PREVENTING OR TREATMENT OF SJÖGREN'S SYNDROME

Abstract

A method for preventing or treating Sjögren's syndrome. The method comprises administering to a subject in need an effective amount of N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

Description

Prevention or treatment of Sjögren's syndrome

[0001] Citation of Related Applications

[0002] This disclosure claims all rights and interests in the Chinese invention patent application with application number 202311516190.8, filed with the State Intellectual Property Office of the People's Republic of China on November 14, 2023, and entitled "Treatment of Sjögren's Syndrome", and incorporates its entire contents into this disclosure by reference.

[0003] field

[0004] The present disclosure relates generally to the field of medicine, and more particularly, to the prevention or treatment of Sjögren's syndrome.

[0005] background

[0006] Sjögren's syndrome ( Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocyte proliferation and progressive exocrine gland damage. It is characterized by lymphocytic infiltration of multiple exocrine glands and epithelial cells, as well as the presence of serum autoantibodies, including anti-Sjögren's syndrome antigens. It primarily attacks the lacrimal and salivary glands, causing dry eyes and dry mouth. Sjögren's syndrome can also affect numerous extraglandular organs and systems.

[0007] The exact etiology and pathogenesis of Sjögren's syndrome remain unclear. Currently, it is generally believed to be an immune dysfunction caused by multiple factors, including genetics, viral infection, and sex hormone abnormalities. Clinical manifestations range from impaired salivary and lacrimal gland secretion to multi-organ and multi-system involvement, systemic symptoms, and even lymphoma complications. There is no satisfactory treatment for Sjögren's syndrome. Whether it is dryness, fatigue, pain, or organ damage, there is a lack of effective, evidence-based medications, and most clinical treatments are empirical.

[0008] Patients with Sjögren's syndrome often have weakened or disrupted immune function, increasing their risk of infection. Long-term use of existing Sjögren's syndrome treatments can further weaken their immune system, further increasing their risk of infection. Mycobacterium tuberculosis is a common pathogen during treatment. Approximately one-third of the global population is infected with M. tuberculosis, and 90% of infected individuals can harbor the bacteria for a long time, becoming latent tuberculosis patients. Latent tuberculosis, a breeding ground for active tuberculosis, presents a highly uncertain outcome for patients with latent tuberculosis, making it a hidden minefield in tuberculosis control. The weakened immune system in patients with latent tuberculosis can easily lead to the progression of latent tuberculosis to active tuberculosis. Focusing on the special patient population of latent tuberculosis during treatment, providing appropriate treatment options for patients with Sjögren's syndrome and those with latent tuberculosis infection or a history of tuberculosis, improving efficacy, reducing adverse reactions, and the potential risk of progression to active tuberculosis, and ultimately achieving greater benefits for patients, is of far-reaching significance and impact.

[0009] Overview

[0010] In one aspect, the present disclosure relates to a method for preventing or treating Sjögren's syndrome, comprising administering to an individual in need thereof a preventive or therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0011] In another aspect, the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in preventing or treating Sjögren's syndrome in an individual.

[0012] In another aspect, the present disclosure relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating Sjögren's syndrome in an individual.

[0013] In another aspect, the present disclosure relates to a pharmaceutical composition for preventing or treating Sjögren's syndrome in an individual, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0014] Details

[0015] In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can still be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0016] Unless otherwise required in this application, throughout the specification and the appended claims, the words "including," "comprising," "containing," and "having" should be interpreted in an open, inclusive sense, that is, "including but not limited to."

[0017] As used in this disclosure and the appended claims, singular references without indications of quantity include plural references unless the context clearly dictates otherwise.

[0018] Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that at least one embodiment includes the specific referenced elements, structures, or features described in connection with that embodiment. Thus, appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0019] It should be understood that the singular articles "a," "an," and "the" as used in the specification and appended claims of this disclosure include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a pharmaceutical composition comprising "an excipient" includes pharmaceutical compositions of one excipient or pharmaceutical compositions of two or more excipients.

[0020] definition

[0021] Accordingly, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0022] In this disclosure, the term "Sjögren's syndrome ( Sjögren's syndrome (SS) refers to an autoimmune disease that causes glands to produce less water than normal. Sjögren's syndrome causes chronic (long-term) dryness throughout the body, especially the eyes and mouth.

[0023] In the present disclosure, there are two commonly used classification methods for classifying adverse events occurring in clinical trials. One is to classify adverse reactions into mild, moderate and severe categories. Mild means that they are usually transient and generally do not affect the subject's daily life activities and may only require minimal treatment. Moderate means that the subject feels uncomfortable and his daily life activities are affected, usually requiring treatment to relieve, but there is no risk of major or permanent harm to the subject. Severe means that it has a significant impact on the subject's daily life, or seriously affects the clinical condition, and requires intensive treatment and intervention. Another classification method is to refer to the Common Terminology Criteria for Adverse Events (CTCAE) and grade them from 1 to 5. Grade 1, mild, no clinical symptoms or mild clinical symptoms; only clinical or diagnostic findings; no treatment required. Grade 2, moderate, requiring minor, local or non-invasive treatment; age-appropriate instrumental activities of daily living (ADL) are limited, instrumental activities of daily living refer to cooking, buying clothes, using the phone, managing finances, etc. Instrumental activities of daily living include cooking, shopping for clothes, using the phone, and managing finances; self-care activities of daily living include bathing, dressing and undressing, eating, washing, and taking medications, without being bedridden. Grade 3: Severe or medically significant but not immediately life-threatening; resulting in hospitalization or prolonged hospitalization; disability; or limitation of self-care activities of daily living. Self-care activities of daily living include bathing, dressing and undressing, eating, washing, and taking medications, without being bedridden. Grade 4: Life-threatening, requiring urgent medical attention. Grade 5: Death related to the adverse event.

[0024] In the present disclosure, the term "HADS" refers to the Hospital Anxiety and Depression Scale, which is used to screen anxiety and depression in patients in general hospitals. The questionnaire is simple, concise and practical, and has been widely studied in general medical settings. The questionnaire contains 7 questions related to anxiety (A) and 7 questions related to depression (D). The answers to all questions are based on a 4-point system (0 to 3 points). The total score for anxiety or depression is the sum of the scores of each answer to the anxiety- or depression-related questions, and the score range is 0 to 21 points, where 0 to 7 points indicate no anxiety or depression, 8 to 10 points indicate mild anxiety or depression, 11 to 14 points indicate moderate anxiety or depression, and 15 to 21 points indicate severe anxiety or depression.

[0025] As used herein, the term "latent tuberculosis infection (LTBI)" refers to infection with Mycobacterium tuberculosis without clinical tuberculosis, clinical symptoms, or bacteriological or radiological evidence of active tuberculosis. The diagnostic criteria for latent tuberculosis are a positive T-lymphocyte spot test (T-SPOT) for Mycobacterium tuberculosis infection and the absence of clinical manifestations of active tuberculosis.

[0026] In the present disclosure, the term "activation" refers to the transformation of the patient's Mycobacterium tuberculosis infection status from latent tuberculosis infection to active tuberculosis infection, that is, the patient's Mycobacterium tuberculosis infection status turns to the active stage, the patient is in an active tuberculosis state, and requires active and standardized treatment.

[0027] In this disclosure, the term "FCA" refers to Freund's complete adjuvant.

[0028] In the present disclosure, the term "compound of formula (I)" refers to N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, the structural formula of which is shown below:

[0029] In the present disclosure, the term "compound of formula (I) and its stereoisomers" refers to (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, the structural formula of which is shown below:

[0030] In this disclosure, the term "pharmaceutically acceptable" refers to carriers, vehicles, diluents, excipients and / or salts that must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0031] In the present disclosure, the term "pharmaceutically acceptable carrier, diluent or excipient" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.

[0032] In this disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

[0033] In the present disclosure, the term "pharmaceutically acceptable salt" includes "acceptable acid addition salts" and "acceptable base addition salts".

[0034] In this disclosure, the term "acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are biologically or otherwise suitable and are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0035] In this disclosure, the term "acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acids, and the base addition salts are biologically or otherwise suitable. These salts are prepared by adding inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0036] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans, etc. In certain embodiments, the mammal includes humans.

[0037] In the present disclosure, the term "pharmaceutical composition" refers to a formulation of a compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof described in the present disclosure and a medium generally accepted in the art for delivering the bioactive compound to mammals such as humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0038] In the present disclosure, the term "therapeutically effective amount" refers to an amount of a compound or combination of compounds that improves, reduces, or eliminates a particular disease or condition and the symptoms of a particular disease or condition, or that prevents or delays the onset of a particular disease or condition or the symptoms of a particular disease or condition. The amount of the compound of formula (I) and its stereoisomers described in the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age, weight, etc. of the mammal to be treated, but the amount of the compound described in the present disclosure can be determined routinely by those skilled in the art based on their own knowledge and this disclosure.

[0039] As used herein, "prophylactic treatment" or "prevention" encompasses preventing a disease or disease state from occurring in a mammal (e.g., a human), especially when the mammal (e.g., a human) is susceptible to the disease state but has not yet been diagnosed with the disease state.

[0040] As used herein, "treating" or "treatment" encompasses treating a relevant disease or condition in a mammal, such as a human, suffering from the relevant disease or condition, and includes:

[0041] (i) inhibit the disease or disease state, i.e. prevent its occurrence; or

[0042] (ii) alleviate the disease or condition, i.e., relieve the disease or condition, i.e., reduce or prevent the disease or condition from progressing. In this disclosure, the term "unit dose" refers to a dose that is taken for a single dose. For example, for a tablet, a unit dose refers to the dose of one tablet of the drug. DETAILED DESCRIPTION

[0043] In one aspect, the present disclosure relates to a method for preventing or treating Sjögren's syndrome, comprising administering to an individual in need thereof a preventive or therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0044] In certain embodiments, the subject is administered 30 mg to 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0045] In certain embodiments, the subject is administered 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0046] In certain embodiments, the subject is administered 60 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0047] In certain embodiments, the subject is administered 30 mg, 60 mg, 120 mg, 150 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0048] In certain embodiments, the subject is administered 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0049] In certain embodiments, the subject is administered 120 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0050] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least once daily.

[0051] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily.

[0052] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0053] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject three times daily.

[0054] In certain embodiments, the subject is administered 30 mg to 75 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0055] In certain embodiments, the subject is administered 30 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0056] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 2.5 mg to 150 mg.

[0057] In certain embodiments, illustrative examples of unit doses of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and 150 mg.

[0058] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 150 mg.

[0059] In certain embodiments, the unit dosage of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, 150 mg.

[0060] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject in the form of a tablet or capsule.

[0061] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0062] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0063] In certain embodiments, illustrative examples of mammals that can be used with the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0064] In certain embodiments, the subject is a human.

[0065] In certain embodiments, the individual has latent tuberculosis infection.

[0066] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0067] In certain embodiments, the Sjögren's syndrome of the present disclosure is primary Sjögren's syndrome.

[0068] In certain embodiments, the Sjögren's syndrome of the present disclosure is secondary Sjögren's syndrome.

[0069] In another aspect, the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in preventing or treating Sjögren's syndrome in an individual.

[0070] In certain embodiments, the subject is administered 30 mg to 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0071] In certain embodiments, a subject is administered 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, or 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0072] In certain embodiments, the subject is administered 60 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0073] In certain embodiments, the subject is administered 30 mg, 60 mg, 120 mg, or 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0074] In certain embodiments, the subject is administered 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0075] In certain embodiments, the subject is administered 120 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0076] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least once daily.

[0077] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily.

[0078] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0079] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject three times daily.

[0080] In certain embodiments, the subject is administered 30 mg to 75 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0081] In certain embodiments, the subject is administered 30 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0082] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 2.5 mg to 150 mg.

[0083] In certain embodiments, illustrative examples of unit doses of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and 150 mg.

[0084] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 150 mg.

[0085] In certain embodiments, illustrative examples of unit dosages of compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, and 150 mg.

[0086] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject in the form of a tablet or capsule.

[0087] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0088] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0089] In certain embodiments, illustrative examples of mammals that can be used with the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0090] In certain embodiments, the subject is a human.

[0091] In certain embodiments, the individual has latent tuberculosis infection.

[0092] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0093] In certain embodiments, the Sjögren's syndrome of the present disclosure is primary Sjögren's syndrome.

[0094] In certain embodiments, the Sjögren's syndrome of the present disclosure is secondary Sjögren's syndrome.

[0095] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are used to prevent or treat Sjögren's syndrome in individuals with latent tuberculosis infection that has not been reactivated after treatment.

[0096] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are used to prevent or treat Sjögren's syndrome in individuals with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy that has not been reactivated after treatment.

[0097] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof, does not require titration for the prevention or treatment of Sjögren's syndrome.

[0098] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein can alleviate dry mouth in a subject during the prevention or treatment of Sjögren's syndrome.

[0099] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein alleviate dry eye in a subject during the prevention or treatment of Sjögren's syndrome.

[0100] In certain embodiments, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof disclosed herein improves the pathology of minor salivary gland tissue in an individual in the prevention or treatment of Sjögren's syndrome.

[0101] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein does not cause anxiety or aggravate anxiety in a subject in the prevention or treatment of Sjögren's syndrome.

[0102] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein does not cause depression or aggravate depression in a subject in the prevention or treatment of Sjögren's syndrome.

[0103] In another aspect, the present disclosure relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating Sjögren's syndrome in an individual.

[0104] In certain embodiments, the subject is administered 30 mg to 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0105] In certain embodiments, a subject is administered 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, or 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0106] In certain embodiments, the subject is administered 60 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0107] In certain embodiments, the subject is administered 30 mg, 60 mg, 120 mg, or 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0108] In certain embodiments, the subject is administered 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0109] In certain embodiments, the subject is administered 120 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0110] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least once daily.

[0111] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily.

[0112] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0113] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject three times daily.

[0114] In certain embodiments, the subject is administered 30 mg to 75 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0115] In certain embodiments, the subject is administered 30 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0116] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 2.5 mg to 150 mg.

[0117] In certain embodiments, illustrative examples of unit doses of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg and 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg.

[0118] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 150 mg.

[0119] In certain embodiments, illustrative examples of unit dosages of compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, and 150 mg.

[0120] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject in the form of a tablet or capsule.

[0121] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0122] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0123] In certain embodiments, illustrative examples of mammals that can be used with the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0124] In certain embodiments, the subject is a human.

[0125] In certain embodiments, the individual has latent tuberculosis infection.

[0126] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0127] In certain embodiments, the Sjögren's syndrome of the present disclosure is primary Sjögren's syndrome.

[0128] In certain embodiments, the Sjögren's syndrome of the present disclosure is secondary Sjögren's syndrome.

[0129] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are used to prevent or treat Sjögren's syndrome in individuals with latent tuberculosis infection that has not been reactivated after treatment.

[0130] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are used to prevent or treat Sjögren's syndrome in individuals with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy that has not been reactivated after treatment.

[0131] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein do not require titration for the prevention or treatment of Sjögren's syndrome.

[0132] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein can alleviate dry mouth in a subject during the prevention or treatment of Sjögren's syndrome.

[0133] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein alleviate dry eye in a subject during the prevention or treatment of Sjögren's syndrome.

[0134] In certain embodiments, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof disclosed herein improves the pathology of minor salivary gland tissue in an individual in the prevention or treatment of Sjögren's syndrome.

[0135] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein does not cause anxiety or aggravate anxiety in a subject in the prevention or treatment of Sjögren's syndrome.

[0136] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein does not cause depression or aggravate depression in a subject in the prevention or treatment of Sjögren's syndrome.

[0137] In another aspect, the present disclosure relates to a pharmaceutical composition for preventing or treating Sjögren's syndrome in an individual, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0138] In certain embodiments, the subject is administered 30 mg to 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0139] In certain embodiments, a subject is administered 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 150 mg, or 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0140] In certain embodiments, the subject is administered 60 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0141] In certain embodiments, the subject is administered 30 mg, 45 mg, 60 mg, 120 mg, or 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, the subject is administered 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, the subject is administered 120 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least once daily.

[0145] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily.

[0146] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0147] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject three times daily.

[0148] In certain embodiments, the subject is administered 30 mg to 75 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0149] In certain embodiments, the subject is administered 30 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0150] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 2.5 mg to 150 mg.

[0151] In certain embodiments, illustrative examples of unit doses of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and 150 mg.

[0152] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 150 mg.

[0153] In certain embodiments, illustrative examples of unit dosages of compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, and 150 mg.

[0154] In certain embodiments, the pharmaceutical composition comprising the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a tablet or a capsule.

[0155] In certain embodiments, a pharmaceutical composition comprising a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is orally administered to a subject.

[0156] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0157] In certain embodiments, illustrative examples of mammals that can be used with the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0158] In certain embodiments, the subject is a human.

[0159] In certain embodiments, the individual has latent tuberculosis infection.

[0160] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0161] In certain embodiments, the Sjögren's syndrome of the present disclosure is primary Sjögren's syndrome.

[0162] In certain embodiments, the Sjögren's syndrome of the present disclosure is secondary Sjögren's syndrome.

[0163] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are used to prevent or treat Sjögren's syndrome in individuals with latent tuberculosis infection that has not been reactivated after treatment.

[0164] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are used to prevent or treat Sjögren's syndrome in individuals with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy that has not been reactivated after treatment.

[0165] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein do not require titration for the prevention or treatment of Sjögren's syndrome.

[0166] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein can alleviate dry mouth in a subject during the prevention or treatment of Sjögren's syndrome.

[0167] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein alleviate dry eye in a subject during the prevention or treatment of Sjögren's syndrome.

[0168] In certain embodiments, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof disclosed herein improves the pathology of minor salivary gland tissue in an individual in the prevention or treatment of Sjögren's syndrome.

[0169] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein does not cause anxiety or aggravate anxiety in a subject in the prevention or treatment of Sjögren's syndrome.

[0170] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein does not cause depression or aggravate depression in a subject in the prevention or treatment of Sjögren's syndrome.

[0171] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand the various aspects and advantages of the present disclosure. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

[0172] Example 1

[0173] Preparation of compounds of formula (I)

[0174] Prepared by referring to the preparation method 2 of Example 3 in CN101885731A.

[0175] Example 2

[0176] Preparation of S-configuration compound of formula (I)

[0177] The obtained product was prepared according to the preparation method of Example 1 in CN116332954 A.

[0178] Example 3

[0179] Experiment on the induced Sjögren's syndrome model in mice

[0180] 1. Induction Modeling

[0181] Female 6- to 8-week-old C57BL / 6 mice were sacrificed after transcardial perfusion and exsanguination. The submandibular glands were removed, the surrounding capsule was cut off, and the tissues were washed with physiological saline containing 0.5 g / L sodium azide (NaN3). The tissues were minced and homogenized with an equal amount of PBS buffer. The homogenate was frozen and thawed five times at -80°C and sonicated on ice for 5 minutes to disrupt the cells. The homogenate was then centrifuged in a high-speed refrigerated centrifuge (13,000 rpm for 10 minutes). The supernatant was removed and the protein antigen content, which was the submandibular gland antigen, was determined. The antigen supernatant was diluted to 4 mg / mL with PBS and emulsified with an equal volume of Freund's complete adjuvant (the oil phase was pushed into the water phase) to prepare a 2 mg / mL submandibular gland antigen emulsion.

[0182] The model animals were anesthetized and the prepared antigen emulsifier was injected subcutaneously at multiple points on the back of the model animals, 0.1 ml / animal. The first induction was d0 (day 0), and booster immunizations were performed on d7, d14, d21, d28, and d35 of the experiment. The induction method was the same as the first immunization (the number of induced immunizations could be adjusted according to the saliva flow rate monitoring).

[0183] 2. Grouped Dosing

[0184] Before the first immunization of the experimental animals, a basal salivary flow rate test was performed (the test method is detailed below). The experimental animals were randomly divided into groups according to the salivary flow rate, and the experimental animals were grouped and dosed starting from the first day after the first immunization. A total of 8 experimental animals were divided into a blank control group, a model control group, an Example 2 (60 mg / kg) group, an Example 2 (100 mg / kg) group, and a cyclophosphamide (30 mg / kg) group. Example 2 (gavage administration was once a day, and cyclophosphamide was intraperitoneally injected once every 2 days. Each drug was administered continuously for 6 weeks.

[0185] 3. Monitoring indicators

[0186] 3.1 Saliva flow rate

[0187] Mice were anesthetized with isoflurane inhalation, and a dry cotton ball (weighed dry weight) was placed sublingually. Pilocarpine (5 mg / kg) was injected intraperitoneally. Saliva was collected 7 minutes after injection, and the wet weight was measured after the cotton ball was removed. Saliva was collected from mice 0 week before the first immunization and 2, 4, and 6 weeks after immunization. Saliva flow rate (mg / g / min) was calculated and changes in saliva flow rate were observed.

[0188] Saliva flow rate (mg / g / min) = (wet weight of cotton ball - dry weight of cotton ball) / body weight / 7

[0189] 3.3 Pathological examination

[0190] One side of the submandibular gland was harvested for pathological examination, and the other salivary glands and serum were used to detect cytokines IL-17, IL-6, and TNF-α.

[0191] Pathological scoring criteria:

[0192] Microscopic observation was performed to check the integrity of the submandibular gland tissue structure, the presence of lymphocyte infiltration, and the presence of obvious abnormalities in the blood vessels and glandular ducts (such as dilation, edema, lymphoid foci formation, etc.). Scoring was performed based on the degree of injury.

[0193] 0 points: no lymphocytes or scattered lymphocyte infiltration

[0194] 1 point: A small amount of lymphocyte infiltration, no lymphoid foci, and no other obvious abnormalities

[0195] 2 points: moderate lymphocytic infiltration, no lymphoid foci, mild vascular and glandular duct edema

[0196] 3 points: every 4 mm 2 In the visual field, there is one lymphoid foci (infiltrating lymphocytes >50), moderate edema and dilation of blood vessels and glandular ducts

[0197] 4 points: every 4 mm 2 In the visual field, there are 2 to 3 lymph nodes, acinar atrophy, severe vascular and glandular duct edema and other injuries

[0198] 4. The test plan is detailed in the table below:

[0199] Table 1. Experimental plan

[0200] Adjust the induction times and observation time according to the animal's salivary flow rate indicators, and adjust the dosing cycle according to the animal's tolerance.

[0201] 5. Data Processing

[0202] Animal weight data were statistically analyzed using the general linear model test in SPSS 22.0 software. Repeated measures analysis of variance was first used for sphericity testing. If P > 0.05, the repeated measurements were considered to be non-correlated, and one-way analysis of variance was used for inter-group statistical analysis. If P ≤ 0.05, the repeated measurements were considered to be correlated, and multivariate analysis of variance was used for inter-group statistical analysis.

[0203] The salivary flow rate was tested for homogeneity of variance using Levene's Test in SPSS 22.0 software. If the variance was homogeneous (P>0.05), one-way analysis of variance (One-Way Anova test) was used for statistical analysis between groups. If the variance was unequal (P≤0.05), the Kruskal-Wallis nonparametric test was performed. If the result of the Kruskal-Wallis nonparametric test was significant (P≤0.05), the Mann-Whitney U test method of the nonparametric test was used for pairwise comparison between groups.

[0204] 6. Test results

[0205] 6.1 Changes in Animal Weight

[0206] By the end of the experiment, the actual dosing cycle for each dose group of Example 2 compound was qd×54, and the actual dosing cycle for the cyclophosphamide group was q2d×27. By the end of the experiment, the body weight of animals in each dosing group showed an increasing trend, indicating that the animals tolerated the dosing regimen well.

[0207] 6.2 Salivary flow rate measurement results

[0208] The results of salivary flow rate measurement showed that the salivary flow rate of the model was significantly different from that of the blank control group on day 46, indicating that the model was successfully established. The results of salivary flow rate measurement are shown in Table 2.

[0209] Table 2. Changes in salivary flow rate of experimental animals in each group (mg / g / min, )

[0210] Note: *p<0.05 compared with blank control group; #p<0.05, ##p<0.01 compared with model control group.

[0211] 6.3 Pathological examination

[0212] Table 3. Cytokine detection results in submandibular gland tissue homogenate (pg / ml, )

[0213] Note: *p<0.05, **p<0.01, ***p<0.001 compared with blank control group; #p<0.05, ##p<0.01, ###p<0.001 compared with model control group

[0214] Submandibular gland tissue samples were histopathologically examined. According to relevant literature, the main pathological changes in the submandibular gland tissue of this model animal are inflammatory cell infiltration and glandular duct deformation. The results of this experiment showed that the submandibular gland tissue morphology of the blank control group was intact, with no or a small amount of lymphocyte infiltration, and no other abnormalities; the glandular duct and blood vessel morphology of the model control group showed deformation and edema, with frequent infiltration of lymphocytes and inflammatory cells, and lymphoid foci formed in the field of view, with obvious lesions. Further histopathological scoring results showed that the histopathological scores of the blank, model, Example 2 (60 mg / kg), Example 2 (100 mg / kg), and cyclophosphamide were 0.13, 2.50, 0.88, 1.25, and 1.00, respectively.

[0215] Example 4

[0216] Clinical studies on patients

[0217] In a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase III clinical study evaluating the efficacy and safety of sedative fortified sedative fortified sedative in patients with moderate-to-severe chronic plaque psoriasis, including 105 subjects with T-SPOT-positive tuberculosis but not active, clinical observations and evaluations were conducted during a 16-week core treatment period, a 36-week extension treatment period, and a 4-week follow-up period. Anxiety and depression were also assessed using the Anxiety and Depression Scale during the screening period, at the end of the 16-week core period, and 4 weeks after the last dose.

[0218] The experimental results showed that by the end of the clinical study, 105 subjects with positive T-SPOT but non-active tuberculosis, 7 patients with previous diagnosis of pulmonary tuberculosis, 76 patients with previous tuberculosis, and 1 patient with previous tuberculous pleurisy had no tuberculosis reactivation. No tuberculosis-related clinical abnormalities were found in chest X-ray or CT examinations of all subjects.

[0219] Table 4. Depression Scale Scores in Phase III Clinical Study of Moderate to Severe Plaque Psoriasis

[0220] By the end of the clinical study, there were no statistically significant differences in the mean Hospital Anxiety and Depression Scale anxiety scores and mean Hospital Anxiety and Depression Scale depression scores (± standard deviation) between the experimental and placebo groups (P>0.05). No subjects reported adverse events of depression or anxiety, and no depression or suicidal tendencies related to the study drug were observed.

[0221] Example 5

[0222] Clinical studies on patients

[0223] A total of 36 healthy Chinese subjects participated in a Phase I clinical study, with multiple oral administrations of Example 2 at doses of 15 mg BID, 30 mg BID, 60 mg BID, 75 mg BID and placebo. The clinical trial showed good safety and good tolerance.

[0224] In this disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any actual relationship or order between these entities or operations.

[0225] It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the appended claims of the present disclosure.

Claims

1. A method for preventing or treating Sjögren's syndrome, which comprises administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, formula (I).

2. The use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of Sjögren's syndrome in a subject, formula (I).

3. The method according to claim 1 or the use according to claim 2, wherein the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is administered to the subject daily in a dose of 30 mg to 180 mg, 60 mg to 150 mg, 150 mg or 120 mg.

4. The method according to claim 1 or 3 or the use according to claim 2 or 3, wherein the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is administered to the subject at least once a day or at least twice a day.

5. The method according to any one of claims 1 and 3-4 or the use according to any one of claims 2 and 3-4, in which the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is administered to the subject twice a day, each time in a dose of 30 mg to 75 mg or 30 mg to 60 mg.

6. The method according to any one of claims 1 and 3-5 or the use according to any one of claims 2 and 3-5, wherein the dosage of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt per unit is from 2.5 mg to 150 mg, from 15 mg to 150 mg, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg or 150 mg.

7. The method according to any one of claims 1 and 3-6 or the use according to any one of claims 2 and 3-6, in which the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is administered to the subject in the form of a tablet or capsule; and / or the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is administered to the subject orally.

8. The method according to any one of claims 1 and 3-7 or the use according to any one of claims 2 and 3-7, wherein the subject is a mammal, preferably a human.

9. The method according to any one of paragraphs 1 and 3-8 or the use according to any one of paragraphs 2 and 3-8, wherein the subject has a latent tuberculosis infection.

10. The method according to any one of paragraphs 1 and 3-8 or the use according to any one of paragraphs 2 and 3-8, wherein the subject has a medical history of pulmonary tuberculosis infection, tuberculosis and / or tuberculous pleurisy.

11. The method according to any one of claims 1 and 3-10 or the use according to any one of claims 2 and 3-10, wherein the treatment of the subject does not require titration of the dose.

12. The method or use according to claim 9, wherein the subject has a latent tuberculosis infection, and there is no reactivation of the latent tuberculosis infection after treatment.

13. The method or use according to claim 10, wherein the subject has a medical history of pulmonary tuberculosis infection, tuberculosis and / or tuberculous pleurisy, and there is no reactivation of pulmonary tuberculosis infection, tuberculosis and / or tuberculous pleurisy after treatment.

14. The method according to any one of claims 1 and 3-13 or the use according to any one of claims 2 and 3-13, wherein xerostomia is relieved in the subject and / or xerophthalmia is relieved in the subject.

15. The method according to any one of claims 1 and 3-14 or the use according to any one of claims 2 and 3-14, wherein the histopathology of the minor salivary glands in the subject is improved.

16. The method according to any one of paragraphs 1 and 3-15 or the use according to any one of paragraphs 2 and 3-15, wherein they do not provoke or increase anxiety or depression in the subject.

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