1 or BSA≦3% - Patient global assessment of PsA pain intensity score ≤ 15 (0-100mm VAS) - Patient Global Assessment of Disease Activity ≤ 20 (0-100mm VAS) -HAQ-DI≦0.5 -SPARCC Enthesitis Index ≤1 Table 4-MDA [Table 4]

[0124] Significant differences between anti-TNF drug-naive and previously anti-TNF treated patients is not observed.

[0125] (1.5.3. Psoriasis (PASI)) The four disease areas, head (h), upper limbs (u), trunk (t), and lower limbs (l), are each graded on a scale of 0 to 4. The symptoms were graded on a severity scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe). By using three parameters, erythema (E), induration (I), and desquamation (D), The area-wise failure rate is: 1 = less than 10% Area of ​​fullness: 2 = 10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70-89%; and 6 = over 90%. The final formula for the PASI score is:

[0126] PASI=0.1×(Eh+Ih+Dh)×Ah+0.2×(Eu+Iu+Du)×Au+0.3×(Et+It+Dt)×At+0.4× (El+Il+Dl)×Al

[0127] The total PASI score ranges from 0 (no disease) to 72 (maximal disease), but if BSA is <3%, Therefore, the PASI is not considered reliable if the BSA level is ≥ 3% at baseline. Only the subpopulation of subjects with psoriasis was analyzed.

[0128] The following PASI parameters can be derived: - Change in PASI from baseline -50% improvement in PASI (PASI50) -75% improvement in PASI (PASI75) -90% improvement in PASI (PASI90) - 100% improvement in PASI or complete resolution of all disease (PASI100) Table 5-PASI [Table 5] Table 6-PASI75 [Table 6]

[0129] Significant differences between anti-TNF drug-naive and previously anti-TNF treated patients is not observed.

[0130] (1.5.4. Enthesitis) Enthesitis was assessed using the SPARCC Enthesitis Index and the Leeds Enthesitis Index (LEI). Enthesitis parameters were assessed in a subgroup of subjects with enthesitis (LEI>0) at baseline. Only the population was analyzed. The analysis focused on change from baseline.

[0131] Compound I improved enthesitis compared to placebo. For example, among 85 (65%) patients with enthesitis at baseline, baseline at 16 weeks The mean change from placebo was greater with filgotinib compared with placebo (LS mean The resolution of enthesitis was not significantly different between the two groups. (treatment difference 12% [-6.5 to 31.0], p=0.1583).

[0132] When assessed according to the LEI, 76 (58%) patients had enthesitis at baseline. Treatment effects are reported in Table 7. Enthesitis occurred in 10 patients who received placebo. More patients receiving filgotinib than those receiving filgotinib resolved their morbidity and mortality (treatment difference 26% [95% CI 4.0 to 45.1]). ], p=0.0059). Table 7 - LEI score (change from baseline) [Table 7]

[0133] Significant differences between anti-TNF drug-naive and previously anti-TNF treated patients is not observed.

[0134] (1.5.5. Physical Function (HAQ-DI)) The HAQ-DI is scored on a scale of 0 to 3, and change from baseline is reported. A reduction of at least 0.22 points compared to baseline was considered clinically meaningful. will be done. HAQ-DI [Table 8]

[0135] Significant differences between anti-TNF drug-naive and previously anti-TNF treated patients is not observed. The present application provides the following aspects of the invention. (Aspect 1) A compound according to formula I, or or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt of a solvate thereof, or an active ingredient thereof Sex metabolites: (chemical 1) TIFF2025183397000015.tif58170 (wherein the compound is administered at a daily dose of 100-200 mg). (Aspect 2) 2. The compound for use according to embodiment 1, wherein the compound is administered once (qd) or twice (bid) per day. Compound. (Aspect 3) the compound is administered for a period of at least 1, 2, 3, 4, 6, 8, 10, 12, or 16 weeks; 3. A compound for use according to embodiment 1 or 2. (Aspect 4) The treatment is characterized by an ACR20 of at least 70%, at least 75%, or at least 80%. A compound for use according to embodiment 1, 2 or 3, which induces a therapeutic effect as characterized. (Aspect 5) The treatment is at least 40%, at least 41%, at least 42%, at least 43%, Induce a therapeutic response characterized by an ACR50 of at least 44%, at least 45%, 4. A compound for use as described in claim 1, 2 or 3. (Aspect 6) Aspects 1-5, wherein the patient diagnosed with psoriatic arthritis exhibits clinical signs and symptoms of enthesitis. The compound for use according to any one of the preceding claims. (Aspect 7) The patient diagnosed with psoriatic arthritis has a score greater than 0, greater than 0.5, or greater than 1.0. 7. The method of claim 1, wherein the patient has a Leeds Enthesitis Index (LEI) score of A compound used for (Aspect 8) The treatment has a saturation of at least 0.8, at least 0.9, at least 1.0, at least 1.1, At least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1 Treatment characterized by a decrease in LEI score of at least 0.7, at least 1.8, or at least 1.9 8. The compound for use according to embodiment 6 or 7, which induces an effect. (Aspect 9) The treatment has a β-glucan concentration of at least 0.35, at least 0.40, at least 0.43, at least 0.50, at least 0.52, at least 0.56, at least 0.58, at least 0.59, at least 0.60, at least 0.61, at least 0.62, at least 0.63, at least 0.64, at least 0.65, at least at least 0.44, at least 0.45, at least 0.46, at least 0.47, at least 0.48, at least at least 0.49, at least 0.50, at least 0.51, at least 0.52, at least 0.53, at least These were characterized by a decrease in HAQ-DI score of at least 0.54, at least 0.55, or at least 0.57. 9. The compound for use according to any one of embodiments 1 to 8, which induces a therapeutic effect in a patient suffering from atopic dermatitis. (Aspect 10) 9. The compound for use according to embodiment 4, 5, or 8, wherein the therapeutic effect is observed at week 12 of the treatment. Compound. (Aspect 11) 9. The compound for use according to embodiment 4, 5, or 8, wherein the therapeutic effect is observed at 16 weeks of the treatment. Compound. (Aspect 12) Any of embodiments 1 to 6, wherein the patient diagnosed with psoriatic arthritis exhibits greater than 3% BSA psoriasis. A compound for use as described in claim 1. (Aspect 13) The patient is not receiving any additional treatment for psoriatic arthritis at the same time, or the patient is not receiving any anti-inflammatory drug. 12. The compound for use according to any one of embodiments 1 to 11, without concomitant TNF treatment. (Aspect 14) 12. The use according to any one of embodiments 1 to 11, wherein said patient has never received an anti-TNF treatment. Compound for. (Aspect 15) Any one of aspects 1-11, wherein the patient had an inadequate response to prior anti-TNF therapy. Compounds for the described uses.

Claims

1. A compound according to formula I, or a pharmaceutically acceptable salt thereof, or a solvate or solvent thereof PHARMACEUTICAL COMPOSITIONS FOR USE IN THE TREATMENT OF PATIENTS DIAGNOSED WITH PSORIATICA ARTHRITIS, COMPRISING SALT OF A PHARMACEUTICAL COMPOSITION ... The object is: 【Chemistry 1】 The compound was administered at a daily dose of 200 mg, and the patient suffered from enthesitis. The pharmaceutical composition.

2. The compound is administered once daily (qd) or twice daily (bid). The pharmaceutical composition according to claim 1.

3. 10. The method of claim 1, wherein the compound is administered at a dose of 200 mg once daily (qd).

2. A pharmaceutical composition according to claim 2.

4. The compound is administered for a period of at least 1, 2, 3, 4, 6, 8, 10, 12, or 16 weeks. The pharmaceutical composition according to any one of claims 1 to 3, which is used as follows:

5. The treatment is characterized by an ACR20 of at least 70%, at least 75%, or at least 80%.

5. The pharmaceutical composition according to any one of claims 1 to 4, which induces a therapeutic effect as characterized.

6. The treatment is at least 40%, at least 41%, at least 42%, at least 43%, induce a therapeutic response characterized by an ACR50 of at least 44%, or at least 45% The pharmaceutical composition according to any one of claims 1 to 4.

7. The patient has a Leeds Enthesitis Index (LE) greater than 0, greater than 0.5, or greater than 1.

0. The pharmaceutical composition according to any one of claims 1 to 6, having a score of I).

8. The treatment has a saturation of at least 0.8, at least 0.9, at least 1.0, at least 1.1, At least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1 Treatment characterized by a decrease in LEI score of 0.7, at least 1.8, or at least 1.9 The pharmaceutical composition of claim 7, which induces an effect.

9. The treatment has a β-glucan concentration of at least 0.35, at least 0.40, at least 0.43, at least at least 0.44, at least 0.45, at least 0.46, at least 0.47, at least 0.48, at least at least 0.49, at least 0.50, at least 0.51, at least 0.52, at least 0.53, at least These were characterized by a decrease in HAQ-DI score of at least 0.54, at least 0.55, or at least 0.

57. The pharmaceutical composition according to any one of claims 1 to 8, which induces a therapeutic effect.

10. 9. The pharmaceutical composition of claim 5, 6, or 8, wherein the therapeutic effect is observed at week 12 of the treatment. 。

11. 9. The pharmaceutical composition of claim 5, 6, or 8, wherein the therapeutic effect is observed at 16 weeks of the treatment. 。

12. The pharmaceutical composition of any one of claims 1 to 6, wherein the patient exhibits BSA psoriasis of more than 3%. 。

13. The patient is not receiving any additional treatment for psoriatic arthritis at the same time, or the patient is not receiving any The pharmaceutical composition of any one of claims 1 to 12, wherein the patient is not receiving concomitant anti-TNF therapy.

14. The method of any one of claims 1 to 12, wherein the patient has never received an anti-TNF treatment. Pharmaceutical compositions.

15. Any of claims 1 to 12, wherein the patient has had an inadequate response to prior anti-TNF treatment. The pharmaceutical composition according to claim 1.

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