CN111249277A - Application of carboxyamine triazole compounds in the preparation of medicaments for treating or preventing autoinflammatory diseases - Google Patents

Abstract

The invention belongs to the field of medicine, in particular to the application of a carboxamine triazole compound or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating or preventing autoinflammatory diseases.

Description

Carboxamide triazole compounds in the preparation of medicines for treating or preventing autoinflammatory diseases applications in

technical field

The invention belongs to the field of medicine, in particular to the application of a carboxamine triazole compound or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating or preventing autoinflammatory diseases.

Background technique

Autoinflammatory diseases (AUID) are a group of diseases mediated by innate immunity (innate immunity) that have been gradually recognized in recent years, and are characterized by abnormally increased inflammatory responses. Sexual immune system disease. AUID is mostly a rare disease. It was first proposed in 1999 (Non-Patent Document 1), and it has developed into a group of diseases covering a wide range, ranging from monogenic diseases such as familial Mediterranean fever (FMF), tumor necrosis factor TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), NLRP12 autoinflammatory disease (the nucleotide-binding oligomerization domain-like receptor protein (NLRP) 12autoinflammatory disease (NLRP12AD)) wait until polygenic diseases such as adult Still disease (adult onset still disease, AOSD), Crohn's disease (Crohn's disease, CD) and so on.

The clinical manifestations of AUID are recurrent febrile symptoms, acute arthritis symptoms and systemic chronic inflammatory response symptoms caused by systemic inflammatory response. Monogenic AUID mostly occurs in neonates or early infancy, polygenic AUID occurs later, and can reach adolescence or even adults. Most of them have recurrent fever for several days to several weeks, accompanied by weight loss, fatigue, general malaise, and flu-like symptoms. Nonspecific manifestations such as symptoms, lymphadenopathy, and splenomegaly, which often disappear with the recovery of body temperature; may also have skin, muscles, joints, eyes, ears, blood system, gastrointestinal tract, respiratory tract, nervous system, and cardiovascular system Involvement can lead to disability or even death.

Since AUID is a hereditary disease that lasts for life, the main goal of its treatment is to rapidly relieve disease activity as soon as possible and restore the inflammatory response in the body to normal, thereby reducing tissue damage and complications (including amyloidosis) and allowing patients to return to normal life. and improve the quality of life of patients. Currently, first-line treatments for AUID include colchicine, nonsteroidal anti-inflammatory drugs, and glucocorticoids. However, the long-term use of the above drugs has many and serious adverse reactions, such as colchicine, which is common in the early gastrointestinal tract, with an incidence of up to 80%. In severe cases, it can cause dehydration and electrolyte imbalance. Long-term use can cause severe hemorrhagic gastrointestinal inflammation, nervous system toxicity, abnormal hematopoietic function, impaired renal function, etc. Moreover, as AUID is a disease mediated by innate immune disorders, the above-mentioned drugs are not specific therapeutic drugs, and some patients are ineffective against the above-mentioned drugs.

Recently, with the deepening of the understanding of the disease mechanism, targeted biological agents targeting the activated inflammatory factors in the inflammatory response pathway have brought the light of clinical treatment of AUID: IL-1 inhibitors have become the therapeutic IL-1 receptor antagonists. First-line drugs for deficiency of the interleukin 1receptor antagonist (DIRA) and cryopyrin-associated periodic syndromes (CAPS), also recognized as other AUID patients who are ineffective against first-line drugs such as colchicine In addition, TNF-α inhibitors and IL-6 inhibitors are also used (Non-Patent Documents 2-5).

Carboxamine triazole is a new type of antitumor drug, the chemical name is 5-amino-1-{[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl}-1H- 1,2,3-Triazole-4-carboxamide, the chemical structural formula is:

In Patent Document 1, it is disclosed that this compound has an antitumor effect. In addition, in Patent Document 2, it is disclosed that carboxamine triazole or a pharmaceutically acceptable salt thereof has preventive and/or therapeutic effects on silicosis.

However, so far, there is no report on the effect of carboxamide triazoles on the treatment of autoinflammatory diseases.

prior art literature

Patent Literature

Patent Document 1: European Patent EP0644880

Patent Document 2: Chinese Patent CN101919843

Non-patent literature

Non-Patent Document 1: Cell. 1999, 97: 133-144

Non-Patent Document 2: Clin Rev Allergy Immunol. 2013, 45; 2: 227-235

Non-Patent Document 3: Ann Rheum Dis. 2015, 74;9:1636-1644

Non-Patent Document 4: Front Pharmacol. 2017, 22;8:278

Non-patent document 5: Clin Immunol. 2018, pii: S1521-6616(18): 30432-30437

SUMMARY OF THE INVENTION

The problem to be solved by the invention

As mentioned above, the treatment of AUID, including first-line drugs such as colchicine, non-steroidal anti-inflammatory drugs and glucocorticoids, has serious adverse reactions, and the problem of disease recurrence often occurs after drug withdrawal, and some patients have The drug appears to be ineffective. In recent years, biological agents with targeted targeting effects, such as IL-1 inhibitors, TNF-α inhibitors and IL-6 inhibitors, are protein-based preparations and can only be administered by injection, which is prone to infusion and local The reaction at the injection site can also become a new antigen to stimulate the body to produce antibodies and make the drug ineffective; moreover, the above drugs have immunosuppressive effects, so long-term use can lead to fatal adverse reactions such as serious infections; in addition, the price is very expensive. More importantly, the IL-1 inhibitor as the main choice has not yet been introduced in the domestic market. Therefore, the development of new therapeutic agents effective for autoinflammatory diseases is urgently desired.

Therefore, an object of the present invention is to provide a novel method for treating or preventing autoinflammatory diseases, and more specifically, to provide an effective preventive/therapeutic agent for autoinflammatory diseases.

method used to solve the problem

In order to solve the above-mentioned problems, the present inventors found that carboxamine triazole compounds or pharmaceutically acceptable salts thereof are effective for the prevention/treatment of autoinflammatory diseases after repeated and in-depth research, thus completing the present invention. That is, the present invention relates to the following (1) to (5).

(1) the application of the carboxyamine triazole compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicine for the treatment or prevention of autoinflammatory diseases,

In the formula, X represents CH ₂ , S, O or C═O; R ₄ represents Cl, CF ₃ , Br or CH ₃ ; R ₅ represents Cl, Br or NO ₂ .

(2) The application according to (1), wherein the carboxyamine triazole compound is 5-amino-1-{[3,5-dichloro-4-(4-chlorobenzoyl)phenyl] ]methyl}-1H-1,2,3-triazole-4-carboxamide.

(3) The use according to (1), wherein the pharmaceutically acceptable salt is any one or more selected from the group consisting of hydrochloride, sulfate, orotate and acetate.

(4) The use according to any one of (1) to (3), wherein the autoinflammatory disease is selected from familial Mediterranean fever, tumor necrosis factor receptor-related periodic syndrome, and mevalon Acid Kinase Deficiency, NLRP12 Autoinflammatory Disorders, Cold Inflammasome-Associated Cyclic Fever Syndrome, Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, Neonatal Multisystem Inflammatory Disorders/Chronic Infantile Neurocutaneous Joint Syndrome , Blau syndrome, chronic relapsing multifocal osteomyelitis, septic arthritis-pyoderma gangrenosum-acne syndrome, Majeed syndrome, IL-1 receptor antagonist deficiency, IL-36 receptor antagonist Deficiency, PFAPA syndrome, nucleotide oligomerization domain 2-related autoinflammatory disorders, Yao's syndrome, STING-related vascular disease, infant-onset STING-related vascular disease, adenosine deaminase 2 deficiency, protease Body-related autoinflammatory syndrome, Nakajo-Nishimura syndrome, joint contracture-amyotrophy-microcytic anemia-pannicitis-related lipodystrophy syndrome, chronic atypical neutrophilic dermatosis with fever and lipoatrophy, Panniculitis-induced juvenile lipodystrophy syndrome, Schnitzler syndrome, interferon-mediated autoinflammatory disease, Aicardi-Goutières syndrome, interferon-stimulated response gene 15 deficiency disease, spinal chondrodysplasia with immune dysregulation , Phospholipase Cγ2-related antibody deficiency and immune dysregulation, CARD14-mediated psoriasis, linear ubiquitin chain assembly complex deficiency, sideroblastic anemia, immunodeficiency, fever, and prolonged developmental syndrome, familial macrognathia disease, early-onset sarcoidosis, recurrent mole type 1, HOIL-1 deficiency, HOIP deficiency, generalized pustulosis, palmoplantar pustulosis, substratum corneum pustulosis, delayed pressure urticaria Measles, inflammatory acrodermatitis, neutrophilic panniculitis, PASH syndrome, SAPHO syndrome, childhood SAPHO syndrome, autoinflammatory bone disease, chronic aseptic osteomyelitis, disseminated superficial actinic Porokeratosis, Familial Lichenoid Keratosis Chronic, Syndrome H, Pyrin-Associated Autoinflammatory Disorders with Neutrophilic Skin Disease, Macrophage Activation Syndrome, Singleton-Merten Syndrome, X Linked reticulopigmentation, TORCH syndrome, OTULIN-related autoinflammatory disease, A20 haploinsufficiency, adult Still's disease, pseudogout, systemic juvenile idiopathic arthritis, Crohn's disease, inflammatory bowel disease disease, severe infantile inflammatory bowel disease, Sweet syndrome, familial hemophagocytic lymphocytosis, inflammasome disease, NLRC4-related macrophage activation syndrome, and NLRP1-related syndrome with arthritis and dyskeratosis Any one or more of autoinflammatory diseases.

(5) The use according to (4), wherein the autoinflammatory disease is selected from familial Mediterranean fever, chronic relapsing multifocal osteomyelitis, mevalonate kinase deficiency, and NLRP12 autoinflammatory disease , Cold inflammatory associated periodic fever syndrome, Familial cold autoinflammatory syndrome, Muckle-Wells syndrome, Neonatal multisystem inflammatory disease/chronic infantile neurocutaneous joint syndrome, Septic arthritis-pyoderma gangrenosum Disease - acne syndrome, Majeed syndrome, IL-1 receptor antagonist deficiency, IL-36 receptor antagonist deficiency, Schnitzler syndrome, recurrent mole type 1, SAPHO syndrome, childhood SAPHO syndrome, Autoinflammatory bone disease, chronic aseptic osteomyelitis, familial lichenoid keratosis, Pyrin-related autoinflammatory disease with neutrophilic dermatosis, A20 haploinsufficiency, adult Still's disease, pseudo Gout, systemic juvenile idiopathic arthritis, severe infantile inflammatory bowel disease, Sweet syndrome, NLRC4-related macrophage activation syndrome, NLRP1-related autoinflammatory disease with arthritis and dyskeratosis, phospholipids Enzyme Cγ2-related antibody deficiency and immune dysregulation, Blau syndrome, nucleotide oligomerization domain 2-related autoinflammatory disorders, Yao's syndrome, CARD14-mediated psoriasis, linear ubiquitin chain assembly complex deficiency, Early-onset sarcoidosis, HOIL-1 deficiency, HOIP deficiency, generalized pustulosis, inflammatory acrodermatitis, OTULIN-associated autoinflammatory disease, tumor necrosis factor receptor-associated periodic syndrome, PFAPA syndrome, More than any one of substratum corneum pustular dermatosis, disseminated superficial actinic porokeratosis, X-linked reticular hyperpigmentation, and H syndrome.

Invention effect

According to the present invention, it is possible to provide a novel preventive/therapeutic agent effective for autoinflammatory diseases containing a carboxamine triazole compound or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, according to the present invention, a novel method of treating or preventing autoinflammatory diseases can be provided.

Description of drawings

Figure 1 shows the effect of CAI (carboxyamidotriazole, carboxyamidotriazole) on the levels of IL-1β, IL-6 and TNF-α secreted by peripheral blood mononuclear cells (PBMCs) in patients with Blau syndrome (BS). ^* P<0.05, ^** P<0.01.

Figure 2 shows the effect of CAI on nuclear translocation of NF-κB p65 in PBMCs of BS patients.

Figure 3 shows the effect of CAI on the expression of IκB and p-p65 in PBMCs of BS patients.

Figure 4 shows the effect of CAI on the levels of IL-1β, IL-6 and TNF-α secreted by PBMCs of familial Mediterranean fever (FMF) patients. ^* P<0.05, ^** P<0.01, ^*** P<0.001.

Figure 5 shows the effect of CAI on the levels of IL-1β and IL-6 secreted by PBMCs of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) patients. ^* P<0.05.

Figure 6 shows the effect of CAI on the levels of IL-1β and IL-6 secreted by PBMCs of patients with NLRP12 autoinflammatory disease (NLRP12AD). ^* P<0.05.

Figure 7 shows the effect of CAI on the levels of IL-1β and IL-6 secreted by PBMCs of patients with YAO syndrome. ^** P<0.01, ^*** P<0.001.

Figure 8 shows the effect of CAI on the levels of IL-1β secreted by PBMCs in patients with cold inflammatory hormone-associated periodic fever syndrome (CAPS)-Muckle-Wells syndrome (MWS). ^* P<0.05, ^** P<0.01, ^*** P<0.001.

Figure 9 shows the effect of CAI on the levels of IL-1β, IL-6 and TNF-α secreted by PBMCs of adult Still's disease (AOSD). ^* P<0.05.

Detailed ways

The carboxylamine triazole compounds described in the present invention include carboxylamine triazole and its analogs and derivatives. Specifically, the carboxylamine triazole compounds described in the present invention include compounds having the structure shown in the following formula (I):

Wherein, R ₁ has the structure of formula (II):

where p is an integer from 0 to 2; m is an integer from 0 to 4; n is an integer from 0 to 5; X can be O, S, SO, SO ₂ , C=O, CHCN, CH ₂ or C=NR ₆ ;

Wherein, R ₆ is hydrogen, (C1-C6) alkane, hydroxyl, (C1-C6) alkoxy, amino, (C1-C6) alkaneamino, dialkylamino or cyano;

R ₄ and R ₅ are respectively halogen, cyano, trifluoromethyl, (C1-C6) alkanoyl, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, carbonyl, Alkyl ester, trifluoromethoxy, acetamido, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylidene Sulfonyl or trifluoromethylsulfonyl;

R ₂ is amino, (C1-C6) alkylamino, dialkylamino, acetamido, acetimide, ureidoacyl, formamido, carboximide or guanidino;

R ₃ is carbamoyl, cyano, carbamoyl, imino or N-hydroxycarbamoyl.

As a more specific carboxylamine triazole compound represented by formula (I), in formula (II), n and m are respectively 0, 1 or 2; P is 1; X is O, S, C=O or CH ₂ ; R ₄ is fluorine, chlorine, bromine, methyl, trifluoromethyl, cyano, methoxycarbonyl, trifluoromethoxy, trifluoromethylthio, nitro or trichlorovinyl; R ₅ is Chlorine, bromine, fluorine, methyl, trifluoromethyl, cyano, alkylester, trifluorovinyl or nitro.

As a more specific carboxylamine triazole compound shown in formula (I), it has the structural formula shown in the following formula (A):

In the formula, X is CH ₂ , S, O or C=O; R ₄ is Cl, CF ₃ , Br or CH ₃ ; R ₅ is Cl, Br or NO ₂ .

As a more specific carboxylamine triazole compound represented by formula (I), it is 5-amino-1-{[3,5-dichloro-4-(4-chlorobenzoyl)benzene represented by the following structural formula base]methyl}-1H-1,2,3-triazole-4-carboxamide, namely carboxyamidotriazole (hereinafter sometimes referred to as CAI).

As the pharmaceutically acceptable salt of the carboxamine triazole compound, hydrochloride, sulfate, orotate or acetate can be exemplified.

The present invention includes the use of the above-mentioned carboxyamine triazole compounds or their pharmaceutically acceptable salts in the preparation of medicines for treating or preventing autoinflammatory diseases (AUID).

AUID is caused by abnormalities of the innate immune system, including dysregulation of neutrophils, macrophages, NK cells, and innate immunity-related molecules that protect the body from external pathogens. Different from autoimmune diseases (such as systemic lupus erythematosus), mononuclear macrophages, rather than T and B lymphocytes, are mainly involved in the process of inflammatory response damage in AUID, and there are no autoantibodies or antigen-specific T cells in AUID patients. cell.

At present, AUID has developed into a group of diseases covering a wide range, specifically, including the following: familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS) , (also known as: tumor necrosis factor receptor-associated periodic fever syndrome (TNF receptor-associated periodic_fever syndrome)), mevalonate kinase deficiency (MKD, high IgD was once considered to be the diagnosis of this NLRP12 autoinflammatory disease (the nucleotide-bindingoligomerization domain- like receptor protein (NLRP) 12autoinflammatory disease (NLRP12AD), also known as NLRP12-related autoinflammatory disease (NLRP12-related autoinflammatorydisease) or familial cold autoinflammatory syndrome type 2 (familial cold autoinflammatory syndrome 2, FCAS 2)), cold inflammatory hormone Associated periodic fever syndrome (also known as cryopyrin-associated periodic syndrome, CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (Muckle-Wells syndrome) , MWS), neonatal-onsetmultisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome (NOMID/CINCA), Blau syndrome (BS), chronic relapse Chronic recurrent multifocal osteomyelitis (chronic recurrent multifocal osteomyelitis, CRMO), septic arthritis-pyoderma gangrenosum-acne syndrome (pyogenic arthritis, pyoderma gangrenosum and acne syndrome, PAPAS, also known as PAPA syndrome), Majeed syndrome (Majeed syndrome), IL-1 receptor antagonism Deficiency of the interleukin 1receptor antagonist (DIRA), deficiency of IL-36 receptor antagonist (DITRA), PFAPA syndrome (PFAPA syndrome, also known as Marshall syndrome or periodic fever) , aphthous stomatitis, pharyngitis and lymphadenitis syndrome (periodicfever, aphthosis stomatitis, pharyngitis, and adenitis syndrome), nucleotide-binding oligomerization domain 2-associated autoinflammatory disease, NAID, also known as NOD2-associated autoinflammatory disease), Yaosyndrome (formerly NOD2-associated autoinflammatory disease (NAID)), STING-associated vasculopathy, infant-onset STING-associated vasculopathy disease (also known as juvenile-onset STING-associated vasculopathy, STING-associated vasculopathy with onset in infancy, SAVI), Deficiency of Adenosine Deaminase 2 (ADA2) (DADA2), proteasome-associated Autoinflammatory syndromes (proteasome-associated autoinflammatory syndromes, PRAAS), Nakajo-Nishimura syndrome (NNS, also known as Nakajo-Nishimura syndrome, also known as Japanese autoinflammatory syndrome with lipoatrophy ( Japanese autoinflammatory syndrome with lipodystrophy, JASL)), joint contracture-muscular atrophy-microcytic anemia-lipidemia Joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy (JMP), chronic atypical neutrophilic dermatosis with lipodystrophy and lipodystrophy elevated temperature syndrome, also known as CANDLE syndrome, CANDLE syndrome), panniculitis-induced childhood-onset lipodystrophy syndrome, Schnitzler syndrome (Schnitzler syndrome), interferon-mediated autoinflammation Sexual diseases (also known as interferon disease), Aicardi-Goutières syndrome (AGS), interferon stimulated gene (ISG) 15 deficiency (ISG15 deficiency), spinal chondrodysplasia with immune Spondyloenchondrodysplasia with immune dysregulation (SPENCDI), Phospholipase-Cγ2-associated antibody deficiency and immune dysregulation (PLAID), CARD14-mediated psoriasis (CAMPS) ), linear ubiquitin chainassembly complex (LUBAC) deficiency, sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD), Familial macrognathia (Cherubism), early-onset sarcoidosis (EOS), recurrent hydatidiform mole 1 (RHM) 1), HOIL-1 deficiency (HOIL-1 deficiency), HOIP deficiency (HOIP deficiency), generalized pustulosis (GPP), palmoplantar pustulosis (PPP), substratum corneum pustular skin disease (SCPD), late Idiopathic pressure urticaria, inflammatory acrodermatitis, neutrophilic panniculitis, PASH syndrome (PASH syndrome, namely pyoderma gangrenosum, acne, hidradenitis suppurativa hidradenitis syndrome), SAPHO syndrome (SAPHO syndrome, synovitis, acne, impetigo, hyperostosis and osteomyelitis syndrome, synovitis-acne-pustulosis-hyperostosis-osteomyelitis syndrome), SAPHO syndrome in children, autoinflammation autoinflammatory bonediseases, chronic nonbacterial osteomyelitis (CNO), disseminated superficial actinic porokeratosis (DSAP), familial chronic lichenoid horns Chemopathy, H syndrome (H syndrome, SCL29A3 mutation), Pyrin-associated autoinflammation with neutrophilicdermatosis (PAAND), macrophage activation syndrome (PAAND) , MAS), Singleton-Merten Syndrome (Singleton-Merten Syndrome, SMS), X-linked reticulate pigmentary disorder (XLPDR), TORCH syndrome (TORCH Syndrome), OTULIN-related autoinflammatory Disease (The OTULIN-related autoinflammatory syndrome, ORAS), A20 haploinsufficiency (HA20), adult Still disease (AOSD), gout (gout), pseudogout, systemic juvenile idiopathic joint Inflammation (systemic ons etjuvenile idiopathic arthritis (SoJIA), Behcet's disease (BD, also known as Behcet syndrome), Crohn's disease (CD), inflammatory bowel disease (IBD), severe infantile inflammatory bowel disease (severe infantile inflammatory bowel disease), sweet syndrome, familial hemophagocytic lymphohistiocytosis (also known as familial hemophagocytic lymphohistiocytosis, FHL), inflammasompathies , NLRC4-related macrophage activation syndrome (NLRC4-MAS, also known as syndrome of enterocolitis and autoinflammation associated with mutation in NLRC4 (SCAN4)), NLRP1-related autoinflammatory diseases associated with arthritis and dyskeratosis, etc.

According to the different pathogenesis, AUID can be divided into inflammasomopathies (also known as IL-1β activation disorders), NF-κB activation disorders (NF-κB activation disorders), and protein folding disorders. disorders of the innate immune system, complement disorders, macrophage activation related diseases, mitochondrial dysfunction related diseases, cytokine signaling disorders ), proteasome disability disorders, and other autoinflammatory diseases of unknown etiology. Specifically, the above-mentioned inflammasome diseases include: Familial Mediterranean Fever, Mevalonate Kinase Deficiency, NLRP12 Autoinflammatory Disease, Cold Inflammasome-Associated Periodic Fever Syndrome, Familial Cold Autoinflammatory Syndrome, Muckle- Wells syndrome, neonatal multisystem inflammatory disease/chronic infantile neurocutaneous joint syndrome, chronic relapsing multifocal osteomyelitis, septic arthritis-pyoderma gangrenosum-acne syndrome, Majeed syndrome, IL- 1 receptor antagonist deficiency, IL-36 receptor antagonist deficiency, Schnitzler syndrome, recurrent mole type 1, SAPHO syndrome, childhood SAPHO syndrome, autoinflammatory bone disease, chronic aseptic osteomyelitis , familial lichenoid keratosis, Pyrin-related autoinflammatory disease with neutrophilic dermatosis, A20 haploinsufficiency, adult Still's disease, gout, pseudogout, systemic juvenile idiopathic arthritis , Behçet's disease, severe infantile inflammatory bowel disease, Sweet syndrome, NLRC4-related macrophage activation syndrome, NLRP1-related autoinflammatory disease with arthritis and dyskeratosis, phospholipase Cγ2-related antibody deficiency and immune disorders; the above-mentioned NF-κB activation diseases include: Blau syndrome, nucleotide oligomerization domain 2-related autoinflammatory diseases, Yao's syndrome, CARD14-mediated psoriasis, linear ubiquitin chain assembly complex disease, early-onset sarcoidosis, HOIL-1 deficiency, HOIP deficiency, generalized impetigo, inflammatory acrodermatitis, OTULIN-related autoinflammatory diseases, etc.; the above protein folding diseases include: tumor necrosis factor receptor related periodic syndromes, etc.; the above-mentioned complement-related diseases include: atypical hemolytic-uremic syndrome, age-related macular degeneration, etc.; the above-mentioned macrophage activation-related diseases include: adenosine deaminase 2 deficiency, macrophage activation syndrome The above-mentioned diseases related to mitochondrial dysfunction include: sideroblast anemia, immunodeficiency, fever and prolonged development syndrome, etc.; the above-mentioned diseases related to dysregulation of cytokine signal transduction include: interferon-mediated autoinflammatory diseases, STING-associated vascular disease, infant-onset STING-associated vascular disease, joint contracture-muscular atrophy-microcytic anemia-pannicitis-associated lipodystrophy syndrome, Aicardi-Goutières syndrome, interferon-stimulated response gene 15 deficiency, spine Chondrodysplasia with immune dysregulation, Singleton-Merten syndrome, TORCH syndrome, familial macrognathia, palmoplantar pustulosis, PASH syndrome, familial hemophagocytic lymphocytosis, late-onset stress Urticaria, etc.; the above-mentioned proteasome-deficient diseases include: proteasome-related autoinflammatory syndrome, Nakajo-Nishimura syndrome, chronic atypical neutrophilic dermatosis with fever and lipoatrophy, juvenile fat metabolism induced by panniculitis Disorder syndrome, neutrophil panniculitis, etc.; the above autoinflammatory diseases of unknown etiology include: PF APA syndrome, subhorny pustular dermatosis, disseminated superficial actinic porokeratosis, X-linked reticular pigmentation, H syndrome, etc. (Horror autoinflammaticus: the molecular pathophysiology of autoinflammatorydisease (*) . Annu Rev Immunol, 2009. 27: 621-668 et al).

In addition, the present invention includes a method of treating a patient suffering from AUID, the method comprising the step of administering to the patient an effective amount of a carboxamine triazole or a pharmaceutically acceptable salt thereof.

The dosage employed will, of course, depend on the particular disease being treated, as well as other factors including age, weight, health, severity of symptoms, route of administration, frequency of treatment and whether other drugs are concomitant during treatment. The dosage of active compound to be employed can be readily determined by conventional methods known to those of ordinary skill in the art. For the carboxyamine triazole compound of the present invention or a pharmaceutically acceptable salt thereof, the daily dose for an adult is usually in the range of about 10 mg to 300 mg, preferably in the range of about 50 mg to 200 mg. For example, a human suffering from AUID can be administered orally with a total daily dose of between 50 mg and 200 mg of the carboxamine triazoles of the present invention. Alternatively, the carboxamine triazoles of the present invention may be administered rectally to a human with AUID in a total daily dose of between 50 mg and 200 mg.

In addition, the present invention also includes a pharmaceutical composition comprising the carboxyamine triazole compound of the present invention or a pharmaceutically acceptable salt thereof. More specifically, standard pharmaceutically acceptable carriers, fillers, solubilizers and stabilizers, etc. well known to those skilled in the art can be used to formulate the carboxyamine triazoles or their pharmaceutically acceptable salts into a pharmaceutical combination. thing.

A pharmaceutical composition comprising a carboxyamine triazole compound or a pharmaceutically acceptable salt thereof is administered to an individual in need of such a medicament by any of a variety of routes including, but not limited to, topical, oral, intravenous, intramuscular , intraarterial, intramedullary, intrathecal, intraventricular, percutaneous, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal.

Oral preparations can be solid preparations such as tablets, capsules, powders, granules, or liquid preparations such as solutions, suspensions, and the like. Formulations suitable for oral administration may contain pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carriers or excipients suitable for solid preparations (such as tablets or capsules) may be: for example, binders (such as acacia, gelatin, dextrin, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone), diluents (such as lactose, sucrose, mannitol, cornstarch, potato starch, calcium phosphate, calcium citrate, crystalline cellulose), lubricants (such as magnesium stearate, calcium stearate, stearic acid) acid, talc, anhydrous silica gel), disintegrating agents (eg, corn starch, potato starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid), and humectants (eg, sodium lauryl sulfate). Pharmaceutically acceptable carriers or excipients suitable for liquid preparations (such as solutions or suspensions) may be: for example, aqueous lysozyme (such as water), suspending agents (such as acacia, gelatin, methylcellulose, carboxymethyl) Sodium cellulose, hydroxymethyl cellulose, aluminum stearate gel), surfactants (such as lecithin, sorbitan monooleate, glycerol monostearate) and non-aqueous lysozymes (such as poly Ethylene Glycol 400, Glycerin, Propylene Glycol, Vegetable Oil). In addition, liquid preparations may contain preservatives (eg, methylparaben, propylparaben), flavoring and/or coloring agents.

Enteral infusion formulations (enemas) may be in the form of aqueous or suspension formulations prepared using the above-described aqueous enzymes or suspending agents. When necessary, the enema may be a sol or gel formulation prepared using a thickening agent such as polyacrylic acid, gelatin, and the like.

Suppositories can be prepared by conventional methods by mixing carboxyamine triazole or a pharmaceutically acceptable salt, analog, derivative thereof with a commercially available oily base such as Witepsole or the like or a water-soluble base such as polyethylene glycol, glycerin, gelatin, etc. . Suppositories can be capsule-type suppositories, tablet-type suppositories, or ointment-type suppositories.

External preparations may include external powders, ointments, creams, and the like.

Example

The present invention is further illustrated by the following examples, but the present invention is not limited by the following examples.

AUID covers a broad but uniform spectrum of systemic inflammatory responses due to elevated pro-inflammatory factors IL-1β, TNF-α, and IL-6, including recurrent febrile symptoms, acute arthritis symptoms, and systemic chronic inflammation Symptoms, and reductions in cytokine levels directly reflect disease remission. In recent years, inhibitors targeting these three cytokines have also been increasingly used in the treatment of AUID and have shown good efficacy (for example, see Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015, 74 (9 ): 1636-1644 etc.). Due to the lack of suitable animal models, when scientists evaluate the efficacy of drugs on AUID, they often use the detection of the levels of cytokines secreted by peripheral blood mononuclear cells (PBMC) of patients after administration to evaluate the efficacy of drugs. (See, eg, Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasomeactivation Proc Natl Acad Sci US A. 2016;113(50):14384-14389 et al). Therefore, the inventors isolated and cultured PBMCs of various AUID patients, and detected the levels of IL-1β, TNF-α, and IL-6 to evaluate the therapeutic effect of CAI on AUID.

Example 1 The effect of CAI on the secretion of pro-inflammatory cytokines by PBMC of patients with Blau syndrome (BS)

PBMCs from BS patients were routinely isolated, and the cell suspension was prepared in DMEM high-glucose medium containing 10% fetal bovine serum, and seeded in a 24-well plate at 1×10 ⁶ cells/well. The experimental groups are as follows:

(1) BS group: only medium was added;

(2) CAI treatment group: CAI was added at a final concentration of 40 μM;

(3) LPS+muramyl dipeptide (MDP) group: add LPS (final concentration 10ng/ml) and MDP (final concentration 10μg/ml) at the same time;

(4) LPS+MDP+CAI group: LPS (final concentration 10 ng/ml), MDP (final concentration 10 μg/ml) and CAI (final concentration 40 μM) were added simultaneously.

The cell supernatant was collected after culturing in a 37°C, 5% CO ₂ incubator for 22h, and frozen at -20°C. The levels of IL-1β, IL-6 and TNF-α in the cell supernatants were determined by enzyme-linked immunosorbent assay (ELISA).

As shown in Figure 1, PBMCs of patients with BS secreted higher levels of IL-1β, IL-6 and TNF-α, and 40 μM CAI treatment could significantly reduce the levels of these cytokines in the supernatant, with the inhibition rates of 25.66%, respectively (P <0.05), 87.84% (P<0.05) and 90.75% (P<0.01). The levels of IL-1β, IL-6 and TNF-α secreted were further significantly increased after PBMC cells from BS patients were stimulated with LPS and MDP for 22 h, while 40 μM CAI had no effect on LPS and MDP-induced IL-1β, IL-6 and TNF-α. The increase in the secretion level of α had a significant inhibitory effect, and the inhibition rates were 66.90% (P<0.05), 54.93% (P<0.05) and 44.66% (P<0.05), respectively. The results suggest that CAI may have a good therapeutic effect on BS.

Example 2 Effects of CAI on nuclear translocation of NF-κB p65 in PBMC of BS patients

NF-κB is a kind of nuclear transcription factor, which has important transcriptional regulatory effects on cytokines such as IL-1β, IL-6 and TNF-α. The NF-κB family includes p50/p105, p52/p100, Rel(p65), RelB, and c-Rel, which usually exist in the form of homologous or heterodimers, and the most common form is heterologous composed of p50/p65 dimer. In the resting state, p50/p65 binds to its inhibitory protein IκB and exists in the cytoplasm as an inactive complex. When subjected to various stimuli, IκB is degraded, and the active p50/p65 dimer is released and translocated to the nucleus, where it binds to specific DNA sequences in the promoter/enhancer regions of the corresponding cytokine target genes, thereby activating the transcription process . Since the expression of p65 protein in the nucleus can be considered as a marker of NF-κB activation, the nuclear translocation of p65 in PBMCs of BS patients was examined.

PBMCs from BS patients were routinely isolated, and the cell suspension was prepared in DMEM high-glucose medium containing 10% fetal bovine serum, and 1×10 ⁶ cells/well were seeded in a 24-well plate pre-coated with sterile glass slides. The experiments were divided into groups. Same as Example 1. After culturing in a 37°C, 5% CO ₂ incubator for 22 h, the medium in the wells was discarded, and the nuclear translocation of NF-κB p65 was observed by immunofluorescence staining combined with laser confocal microscopy. NF-κB p65 antibody was purchased from Cell Signaling Company, and anti-rabbit Alexa Fluor488 was purchased from Biyuntian Biotechnology Company.

As shown in Figure 2, NF-κB p65 was expressed at a high level in the PBMCs of the BS group and was located in the nucleus. After treatment with 40 μM CAI, the green fluorescence expression and fluorescence intensity of NF-κB p65 in the nucleus were significantly reduced. After the PBMCs of BS patients were stimulated with LPS and MDP, the fluorescence intensity of NF-κB p65 was further enhanced, and the expression level was significantly increased, while 40 μM CAI could significantly attenuate the LPS and MDP-induced enhancement of the fluorescence intensity of NF-κB p65, and part of the fluorescence distribution in the cytoplasm. The results suggest that CAI has a significant inhibitory effect on the enhanced nuclear translocation of NF-κB p65 in PBMCs of BS patients, and CAI may inhibit the activation of NF-κB in PBMCs of BS patients.

Example 3 Effects of CAI on the expression of IκB and p-p65 in PBMC of BS patients

In the process of NF-κB activation, it is accompanied by the degradation of IκBα. In addition, phosphorylation of p65 can increase its ability to bind to DNA and enhance its transcriptional activation ability. Therefore, the degradation of IκBα and the phosphorylation level of p65 in PBMCs of BS patients were detected.

PBMCs from BS patients were routinely isolated, and the cell suspension was prepared in DMEM high-glucose medium containing 10% fetal bovine serum, and seeded in a 24-well plate at 1×10 ⁶ cells/well. The experimental groups are as follows:

(1) BS group: only add medium;

(2) CAI 10μM group: add CAI at a final concentration of 10μM

(3) CAI 20μM group: add CAI at a final concentration of 20μM

(4) CAI 40μM group: add CAI at a final concentration of 40μM

After culturing in a 37°C, 5% CO ₂ incubator for 22h, the total protein of cells in each well was extracted and frozen at -80°C. The expression levels of IκB and p-p65 were detected by western blot, and β-actin was used as an internal reference.

As shown in Figure 3, compared with the BS group, the expression level of IκB in the CAI (10, 20, 40 μM) group was significantly increased, while the expression level of p-p65 was significantly decreased. The results suggest that CAI may inhibit the nuclear translocation of NF-κB p65 by reducing the degradation of IκB and the phosphorylation of p65 in PBMC cells of patients with BS, thereby reducing the levels of IL-1β, IL-6 and TNF-α, and exerting its effect on BS. Therapeutic effect.

Example 4 The effect of CAI on the secretion of pro-inflammatory cytokines by PBMC of patients with familial Mediterranean fever (FMF)

PBMCs from patients with FMF were routinely isolated, and the cell suspension was prepared in DMEM high-glucose medium containing 10% fetal bovine serum, and seeded in a 24-well plate at 1×10 ⁶ cells/well. The experimental groups are as follows:

(1) FMF group: only medium was added;

(2) CAI 10μM group: CAI at a final concentration of 10μM was added;

(3) CAI 20μM group: CAI at a final concentration of 20μM was added;

(4) CAI 40μM group: CAI at a final concentration of 40μM was added;

The cell supernatant was collected after culturing in a 37°C, 5% CO ₂ incubator for 24h, and frozen at -20°C. The levels of IL-1β, IL-6 and TNF-α in the cell supernatant were determined by ELISA.

As shown in Figure 4, CAI can significantly reduce the higher levels of IL-1β, IL-6 and TNF-α secreted by PBMCs of FMF patients, and the inhibition rates of IL-1β secretion by CAI (10, 20, and 40 μM), respectively 26.71% (P<0.05), 38.44% (P<0.01) and 49.87% (P<0.001), the inhibition rate of 40μM CAI on IL-6 secretion was 51.26% (P<0.001), and 40μM CAI on TNF-α secretion The inhibition rate was 22.07% (P<0.05). The results suggest that CAI may have a good therapeutic effect on FMF.

Example 5 The effect of CAI on the secretion of pro-inflammatory cytokines by PBMC of patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

PBMCs from TRAPS patients were routinely isolated, and the cell suspension was prepared in DMEM high-glucose medium containing 10% fetal bovine serum, and seeded in 24-well plates at 2×10 ⁶ cells/well. The experimental groups are as follows:

(1) TRAPS group: only medium was added;

(2) CAI treatment group: CAI was added at a final concentration of 40 μM;

(3) LPS group: add LPS (final concentration 1 μg/ml);

(4) LPS+CAI 40μM group: add LPS (final concentration 1μg/ml) and CAI (final concentration 40μM) at the same time;

The cell supernatant was collected after culturing in a 37°C, 5% CO ₂ incubator for 3 h, and stored at -20°C. The levels of IL-1β and IL-6 in the cell supernatant were determined by ELISA.

As shown in Figure 5, 40 μM CAI reduced the higher levels of IL-1β and IL-6 in the culture supernatant of PBMCs from TRAPS patients, with inhibition rates of 17.49% (P<0.05) and 61.11% (P<0.05), respectively. The results suggest that CAI may have a good therapeutic effect on TRAPS.

Example 6 The effect of CAI on the secretion of pro-inflammatory cytokines by PBMC of patients with NLRP12 autoinflammatory disease (NLRP12AD)

PBMCs from patients with NLRP12AD were routinely isolated, and cell suspensions were prepared in DMEM high-glucose medium containing 10% fetal bovine serum, and seeded in 24-well plates at 2×10 ⁶ cells/well. The experimental groups are as follows:

(1) NLRP12AD group: only medium was added;

(2) CAI 10μM group: CAI at a final concentration of 10μM was added;

(3) CAI 20μM group: CAI at a final concentration of 20μM was added;

(4) CAI 40μM group: CAI at a final concentration of 40μM was added;

The cell supernatant was collected after culturing in a 37°C, 5% CO ₂ incubator for 3 h, and stored at -20°C. The levels of IL-1β and IL-6 in the cell supernatant were determined by ELISA.

As shown in Figure 6, CAI could significantly reduce the higher levels of IL-1β and IL-6 in the culture supernatant of PBMCs from NLRP12AD patients, and the inhibition rates of CAI (20, 40 μM) on IL-1β were 75.79% (P <0.05) and 55.98% (P<0.05), the inhibition rates of CAI (10, 20, 40μM) on IL-6 were 62.22% (P<0.05), 72.56% (P<0.05) and 69.51% (P<0.05), respectively. 0.05). The results suggest that CAI may have a good therapeutic effect on NLRP12AD.

Example 7 The effect of CAI on the secretion of pro-inflammatory cytokines by PBMC of Yao syndrome (previously known as NOD2-associated autoinflammatory disease (NAID)) patients

PBMCs from patients with Yao's syndrome were routinely isolated, and the cell suspension was prepared in DMEM high-glucose medium containing 10% fetal bovine serum, and seeded in a 24-well plate at 1×10 ⁶ cells/well. The experimental groups are as follows:

(1) Yao's syndrome group: only medium was added;

(2) CAI 10μM group: CAI at a final concentration of 10μM was added;

(3) CAI 20μM group: CAI at a final concentration of 20μM was added;

(4) CAI 40μM group: CAI at a final concentration of 40μM was added;

The cell supernatant was collected after culturing in a 37°C, 5% CO ₂ incubator for 22h, and frozen at -20°C. The levels of IL-1β and IL-6 in the cell supernatant were determined by ELISA.

As shown in Figure 7, CAI can significantly reduce the higher levels of IL-1β and IL-6 in the culture supernatant of PBMCs of patients with Yao's syndrome, and the inhibition rates of CAI (20, 40 μM) on IL-1β secretion were respectively 55.53% (P<0.01) and 56.98% (P<0.01), the inhibition rates of CAI (10, 20, 40 μM) on IL-6 secretion were 31.43% (P<0.01), 30.69% (P<0.01) and 52.72% (P<0.001). The results suggest that CAI may have a good therapeutic effect on Yao's syndrome.

Example 8 The effect of CAI on the secretion of pro-inflammatory cytokines from PBMC of CAPS patients

CAPS is caused by the persistent activation of the NLRP3 inflammasome due to mutations in the NLRP3 gene, which is characterized by increased IL-1β, leading to periodic flare-ups of inflammation. CAPS is divided into familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurocutaneous joint syndrome (NOMID/CINCA) according to the clinical manifestations from mild to severe.

PBMCs from CAPS-MWS patients were routinely isolated, and cell suspensions were prepared in DMEM high-glucose medium containing 10% fetal bovine serum, and seeded in 24-well plates at 2×10 ⁶ cells/well. The experimental groups are as follows:

(1) Normal control group (CON): normal human PBMC, only the medium was added without any treatment;

(2) CAPS group: CAPS is only added to the medium;

(3) CAI treatment group: CAI was added at a final concentration of 40 μM;

(4) LPS group: add LPS (final concentration 1 μg/ml);

(5) LPS+CAI 10 μM group: add LPS (final concentration 1 μg/ml) and CAI (final concentration 10 μM) at the same time;

(6) LPS+CAI 20 μM group: add LPS (final concentration 1 μg/ml) and CAI (final concentration 20 μM) at the same time;

(7) LPS+CAI 40μM group: add LPS (final concentration 1μg/ml) and CAI (final concentration 40μM) at the same time;

The cell supernatant was collected after culturing in a 37°C, 5% CO ₂ incubator for 3 h, and stored at -20°C. The level of IL-1β in the cell supernatant was determined by ELISA.

As shown in Figure 8, compared with normal human PBMC, the level of IL-1β secreted by PBMC of CAPS-MWS patients was significantly increased (P<0.05). Administration of 40 μM CAI could significantly reduce the level of IL-1β in the supernatant, and the inhibition rate was 85.95%, with a significant difference (P<0.01). LPS-stimulated PBMC cells from CAPS-MWS patients significantly increased the level of secreted IL-1β (P<0.01), while CAI (10, 20, 40 μM) could significantly inhibit LPS-induced IL-1β secretion, and the inhibition rates reached 74.15% (P<0.001), 73.11% (P<0.01) and 93.42% (P<0.001). The results suggest that CAI may have a good therapeutic effect on CAPS-MWS.

Example 9 The effect of CAI on the secretion of pro-inflammatory cytokines by PBMC of adult onset still disease (AOSD) patients

PBMCs from AOSD patients were routinely isolated, and the cell suspension was prepared in DMEM high-glucose medium containing 10% fetal bovine serum, and seeded in 24-well plates at 2×10 ⁶ cells/well. The experimental groups are as follows:

(1) AOSD group: only medium was added;

(2) CAI treatment group: CAI was added at a final concentration of 40 μM;

The cell supernatant was collected after culturing in a 37°C, 5% CO ₂ incubator for 3 h, and stored at -20°C. The levels of IL-1β, IL-6 and TNF-α in the cell supernatant were determined by ELISA.

As shown in Figure 9, administration of 40 μM CAI treatment can significantly reduce the levels of IL-1β, IL-6 and TNF-α in the supernatant, with the inhibition rates of 10.25% (P<0.05), 70.20% (P<0.05) and 10.25% (P<0.05), respectively. 48.01% (P<0.05). The results suggest that CAI may have a good therapeutic effect on AOSD.

From the results of Examples 1 to 9, it can be seen that CAI is useful for the treatment of Blau syndrome, familial Mediterranean fever, tumor necrosis factor receptor-related periodic syndrome, NLRP12 autoinflammatory disease, Yao's syndrome, and cold inflammatory hormone-related cycle. It is effective in autoinflammatory diseases including fever syndrome and adult Still's disease.

As mentioned above, although this invention was demonstrated in detail in the specific form, it is clear for those skilled in the art that various changes and deformation|transformation can be added without deviating from the mind and range of this invention.

Claims (5)

1. the application of the carboxylamine triazole compound shown in the following formula (A) or its pharmaceutically acceptable salt in the preparation of the medicine for the treatment or prevention of autoinflammatory diseases,

In the formula, X represents CH ₂ , S, O or C═O; R ₄ represents Cl, CF ₃ , Br or CH ₃ ; R ₅ represents Cl, Br or NO ₂ . 2. The application according to claim 1, wherein the carboxyamine triazole compound is 5-amino-1-{[3,5-dichloro-4-(4-chlorobenzoyl)phenyl] Methyl}-1H-1,2,3-triazole-4-carboxamide. 3. The use according to claim 1, wherein the pharmaceutically acceptable salt is selected from any one or more of the group consisting of hydrochloride, sulfate, orotate and acetate. 4. The use according to any one of claims 1 to 3, wherein the autoinflammatory disease is selected from the group consisting of familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and mevalonate kinase deficiency Syndrome, NLRP12 autoinflammatory disease, cold inflammatory hormone-related periodic fever syndrome, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal multisystem inflammatory disease/chronic infantile neurocutaneous joint syndrome, Blau syndrome symptoms, chronic relapsing multifocal osteomyelitis, septic arthritis-pyoderma gangrenosum-acne syndrome, Majeed syndrome, IL-1 receptor antagonist deficiency, IL-36 receptor antagonist deficiency, PFAPA syndrome, nucleotide oligomerization domain 2-related autoinflammatory disease, Yao's syndrome, STING-related vascular disease, infant-onset STING-related vascular disease, adenosine deaminase 2 deficiency, proteasome-related autologous disease Inflammatory syndrome, Nakajo-Nishimura syndrome, joint contracture-muscular atrophy-microcytic anemia-pannicitis-associated lipodystrophy syndrome, chronic atypical neutrophilic dermatosis with fever and lipoatrophy, panniculitis Induced Juvenile Lipodystrophy Syndrome, Schnitzler Syndrome, Interferon-Mediated Autoinflammatory Disorders, Aicardi-Goutières Syndrome, Interferon-stimulated Response Gene 15 Deficient Disease, Spinal Chondrodysplasia with Immunomodulatory Dysregulation, Phospholipase Cγ2-related antibody deficiency and immune dysregulation, CARD14-mediated psoriasis, linear ubiquitin chain assembly complex deficiency, sideroblastic anemia, immunodeficiency, febrile and developmental prolongation syndrome, familial macrognathia, premature Primary sarcoidosis, recurrent mole type 1, HOIL-1 deficiency, HOIP deficiency, generalized pustulosis, palmoplantar pustulosis, substratum corneum pustulosis, delayed pressure urticaria, inflammation Acrodermatitis, neutrophil panniculitis, PASH syndrome, SAPHO syndrome, childhood SAPHO syndrome, autoinflammatory bone disease, chronic aseptic osteomyelitis, disseminated superficial actinic porosity Keratosis, Familial Lichenoid Keratosis Chronic, Syndrome H, Pyrin-Associated Autoinflammatory Disorders with Neutrophilic Skin Disease, Macrophage Activation Syndrome, Singleton-Merten Syndrome, X-Linked Nets dyspigmentation, TORCH syndrome, OTULIN-related autoinflammatory disease, A20 haploinsufficiency, adult Still's disease, pseudogout, systemic juvenile idiopathic arthritis, severe infantile inflammatory bowel disease, Sweet syndrome, Any one or more of familial hemophagocytic lymphocytosis, inflammasome disease, NLRC4-related macrophage activation syndrome, and NLRP1-related autoinflammatory disease with arthritis and dyskeratosis. 5. The use according to claim 4, wherein the autoinflammatory disease is selected from familial Mediterranean fever, chronic relapsing multifocal osteomyelitis, mevalonate kinase deficiency, NLRP12 autoinflammatory disease, Cold inflammation-associated periodic fever syndrome, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal multisystem inflammatory disease/chronic infantile neurocutaneous joint syndrome, septic arthritis-pyoderma gangrenosum -Acne syndrome, Majeed syndrome, IL-1 receptor antagonist deficiency, IL-36 receptor antagonist deficiency, Schnitzler syndrome, recurrent mole type 1, SAPHO syndrome, childhood SAPHO syndrome, autologous Inflammatory bone disease, chronic aseptic osteomyelitis, familial lichenoid keratosis, Pyrin-related autoinflammatory disease with neutrophilic dermatosis, A20 haploinsufficiency, adult Still's disease, pseudogout , systemic juvenile idiopathic arthritis, severe infantile inflammatory bowel disease, Sweet syndrome, NLRC4-related macrophage activation syndrome, NLRP1-related autoinflammatory disease with arthritis and dyskeratosis, phospholipase Cγ2-related antibody deficiency and immune dysregulation, Blau syndrome, nucleotide oligomerization domain 2-related autoinflammatory disease, Yao's syndrome, CARD14-mediated psoriasis, linear ubiquitin chain assembly complex deficiency, early Primary sarcoidosis, HOIL-1 deficiency, HOIP deficiency, generalized pustulosis, inflammatory acrodermatitis, OTULIN-associated autoinflammatory disease, tumor necrosis factor receptor-associated periodic syndrome, PFAPA syndrome, keratin More than any one of substratum pustular dermatosis, disseminated superficial actinic porokeratosis, X-linked reticular hyperpigmentation, and H syndrome.

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