Prevention or treatment of Sjögren's syndrome

Abstract

The present invention discloses a method for the prevention or treatment of Sjögren's syndrome comprising the step of administering a prophylactic or therapeutically 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 to an individual in need thereof. Equation (I)

Description

Technology Field

[0001] Cross-reference of related applications

[0002] The present invention claims all rights and interests of the Chinese invention patent application filed with the State Intellectual Property Administration of the People's Republic of China on November 14, 2023, with application number 202311516190.8 and title of the invention “Treatment of Sjögren’s Syndrome,” the entire contents of which are incorporated by reference into the present invention.

[0003] The present invention generally relates to the field of medicine, and more specifically, the present invention relates to the prevention or treatment of Sjögren's syndrome. Background Technology

[0004] Sjögren's Syndrome (SS) is a systemic autoimmune disease characterized by lymphocyte proliferation and progressive damage to exocrine glands. It is characterized by lymphocyte infiltration into exocrine glands and epithelial cells in various locations, as well as the positive detection of serum autoantibodies, such as anti-Sjögren's syndrome antibodies. It primarily attacks the tear glands and salivary glands, causing dry eyes and dry mouth. Additionally, Sjögren's syndrome can affect various other organs and systems.

[0005] Although the exact cause and pathophysiology of Sjögren's syndrome remain unclear, it is currently regarded as an immune dysfunction caused by various factors, including genetic factors, viral infections, and sex hormone abnormalities. Clinical symptoms vary widely, ranging from secretory dysfunction of the salivary and lacrimal glands to multiple organ and system involvement accompanied by systemic symptoms, and even lymphoma complications. There is currently no satisfactory cure for Sjögren's syndrome, nor are there any drugs proven effective for dryness, fatigue, pain, or visceral damage; most medications used in clinical practice are empirical treatments.

[0006] Patients with Sjögren's syndrome often have compromised or impaired immune function, which increases the risk of infection by pathogens. Long-term administration of existing Sjögren's syndrome treatments can further degrade the patient's immune function, potentially increasing the risk of infection. Among these pathogens, Mycobacterium tuberculosis (TB) is a common infectious bacterium encountered during treatment. Approximately one-third of the world's population is infected with TB, and 90% of infected individuals harbor the pathogen for a long period, becoming patients with latent TB infection. Latent TB infection serves as a breeding ground for the development of active TB, and because the disease progression of patients with latent TB infection is highly uncertain, it acts as a serious hidden risk factor in TB management. The compromised immune function of patients with latent TB infection facilitates the progression from latent TB to active TB. Therefore, it is very important and significant to focus on a special patient group of patients with latent tuberculosis infection during treatment, and to provide appropriate treatment not only to patients with Sjögren's syndrome but also to patients with Sjögren's syndrome who have a history of latent tuberculosis infection or tuberculosis, in order to enhance treatment efficacy and reduce the risk of side effects and progression to active tuberculosis, thereby providing maximum benefit to the patients.

[0007] Summary of the Invention

[0008] In one embodiment, the present invention relates to a method for preventing or treating Sjögren's syndrome, comprising the step of administering a prophylactic or therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0009]

[0010] Equation (I)

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

[0012]

[0013] Equation (I)

[0014] In another aspect, the present invention relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the prevention or treatment of Sjögren's syndrome in an individual.

[0015]

[0016] Equation (I)

[0017] In another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of 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.

[0018]

[0019] Detailed description of the invention

[0020] In the following description, each disclosed embodiment is understood in its entirety, including some specific details. However, those skilled in the art will understand that the embodiments can still be implemented using other methods, components, materials, etc., without using one or more of the specific details.

[0021] Unless otherwise required, throughout the entire specification and claims, the terms “comprehensive,” “include,” “contain,” and “have” shall be interpreted in the open, inclusive sense of “include, but not limited thereto.”

[0022] Unless otherwise specified in the context, singular names without quantity indications in the present invention and claims include plural names.

[0023] The terms “one embodiment,” “an embodiment,” “another embodiment,” or “some embodiments” as used throughout the entire specification mean that at least one embodiment includes the specific reference elements, structures, or features described in relation to said embodiment. Accordingly, phrases “one embodiment,” “an embodiment,” “another embodiment,” or “some embodiments” appearing at different locations throughout the entire specification do not necessarily refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any appropriate manner.

[0024] It should be understood that the singular form of the article “one” (corresponding to the English “a,” “an,” and “the”) used in the specification and claims of the present invention includes multiple objects unless otherwise explicitly specified. Accordingly, for example, a reference to a pharmaceutical composition containing “an excipient” includes a pharmaceutical composition containing one excipient or a pharmaceutical composition containing two or more excipients.

[0025] definition

[0026] Therefore, unless otherwise explained, the following terms used in the specification and claims have the following meanings.

[0027] In the present invention, the term “Sjogren’s Syndrome (SS)” refers to an autoimmune disease that causes secretory glands to produce less water than normal. Sjogren’s Syndrome causes chronic (long-term) dryness throughout the body (especially the eyes and mouth).

[0028] In this invention, adverse reactions occurring in clinical trials are classified, and generally, there are two classification methods. One is to classify adverse reactions into mild, moderate, and severe. Mild generally refers to cases that are temporary, do not interfere with the subject's daily life, and may require only minimal treatment. Moderate refers to cases that cause discomfort to the subject, interfere with daily life, and generally require treatment for symptom relief, but do not pose a risk of causing serious or permanent harm to the subject. Severe refers to cases that significantly affect the subject's daily life or severely worsen the clinical condition, requiring intensive treatment and intervention. The other classification method classifies adverse reactions into grades 1 through 5 according to the Common Terminology Criteria for Adverse Events (CTCAE). Grade 1: Mild, no or mild clinical symptoms; requiring only clinical or diagnostic observation; requiring no treatment. Grade 2: Moderate, requiring mild local or non-invasive treatment; Restrictions on age-appropriate Activities of Daily Living (ADLs), which include cooking, shopping for clothes, using a telephone, and managing finances; Autonomous Activities of Daily Living (ADLs) refer to activities such as bathing, dressing, eating, washing hands, and taking medication, and do not include being bedridden. Grade 3: Severe or medically important but not immediately life-threatening; requires hospitalization or long-term hospitalization; disability; limitations in basic activities of daily living. Autonomous Activities of Daily Living refer to activities such as bathing, dressing, eating, washing hands, and taking medication, and do not include being bedridden. Grade 4: Life-threatening, requires urgent care. Grade 5: Death related to adverse events.

[0029] In the present invention, the term “HADS” refers to a hospital anxiety and depression scale used to screen for anxiety and depressive symptoms in patients at a general hospital. The questionnaire is concise, clear, practical, and has been extensively studied in everyday medical settings. The questionnaire includes seven anxiety-related items (A) and seven depression-related items (D). Responses to all items are evaluated on a 4-point scale (0 to 3 points). The total anxiety or depression score is the sum of individual response scores for each item, ranging from 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.

[0030] In the present invention, the term “Latent Tuberculosis Infection (LTBI)” means infection with Mycobacterium tuberculosis but without clinical tuberculosis, without clinical symptoms, and without bacteriological or imaging evidence of active tuberculosis. Diagnostic criteria for latent tuberculosis include a positive T-spot test (T-SPOT) for Mycobacterium tuberculosis infection and the absence of clinical signs of active tuberculosis.

[0031] In the present invention, the term “activation” refers to the transition of a patient’s tuberculosis infection status from latent tuberculosis infection to active tuberculosis infection; that is, it signifies a state in which the patient’s tuberculosis infection status progresses to an active phase, the patient is in an active tuberculosis state, and standardized and intensive treatment is required.

[0032] In the present invention, the term “FCA” refers to a prune complete aid.

[0033] In the present invention, the term “compound of formula (I)” means 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, and its structural formula is as shown below.

[0034]

[0035] In the present invention, the term “compound of formula (I) and stereoisomers thereof” refers to (S)-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, and its structural formula is as shown below.

[0036]

[0037] In the present invention, the term “pharmaceuticalally acceptable” means a carrier, transporter, diluent, excipient, and / or salt that is compatible with other components of the formulation and is not harmful to the recipient thereof.

[0038] In the present invention, the term “pharmaceutically acceptable carrier, diluent or excipient” includes, but is not limited to, various forms of carriers that do not cause adverse effects in pharmaceutical compositions, such as any adjuvant, carrier, excipient, lubricant, 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.

[0039] In the present invention, the term “carrier” is defined as a compound that facilitates the introduction of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it can easily introduce certain organic compounds into the cells or tissues of an organism.

[0040] In the present invention, the term “pharmaceutically acceptable salt” includes “acid-added salt” and “acid-added salt”.

[0041] In the present invention, the term “acceptable acid addition salt” means such a salt that maintains the biological efficacy and properties of a free base, said acid addition salt is biologically or otherwise suitable and is formed by combining with an inorganic acid or an organic acid, said inorganic acid is, for example, hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, and phosphoric acid, but is not limited thereto, and said organic acid is, for example, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphor acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, Genticic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hipfuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic 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, parmoic acid, propionic acid, pyroglutamic acid, pyruvate, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, Undecylenic acid, etc., but is not limited to these.

[0042] In the present invention, the term “acceptable base-added salt” means such a salt that maintains the biological efficacy and properties of a free acid, and said base-added salt is suitable biologically or otherwise. Such a salt is prepared by adding an inorganic base or an organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. In some 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 natural substituted amines, cyclic amines, and salts of basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucarmin, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. In some embodiments, the organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0043] In the present invention, the term “mammal” means an animal including dogs, cats, cattle, sheep, horses, and humans. In some embodiments, the mammal is a human.

[0044] In the present invention, the term “pharmaceutical composition” means a formulation formed of the compound of formula (I) of the present invention and its stereoisomers or pharmaceutically acceptable salts thereof and a medium generally accepted in the art for delivering the biologically active compound to mammals such as humans. Such media include all pharmaceutically acceptable carriers, diluents, or excipients.

[0045] In the present invention, the term “therapeutic effective dose” means an amount of a compound or combination of compounds that improves, alleviates, or eliminates a specific disease or condition and its symptoms, or prevents or delays the onset of such specific disease or condition or its symptoms. Depending on the compound, the disease and its severity, and the age and weight of the mammal being treated, the amount of the compound of Formula (I) and its stereoisomers constituting the “therapeutic effective dose” of the present invention may vary, but a person skilled in the art may determine the amount of said compound of the present invention by considering their knowledge and the present specification.

[0046] The “preventive treatment” or “prevention” used in the present invention includes preventing a disease or the occurrence of a disease in a mammal (e.g., human), in particular in cases where the mammal (e.g., human) is susceptible to the disease state but has not been diagnosed with such a disease.

[0047] The terms “during treatment” or “treatment” as used in the present invention include treating a related disease or disease state in mammals, such as humans, having a related disease or condition, and include the following cases.

[0048] (i) suppressing a disease or disease state, that is, preventing its occurrence; or

[0049] (ii) Cases where the disease or disease state is alleviated, or where the disease or disease state is alleviated even if it does not progress. In the present invention, the term “unit dose” refers to the dose required for a single use. For example, in the case of a tablet, the unit dose refers to the dose of one tablet. Specific details for implementing the invention

[0050] In one embodiment, the present invention relates to a method for preventing or treating Sjögren's syndrome and comprises the step of administering a prophylactic or therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0051]

[0052] Equation (I)

[0053] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 30 mg to 180 mg per day.

[0054] In some embodiments, an individual is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a dose of 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, or 180 mg per day.

[0055] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 60 mg to 150 mg per day.

[0056] In some embodiments, an individual is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a dose of 30 mg, 60 mg, or 120 mg, or 150 mg per day.

[0057] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 150 mg per day.

[0058] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 120 mg per day.

[0059] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at least once a day.

[0060] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at least twice a day.

[0061] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day.

[0062] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual three times a day.

[0063] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day at a dose of 30 mg to 75 mg per dose.

[0064] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day at a dose of 30 mg to 60 mg per dose.

[0065] In some embodiments, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 2.5 mg to 150 mg.

[0066] In some embodiments, exemplary unit doses of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt that may be used in the present invention 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.

[0067] In some embodiments, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg to 150 mg.

[0068] In some embodiments, unit doses of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt are 15 mg, 30 mg, 45 mg, 60 mg, and 75 mg, 120 mg, 150 mg.

[0069] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual in the form of a tablet or capsule.

[0070] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is orally administered to an individual.

[0071] In some embodiments, exemplary embodiments of the entities that can be used in the present invention include, but are not limited to, mammals.

[0072] In some embodiments, exemplary embodiments of mammals that may be used in the present invention include, but are not limited to, dogs, cats, cattle, sheep, horses, and humans.

[0073] In some embodiments, the entity is a human.

[0074] In some embodiments, the individual has a latent tuberculosis infection.

[0075] In some embodiments, the individual has a history of pulmonary tuberculosis infection, tuberculosis, and tuberculous pleuritis.

[0076] In some embodiments, the Sjögren's syndrome of the present invention is primary Sjögren's syndrome.

[0077] In some embodiments, the Sjögren's syndrome of the present invention is secondary Sjögren's syndrome.

[0078] In another aspect, the present invention relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating Sjögren's syndrome in an individual.

[0079]

[0080] Equation (I)

[0081] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 30 mg to 180 mg per day.

[0082] In some embodiments, an individual is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a dose of 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 per day.

[0083] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 60 mg to 150 mg per day.

[0084] In some embodiments, an individual is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a dose of 30 mg, 60 mg, 120 mg, or 150 mg per day.

[0085] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 150 mg per day.

[0086] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 120 mg per day.

[0087] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at least once a day.

[0088] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at least twice a day.

[0089] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day.

[0090] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual three times a day.

[0091] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day at a dose of 30 mg to 75 mg per dose.

[0092] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day at a dose of 30 mg to 60 mg per dose.

[0093] In some embodiments, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 2.5 mg to 150 mg.

[0094] In some embodiments, exemplary unit doses of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt that may be used in the present invention 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.

[0095] In some embodiments, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg to 150 mg.

[0096] In some embodiments, exemplary embodiments of unit doses of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt that can be used in the present invention include, but are not limited to, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, and 150 mg.

[0097] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual in the form of a tablet or capsule.

[0098] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is orally administered to an individual.

[0099] In some embodiments, exemplary embodiments of the entities that can be used in the present invention include, but are not limited to, mammals.

[0100] In some embodiments, exemplary embodiments of mammals that may be used in the present invention include, but are not limited to, dogs, cats, cattle, sheep, horses, and humans.

[0101] In some embodiments, the entity is a human.

[0102] In some embodiments, the individual has a latent tuberculosis infection.

[0103] In some embodiments, the individual has a history of pulmonary tuberculosis infection, tuberculosis, and tuberculous pleuritis.

[0104] In some embodiments, the Sjögren's syndrome of the present invention is primary Sjögren's syndrome.

[0105] In some embodiments, the Sjögren's syndrome of the present invention is secondary Sjögren's syndrome.

[0106] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is used for the prevention or treatment of Sjögren's syndrome in individuals who have suffered from latent tuberculosis infection but have not reactivated it after treatment.

[0107] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is used for the prevention or treatment of Sjögren's syndrome in individuals who have a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleuritis but have not reactivated it after treatment.

[0108] In some embodiments, the compound of formula (I) of the present invention, its stereoisomer, or its pharmaceutically acceptable salt does not require dose titration in the prevention or treatment of Sjögren's syndrome.

[0109] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof alleviates dry mouth in individuals in the prevention or treatment of Sjögren's syndrome.

[0110] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof alleviates dry eye syndrome in individuals in the prevention or treatment of Sjögren's syndrome.

[0111] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof improves the histopathological condition of the minor salivary glands of an individual in the prevention or treatment of Sjögren's syndrome.

[0112] In some embodiments, the compound of formula (I) of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof do not cause or worsen anxiety in individuals in the prevention or treatment of Sjögren's syndrome.

[0113] In some embodiments, the compound of formula (I) of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof do not cause or worsen depression in individuals in the prevention or treatment of Sjögren's syndrome.

[0114] In another aspect, the present invention relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the prevention or treatment of Sjögren's syndrome in an individual.

[0115]

[0116] Equation (I)

[0117] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 30 mg to 180 mg per day.

[0118] In some embodiments, an individual is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a dose of 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 per day.

[0119] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 60 mg to 150 mg per day.

[0120] In some embodiments, an individual is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a dose of 30 mg, 60 mg, 120 mg, or 150 mg per day.

[0121] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 150 mg per day.

[0122] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 120 mg per day.

[0123] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at least once a day.

[0124] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at least twice a day.

[0125] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day.

[0126] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual three times a day.

[0127] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day at a dose of 30 mg to 75 mg per dose.

[0128] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day at a dose of 30 mg to 60 mg per dose.

[0129] In some embodiments, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 2.5 mg to 150 mg.

[0130] In some embodiments, exemplary unit doses of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt that may be used in the present invention 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, and 150 mg.

[0131] In some embodiments, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg to 150 mg.

[0132] In some embodiments, exemplary embodiments of unit doses of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt that can be used in the present invention include, but are not limited to, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, and 150 mg.

[0133] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual in the form of a tablet or capsule.

[0134] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is orally administered to an individual.

[0135] In some embodiments, exemplary embodiments of the entities that can be used in the present invention include, but are not limited to, mammals.

[0136] In some embodiments, exemplary embodiments of mammals that may be used in the present invention include, but are not limited to, dogs, cats, cattle, sheep, horses, and humans.

[0137] In some embodiments, the entity is a human.

[0138] In some embodiments, the individual has a latent tuberculosis infection.

[0139] In some embodiments, the individual has a history of pulmonary tuberculosis infection, tuberculosis, and tuberculous pleuritis.

[0140] In some embodiments, the Sjögren's syndrome of the present invention is primary Sjögren's syndrome.

[0141] In some embodiments, the Sjögren's syndrome of the present invention is secondary Sjögren's syndrome.

[0142] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is used for the prevention or treatment of Sjögren's syndrome in individuals who have suffered from latent tuberculosis infection but have not reactivated it after treatment.

[0143] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is used for the prevention or treatment of Sjögren's syndrome in individuals who have a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleuritis but have not reactivated it after treatment.

[0144] In some embodiments, the compound of formula (I) of the present invention, its stereoisomer, or its pharmaceutically acceptable salt does not require dose titration in the prevention or treatment of Sjögren's syndrome.

[0145] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof alleviates dry mouth in individuals in the prevention or treatment of Sjögren's syndrome.

[0146] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof alleviates dry eye syndrome in individuals in the prevention or treatment of Sjögren's syndrome.

[0147] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof improves the histopathological condition of the minor salivary glands of an individual in the prevention or treatment of Sjögren's syndrome.

[0148] In some embodiments, the compound of formula (I) of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof do not cause or worsen anxiety in individuals in the prevention or treatment of Sjögren's syndrome.

[0149] In some embodiments, the compound of formula (I) of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof do not cause or worsen depression in individuals in the prevention or treatment of Sjögren's syndrome.

[0150] In another aspect, the present invention 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.

[0151]

[0152] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 30 mg to 180 mg per day.

[0153] In some embodiments, an individual is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a dose of 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 per day.

[0154] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 60 mg to 150 mg per day.

[0155] In some embodiments, an individual is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a dose of 30 mg, 45 mg, 60 mg, 120 mg, or 150 mg per day.

[0156] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 150 mg per day.

[0157] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at a dose of 120 mg per day.

[0158] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at least once a day.

[0159] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual at least twice a day.

[0160] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day.

[0161] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual three times a day.

[0162] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day at a dose of 30 mg to 75 mg per dose.

[0163] In some embodiments, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to an individual twice a day at a dose of 30 mg to 60 mg per dose.

[0164] In some embodiments, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 2.5 mg to 150 mg.

[0165] In some embodiments, exemplary unit doses of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt that may be used in the present invention 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.

[0166] In some embodiments, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg to 150 mg.

[0167] In some embodiments, exemplary embodiments of unit doses of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt that can be used in the present invention include, but are not limited to, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, and 150 mg.

[0168] In some embodiments, a pharmaceutical composition comprising the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a tablet or capsule.

[0169] In some embodiments, a pharmaceutical composition comprising the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is orally administered to an individual.

[0170] In some embodiments, exemplary embodiments of the entities that can be used in the present invention include, but are not limited to, mammals.

[0171] In some embodiments, mammals that may be used in the present invention include, but are not limited to, dogs, cats, cattle, sheep, horses, and humans as exemplary embodiments.

[0172] In some embodiments, the entity is a human.

[0173] In some embodiments, the individual has a latent tuberculosis infection.

[0174] In some embodiments, the individual has a history of pulmonary tuberculosis infection, tuberculosis, and tuberculous pleuritis.

[0175] In some embodiments, the Sjögren's syndrome of the present invention is primary Sjögren's syndrome.

[0176] In some embodiments, the Sjögren's syndrome of the present invention is secondary Sjögren's syndrome.

[0177] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is used for the prevention or treatment of Sjögren's syndrome in individuals who have suffered from latent tuberculosis infection but have not reactivated it after treatment.

[0178] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is used for the prevention or treatment of Sjögren's syndrome in individuals who have a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleuritis but have not reactivated it after treatment.

[0179] In some embodiments, the compound of formula (I) of the present invention, its stereoisomer, or its pharmaceutically acceptable salt does not require dose titration in the prevention or treatment of Sjögren's syndrome.

[0180] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof alleviates dry mouth in individuals in the prevention or treatment of Sjögren's syndrome.

[0181] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof alleviates dry eye syndrome in individuals in the prevention or treatment of Sjögren's syndrome.

[0182] In some embodiments, the compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof improves the histopathological condition of the minor salivary glands of an individual in the prevention or treatment of Sjögren's syndrome.

[0183] In some embodiments, the compound of formula (I) of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof do not cause or worsen anxiety in individuals in the prevention or treatment of Sjögren's syndrome.

[0184] In some embodiments, the compound of formula (I) of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof do not cause or worsen depression in individuals in the prevention or treatment of Sjögren's syndrome.

[0185] Below, the present invention is described in detail through the following examples to better understand the various aspects of the invention and their advantages. However, it should be understood that the following examples are non-limiting and are intended to describe only some embodiments of the invention.

[0186] Example 1

[0187] Preparation of the compound of formula (I)

[0188] It was prepared by referring to Method 2 of Example 3 in CN101885731A.

[0189] Example 2

[0190] Preparation of the compound of formula (I) using the S-form

[0191] It was prepared by referring to the manufacturing method of Example 1 in CN116332954 A.

[0192] Example 3

[0193] Induced mouse Sjögren's syndrome model test

[0194] 1. Derivative Modeling

[0195] Female C57BL / 6 mice aged 6–8 weeks were sacrificed after cardiac perfusion and blood removal. The submandibular gland was isolated, and the membrane surrounding the submandibular gland was resected. The tissue was washed with physiological saline containing 0.5 g / L sodium azide (NaN3), finely chopped, and homogenized with an equal volume of PBS buffer. The homogenate was frozen and thawed five times at -80°C and sonicated in an ice bath for 5 minutes to achieve cell disruption. Subsequently, the mixture was centrifuged using a high-speed freezing centrifuge (13,000 rpm, 10 minutes), and the supernatant was collected to measure the content of the protein antigen, namely the submandibular gland antigen. The antigen supernatant was diluted with PBS to a concentration of 4 mg / mL and uniformly emulsified with an equal volume of Prund's complete adjuvant (the emulsion was injected into the aqueous phase) to prepare a submandibular gland antigen emulsifier at a concentration of 2 mg / mL.

[0196] An anesthetic was administered to experimental animals, and the prepared antigen emulsifier was subcutaneously injected at a rate of 0.1 ml per mouse into various sites on the back of the animals. The first induction was designated as d0 (Day 0), and immunity was intensified on days 7, 14, 21, 28, and 35 of the experiment, respectively. The induction method was the same as that of the first immunity (the number of induction immunizations can be adjusted by monitoring salivary secretion volume).

[0197] 2. Grouped administration

[0198] Baseline values ​​of salivary secretion were measured prior to the first immunization of the experimental animals (the detection method is described later), and the experimental animals were randomly divided into groups based on salivary secretion. Starting from the first day after the first immunization, the animals were divided into groups and administration began. The administration groups were divided into a control group, a model control group, an Example 2 (60 mg / kg) administration group, an Example 2 (100 mg / kg) administration group, and a cyclophosphamide (30 mg / kg) administration group, with 8 animals per group. The Example 2 administration group was administered once daily via gastric tube feeding, and the cyclophosphamide administration group was administered once every 2 days via intraperitoneal injection. Each drug was administered for 6 consecutive weeks.

[0199] 3. Monitoring Indicators

[0200] 3.1 Salivary secretion volume

[0201] Mice were administered isoflurane inhalation anesthesia, and a pre-weighed dry cotton ball was placed under the mouse's tongue. After injecting pilocarpine (5 mg / kg) intraperitoneally, saliva was collected for 7 minutes, and the wet weight was measured after removing the cotton ball. Mouse saliva was collected at week 0, before the first immunization, and at weeks 2, 4, and 6, respectively, after immunization; the salivary volume (mg / g / min) was calculated, and changes in salivary volume were observed.

[0202] Salivary secretion volume (mg / g / min) = (Wet weight of cotton - Dry weight of cotton) / Body weight / 7

[0203] 3.3 Pathological Detection

[0204] One submandibular gland was collected and used for pathological examination, while the remaining salivary gland and serum were used for the detection of cytokines, including IL-17, IL-6, and TNF-α.

[0205] Pathological scoring criteria:

[0206] The integrity of the submandibular gland tissue structure, the presence or absence of lymphocyte infiltration, and abnormal findings in blood vessels and glandular ducts (e.g., dilation, edema, lymphocyte colony formation, etc.) were evaluated through microscopic observation, and scores were assigned according to the degree of damage.

[0207] 0 points: No lymphocyte infiltration or sporadic lymphocyte infiltration observed.

[0208] 1 point: Mild lymphocyte infiltration, no lymphocyte colony formation, no other distinct abnormalities.

[0209] 2 points: Moderate lymphocytic infiltration, no lymphocytic lesion formation, mild edema of blood vessels and glandular ducts.

[0210] 3 points: 4mm 2 One lymphocytic lesion per field of view (more than 50 infiltrating lymphocytes), moderate edema, and dilation of blood vessels and glandular ducts.

[0211] 4 points: 4mm 2 2 to 3 lymphocytic lesions per field of view, damage including lobular atrophy, severe edema of blood vessels and glandular ducts.

[0212] 4. The test solution is described in detail in the table below.

[0213] Table 1. Test Solution

[0214]

[0215] The number of inductions and observation time were adjusted according to the animals' salivary secretion indicators, and the administration cycle was adjusted according to the animals' tolerance.

[0216] 5. Data Processing

[0217] Animal body weight data were statistically analyzed using the general linear model test in SPSS 22.0 software. First, a test of sphericity was performed using repeated measures analysis of variance. If P > 0.05, it was assumed that there was no correlation between the repeated measures data, and a statistical analysis between groups was performed using one-way analysis of variance (One-Way ANOVA). If P ≤ 0.05, it was assumed that there was a correlation between the repeated measures data, and a statistical analysis between groups was performed using multivariate analysis of variance (Multivariate).

[0218] For salivary secretion volume, the homogeneity of variances was confirmed by performing the Levene test in SPSS 22.0 software; if the variances were homogeneous (P>0.05), statistical analysis between groups was performed using one-way ANOVA; if the variances were heterogeneous (P≤0.05), the Kruskal-Wallis nonparametric test was performed, and if the Kruskal-Wallis nonparametric test result was significant (P≤0.05), a comparison between groups was performed using the nonparametric Mann-Whitney U test.

[0219] 6. Test Results

[0220] 6.1 Situations of Animal Body Weight Change

[0221] At the end of the study, the actual administration cycle for each group of the compound of Example 2 was once a day for 54 times, and the actual administration cycle for the cyclophosphamide group was once every two days for 27 times. At the end of the study, the animal body weight of each administration group showed an increasing trend, which indicates that the animals had good tolerance to the administration regimen adopted in this study.

[0222] 6.2 Results of Salivary Secretion Volume Measurement

[0223] The results of measuring salivary secretion showed that the model group had a significantly increased salivary secretion compared to the control group on day 46, demonstrating that the animal model was successfully established. The results of measuring salivary secretion are shown in Table 2.

[0224] Table 2. Changes in salivary secretion volume of experimental animals in each administration group (mg / g / min, ±SD)

[0225]

[0226] Note: *p<0.05 indicates a significant difference compared to the blank control group; #p<0.05, ##p<0.01 indicates a significant difference compared to the model control group.

[0227] 6.3 Pathological Examination

[0228] Table 3. Results of cytokine detection in submandibular gland tissue homogenate (pg / ml, ±SD)

[0229]

[0230] Note: *p<0.05, **p<0.01, ***p<0.001 indicate a significant difference compared to the blank control group; #p<0.05, ##p<0.01, ###p<0.001 indicate a significant difference compared to the model control group.

[0231] Histopathological examination was performed on submandibular gland tissue samples. As reported in the relevant literature, the major pathological changes observed in the submandibular gland tissue of this model animal were inflammatory cell infiltration and morphological deformation of the glandular ducts. The results of the pathological examination in this experiment showed that the tissue morphology in the blank control group was intact, with no or only mild local lymphocyte infiltration, and no other abnormal findings were observed. In the model control group, morphological deformation and edema of the glandular ducts and blood vessels were observed, lymphocyte and inflammatory cell infiltration were more severe, and lymphocyte colony formation was observed in the field of view, indicating a distinct lesion. Further analysis of histopathological scores revealed that the histopathological scores for the blank control group, model group, Example 2 (60 mg / kg), Example 2 (100 mg / kg), and cyclophosphamide administration group were 0.13, 2.50, 0.88, 1.25, and 1.00, respectively.

[0232] Example 4

[0233] Clinical study on patients

[0234] A multicenter, randomized, double-blind, placebo-parallel-controlled Phase 3 clinical study was conducted to evaluate efficacy and safety in 305 patients with moderate to severe chronic plaque psoriasis (of whom 105 were T-SPOT-positive patients without active tuberculosis). Clinical observation and evaluation were performed during a 16-week core treatment period, a 36-week extension treatment period, and a 4-week follow-up period. Anxiety and depression scales were used as assessment tools to observe and evaluate patients' anxiety and depression status during the screening period, at the completion of the 16-week core treatment period, and 4 weeks after the last administration.

[0235] As a result of the experiment, tuberculosis reactivation did not occur in any of the 105 T-SPOT-positive subjects without active tuberculosis, 7 subjects previously diagnosed with pulmonary tuberculosis, 76 subjects with a history of tuberculosis, and 1 subject with a history of tuberculous pleuritis by the time the clinical study was completed, and no tuberculosis-related clinical abnormalities were observed in the chest X-ray or CT scans of any of the subjects.

[0236] Table 4. Depression scale scores in a Phase 3 clinical study for moderate to severe plaque psoriasis

[0237]

[0238] No statistically significant difference (P>0.05) was observed in the mean HADS anxiety score and mean HADS depression score (±standard deviation) between the experimental group and the placebo group by the time of completion of the clinical study. The subjects did not report any adverse reactions related to depression or anxiety, and no depression or suicidal tendencies related to the study drug were observed.

[0239] Example 5

[0240] Clinical study on patients

[0241] In a Phase 1 clinical study involving a total of 36 healthy Chinese subjects, the compound of Example 2 was orally administered at doses of 15 mg BID, 30 mg BID, 60 mg BID, and 75 mg BID, and a placebo was administered. The results showed that the safety and tolerability were good in the clinical study.

[0242] In this invention, relational terms such as “first” and “second” are used merely to distinguish one entity or operation from another entity or operation, and any actual relationship or order between these entities or operations does not necessarily exist or are implied.

[0243] It can be understood from the foregoing that while specific embodiments of the present invention have been described for illustrative purposes, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the invention. All such modifications or variations shall be included within the claims of the present invention.

Claims

Claim 1 A method for the prevention or treatment of Sjögren's syndrome comprising the step of administering a prophylactically or therapeutically effective amount of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof: Equation (I). Claim 2 A method for the prevention or treatment of Sjögren's syndrome according to claim 1, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual at a dose of 30 mg to 180 mg per day. Claim 3 A method for the prevention or treatment of Sjögren's syndrome according to claim 1 or 2, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual at a dose of 60 mg to 150 mg per day. Claim 4 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 3, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual at a dose of 150 mg per day. Claim 5 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 4, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual at a dose of 120 mg per day. Claim 6 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 5, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual at least once a day. Claim 7 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 5, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual at least twice a day. Claim 8 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 7, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual twice a day at a dose of 30 mg to 75 mg per dose. Claim 9 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 8, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual twice a day at a dose of 30 mg to 60 mg per dose. Claim 10 A method for the prevention or treatment of Sjögren's syndrome, wherein, in any one of claims 1 to 9, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 2.5 mg to 150 mg. Claim 11 A method for the prevention or treatment of Sjögren's syndrome, wherein, in any one of claims 1 to 10, the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg to 150 mg. Claim 12 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 11, wherein the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, or 150 mg. Claim 13 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 12, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual in the form of a tablet or capsule. Claim 14 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 13, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is orally administered to the individual. Claim 15 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 14, wherein the individual is a mammal, preferably a human. Claim 16 A method for the prevention or treatment of Sjögren's syndrome, wherein, in any one of claims 1 to 15, the individual has a latent tuberculosis infection. Claim 17 A method for the prevention or treatment of Sjögren's syndrome, wherein, in any one of claims 1 to 16, the individual has a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleuritis. Claim 18 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 17, wherein dose titration is not required for the treatment of the individual. Claim 19 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 17, wherein the individual had a latent tuberculosis infection but it was not reactivated after treatment. Claim 20 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 17, wherein the individual has a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleuritis but has not been reactivated after treatment. Claim 21 A method for the prevention or treatment of Sjögren's syndrome, wherein, in any one of claims 1 to 17, the dry mouth of the individual is alleviated. Claim 22 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 17, wherein the dry eye syndrome of the individual is alleviated. Claim 23 A method for the prevention or treatment of Sjögren's syndrome, wherein, in any one of claims 1 to 17, the histopathological condition of the minor salivary glands of the individual is improved. Claim 24 A method for the prevention or treatment of Sjögren's syndrome according to any one of claims 1 to 17, which does not cause or worsen anxiety / depression in the individual. Claim 25 Compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof for preventing or treating Sjögren's syndrome in an individual: Equation (I). Claim 26 In claim 25, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is administered to the individual at a dose of 30 mg to 180 mg per day. Claim 27 In claim 25 or 26, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is administered to the individual at a dose of 60 mg to 150 mg per day. Claim 28 In any one of claims 25 to 27, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is administered to the individual at a dose of 150 mg per day. Claim 29 In any one of claims 25 to 28, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is administered to the individual at a dose of 120 mg per day. Claim 30 In any one of claims 25 to 29, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is administered to the individual at least once a day. Claim 31 In any one of claims 25 to 30, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is administered to the individual at least twice a day. Claim 32 In any one of claims 25 to 31, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is administered to the individual twice daily at a dose of 30 mg to 75 mg per dose. Claim 33 In any one of claims 25 to 32, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is administered to the individual twice a day at a dose of 30 mg to 60 mg per dose. Claim 34 A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 2.5 mg to 150 mg in any one of claims 25 to 33. Claim 35 A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg to 150 mg in any one of claims 25 to 34. Claim 36 A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, or 150 mg. Claim 37 In any one of claims 25 to 36, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual in the form of a tablet or capsule. Claim 38 In any one of claims 25 to 37, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is orally administered to the individual. Claim 39 In any one of claims 25 to 38, the individual is a mammal, preferably a human, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 40 In any one of paragraphs 25 to 39, the individual having a latent tuberculosis infection, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 41 In any one of paragraphs 25 to 40, the individual has a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleuritis, and is a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 42 In any one of claims 25 to 41, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for which dose titration is not required for the treatment of the individual. Claim 43 In any one of claims 25 to 41, the individual having suffered from latent tuberculosis infection but not reactivated after treatment, compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof. Claim 44 In any one of paragraphs 25 to 41, the individual has a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleuritis, but the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has not been reactivated after treatment. Claim 45 In any one of claims 25 to 41, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof that alleviates dry mouth of the individual. Claim 46 In any one of claims 25 to 41, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof that alleviates dry eye disease of the individual. Claim 47 In any one of claims 25 to 41, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the histopathological condition of the minor salivary gland of the individual is improved. Claim 48 In any one of claims 25 to 41, a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof that does not cause or worsen anxiety / depression in the individual. Claim 49 Use of the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts in the manufacture of drugs for the prevention or treatment of Sjögren's syndrome in individuals: Equation (I). Claim 50 In claim 49, use of administering the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to the above individual at a dose of 30 mg to 180 mg per day. Claim 51 In claim 49 or 50, use of administering the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to the individual at a dose of 60 mg to 150 mg per day. Claim 52 In any one of claims 49 to 51, use of administering to the individual a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a dose of 150 mg per day. Claim 53 A use according to any one of claims 49 to 52, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual at a dose of 120 mg per day. Claim 54 A use according to any one of claims 49 to 53, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual at least once a day. Claim 55 A use according to any one of claims 49 to 54, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual at least twice a day. Claim 56 A use according to any one of claims 49 to 55, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual twice daily at a dose of 30 mg to 75 mg per dose. Claim 57 A use according to any one of claims 49 to 56, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the individual twice daily at a dose of 30 mg to 60 mg per dose. Claim 58 Uses according to any one of claims 49 to 57, wherein the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 2.5 mg to 150 mg. Claim 59 Uses according to any one of claims 49 to 58, wherein the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg to 150 mg. Claim 60 Uses according to any one of claims 49 to 59, wherein the unit dose of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, or 150 mg. Claim 61 In any one of claims 49 to 60, use of administering the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to the individual in the form of a tablet or capsule. Claim 62 A use in any one of claims 49 to 61, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is orally administered to the individual. Claim 63 In any one of paragraphs 49 to 62, the use is that the individual is a mammal, preferably a human. Claim 64 In any one of paragraphs 49 to 63, the above-mentioned individual has a latent tuberculosis infection. Claim 65 In any one of paragraphs 49 to 64, the above-mentioned individual has a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleuritis. Claim 66 In any one of paragraphs 49 to 65, an application for which dose titration is not required for the treatment of the above-mentioned individual. Claim 67 In any one of paragraphs 49 to 65, the above-mentioned individual had a latent tuberculosis infection but was not reactivated after treatment. Claim 68 In any one of paragraphs 49 to 65, the above-mentioned individual has a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleuritis, but has not been reactivated after treatment. Claim 69 In any one of paragraphs 49 to 65, the use of alleviating dry mouth of the individual. Claim 70 An application in any one of paragraphs 49 to 65 for which dry eye syndrome of the individual is alleviated. Claim 71 A use in any one of claims 49 to 65, wherein the histopathological condition of the minor salivary gland of the individual is improved. Claim 72 In any one of paragraphs 49 to 65, a use that does not cause or worsen anxiety / depression in the said individual.

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