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WO2003087072A1 - Agent therapeutique destine a des troubles endotheliaux - Google Patents

Agent therapeutique destine a des troubles endotheliaux Download PDF

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Publication number
WO2003087072A1
WO2003087072A1 PCT/JP2003/004108 JP0304108W WO03087072A1 WO 2003087072 A1 WO2003087072 A1 WO 2003087072A1 JP 0304108 W JP0304108 W JP 0304108W WO 03087072 A1 WO03087072 A1 WO 03087072A1
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WIPO (PCT)
Prior art keywords
group
amino
benzoisothiazole
formula
compound
Prior art date
Application number
PCT/JP2003/004108
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English (en)
Japanese (ja)
Inventor
Shoji Furusako
Tsutomu Satoh
Masaki Nakamura
Masashi Mizuno
Sadao Mori
Original Assignee
Mochida Pharmaceutical Co., Ltd.
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Priority to AU2003221184A priority Critical patent/AU2003221184A1/en
Publication of WO2003087072A1 publication Critical patent/WO2003087072A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • the present invention relates to a prophylactic and / or therapeutic agent for a disease associated with mesothelial cell damage of 3-amino-1,2 and benzo-isothiazole and a derivative thereof, and a pharmaceutical composition for preventing and / or treating the disease.
  • a prophylactic and / or therapeutic agent for a disease associated with mesothelial cell damage of 3-amino-1,2 and benzo-isothiazole and a derivative thereof and a pharmaceutical composition for preventing and / or treating the disease.
  • the present invention relates to an agent for preventing and / or treating a disease, or a pharmaceutical composition for preventing and / or treating the disease. Further, the present invention relates to a prophylactic and / or therapeutic agent for a disease involving a signal mediated by a To11 Like Receptor (TLR), a pharmaceutical composition for preventing and / or treating the disease, or an inhibitor of the signal. About.
  • TLR To11 Like Receptor
  • the present invention also relates to a novel 3-amino-1,2-benzoisothiazole derivative useful for these pharmaceutical compositions and a pharmaceutically acceptable salt thereof.
  • Vascular endothelial cells have the effect of suppressing the activity of monocytes and neutrophils during invasion such as endotoxin stimulation and reperfusion of organ ischemia. It is responsible for the secretion of plasminogen and is thought to suppress excessive inflammation. However, when the degree of invasion is large, vascular endothelial cells are damaged by activated inflammatory cells or active oxygen, and the secretory substances are reduced. Furthermore, endothelial cell damage is followed by other inflammation 8
  • vascular endothelium spans to 100 cm 2 alone lung, substances secreted from here is considered to play an important role in anti-inflammatory effects of systemic organs, the substance systemic organ from which they are secreted It plays an important role in anti-inflammatory action (Kenji Okajima, Me bio, 2003, Vol. 29, No. 1, ⁇ 31-40, Bon RC. Et. A 1., Chest, 1992 , 101, p 320—326).
  • suppressing vascular endothelial damage is important for preventing / treating systemic organ damage due to sepsis, systemic and cardiovascular diseases, sepsis and related diseases, infectious diseases, inflammatory diseases, respiratory failure, It is thought to lead to the prevention / treatment of diseases such as organ failure (MODS), autoimmune diseases and individual organ failure.
  • MODS organ failure
  • autoimmune diseases and individual organ failure.
  • Sepsis is included in the systemic inflammatory response syndrome (SIRS), but it is always systemic to the infection because it is clear that there is progression of infection by bacteria, fungi, viruses, parasites, etc. Defined as a disease with an inflammatory response (SIRS)
  • Is defined as Impaired blood flow and circulatory disturbances include lactic acidosis, oliguria, and sudden changes in mental status.
  • Septic shock is a so-called refractory condition in which blood pressure drops, or tissue hypoperfusion persists despite adequate fluid infusion, lactic acidosis, oliguria, acute changes in mental status, or other tissues. Defined as showing signs of circulatory disturbance. (Mechanism of action of cardiovascular drugs Nankodo (see above))
  • endotoxin such as lipopolysaccharide (1 ippoplysacccharide. LPS) released from cells and the like.
  • Endotoxin acts on monocytes, Z macrophages, neutrophils, NK cells, vascular endothelial cells, and fibroblasts in the blood, and acts on a large amount of inflammatory site force-in, platelet activating factor (PAF), leukotriene, Releases various mediators such as prostaglandins, activated oxygen, N0, and elastase, and causes endothelial cell damage. This results in organ damage and circulatory problems.
  • PAF platelet activating factor
  • immunosupplementation therapy such as immunoglobulin
  • therapy with drugs for various mediators such as cytodynamics and coagulation system, organs such as circulatory disorder (shock), respiratory disorder, etc.
  • Disorder therapy is also being used (Noboru Toda, et al., “Mechanism of Action of Cardiovascular Drugs,” Nankodo, April 10, 1998, p. 342-347).
  • Antibacterial therapy has different effects depending on the pathogenic bacteria.
  • sepsis often has no known pathogenic bacteria or a mixed infection.
  • antibacterial agents causes gram-negative bacilli to release LPS, causing rapid release of various mediators, resulting in shock.
  • the therapeutic effect is often not sufficient (Pharmacy, 2001, Vol. 52, No. 9, p. 2162—2168).
  • Bacteria may be detected in Peudomon ousareuginos sepsis in patients with acute leukemia even if the blood concentration of imidenem is several hundred times the minimum inhibitory concentration against the bacterium (Jouran ann. lof I nfectiou s Disease), (USA), 1992, 165, p. 1033—1041).
  • antibacterial therapy is a causal therapy in sepsis, but its therapeutic effect cannot be fully expected.
  • TLR is a type 1 membrane protein containing a leucine-rich region (LRR) in the extracellular domain discovered by Medzhitov et al. At Yale University in 1997, and 10 types are currently known (Nature, (UK), 1997, Vol. 388, pp. 394—397, Proceedin's of the National Academy of Sciences of the United States of America, USA ci enc eoft he United States of America), (United States), 1998, Vol. 95, p. 588—593, Gene (Netherlands), 1999, Vol. 231, p. 59 — 65).
  • LRR leucine-rich region
  • the TLR was originally cloned as a mammalian homolog of the Drosophila Tol 1 gene.
  • the Toll gene functions as a determinant of the dorsal-ventral axis during the development of Drosophila, while it is a gene involved in the protection of fungal infection during the adult stage. It is involved in the induction of antifungal peptides such as drosomycin and metchinikowin via the kinase Pelle and the transcription factor Dorsal. Mutants of TLR have been reported to have significantly reduced fungal protection (Cell (Ce 11), (USA), 1996, Vol. 86, p. 973-983).
  • TLR4 LPS responsiveness of C3HHe /; TLR4 has been shown to be involved in LPS signaling in vivo (Science, (USA), 1998, Vol. 282, p. 2085-2088). Later, Akira et al. Analyzed the reactivity of TLR4-deficient mice, TLR2-deficient mice, and macrophages isolated from them with bacterial cell components, and found that TLR2 was a component of Gram-positive bacteria.
  • LTA Lilethyl-Nature Immunoloy
  • PPN peptide darican
  • TLR4-deficient mice showed tolerance to damage caused by excessive LPS administration (Immunity 1999, Vol. 4, p. 443-451). , Which is thought to form a complex with CD14 and function as an LPS receptor ("Journal of Biological Chemistry", (USA), 2001, vol. 276) ,:. 21129—21135).
  • TLR 3 is dsRNA
  • TLR 5 is flagella protein
  • TLR7 is IFN Q! Inducible activity of imidazoquinoline compound, R-848, as ligand
  • TLR9 is reported to ligand CpG
  • TLR family plays a protective role in bacterial infection Acquired from innate immunity It is increasingly becoming clear that it is a molecule that links immunity (Nature, (UK), 2001, Vol. 413, p. 732, Journal of Clinical Investigation> ⁇ Jou rnalof C li nc al I nv estigati on; 2001, Vol. 107, p. 27, Nature
  • TLR9 in cooperation with DNA-containing immune complexes, promotes the proliferation of autoreactive B cells and the production of autoantibodies (Nature, 2002, Vol. 416, p. 603-607). It is known that antinuclear antibodies and anti-DNA antibodies are detected in patient sera in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (SLE), but the DNA contained in these antigens is B cell This suggests that TLR9 is involved in the exacerbation of autoimmune diseases as well as receptors.
  • TLR families are now thought to play a central role in innate immunity.
  • ligands are LPS, lipoarabinomannan (LAM), LTA, PGN, which are the major components of bacterial cells, oligo DNA containing CpG sequences characteristic of bacteria, flagellin which is a bacterial flagellar protein, and viral flagellin.
  • TLRfamily is widely involved in the defense of bacterial and viral infections. It is thought that there is. In particular, of these, TLR4, which recognizes the major cell wall component of Gram-negative bacteria, and TLR2, which recognizes the major cell wall component of Gram-positive bacteria, play a central role in protecting against Pacteria infection.
  • TL Rfamily is considered to induce biological reactions by recognizing the unique molecular structure of pathogenic microorganisms called PAMPS (Pathogen-Associated Molecular Patterns).
  • PAMPS Pulthogen-Associated Molecular Patterns
  • TLR tumor necrosis virus
  • TLR may be involved in a wide range of inflammation and immune diseases, such as autoimmune diseases as well as sepsis.
  • TIR Toll / IL-l receptor
  • MyD88, IRAK, and TRAF6 associate with the TIR domain to activate NF-kB (Biochemica Biophysica Acta) ), (Netherlands), 2002, Vol. 1592, p. 265-280). It is thought that the information transfer system of the TLR family has a common part. However, to date no small molecule compounds that block TLR-mediated signals extracellularly or intracellularly are unknown. Furthermore, there are no known preventive and / or therapeutic agents for diseases associated with TLR.
  • endothelial cell damage is involved in the mechanism of suppressing endothelial damage. It is desired to show a preventive and / or therapeutic effect for the disease to be given.
  • antibacterial agents and antibiotics are conventionally used for sepsis, but it is necessary to use different drugs depending on the pathogenic bacteria, but it is not possible to use them properly.
  • Bacterial release of endotoxin by use may cause a shock condition, which has not been sufficiently effective as a therapeutic agent.
  • clinical effects on severe sepsis and septic shock cannot be expected due to its antibacterial mechanism.
  • immunotherapeutic agents have not been sufficiently effective because they are treatments that enhance or suppress one of the balance of inflammatory and anti-inflammatory cytokines. Since these are symptomatic treatments, it is considered that no fundamental therapeutic effect has been obtained.
  • a pharmaceutical composition for sepsis, severe sepsis or septic shock which can be used as a causative therapy, does not depend on the type of pathogenic bacteria, and exhibits a therapeutic effect by a mechanism of inhibiting vascular endothelial damage. desired.
  • TLR is involved in inflammation and immune diseases such as sepsis and autoimmune diseases.
  • drugs that commonly suppress signals related to TLR fami1y are not limited to individual PAMPS such as endotoxin, and are considered to be useful widely for the above diseases. Can be For this reason, there is also a demand for a compound that exhibits a preventive and / or therapeutic effect on a disease associated with a signal via the TLR.
  • the present inventors have conducted intensive studies on drugs for diseases involving endothelial cell damage by a mechanism of suppressing endothelial damage, and as a result, have found that the compound of formula (I) described below has the above-mentioned effects.
  • prevention of sepsis, severe sepsis or septic shock by a mechanism that suppresses vascular endothelial damage, regardless of the type of pathogenic bacteria, which can also be used as a causative therapy, and Z or therapeutic agents, prevention and / or treatment A method or a pharmaceutical composition for the prophylaxis or treatment of the disease has been completed.
  • the compound of the formula I has an action of blocking a signal mediated by TLR, a prophylactic and / or therapeutic agent for a disease associated with the signal, a method for prevention and / or treatment, prevention of the disease and Z or A pharmaceutical composition for therapy, or an inhibitor of the signal, and a method of inhibiting the same have been completed.
  • novel compounds useful in these pharmaceutical compositions compounds of the following formula (la) and 3-amino-5-promo1, '2_benzoisothiazol, 3-amino-5-fluoro-1,2 —Benzoisothiazol, 3-amino-5-trifluoromethyl-1,2-benzoisothiazole, 3 _amino-5-methoxy 1,2-benzoisothiazol, 3-amino-5-hydroxy-1,2-benzoiso Thiazole, 3-amino-6-methoxy-1,2-benzoisothiazole, 3-amino-5-odo-1,1,2-benzoisothiazole, 3-amino-6, odo-1,2-benzoisothiazole, 3- Amino-6-methyl 1, 2 PT / parents / 04108
  • FIG. 1 is an electrophoretogram of soluble CD14 by SDS-PAGE.
  • FIG. 2 is a view showing the activation of pNF- ⁇ B by LPS and soluble CD14 in HEK293 cells and # 4-14 cells into which pNF- was introduced.
  • FIG. 3 is a diagram showing pNF- ⁇ NF activation of PNF- ⁇ B-introduced HEK293 cells and HEKT2-6 cells by PGN and soluble CD14.
  • FIG. 4 is a graph showing the effect of the compound of Example 1 in a mouse galactosamine-loaded endotoxin lethal model.
  • FIG. 5 is a graph showing the effects of the compound of Example 96 on plasma soluble topomodulin concentration in plasma and soluble ⁇ -selectin concentration in plasma in a mouse galactosamine-loaded endotoxin lethal model. 4108
  • FIG. 6 is a graph showing the evaluation of the effect of the compound of Example 96 on plasma soluble E-secretin concentration in a mouse galactosamine-loaded endotoxin lethal model.
  • FIG. 7 is a view showing the effect of the compound of Example 1 in a mouse cecal ligation-puncture peritonitis model.
  • FIG. 8 shows the effect of the compound of Example 96 in a mouse cecal ligation-puncture peritonitis model.
  • a disease to be treated or prevented according to the present invention is defined.
  • Disease involving endothelial cell damage refers to the release of various cytokins such as IL-16 and nitric oxide (NO) due to endothelial cell damage, and the release of other cells following endothelial cell damage Various mediators such as TN F ⁇ , IL-11 and IL-18, superoxide, platelet activating factor (PAF) and arachidonic acid cascade-related factors are involved, or endothelial cells It is a disease that is exacerbated by decreased secretion of more secreted anti-inflammatory substances, etc., due to endothelial cell damage. Examples include diseases such as sepsis and its related diseases, systemic and cardiovascular diseases, infectious diseases, inflammatory diseases, respiratory failure, multiple organ failure (MODS), autoimmune diseases, and individual organ failure. However, it is not limited to these diseases.
  • “Sepsis” is defined as the presence of a progressive infection by bacteria, fungi, viruses, parasites, and others (hereinafter, bacteria, etc.).
  • SIRS systemic inflammatory response
  • SIRS systemic inflammatory response
  • SIRS systemic inflammatory response
  • SIRS systemic inflammatory response
  • “Severe sepsis” is a disease that indicates a condition accompanied by impaired organ function and decreased blood flow secondary to sepsis. Impaired blood flow and impaired circulation include lactic acidosis, oliguria, and acute changes in mental status.
  • “Sepsis shock” is a disease that exhibits a so-called refractory state in which blood pressure is reduced or tissue is hypoperfused despite sufficient infusion. Includes acid acidosis, oliguria, acute changes in mental status, or other indications of impaired tissue circulation.
  • Endotoxin refers to bacterial membrane components such as LPS, LAM, LTA, and PGN, oligo DNA containing the CpG sequence characteristic of bacteria, bacterial flagellin flagellin, and viral dsRNA. , A bacterial component, a protein, a nucleic acid, etc., which cause an inflammatory site force-in by infection by a bacterium, a fungus, a virus, a parasite, or the like.
  • Disease involving TLR-mediated signal refers to PAM such as endotoxin. It is a disease derived from PS, a signal is transmitted into cells via TLR, and the signal is at least partially involved in causing the disease.
  • infectious diseases such as endotoxin shock, sepsis and related diseases, hemorrhagic shock, alcoholic hepatitis, periodontal disease, ARDS, infective endocarditis, tissue damage and rejection after organ transplantation, chronic
  • infectious diseases such as endotoxin shock, sepsis and related diseases, hemorrhagic shock, alcoholic hepatitis, periodontal disease, ARDS, infective endocarditis, tissue damage and rejection after organ transplantation, chronic These include autoimmune diseases such as rheumatoid arthritis, refractory colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, SLE, scleroderma, Shederdalen syndrome, and multiple sclerosis. It is
  • An “inhibitor of TLR-mediated signal” is an agent that prevents or treats a disease associated with a TLR-mediated signal. It also includes drugs as reagents for testing and research.
  • a first aspect of the present invention relates to a method for treating a disease associated with endothelial cell damage, comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Prophylactic and / or therapeutic agents and pharmaceutical compositions for the prevention and / or treatment of said diseases.
  • vascular endothelial cells such as vascular endothelial cells or lymphatic endothelial cells, or in each organ or each mucosa
  • the target is a disease involving vascular endothelial cell damage, and more preferably, a disease involving vascular endothelial cell damage.
  • the prophylactic and / or therapeutic or therapeutic agent and the pharmaceutical composition of the present invention are more preferably a prophylactic and / or therapeutic agent and / or a pharmaceutical composition for a disease involving vascular endothelial cell damage.
  • diseases such as sepsis and its related diseases, systemic and cardiovascular diseases, infectious diseases, inflammatory diseases, respiratory failure, multiple organ failure (MODS), autoimmune diseases, individual organ failure, etc. . Detailed diseases will be described later.
  • sepsis, severe sepsis or sepsis characterized by containing a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for preventing and treating sexual shock and preventing or treating the disease a compound represented by the following formula (I) or a compound thereof for treating and preventing or treating sepsis, severe sepsis or septic shock or Z, or treating sepsis, severe sepsis or septic shock.
  • a preventive and / or therapeutic agent for sepsis containing the active ingredient does not depend on the type of the causative bacterium, it can be used without specifying the causative bacterium prior to prevention / treatment. That is, it is a prophylactic / therapeutic agent for sepsis caused by gram-negative bacteria, gram-positive bacteria, fungi, viruses or parasites. Preferably, it is a prophylactic / therapeutic agent for sepsis caused by infection with Gram-negative bacteria or Gram-positive bacteria or caused by these endotoxins.
  • the prophylactic agent is, in particular, a septic prophylactic agent used for humans or patients in a condition that may potentially cause sepsis.
  • a septic prophylactic agent used for humans or patients in a condition that may potentially cause sepsis.
  • a preventive and / or therapeutic agent for severe sepsis containing the active ingredient since the prophylactic / therapeutic agent does not depend on the type of the causative bacterium, it can be used without specifying the causative bacterium prior to prevention / treatment. Preferably, it is a preventive / therapeutic agent for severe sepsis caused by infection with Gram-negative bacteria or Gram-positive bacteria or caused by these endotoxins.
  • preventive and / or therapeutic agent for septic shock containing the active ingredient. Since the preventive Z therapeutic agent does not depend on the species of the causative bacteria, it can be used without specifying the causative bacteria prior to prevention / treatment. It is preferably a therapeutic agent for preventing septic shock caused by infection with Gram-negative bacteria or Gram-positive bacteria, or caused by these endotoxins.
  • a third aspect of the present invention is a disease involving a TLR-mediated signal, comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient: And a pharmaceutical composition for preventing and / or treating Z. Further, a method for treating and / or preventing a disease in which a signal via the TLR is involved, a method for treating and / or preventing a disease in which a signal via the TLR is involved, and a compound represented by the formula (I) described below or a compound thereof. It is a method of using a pharmaceutically acceptable salt. Or it is an inhibitor of TLR-mediated signaling.
  • endotoxin shock for example, endotoxin shock, sepsis and related diseases, hemorrhagic shock, infectious diseases such as alcoholic hepatitis, periodontal disease, ARDS, infective endocarditis, tissue damage and rejection after organ transplantation, rheumatoid arthritis
  • infectious diseases such as alcoholic hepatitis, periodontal disease, ARDS, infective endocarditis, tissue damage and rejection after organ transplantation, rheumatoid arthritis
  • ARDS infective endocarditis
  • tissue damage and rejection after organ transplantation rheumatoid arthritis
  • rheumatoid arthritis It is a prophylactic / therapeutic agent for autoimmune diseases such as intractable colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, SLE, scleroderma, Siedalen syndrome, and multiple sclerosis.
  • it is an agent for preventing and / or treating a disease involving a signal mediated by TLR2, TLR4 and Z or TLR9, or an inhibitor of the signal.
  • TLR4-mediated signals and diseases targeted by Z or therapeutic agents include, for example, gram-negative bacteria-derived sepsis and related diseases, Endotoxin shock, bleeding shock, alcoholic hepatitis, periodontal disease
  • Examples of the disease targeted by the preventive and / or therapeutic agent for a disease in which a signal mediated by TLR2 is involved include, for example, Gram-positive bacteria or mycobacterial sepsis and related diseases, Gram-positive bacteria or mycobacteria. Infectious diseases such as endotoxin shock, hemorrhagic shock, alcoholic hepatitis, periodontal disease, ARDS, and infective endocarditis.
  • TLR9-mediated signaling and diseases targeted by Z or therapeutic agents include, for example, sepsis and related diseases, endotoxin shock, hemorrhagic shock, alcoholic hepatitis, periodontal disease, ARDS, infection Infectious diseases such as endocarditis, tissue damage and rejection after organ transplantation, rheumatoid arthritis, intractable colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, SLE, scleroderma, che It is a prophylactic / therapeutic agent for autoimmune diseases such as monodaren syndrome and multiple sclerosis. Preferably, it is a preventive and / or therapeutic agent for endotoxin shock, sepsis and related diseases, and autoimmune diseases such as rheumatoid arthritis, intractable colitis, and the like.
  • a fourth embodiment of the present invention relates to a compound represented by the following formula (Ia), 3-amino-15-bromo_1,2-benzoisothiazolyl, 3-amino-5-fluoro-1,2-benzene Zoisothiazole, 3-amino-5-trifluoromethyl-1,2-benzoisothiazole, 3-amino-5-methoxy-1,2-benzoisothiazole, 3-amino-5-hydroxy-1,2-benzoisothiazole, 3-amino-6-methoxy_1,2-benzoisothiazole, 3-amino-5-odo-1,2-benzoisothiazole, 3-amino-6-iodo 1,2-benzoiso PC leakage 08
  • a fifth aspect of the present invention is a drug or a pharmaceutical composition containing the compound of the fourth aspect of the present invention or a salt thereof.
  • agents for preventing and / or treating diseases associated with endothelial cell damage and pharmaceutical compositions for preventing and / or treating the diseases.
  • Specific examples of the disease associated with endothelial cell damage are as described in the section of the first embodiment.
  • a pharmaceutical composition for preventing and treating or treating sepsis, severe sepsis or septic shock It is a prophylactic and / or therapeutic agent for disease. More preferably, it is a preventive and / or therapeutic agent for sepsis, severe sepsis or septic shock caused by infection of Gram-negative bacteria or Gram-positive bacteria or caused by these endotoxins.
  • it is an agent for preventing and / or treating a disease in which a signal mediated by TLR is involved, a pharmaceutical composition for preventing and / or treating the disease, or an inhibitor of said sidanal. More preferably, a prophylactic and / or therapeutic agent for a disease involving a signal mediated by TLR 2, TLR 4, and / or TLR 9, a pharmaceutical composition for preventing and / or treating the disease, or an inhibitor of the signal It is. Further, more preferably, a prophylactic and / or therapeutic agent for a disease in which a signal by endotoxin via the TLR is involved, and a physician for the prevention and / or treatment of the disease.
  • a drug composition or an inhibitor of the signal by the endotoxin is a drug composition or an inhibitor of the signal by the endotoxin.
  • a prophylactic and / or therapeutic agent for a disease associated with an endotoxin-mediated signal via TLR2, TLR4 and Z or TLR9 or a pharmaceutical composition for the prevention and / or Z or treatment of the disease Or an inhibitor of the signal by the endotoxin.
  • endotoxin shock for example, endotoxin shock, sepsis and related diseases, hemorrhagic shock, alcoholic hepatitis, periodontal disease, ARDS, and rheumatoid arthritis, intractable colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, infectious
  • It is a prophylactic / therapeutic agent against autoimmune diseases such as endocarditis, SLE, scleroderma, Sheddharen syndrome, tissue damage and rejection after organ transplantation, and multiple sclerosis.
  • it is a prophylactic and / or therapeutic agent for endotoxin shock, sepsis and its related diseases, and autoimmune diseases such as rheumatoid arthritis, intractable colitis, and SLE.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • a linear or branched alkyl group having 1 to 6 carbon atoms means a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group.
  • Rubutyl 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2- It represents an ethylbutyl group, a 1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group, and the like.
  • aryl group is a benzene ring, a naphthalene ring, an aromatic heterocyclic ring having 5 to 6 members containing 1 to 4 heteroatoms arbitrarily selected from N, S, ⁇ ⁇ ⁇ ⁇ , or any of N, S, O 8 to 12 fused bicyclic aromatic heterocycles containing 1 to 4 heteroatoms selected, containing 1 to 4 heteroatoms arbitrarily selected from N, S, O 5 to 6 members
  • Aromatic heterocyclic ring is, for example, a pyrrolyl group, a furyl group, a chenyl group, an imidazolyl group, an oxazolyl group, an isooxazolyl group, a thiazolyl group, an isothiazolyl group, a 1,2,3_triazolyl group, a 1,2,4-triazolyl group Group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidyl group,
  • An aromatic heterocycle is, for example, Drill group, isoindolyl group, 1H-indazolyl group, benzofuranyl (1-2-yl) group, isobenzofuranyl group, benzochel (12-yl) group, isobenzozoenyl group, benzoxazolyl (1-2-yl) group Yl) group, 1,2-benzoisoxazolyl group, benzothiazolyl (1-2-yl) group, 1,2-benzoisothiazolyl group, 2H-benzopyranyl (—3-yl) group ) Group, (1H—) benzimidazolyl (—2-yl) group, 1H—benzotriazolyl group, 4H—1,4-benzoxazinyl group, 4H-1,4 benzothiazinyl group, quinolyl group, isoquinolyl group , Cinnolinyl group, quinazolinyl group, PC orchid painting 08
  • aralkyl group is a lower alkyl group substituted with the above “aryl group”.
  • a saturated monocyclic carbon-containing hydrogen group having 3 to 6 members which may contain 1 to 2 heteroatoms arbitrarily selected from N, S, and O means any of 3 to 6 carbon atoms.
  • Any two groups selected from R 5 , R 6 and R 7 may be taken together to form a bridging group which is a C 1-6 ) linear alkylene group" or "R 5a And any two groups selected from R 6a and R 7a are joined together to form a C ( 1-6 ) May form a cross-linking group which is a kylene group ". .
  • the compound used as an active ingredient of the pharmaceutical composition of the present invention is specifically represented by the formula (I)
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or a lower alkyl group
  • R 5 , R 6 and: R 7 are the same or different and each represents a hydrogen atom, an aryl group, an aralkyl group, a lower alkyl group, a hetero atom arbitrarily selected from N, S, 0.
  • a saturated monocyclic hydrocarbon group having 3 to 6 members which may contain two or Or any two groups selected from R 5 , R 6 and R 7 may be taken together to form a cross-linking group that is a C- 6 , linear alkylene group;
  • the groups represented by R 5 , R 6 and R 7 may be further substituted with 1 to 3 arbitrary groups selected from substituent group Z, and the aryl groups of R 5 , R 5 and R 7
  • the aromatic ring of the aralkyl group may be a benzene ring, a naphthalene ring, an aromatic heterocyclic ring having 5 to 6 members or an N, S, 0 containing 1 to 4 heteroatoms arbitrarily selected from N, S, 0.
  • Substituent group Z is a halogen atom, lower alkyl group, nitro group, hydroxyl group, thiol group, amino group, cyano group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl.
  • R 1 is preferably R 2 is hydrogen atom or a lower alkyl group
  • R 1 is a hydrogen atom
  • R 1 is the R 2 a hydrogen atom is hydrogen atom Is more preferable.
  • R 3 and R 4 are such that R 3 is a hydrogen atom, a halogen atom, a trifluoromethyl group and R 4 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, YR 5, wherein - NR 5 R 6, wherein one CONR 5 R 6, wherein - NR 5 COR 6, wherein - NR 7 CONR 5 R B, wherein - S_ ⁇ 2 NR 5 R 6 or the formula - NR 5 S0 2 R is preferably 6, R 4 is a hydrogen atom in R 3 is a hydrogen atom, a halogen atom, Torifuruo Romechiru group, and more preferably wherein one Y- R 5 or an expression one NR 5 COR 6
  • R 5 , R 6 and R 7 are the same or different and are each preferably a hydrogen atom, an aryl group, an aralkyl group or a lower alkyl group, more preferably a hydrogen atom, an aralkyl group or a lower alkyl group.
  • R 5 is preferably a hydrogen atom or a lower alkyl group, and R 6 is preferably a hydrogen atom, an aryl group, an aralkyl group, or a lower alkyl group.
  • R 6 is preferably a hydrogen atom, an aryl group, an aralkyl group, or a lower alkyl group.
  • R 5 is preferably a hydrogen atom or a lower alkyl group
  • R 6 is preferably a hydrogen atom, an aryl group, an aralkyl group, or a lower alkyl group.
  • Formula 1 NR 7 CONR 5 As R 6 , R 5 and R 7 are the same or different and are each a hydrogen atom or a lower alkyl group, and R 6 is a hydrogen atom, an aryl group, an aralkyl group, a lower alkyl group. It is preferably a group.
  • R 5 is a hydrogen atom or a lower alkyl group and R 6 P picture 3/04108
  • a hydrogen atom, Ariru group, Ararukiru group, the formula one NR 5 S_ ⁇ 2 R 6 is preferably a lower alkyl group
  • R 6 in R 5 is a hydrogen atom or a lower alkyl group is a hydrogen atom, Ariru group, Ararukiru Group, preferably a lower alkyl group. More specifically,
  • “ 1 and R 2 ” are the same or different and each represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group, an isobutyl group or a t-butyl group.
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl Group, isobutyl group, t-butyl group,
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is a hydrogen atom or a methyl group
  • R 1 is a hydrogen atom and R 2 is a hydrogen atom
  • R 3 and R 4 are the same or different and are each a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a cyano group, a trifluoromethyl group, a formula —Y—R 5 , a formula— NR 5 R 6 , Formula 1 CONR 5 R 6 , Formula 1 NR 5 COR 6 , Formula 1 NR 5 CONR 6 R 7 , Formula 1 S0 2 NR 5 R 6 or Formula 1 NR 5 S0 2 R 5 represents a hydrogen atom , a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, Shiano group, triflate Ruo Russia methyl certain, it is preferred that the formula one Y- R 5.
  • R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group
  • R 4 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, Cyano group, trifluoromethyl group
  • Formula 1 Y—R 5 Formula 1 NR 5 R 6 , Formula—CON 5 R 6 , Formula 1 NR 5 COR 6 , Formula—NR 5 CONR 6 R 7 , Formula 1 S 0 2 NR 5 R 6 , Formula 1 NR 5 S 0 2 R 6 is preferable
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, and a trifluoro group.
  • R-methyl group more preferably Y—R 5
  • R 5 , R 6 and R 7 are the same or different and are each a hydrogen atom, an aryl group, an aralkyl group, a lower alkyl group, or a cycloalkyl group having any of 3 to 6 carbon atoms
  • the aryl group include a phenyl group, a pyrrolyl group, a furyl group, a chenyl group, an imidazolyl group, an oxazolyl group, an isooxazolyl group, a thiazolyl group, an isothiazolyl group, a 1,2,3-triazolyl group, a 1,2, 4 Triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidyl group, pyridazyl group, naphthyl group, indolyl group, isoindolyl group, 1H-indazolyl group, benzofur
  • aralkyl group examples include benzyl, 2-phenylethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, pyrrolylmethyl, furylmethyl, and phenylmethyl.
  • Lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n_butyl, s-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl , Neopentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, n_hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group Group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl
  • a saturated monocyclic hydrocarbon having 3 to 6 members which may contain 1 to 2 heteroatoms arbitrarily selected from N, S, and ⁇ is, for example, a cyclopropyl group, a cyclobutyl group.
  • Cyclopentyl, cyclohexyl, azetidinyl, oxilanyl, oxenyl, cetanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolidinyl, piperidyl, tetrahydropyrael, piperagel Represents a morpholinyl group or a thiomorpholinyl group, preferably a cyclohexyl group or a piperidyl group.
  • substituents are further substituted with 1 to 3 arbitrary groups selected from substituent group Z.
  • the substituent group Z is preferably a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylamino group, a nitro group, a cyano group, a lower alkyl group, a hydroxyl group, A lower alkoxy group, a lower alkylamino group and a nitro group are more preferred.
  • a cross-linking group which is a straight-chain alkylene group of ( 1-6) examples thereof include a pyrrolidyl group, a 2-oxopyrrolidyl group, a 2-oxopiperidyl group, and a 2-oxoimidazolyl group.
  • a pyrrolidyl group examples thereof include a pyrrolidyl group, a 2-oxopyrrolidyl group, a 2-oxopiperidyl group, and a 2-oxoimidazolyl group.
  • Piperidyl group, 2-oxopyrrolidyl group and 2-oxopiperidyl group are preferred.
  • n 0, 1, or 2, and preferably 0 or 2.
  • Nylethyl group 1-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, furylmethyl group, chenylmethyl group, furylethyl group, chenylethyl group, methyl group, ethyl group, cyclopropyl Group, cyclopentyl group, phenoxy group, pyridyloxy group, furyloxy group, phenyloxy group, benzyloxy group, pyridylmethoxy group, 2-phenylethoxy group, 1-phenylethoxy group, 1-phenylpropyloxy group, 2 —Phenylpropyloxy group, 3-phenylpropyloxy group, furylmethoxy group, chenylmethoxy group, furylethoxy group, chenylethoxy group, methoxy group, ethoxy group, methansulfonyl group, benzoyl group, acetyl
  • hydroxyl are more preferable, hydroxyl, chenylmethyl, phenoxy, pyridyloxy, benzyloxy, pyridylmethoxy, ethoxy, benzoyl, styryl And a propynyl group is particularly preferred.
  • R 5 and R 6 can be in any combination, but include an amino group, a phenylamino group, a furylamino group, a chenylamino group, a pyridylamino group, a benzylamino group, and 2-phenyl.
  • a acetylamino group, a methylethylamino group, a pyrrolidyl group, a piperidyl group and the like are preferable, and an amino group, a phenylamino group, a benzylamino group, a methylamino group and a dimethylamino group are more preferable.
  • R 5 and R 6 can be in any combination. However, carbamoyl, phenylaminocarbonyl, furylaminocarbonyl, phenylaminocarbonyl, pyridylaminocarbonyl, benzylaminocarbonyl, 2-phenylethylaminocarbonyl, furylmethyl Aminocarbonyl group, phenylmethylaminocarbonyl group, pyridylmethylaminocarbonyl group, cyclopropylaminocarbonyl group, cyclopentylaminocarbonyl group, cyclohexylaminocarbonyl group, methylaminocarbonyl group , A methylaminocarbonyl group, a dimethylaminocarbonyl group, a acetylaminocarbonyl group, a methylethylaminocarbonyl group, a pyrrolidylcarbonyl group, a
  • R 5 and R 6 can be in any combination, but formamide group, benzamide group, furylcarbonylamino group, chenylcarponylamino group, pyridylcarbonyl group Amino group, Benzylcarbonylamino group, 21-phenylethylcarponylamino group, Furylmethylcarbonylamino group, Chenylmethylcarbonylamino group, Pyridylmethylcarbonylamino group, Cyclopropylaminolponylamino group, Cyclopentyl A carbonylamino group, a cyclohexylcarbonylamino group, an acetylamino group, an edylcaronylamino group, a dimethylcarbonylamino group, a getylcarbonylamino group, a 2-ketopyrrolidyl group, and a 2-ketopiperazinyl group are preferred.
  • Formamide group benzamide group, More preferred are a benzylcarbonylamino group, an acetylamino group and a dimethylcarbonylamino group.
  • R 5 , R 6 , and R 7 can be in any combination, but include ureido group, 3-phenylureido group, 3-furylureido group, and 3— Chenylureido group, 3-pyridylureido group, 3-benzyldiureido group, 3- (2-phenylethyl) ureido group, 3-furylmethylureido group, 3-monophenylmethylureido group, 3-pyridylmethylureido group, 3-cyclopro Pyrureido group, 3-cyclopentyl perido group, 3-cyclohexyl perido group, 3-methyl perido group, 3-ethyl perido group,
  • R 5 and R 6 may be in any combination, but may be a sulfamoyl group, a phenylaminosulfonyl group, a furylaminosulfonyl group, a phenylaminosulfonyl group, Pyridylaminosulfonyl, benzylaminosulfonyl, 2-phenylethylsulfonyl, furylmethylaminosulfonyl, phenylmethylaminosulfonyl, pyridylmethylaminosulfonyl, cyclopropylaminosulfonyl, cyclopentylaminosulfonyl, cyclopentylaminosulfonyl, Cyclohexylaminosulfonyl group, methylaminosulfonyl group, X-tylaminosulfonyl group, dimethylaminosulfonyl
  • R 5 and R 6 may be in any combination, but may be benzenesulfonamide, furylsulfonylamino, chenylsulfonylamino, pyridylsulfonylamino, benzyl Sulfonylamino group, 2-phenylethylsulfonylamino group, furylmethylsulfonylamino group, phenylmethylsulfonylamino group, pyridylmethylsulfonylamino group, cyclopropylsulfonylamino group, cyclopentylsulfonylam Preferred are a mino group, a cyclohexylsulfonylamino group, a methanesulfonylamino group, an ethylsulfonylamino group, a dimethylsulfonylamin
  • the compound of the formula (I) is more preferably used as an active ingredient of the pharmaceutical composition of the present invention, wherein R 1 or R 2 is a hydrogen atom or a methyl group, respectively, and R 3 or R 4 is a hydrogen atom.
  • R 1 or R 2 is a hydrogen atom or a methyl group, respectively
  • R 3 or R 4 is a hydrogen atom.
  • a fluorine atom, a chlorine atom, triflate Ruo Russia methyl group or R 5 is good wherein one Y- R 5 may be substituted with Z, one Y- is a single bond, one O- and, R 5 is a hydrogen atom, A methyl group and a benzyl group.
  • novel compound of the present invention has the formula (Ia)
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or a lower alkyl group, and R 3a represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, a hydroxyl group or R 4a represents a lower alkoxyl group
  • R 5a , R 6a and R 7a are the same or different and each represents a hydrogen atom, an aryl group, an aralkyl group, a lower alkyl group, a hetero atom arbitrarily selected from N, S, and 0;
  • a saturated monocyclic hydrocarbon group having 3 to 6 members which may contain 1 to 2 or any two groups selected from R 5a , R ea and R 7a are joined together C may be in the form of a (1 one 6) bridging group is a straight-chain alkylene group, crosslinking group, or group represented by R 5 R 6 a and R 7 a is from substituent group Z Any group chosen 1
  • the aromatic ring of the aralkyl group may be a benzene ring, a naphthalene ring, an aromatic heterocyclic ring of 5 to 6 members containing 1 to 4 heteroatoms arbitrarily selected from N, S, and O, or any of N, S, and 0.
  • R 5 a is 1-3 substituents selected arbitrarily from substituent group Z 1
  • Substituent group Z is a halogen atom, it consists lower alkyl group and a substituent group Z 1, substituent group Z 1 is a nitro group, a hydroxyl group, Chio Ichiru group, an amino group, Shiano group, triflate Ruo b methyl , A lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylamino carbonyl group, a sulfamoyl group and a lower Lower alkyl is a straight-chain or branched carbon chain having any one of 1 to 6 carbon atoms),
  • R 3a is preferably a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, or a lower alkoxy group, and more preferably a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group.
  • R 4a has the formula - Y- R 5a, wherein - NR 5a R 6a, wherein one CONR 5a R 6a, wherein - NR 5a C ⁇ _R 6a, wherein one NR 7a C_ ⁇ _NR 5a R 6a, wherein one S_ ⁇ 2 It represents NR 5a R 6a or formula NR 5a S 0 2 R 6a , but preferably formula Y-R 5a .
  • R 5a, R 6 a and R 7 a are respectively the same as definitions of R 5, R 6 and R 7 in formula (I).
  • R la , R 2a , R 4a , R 5a , R 6a , and R 7a are listed in “Shaku 1 , R 2 , R 4 , R 5 , R 6 , and R 7 ” in the formula (I). Is defined in the same way as However, when R 4a is of the formula Y—R 5a and Y is a single bond or 10—, R 5a is substituted with 1 to 3 substituents arbitrarily selected from substituent group Z 1.
  • substituent group Z 1 is nitro group, hydroxy group, amino Group, a cyano group, a lower alkoxy group, a lower alkylamino group and a lower alkoxycarbonyl group are preferred.
  • R 3a is a hydrogen atom, a halogen atom, a trifluoromethyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group, an isobutyl group, a t-butyl group, a hydroxyl group Group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, isobutoxy group, t-butoxy group is preferable, and hydrogen atom, halogen atom, trifluoromethyl group, A methyl group, an ethyl group, a methoxy group, and an ethoxy group are more preferable, and a hydrogen atom, a halogen atom, a methyl group, and a methoxy group are more preferable.
  • R 1 or R 2 is each a hydrogen atom or a methyl group
  • R 3a is a hydrogen atom, a halogen atom, a trifluoromethyl group, a methyl group, an ethyl group, or a methoxy group. Or an ethoxy group is preferred.
  • R 4a is, R 5a is optionally substituted with Z wherein one Y- R 5a, the expression one NR 5 COR 6 preferably, Y A single bond one O—, —CH—CH— or one C ⁇ C— is preferred.
  • novel compound of the present invention is used as an active ingredient of a pharmaceutical composition.
  • Preferred compounds as the active ingredient of the pharmaceutical composition are as described above for the novel compound of the present invention.
  • the compound (I) used as an active ingredient of the pharmaceutical composition of the present invention or the compound (la) of the present invention may have an asymmetric carbon atom, and may have an optically active or inactive stereoisomer (enantiomer diastereomer, etc.). ) Can exist.
  • the compound of the present invention includes a mixture of various stereoisomers such as a geometric isomer and an optical isomer and an isolated one. Isolation and purification of such geometric isomers are carried out by recrystallization or column chromatography, and isolation and purification of stereoisomers are carried out by preferential crystallization. Optical resolution or asymmetric synthesis using column chromatography. Etc., all of which can be performed by those skilled in the art using ordinary techniques.
  • Compound (I) or compound (Ia) may form an acid addition salt.
  • a salt with a base may be formed depending on the type of the substituent.
  • the salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid
  • Organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, formic acid, malic acid, tartaric acid, citric acid and mandelic acid, methanesulfonic acid, ethanesulfonic acid, ⁇ - Acid addition salts with organic sulfonic acids such as toluenesulfonic acid and 2-hydroxyethanesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid; bases of alkali metals or alkaline earth metals such
  • the salt of the compound (I) or the compound (Ia) includes a monosalt, a disalt or a trisalt. Alternatively, depending on the substituent on the side chain, it can form both an acid addition salt and a salt with a base. Further, the compound (I) or a hydrate of the compound (Ia), various pharmaceutically acceptable solvates and polymorphs thereof are also included in the compound and the pharmaceutical composition of the present invention.
  • the present invention is, of course, not limited to the compounds described in the examples below, but may be a 3-amino-1,2-benzoisothiazole derivative represented by the formula (I) or (Ia) or a derivative thereof. And pharmaceutically acceptable salts thereof.
  • the compound represented by the formula (I) or a salt thereof can be produced from the compound represented by the formula (II), the formula (IV) or the formula (V) as described below in Production Method 1>, ⁇ Production Method 2>, ⁇ Production method 3> or a method analogous thereto, and the compounds represented by the formulas (II), (IV) and (V) are either known in the literature or commercially available compounds. It can be easily synthesized. In the following reaction schemes, each substituent of the formula (I) is defined as described above.
  • the raw materials, intermediates and products can be handled as salts as required.
  • a reactive functional group such as an amino group, a hydroxyl group, a carboxyl group, or a thiol group
  • they should be appropriately protected as necessary in each production process, and the protective group should be removed at an appropriate stage. You can also. Introduction of such protecting groups Insertion and removal are performed as appropriate depending on the type of protected group or protecting group.For example, Protective Groups 'In' Organic Synthesis (Review of the 3rd edition of the Practical Group In Organic Synthesis) Can be performed by the method described in (1).
  • R 3 and R 4 are preferably substituents that are inert during the reaction, for example, a hydrogen atom, a halogen atom, a nitro group, an aryl group, an aralkyl group, an alkyl group, an alkoxy group And an aryloxy group, an aralkyloxy group, an arylthio group, an aralkylthio group, an alkylthio group, a sulfinyl group and a sulfonyl group.
  • an alcohol solvent or an ether solvent is preferable.
  • methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, s-butanol, t-butanol, diisopropyl ether , Diisobutyl ether, methoxyethanol and ethoxyethanol can be used, and ethanol and methoxyethanol are preferred.
  • the compound represented by the formula (I) is obtained by converting the compound represented by the formula (III) into an alkyl aldehyde or an alkyl ketone having 1 to 6 carbon atoms such as acetoaldehyde, propionaldehyde, and acetone. It can be synthesized by reducing with a suitable reducing agent such as sodium triacetoxyborohydride and sodium borohydride. The reaction can be performed at room temperature, and can be performed in the presence or absence of an acid catalyst such as acetic acid and hydrochloric acid.
  • reaction solvents such as aromatic hydrocarbon solvents such as toluene and benzene, halogen solvents such as methylene chloride and chloroform, and alcohol solvents such as methanol and ethanol should be used as reaction solvents. Can be done. If alkyl aldehyde or alkyl ketone is used based on the stoichiometric amount, compound (I) in which either R 1 or R 2 is a hydrogen atom can be synthesized, and if alkyl aldehyde or alkyl ketone is used in excess, PC leaks 08
  • the compound represented by the formula (III) has a carbon atom number such as methyl iodide, propyl iodide, and propyl bromide in the presence of an organic base such as triethylamine or pyridine or an inorganic base such as sodium hydrogen carbonate or potassium carbonate. It can be synthesized by reacting with an alkylating agent represented by an alkylsulfuric acid such as alkyl halide, dimethylsulfuric acid, getylsulfuric acid and the like at 1 to 6 at normal temperature to 60 ° C.
  • an alkylating agent represented by an alkylsulfuric acid such as alkyl halide, dimethylsulfuric acid, getylsulfuric acid and the like at 1 to 6 at normal temperature to 60 ° C.
  • Reactive solvents include inert solvents such as aromatic hydrocarbon solvents such as toluene and benzene, halogenated solvents such as methylene chloride and chloroform, and aprotic polar solvents such as dimethylformamide and dimethylsulfoxide. Can be used.
  • the alkylating agent is used on the basis of the stoichiometric amount, the compound (I) in which either R 1 or R 2 is a hydrogen atom can be synthesized.
  • R 1 Compound (I) in which R 2 represents the same lower alkyl group can be synthesized.
  • compound (I) in which R 1 and R 2 are different lower alkyl groups can be synthesized.
  • the compound represented by the formula (I) or a salt thereof is represented by the formula (IV) (wherein R 3 and R 4 have the same meanings as described above, and A represents a hydrogen atom or lithium, sodium, potassium, etc.) Can be produced according to each of the production steps of the following ⁇ Reaction formula 2>.
  • R 3 and R 4 are groups that are inert during the reaction.
  • A is an alkali metal salt such as lithium, sodium or potassium
  • the conversion of the compound represented by the formula (IV) to the compound represented by the formula (III) can be performed by the method described in Journal of Chemical Society, Parkin Trans I (J. Chem. Soc. Perkin Tran I (I), 1984, 385—389, K.K.
  • the reaction is carried out in a solvent inert to the reaction at 15 ° C to room temperature using a 5% aqueous solution of sodium hypochlorite and aqueous ammonia.
  • A is a hydrogen atom
  • the conversion from the compound represented by the formula (IV) to the compound represented by the formula (III) is performed in the same manner as described above in the presence of a base such as sodium hydroxide.
  • a base such as sodium hydroxide.
  • a compound of the formula (IV) in which A is an amino group may be obtained.
  • the compound of the formula (III) is prepared by using an appropriate base such as sodium methoxide. It can be synthesized by using and cycling.
  • the compound represented by the formula (I) is synthesized from the compound represented by the formula (III) in the same manner as in ⁇ Production method 1> and ⁇ Step 2>.
  • R 3 and R 4 are preferably substituents inert during the reaction, for example, a hydrogen atom, a halogen atom, a nitro group, an aryl group, an aralkyl group, an alkyl group, an alkoxy group, an aryloxy group, Examples include an aralkyloxy group, an arylthio group, an aralkylthio group, an alkylthio group, a sulfinyl group, and a sulfonyl group.
  • the conversion of the compound represented by the formula (V) into the compound represented by the formula (I) is represented by R
  • R 2 is hydrogen
  • the method described in Falmaco Ediée Sentifika (Farmaco Ed. Sci.) 41, 10, 1986, 808-818, Vicini P. or It is performed according to this.
  • the reaction is carried out in a solvent inert to the reaction, in the presence of ammonia, in a sealed tube at 14 Ot to 150 ° C.
  • Ammonia is used on a stoichiometric basis, but preferably the reaction is carried out using ammonia at 10 equivalents of the starting material.
  • the reaction can be carried out by substituting concentrated aqueous ammonia for ammonia.
  • Reaction solvents include aromatic hydrocarbon solvents such as toluene and benzene, halogen solvents such as methylene chloride and chloroform, ether solvents such as tetrahydrofuran, and aprotic polar solvents such as dimethylformamide and dimethylsulfoxide.
  • aromatic hydrocarbon solvents such as toluene and benzene
  • halogen solvents such as methylene chloride and chloroform
  • ether solvents such as tetrahydrofuran
  • aprotic polar solvents such as dimethylformamide and dimethylsulfoxide.
  • An inert solvent is used for the reaction.
  • the reaction is carried out in a solvent inert to the reaction at a reaction temperature of 170 to 150 ° C. at a reaction temperature of from 170 to 150 ° C., after converting an alkylamine such as dimethylamine or diisopropylamine into a lithium salt with a stoichiometric amount of n-butyllithium.
  • the reaction is performed by reacting a compound represented by the formula (V).
  • Each compound synthesized by each of the above production methods can be converted at each stage of the production process according to the following method.
  • R 1 when R at least one of the two is a hydrogen atom, If necessary, Ri R 1 by the deprotecting after the reaction are protected in advance with an appropriate protecting group, A compound in which at least one of R 2 is a hydrogen atom can be synthesized.
  • the compound represented by the formula (I) or the formula (III) has a halogen atom bonded to an aromatic ring as a substituent, The halogen atom can be converted to another functional group by the above method.
  • Such compounds include aryloporanic compounds such as phenylporanic acid, cyano compounds, ethylene derivatives such as styrene, alkyne derivatives such as acetylene, copper catalysts such as copper iodide, tetrakistriphenylphosphine palladium (0), dichlorobistrif
  • aryloporanic compounds such as phenylporanic acid, cyano compounds, ethylene derivatives such as styrene, alkyne derivatives such as acetylene, copper catalysts such as copper iodide, tetrakistriphenylphosphine palladium (0), dichlorobistrif
  • the reaction can be carried out at a reaction temperature of 80 to 160 ° C.
  • a catalyst such as a palladium catalyst such as enylphosphine palladium (II)
  • the halogen atom can be reacted with an aryl group, an alkoxy group, a cyano group, an alkenyl group, It can be converted to an alkynyl group.
  • Inert solvents such as aromatic hydrocarbon solvents such as toluene and benzene, ether solvents such as dioxane, and aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide are used as reaction solvents. I can do it.
  • the carboxylic acid is an alcohol or an amine and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WS C ⁇ HC 1), condensing agents such as dicyclohexyl carpamide (DCC), aromatic hydrocarbon solvents such as toluene and benzene, halogen solvents such as methylene chloride and chloroform, ether solvents such as tetrahydrofuran Conversion to ester derivatives or amide derivatives by reaction in a solvent inert to the reaction, such as aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, etc., at a temperature at which the reaction mixture refluxes from 0 ° C.
  • DCC dicyclohexyl carpamide
  • aromatic hydrocarbon solvents such as toluene and benzene
  • halogen solvents such as methylene chloride and chloroform
  • ether solvents such as tetra
  • the propyloxyl group or the generated ester or amide substitution group can be formed by using a reducing agent such as lithium aluminum hydride or borane-dimethyl sulfate, an aromatic hydrocarbon solvent such as toluene or benzene, or a ether system such as tetrahydrofuran.
  • a reducing agent such as lithium aluminum hydride or borane-dimethyl sulfate
  • an aromatic hydrocarbon solvent such as toluene or benzene
  • a ether system such as tetrahydrofuran.
  • the reaction can be carried out in a solvent inert to the reaction, such as a solvent, at a temperature at which the reaction mixture is refluxed from 0 ° C. to convert to a hydroxylmethyl group or an aminomethyl group.
  • 3-amino-1,2-benzoisothiazole derivatives represented by the formula (Ia) of the present invention or 3-amino-5-bromo_1,2-benzoisothiazole, 3-amino-5- Fluoro-1,2-benzoisothiazole, 3-amino-5-trifluoromethyl-1,2-benzoisothiazole, 3-amino-5-methoxy 1,2-benzoisothiazole, 3-amino-5-hydroxy 1,2-benzoisothiazole, 3-amino-6-methoxy-1,2-benzoisothiazole, 3-amino-5-odo-1,2-benzoisothiazole, 3-amino-6-dodo 1 , 2-Benzisothiazole, 3-Amino-6-methyl _ 1, 2- 03 04108
  • the pharmaceutical composition and the prophylactic / therapeutic agent of the present invention will be described.
  • the pharmaceutical composition, the prophylactic or therapeutic agent of the present invention comprises at least one compound represented by formula (I) or one or more compounds of the present invention (such as a compound represented by formula (Ia)) As an active ingredient, and may contain a pharmaceutically acceptable carrier.
  • Preferred examples of the compound represented by the formula (I) or the compound of the present invention are the same as described above.
  • the compound represented by the formula (I) or the compound of the present invention which is an active ingredient of the pharmaceutical composition, the prophylactic or therapeutic agent of the present invention, is useful for preventing and / or treating a disease associated with endothelial cell damage. It is an active ingredient of a pharmaceutical composition for preventing and / or treating a disease.
  • a pharmaceutical composition comprising the compound as an active ingredient, a prophylactic or therapeutic agent, comprises a useful prophylactic and / or therapeutic agent for a disease associated with endothelial cell damage, or a pharmaceutical composition for the prevention and / or treatment of the disease. Become. 8
  • the pharmaceutical composition of the present invention which is a prophylactic or therapeutic agent, suppresses endothelial cell damage, thereby suppressing the release of these mediators or maintaining the balance of mediators, thereby preventing and / or treating various diseases. It has become one of.
  • sepsis and related diseases include, for example, sepsis and related diseases, systemic and cardiovascular disease, infectious disease, inflammatory disease, respiratory failure, multiple organ failure (MODS), autoimmune disease, individual organ failure And the like.
  • sepsis and its related diseases such as sepsis, severe sepsis and septic shock, SIRS-related diseases, endotoxin shock, exotoxin shock, hemorrhagic shock, various shocks such as intraoperative and postoperative shock, Ischemic reperfusion injury, ischemic encephalopathy, acute ischemic stroke, acute cerebral thrombosis, acute coronary microvascular embolism, shock vascular embolism, generalized intravascular blood coagulation (DIC), myocardial infarction and sequelae, And low blood pressure and other systemic and cardiovascular diseases, psoriasis, acute bacterial meningitis, invasive staphylococcal infections, infectious diseases such as acute viral encephalitis, gastritis, peptic ulcer, tengitis,
  • the target diseases include sepsis, severe sepsis, sepsis such as septic shock, and related diseases, SIRS-related diseases, endotoxin shock, exotoxin shock, hemorrhagic shock, various shocks such as intraoperative and postoperative shock, and imaginary shock.
  • Blood reperfusion injury ischemic encephalopathy, acute ischemic stroke, acute cerebral thrombosis, acute coronary microvascular embolism, shock vascular embolism, DIC, myocardial infarction and systemic and cardiovascular diseases such as sequelae and hypotension , Gastritis, Tengitis, nephritis, myocarditis, pneumonia, hepatitis, cirrhosis, fulminant hepatitis, encephalitis, osteoarthritis, atopic dermatitis, inflammatory diseases such as allergic rhinitis and ankylosing spondylitis, AR DS, infants Respiratory distress syndrome, respiratory failure such as emphysema and asthma, MO DS, rheumatoid arthritis, intractable colitis, ulcerative colitis, Crohn's disease, thread Autoimmune diseases such as systemic nephritis, infectious endocarditis, SLE, scleroderma, Schedalen syndrome, tissue
  • the target disease is sepsis, severe sepsis, and septic shock. And other related diseases, SIRS-related diseases, endotoxin shock, exotoxin shock, hemorrhagic shock, various shocks such as intraoperative and postoperative shock, cardiovascular diseases, respiratory failure such as ARDS, MODS , And rheumatoid arthritis, refractory colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, infective endocarditis, SLE, scleroderma, Shederdalen syndrome, tissue damage and rejection after organ transplantation Reactions, autoimmune diseases such as multiple sclerosis, and the like.
  • the target diseases include sepsis such as sepsis, severe sepsis and septic shock and related diseases, SIRS-related diseases, endotoxin shock, and autoimmune diseases such as rheumatoid arthritis, refractory colitis, and SLE.
  • sepsis such as sepsis, severe sepsis and septic shock and related diseases, SIRS-related diseases, endotoxin shock, and autoimmune diseases such as rheumatoid arthritis, refractory colitis, and SLE.
  • the pharmaceutical composition, prophylactic and therapeutic agent does not directly act on the blood coagulation system, it is advantageous in that it can be used for bleeding patients.
  • bleeding is not rarely caused by the degree of invasion to the living body, and such patients can be used.
  • This drug can be administered orally and has no side effects such as bleeding.
  • an agent for preventing and / or treating sepsis, severe sepsis or septic shock by a mechanism of inhibiting vascular endothelial damage a mechanism of inhibiting vascular endothelial damage
  • a method for preventing and / or treating the disease or a pharmaceutical composition for preventing or treating the disease.
  • the compound represented by the formula (I) or the compound of the present invention which is an active ingredient of a pharmaceutical composition, a prophylactic or therapeutic agent of the present invention, comprises a prophylactic and / or therapeutic agent for sepsis, severe sepsis or septic shock, or It is an active ingredient of a pharmaceutical composition for preventing and / or treating the disease.
  • a pharmaceutical composition comprising the compound as an active ingredient, a prophylactic or therapeutic agent is a useful agent for preventing and / or treating sepsis, severe sepsis or septic shock, or a pharmaceutical composition for preventing and / or treating the disease.
  • the living body is based on a balance between inflammatory and anti-inflammatory site forces. That is, unlike anti-inflammatory cytokine therapy that suppresses only one direction, the present pharmaceutical composition and the prophylactic / therapeutic agent have an advantage that they can be treated without breaking this balance.
  • the pharmaceutical composition and the prophylactic / therapeutic agent of the present invention are effective not only for intravenous administration but also for oral administration. From this, the pharmaceutical composition and the prophylactic / therapeutic agent of the present invention are considered to be widely used without being limited to the administration purpose.
  • the pharmaceutical composition, prophylactic and therapeutic agent does not directly act on the blood coagulation system, it is advantageous in that it can be used for bleeding patients.
  • bleeding is not uncommon due to the degree of invasion of the living body.
  • this drug can be administered orally and has no side effects such as bleeding, it can be administered from the beginning of sepsis before transfusion, and the burden on patients is small.
  • the compound represented by the formula (I) or the compound of the present invention has an action of inhibiting a signal of endotoxin shock such as TPS-mediated LPS.
  • TLR-mediated endotoxin shock signals activate transcription factors such as NFkB, AP1, and IRF3, leading to the production of various inflammatory cytokines, chemokines.
  • Cytokinin amplifies inflammation, accumulates neutrophils in important organs, activates inflammatory factors such as elastase, and activates the blood coagulation system, causing more severe sepsis and inducing shock.
  • the action of the compound to inhibit the signal of endotoxin shock such as LPS via the TLR is to inhibit the signal located upstream of the inflammatory cascade or coagulation cascade. It is thought to contribute to the prevention and treatment of severe sepsis or septic shock.
  • the compound represented by the formula (I) or the compound of the present invention which is an active ingredient of the pharmaceutical composition, the prophylactic or therapeutic agent of the present invention, is used for the prevention of disease associated with a signal mediated by TLR and the Z or therapeutic agent. Or an active ingredient of a pharmaceutical composition for preventing and / or treating the disease. Or, it is an inhibitor of the signal.
  • a pharmaceutical composition comprising the compound as an active ingredient, a prophylactic or therapeutic agent, is a pharmaceutical composition for preventing and / or treating a disease associated with a useful TLR-mediated signal, or for preventing and / or treating the disease. Things.
  • the compound represented by the formula (I) or the compound of the present invention inhibits TLR-mediated signaling of PAMPS such as endotoxin represented by TLR-mediated LPS 8
  • TLR fami 1 y has a common part, a compound that inhibits any of the signals of TLR2, TLR4 and TLR9 is not treated with other TLRf This is because signal transmission via am ily is also considered to be suppressed.
  • TLR-mediated signals activate transcription factors such as NFkB, AP1, and IRF3, and induce the production of various inflammatory cytokines, chemokines.
  • Cytokines amplify inflammation, accumulate neutrophils in important organs, activate inflammatory factors such as elastase, and the blood coagulation system, and induce various diseases.
  • the fact that the compound has an effect of inhibiting a signal mediated by TLR means that the signal is located upstream of the inflammatory cascade ⁇ the coagulation cascade, which means that the compound has an effective component. It is one of the mechanisms of therapeutic agents or pharmaceutical compositions.
  • the agent for preventing and / or treating a disease associated with a signal via the TLR of the present invention or the pharmaceutical composition for preventing and / or treating the disease is preferably a signal via the TLR2, TLR4 and / or TLR9. It is a prophylactic and / or therapeutic agent for an associated disease or an inhibitor of the signal.
  • a preventive and / or therapeutic agent for a disease in which a signal caused by TLR-mediated endotoxin is involved a pharmaceutical composition for preventing and / or treating the disease, or an inhibitor of a signal caused by the endotoxin. More preferably, for the prevention and / or treatment of a disease associated with a signal caused by endotoxin via TLR2, 11 ⁇ 4 and / or 119, or a therapeutic agent for Z, or for the prevention and Z or treatment of the disease Or a signal inhibitor by the endotoxin.
  • the target diseases include, for example, endotoxin shock, sepsis and related diseases, hemorrhagic shock, alcoholic hepatitis, periodontal disease, ARDS, rheumatoid arthritis, intractable colitis, ulcerative colitis, clone Disease, glomerulonephritis, infectious endocarditis, SLE, scleroderma, Sheddharen syndrome, tissue damage and rejection after organ transplantation
  • autoimmune diseases such as multiple sclerosis. It also includes drugs as test and research reagents.
  • the preventive Z therapeutic agent or pharmaceutical composition of the present invention suppresses the damage caused by endotoxin to vascular endothelial cells and suppresses the production of inflammatory cytokines. It also inhibits endotoxin-induced production of inflammatory cytotoxicity on monocyte cells. That is, it suppresses endotoxin-induced NFkB activation in cells expressing any of the TLRs. Therefore, the preventive Z therapeutic agent or the pharmaceutical composition of the present invention is a preventive and / or therapeutic agent for a disease in which a signal caused by TLR-mediated endotoxin is involved, and a pharmaceutical composition for preventing and / or treating the disease.
  • the inhibitory effect of the proto / therapeutic agent or the composition of the present invention by TLR-mediated endotoxin may be caused by the activity of NFkB in TLR4-expressing cells induced by LPS, or by the effect of NGN in TLR2-expressing cells induced by PGN. FkB activity and NFkB activity of TLR9-expressing cells induced by DNA containing the CpG sequence were confirmed, indicating that it has TLR signal blocking activity for various ligands. It is.
  • the prophylactic / therapeutic agent or the pharmaceutical composition of the present invention can be used for bacterial infection, that is, LPS, gram-negative and viable bacterial cell components, gram-positive bacterial cell components, and mycobacterial liposome.
  • ⁇ Diseases caused by It is effective in the prevention and treatment of diseases caused by the virus or its own DNA.
  • diseases include gram-negative bacteria-derived gram-positive bacteria, mycobacterial or virus-derived sepsis, severe sepsis, septic shock, neonatal bacterial or viral sepsis, and related diseases, ARDS, as described above.
  • Infectious diseases such as bacterial meningitis, hemorrhagic shock, alcoholic hepatitis, infectious endocarditis and periodontal disease are exemplified. Diseases in which CD14 in the blood is elevated are also included in the disease.
  • the target disease of the preventive Z therapeutic agent or the pharmaceutical composition of the present invention is LPS, a disease caused by a gram-negative bacterial cell component, for example, gram-negative bacterial-derived sepsis, Infectious diseases such as severe sepsis, septic shock, sepsis such as neonatal sepsis and related diseases, ARDS, bacterial meningitis, hemorrhagic shock, alcoholic hepatitis, infectious endocarditis and periodontal disease.
  • LPS a disease caused by a gram-negative bacterial cell component
  • Infectious diseases such as severe sepsis, septic shock, sepsis such as neonatal sepsis and related diseases
  • ARDS bacterial meningitis
  • hemorrhagic shock alcoholic hepatitis
  • infectious endocarditis and periodontal disease An example is shown.
  • the target disease of the preventive Z therapeutic agent or the pharmaceutical composition of the present invention is a disease caused by a gram-positive bacterial cell component, a mycobacterium, for example, a disease derived from a gram-positive bacterium or Septicemia, severe sepsis, septic shock, septicemia such as neonatal sepsis and related diseases derived from mycobacteria, ARDS, bacterial meningitis, hemorrhagic shock, alcoholic hepatitis, infectious endocarditis and periodontal disease And the like.
  • a mycobacterium for example, a disease derived from a gram-positive bacterium or Septicemia, severe sepsis, septic shock, septicemia such as neonatal sepsis and related diseases derived from mycobacteria, ARDS, bacterial meningitis, hemorrhagic shock, alcoholic hepatitis, infectious endocarditis and periodontal disease And the like.
  • the target disease of the pharmaceutical composition is sepsis and its related diseases, endotoxin shock, hemorrhagic shock, alcoholic hepatitis, periodontal disease, ARDS, infective endocarditis derived from these bacterial or viral infections Infectious diseases such as infectious diseases are exemplified.
  • TLR-mediated endotoxin signaling due to the mechanism of inhibiting TLR-mediated endotoxin signaling, it is caused by drug-resistant bacteria, neoplasia / re-infection, and opportunistic infection that cannot be handled by conventional antibiotics, or It is also effective for concurrent diseases.
  • the compound represented by (I) or the compound of the present invention commonly inhibits signal transduction via TLRfami1y.
  • TLRfami1y This indicates that, for example, inhibiting signal transduction via TLR9 associated with autoimmunity is effective for autoimmune diseases.
  • the prophylactic Z therapeutic agent or the pharmaceutical composition of the present invention that inhibits TLR9-mediated signals is also effective against autoimmune diseases.
  • autoimmune diseases include, for example, rheumatoid arthritis, refractory colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, SLE, scleroderma, siedalen syndrome, tissue damage and rejection after organ transplantation, and multiple occurrences Sclerosis and the like.
  • the pharmaceutical composition and the prophylactic / therapeutic agent of the present invention are effective not only for intravenous administration but also for oral administration. From this, the pharmaceutical composition and the prophylactic / therapeutic agent of the present invention are considered to be widely used without being limited to the administration purpose.
  • the present pharmaceutical composition and the prophylactic / therapeutic agent do not directly act on the blood coagulation system, they are advantageous in that they can be used for bleeding patients.
  • patients with cerebral hemorrhage as a preexisting condition or patients with or at risk of gastrointestinal bleeding should It is not uncommon for bleeding to occur, depending on the degree of invasion, and can be used in such patients.
  • the drug can be administered orally, has no side effects such as bleeding, and has little burden on patients.
  • the compound which is an active ingredient of the pharmaceutical composition of the present invention and the therapeutic agent for prophylaxis Z has no toxicity at a concentration showing sufficient efficacy in vivo. That is, the pharmaceutical composition and the prophylactic / therapeutic agent of the present invention are also excellent in safety.
  • compositions containing one or more of compound (I) or the compound of the present invention and pharmaceutically acceptable salts thereof as an active ingredient are commonly used carriers for pharmaceuticals, excipients, and the like.
  • the clinical dose of Compound (I) or the compound of the present invention for humans is appropriately determined in consideration of the patient's symptoms, weight, age, sex, etc., and is usually 0 per day for an adult.
  • Solid compositions for oral administration according to the present invention include capsules, pills, tablets 8
  • one or more active substances is made up in combination with at least one inert carrier. More specifically, excipients (eg, lactose, sucrose, mannitol, dextrose, hydroxypropylcellulose, microcrystalline cellulose, metasilicic acid), binders (eg, crystalline cellulose, saccharides, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose) , Polybierpyrrolidone, Macrogol), Lubricants (eg, magnesium stearate, calcium stearate, talc), Disintegrators (eg, corn starch, carboxymethylcellulose, calcium cellulose glycolate), stabilization Agents (eg, sugar alcohols and sugars such as lactose), solubilizing or solubilizing agents (eg, cholesterol, triethanolamine, glutamic acid, aspartic acid), coloring agents, flavoring agents, preservatives, isotonicity ,
  • excipients eg, lactose, sucrose, mannito
  • Asukorubin acid, heptyl hydroxy ⁇ two sole), buffering agents, preservatives (e.g. parabens, benzyl alcohol Ichiru) may include. Tablets, pills, granules, and the like may be provided with a gastric or enteric film coating such as sucrose, gelatin, or hydroxypropylmethylcellulose monophthalate, if necessary.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solubilizers, suspensions, and emulsions.
  • Carriers for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • Carriers of water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (TM).
  • Such compositions may further comprise the aforementioned tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers. It may contain additives such as a stabilizing agent, a solubilizing agent or a solubilizing agent.
  • a surfactant polyoxyethylene hydrogenated castor oils, polyoxyethylene sorbin higher fatty acid esters, sucrose fatty acid esters, etc.
  • a surfactant polyoxyethylene hydrogenated castor oils, polyoxyethylene sorbin higher fatty acid esters, sucrose fatty acid esters, etc.
  • Methods, drugs and solubilizers for example, polymers (polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), water-soluble polymers such as polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose phthalate (HPMCP), meta
  • PEG polyethylene glycol
  • HPMC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose phthalate
  • meta A method of forming a solid dispersion with a methyl acrylate-methacrylic acid copolymer e.g., an enteric polymer such as Eudragit L, S (TM); manufactured by Rohm and Hase Co., Ltd.
  • a method of forming an inclusion compound using, for example, HI // 3- or arcyclodextrin, hydroxypropylcyclodextrin and the like can also be mentioned.
  • “Pharmaceutical Monograph No. 1, Biochemical Utilization Ability” Tsuneji Nagai et al., Soft Science, 78-82 (1988) or “Recent Formulation Technologies and Their Applications”, Isao Utsumi et al., Pharmaceutical Journal 157-159 ( 1983), etc. the solubilization method can be appropriately changed according to the target drug.
  • a method of forming a solid dispersion of a drug and a solubilizing agent to improve solubility JP-A-56-49314, FR2460667) can be employed.
  • compound M is a compound ( I) or compound (la) or a pharmaceutically acceptable salt thereof, and in particular, any compound selected from the compound examples of the examples is arbitrarily exemplified. Unless otherwise specified,% is% by mass.
  • the components of the compound Ml 00 g, lactose 395.5 g, and magnesium stearate 4.5 g were each weighed and uniformly mixed, and the mixed powder was encapsulated in 25 mg of a hard capsule of No. 1 in a quantity of 25 mg.
  • the amplified DNA fragment was subjected to doubly-editioning with XhoI and Apali and inserted into the XhoI / ApaLI site of pMl650. After transforming the JM109 cells, the resulting colonies were confirmed by PCR to obtain the desired soluble CD14-expressing plasmid (PM1656).
  • Plasmid PM1656 prepared in (1) was introduced into COS-1 cells by the following method to express soluble CD14. That FUGENE 6 (Roche Dia Diagnostics Sticks Co., Ltd.) 50 1 were mixed in accordance with the attached flop Rotokoru and the plasmid DNA each 12. 5 / g, was added to COS- 1 cells grown in semiconfluent E cement to 0.99 cm 2 flasks . After culturing for 72 hours under the conditions of 5% C0 2, 37 ° C , to obtain a soluble CD 14 objects the culture supernatant was collected.
  • FUGENE 6 Roche Dia Diagnostics Sticks Co., Ltd.
  • the expression level of soluble CD14 was measured by EIA using an anti-human CD14 antibody. That was diluted 200 times with pH 8. 3 of 10mM N aHC0 3 buffer / 04108
  • MEM-18 (MONO SAN), an anti-CD14 antibody, was added to a 96-well plate (Maxisorp, Nunc) at 50 1 / we 11 and allowed to stand at 4 ° C overnight. After that, wash with pure water and include 0.5% 83 Blocking was performed at 83 ° (still at room temperature for 60 minutes).
  • the absorbance at a wavelength of 450 nm was measured, and the amount of soluble CD14 produced in the sample was calculated.
  • the culture supernatant containing the soluble CD14 obtained in (2) is an anti-human CD14 antibody
  • Soluble CD14 was confirmed by Western blotting using an anti-human CD14 antibody (3C10 and MEM-18). That was subjected to electrophoresis in a soluble CD 14 30n g / 7 1 ane SDS- po 1 yacry 1 ami de gr ad ient ge l (5-20% ATTO Co., Ltd.), a protein to a PVDF membrane (Nippon Millipore ⁇ Co., Ltd.) After the transfer, a blocking reaction was performed for 1 hour at room temperature in 30 ml of PBS containing 0.5% Sk im Mix, and 10 g / ml of 3C10 and 100-fold diluted MEM-18 were added. The reaction was performed at room temperature for 1 hour.
  • Human vascular endothelial cells HU VEC (Sanko Junyaku) were detached with PBS containing 0.05% Tribcine and 0.53 mM EDTA, and soluble CD14 was isolated from healthy human serum using anti-CD14 antibody.
  • the cells were suspended in RPMI 1640 medium (Asahi Techno Glass Co., Ltd.) containing 2% of the removed serum (hereinafter referred to as 2% CD 14WZOHS / RPMI), and 5 10 4 cells / " ⁇ ⁇ 11 1 (50 lZWe 11) in planting Ekomi 37 ° to 96 ⁇ El plate (:, were cultured for 24 hours under the conditions of 5% C0 2.
  • Example 1 compound 50 ng / m 1 LPS (E. coli 055: B5, Difco) 10 1, 15 g / m 1 of soluble CD 14 (201) and 100 g / m 1 of l% DMSO solution 10 1 of the compound prepared in Example 1 (hereinafter referred to as Example 1 compound) were added. Then, add 10 1 RPM11640 medium containing 10% of human serum from which soluble CD14 has been removed and 120 g / m1 of Cycloeximide (Sigma). Incubated for 18 hours.
  • Table 1 shows the concentrations of the compound of Example 1 that suppressed the degree of cytotoxicity by 50%.
  • example compounds were similarly tested. Table 2 shows the results.
  • THP-1 cells cultured in 10% inactivated FBS / RPM 1 1640 medium supplemented with 40 ng / m 1 of vitamin D 3 (Ca lcitriol, Sigma) for 72 hours in 2% CD 14w oHSZRPM The cells were suspended in I and inoculated in a 96-well plate with 5 ⁇ 10 4 cells sZwe 11 (50 lZwell).
  • a solution containing 1 to 1 g / m1 of the Example 1 compound 10 ⁇ 1 was added to the wells, and the cells were further cultured for 4 hours. Then, the TNF o! In the culture supernatant was converted to hTNF-QiEli- ⁇ . It was measured by R SYSTEM (Invitrogen). The measurement method followed the protocol attached to Kit. That is, the appropriately diluted culture supernatant 1001 was transferred to a reaction plate, and 501 of a biotinylated antibody solution was added thereto, and the mixture was allowed to stand at room temperature for 3 hours. The reaction solution was removed, and each well was washed four times with a washing solution of 4001 / we11. Next, an appropriately diluted peroxidase-labeled streptavidin solution was added to 100 ⁇ l.
  • Table 1 shows the concentration of the compound of Example 1 that suppressed the productivity of TNF amount by 50%. In addition, other example compounds were similarly tested. Table 2 shows the results.
  • TLR4 cDNA Since the human TLR4 cDNA has a translation region of about 2.5 kb (Genbank accession on NO. AF17764), cloning of TLR4 cDNA is performed at the 5'-end 1.1 kb and the 3'-end 2. 3 kb were run separately. Human TLR4 cDNA was cloned by the following method. Based on the human TLR4 genomic sequence (GenBank: accession No.
  • sense primer 3 SEQ ID NO: 45'-TCG AGG AAG AG A AGA CAC CA—3 '
  • sense primer 4 SEQ ID NO: 5 5' CCC ATC CAG AGT TTA GCC CT-1 '
  • antisense primer 1 SEQ ID NO: 65'-CCA TCC GAA ATT ATA AGA AAA AGT C-1
  • antisense primer 6 SEQ ID NO: 75'-TGG AAT TAG TCA CCC TTA GC-3 '
  • pB1uescript ⁇ (+) (STRATGEN E) as a vector was digested with EcoRV, dephosphorylated, prepared, and each of the above PCR products was ligated. After that, transfection is performed using the Combinent cell JM109 (TaKaRa) according to a standard method, and a plasmid containing the 5 'fragment of the TLR4 cDNA (PT45F) and a plasmid containing the 3' fragment (PT43F).
  • Plasmid PBTLR4 containing the full-length human TLR4 cDNA was obtained by translating JM109 to transformation. When the inserted sequence of pBTLR4 was confirmed, it was consistent with the eXon sequence of the human TLR4 genomic sequence. Furthermore, in order to express human TLR4 in honey cells, human TLR4 cDNA was cut out from PBTLR4 with Hindlll and inserted into the Hindill site of pcDNA3.1 (1) (Invitrogen). . Transformation of JM109 was performed to obtain a plasmid pcD NAT4 for expressing human TLR4 in honey cells.
  • the human TLR2 cDNA has a translation region of about 2.6 kb (Genbank accession on No. AF051152)
  • the TLR2c DNA is cloned at 5 'as in the case of human TLR4.
  • the 1.5 kb end and 1.6 kb 3 ′ end were performed separately.
  • sense primer 8 SEQ ID NO: 95'-GTA CCC TTA ATG GAG TTG GT-3'
  • antisense primer 9 SEQ ID NO: 10 5'-GTG TAT TCG
  • TGT GCT GGA TA-3 ' and antisense primer 10 SEQ ID NO: 115'-CCC AAG CTT CAA ATG ACG GT A CAT CCA CG-3'
  • sense primer 7 and antisense primer 8 were used.
  • huma nsle en cDNA CLONTE CH
  • a sense primer 9 and an antisense primer 10 to obtain hum an sple en c DNA
  • CL ONTE CH was used to obtain a DNA fragment of about 1.6 k.
  • transfection is performed using a combination cell JM109 (TaKaRa) according to a standard method, and a plasmid (PT25F) having a 5 ′ fragment of the TLR2 cDNA and a 3 ′ fragment are prepared. (PT 23 F) was obtained.
  • each DNA fragment of human TLR2 was excised from XT23 and XcoIV, EcoRV and HindIII, respectively, from pT25-pcho23F, and pcDNA3.1.
  • Transformation of JM109 was performed to obtain plasmid pCDNAT2 that allows human TLR2 to be expressed in honey cells.
  • the expression plasmid pCDNAT4 prepared in 1) was transfected into the human embryonic kidney-derived cell line HEK293 by the following method.
  • 25/1 of FUGENE6 after the combined mixed in accordance with the attached protocol Ichiru the p CDNAT4 of (Roche 'Daiaguno stick, Inc.) and 6. 3 ⁇ g, 75 cm 2 of HEK 293 grown to Lou flask to Semicon full E cement Added to cells.
  • detach the cells from the single flask and use 96we 1 1- The cells were replated on the plate at 250 cells / we 11 each.
  • Stimulation was performed by adding a mixture of 0.5 / 28 1111 soluble form ⁇ 014 (preparation method described in Experimental Example 1) and 10 ng / ml LPS. Six hours later, the culture supernatant was removed, the cells were washed with PBS-, and the cells were lysed with PssivevelssisBufer (Promega) 1001 / we11. The luciferase activity in the cell extract 20 n1 was measured using: Luciferase Assay Substrate (Promega). A 1420 ARVO s X multi-label counter (Wa 11 ac) was used for the measurement.
  • the expression plasmid PCDNAT2 prepared in 1 was transferred to the human embryonic kidney-derived cell line HEK293, as in human TLR-4. Selective culture was performed for 20 days in a medium containing transfusion and G-418. Next, the responsiveness to PGN / soluble CD14 was examined using the obtained 24 strains of G-418 resistant clones. Each of the 24 clones was inoculated into 24 we 11 -p 1 ate at 2.0 ⁇ 10 5 cells / we 11. 37.
  • the luciferase activity in the cell extract 20a1 was measured using Luciferase Assay Substrate (Promega). The measurement was performed using a 1420 ARVO s X multi-label counter (Wa 1 lac). As a result, clone HEKT 2-6 showing luciferase activity in the cell extract was obtained. A similar experiment was performed using HEK293, but no luciferase activity could be confirmed. Induction of luciferase activity by LTAZ-soluble CD14 in HEKT2-6 was dependent on the expressed TLR2 ( Figure 3).
  • ⁇ 4-14 cells are suspended in DMEM medium containing 10% inactivated FBS.
  • X 1 0 5 cells ZWE 1 1 24 6 1 1 1 &1; narrowing sown in e, were cultured for 24 hours under the conditions of 5% C0 2, 37 ° C .
  • FUGENE 6 livo tergene pNF ⁇ B—Luc (CLONTECH) was introduced into lO Ong / well, and the culture was further continued for 24 hours.
  • LPS E.
  • coli 055 B5, Difco) at a final concentration of 1 ngZml, soluble CD14 at a final concentration of 0.5 g / m1, and a final concentration of 0.1 to 1 for the example compounds
  • the cells were lysed with Passive Ve Lysis Buffer (Promega), and the luciferase activity was reduced to Luciferase Assay Substrate (Pr omega) according to the attached protocol.
  • Table 1 shows the inhibitory activity of the compound of Example 1.
  • Itaipushironkappatau2- 6 cells were suspended in DMEM medium containing 10% inactivated FBS, 1 X 10 5 in cells Zwe 1 1 24we 1 1 -p 1 narrowing plated on ate, under conditions of 5% C0 2, 3 7 ° C For 24 hours. Thereafter, using LiGuE6, 10 ngZwe 11 of Ribo Yu—Gene pNF ⁇ B—Luc (CLONTECH) was introduced, and the culture was continued for further 24 hours.
  • P Eptide final concentration 1 ⁇ g / m 1 1 1 ye an Typ e I (En terococcusfaecalis, Wako Pure Chemical), soluble 0,014 final concentration 0.
  • Example Compound 5 ⁇ ⁇ 1111, screening compound obtained in Example Compound was added to the cells at a final concentration of 0.1 to 10 g / m1 and cultivation was continued for 6 hours. The cells were then lysed with Passive Lysis Buffer (Promega), and the luciferase activity was reduced. uciferase As s ay 8
  • the measurement was performed using Substrate (Promega Corporation) according to the attached protocol.
  • Table 1 shows the inhibitory activity of the compound of Example 1.
  • IL-16 was measured according to the protocol attached to the human IL-16 EIA kit. That is, the appropriately diluted culture supernatant 1001 was transferred to an IL-16 antibody-immobilized plate, and a biotin-labeled anti-IL16 antibody solution was added thereto, followed by incubation at room temperature for 60 minutes. After that, the reaction solution was removed, washed four times with a PBS-solution containing 400/1 / We11 in 0.0 l% Tween-20, and a streptavidin solution labeled with peroxidase with 1001 / We11 was removed. 100 1 / We 11 were added, and further incubated for 37 and 20 minutes. TJP03 / 04108
  • Table 1 shows the concentrations of the compound of Example 1 that suppresses the productivity of IL-6 by 50%. In addition, other example compounds were similarly tested. Table 2 shows the results.
  • Example 1 In a mouse (BALB / c, male, 6 weeks old, Nippon Chillers Ripper), dissolve the compound of Example 1 in a solvent (physiological saline containing 10% HC ⁇ -60), and add 10 mg of OmgZkg to the tail vein. Was administered internally. The control group received the solvent. Two minutes later, 10 g Zkg of D-galactosamine hydrochloride 7001! 18 118 cells and 1 ipopolis ac charride (LPS) was administered into the tail vein. 1. Viability was observed and recorded after 5, 6, 12 and 24 hours.
  • a solvent physiological saline containing 10% HC ⁇ -60
  • Example 96 The compound was dissolved in a physiological saline solution containing 0.005 N hydrochloric acid, and 4 mgkg or 1 OmgZkg was administered.
  • physiological saline adjusted to the same pH as the test compound solution was used. ? The tail vein administration of 3 was 187.
  • Example 1 (Efficacy in the galactosamine-loaded endotoxin lethal model)
  • Example 1 A force Blanc Meyer's life table was prepared based on the survival rates of the compound administration group and the control group, and statistically analyzed by the Wilcoxon test. A significant increase in the survival rate was observed when the compound of Example 1 was administered at 10 mg / kg compared to the control group (Fig. 4).
  • RNA prepared from lung tissue of BALBZc mice using RNAzol B was converted into type II PCR Nymouth mass TM cDNA was isolated.
  • a chimeric protein in which the extracellular domain of mouse tonpomodulin was fused to a His tag was expressed.
  • the fusion protein expression plasmid of mouse thrombomodulin extracellular domain and His tag obtained in (2) was introduced into COS cells. Culture the introduced cells for 3 days 0304108
  • the culture supernatant was collected and purified using a nickel column (Hitrap Chelatng HP column, Amersham Biotechnology) to obtain a purified soluble "mouseTM" protein.
  • the rabbit was immunized using the purified "mouse TM" protein to prepare a polyclonal antibody.
  • the antibody obtained here was immobilized on a 96-well plate, and on the other hand, a peroxidase-labeled mouseTM antibody was prepared, and a sandwich ELISA system using a mouseTM antibody solid phase Z-peroxidase-labeled mouseTM antibody was prepared. did.
  • Standards were prepared using purified "mouseTM" protein.
  • a mouse (BALB / c, male, 6 to 8 weeks old, Nippon-Charles River) was incised in the abdominal skin and peritoneum, and the cecum was removed from the intraperitoneal cavity.
  • the cecum was ligated downstream of the ileocecal region, and the cecum upstream of the ileocecal region, opposite to the mesentery, was punctured at one site with an 18-gauge injection needle.
  • the cecum was returned to the intraperitoneal cavity, the peritoneum and the skin at the incision were sutured, and physiological saline was subcutaneously administered to the back of the face at lm1 / body.
  • the compound of Example 1 was dissolved in a solvent (physiological saline solution containing 10% HCO-60), and administered immediately after the operation, 1 day and 2 days after the operation, in the tail vein at 1 OmgZkg.
  • the control group received the solvent. Survival and death were observed and recorded on days 1, 2, and 3 after surgery.
  • a force plan Meyer's life table was prepared based on the survival rates of the control group and the compound administered with the compound of Example 1, and statistically analyzed by Wilcoxon test.
  • Example 96 the compound of Example 96 was tested in the same manner except for the following points.
  • cecal puncture was performed at two sites, and no saline was administered subcutaneously to the dorsal dorsum.
  • Example 96 The compound was dissolved in a physiological saline solution containing 0.0001N hydrochloric acid, and immediately after the operation, continuous intravenous administration was performed from the jugular vein.
  • physiological saline adjusted to the same pH as the test compound solution was used.
  • the inhibitory activity of the signal transduction system from TLR9 to NF-KB can be confirmed by the following method.
  • the TLR9 gene is isolated based on the report of Akira et al. (Nichiya Nature 2000, 408, 681, 3rd volume, p 740-745). Next, in the same manner as in Experimental Example 5, a plasmid was prepared in which the obtained TLR9 gene was incorporated into an expression vector.
  • HEK 293 cells are suspended in DMEM medium containing 10% inactivated FBS, seeded at 1 ⁇ 10 5 cells / we 11 in 24 we 11--p 1 ate, and 5% C ⁇ 2 at 37 ° C. Incubate for 24 hours below.
  • TLR9 expression plasmid and Lipo overnight gene pNF ⁇ B_Luc (CLON TECH) are introduced using FUGENE6, and the culture is further continued for 24 hours.
  • a ligand for TLR9 a DNA containing the CpG sequence at a final concentration of 10 mo1 / L and the example compound are added at a final concentration of 0.1 to 1 O ⁇ g / ml.
  • the cells were lysed with Pasesi Ve Lysis Buffer (Promega);
  • the compound of Example suppresses TLR9 signal, for example, the compound of Example 96 suppresses TLR9 signal by 3 to 10 ⁇ 2 1111 by 20 to 80%.
  • the compound represented by the formula (I) or the compound of the present invention which is an active ingredient of the pharmaceutical composition, prophylactic or therapeutic agent of the present invention, is expressed in endothelial cells in vitro. It showed an inhibitory effect on disability. It also suppresses endothelial cell cytokine production. And THP_1 cells showed inhibition of cytoforce-in production.
  • the compound was also effective in a galactosamine-loaded endotoxin lethal model, which was ineffective with antibacterial agents, and also suppressed increases in plasma soluble tropomodiulin and plasma soluble E-selectin concentrations.
  • Elevated plasma soluble tropomodulin and plasma soluble E-selectin levels in a galactosamine-loaded endotoxin lethal model are indicators of vascular endothelial cell damage. That is, the compound represented by the formula (I) or the compound of the present invention, which is an active ingredient of the pharmaceutical composition, the prophylactic or therapeutic agent of the present invention, is used not only in in vitro but also in an in vivo model. It showed an inhibitory effect on endothelial cell damage.
  • the experimental examples described above show that a prophylactic / therapeutic agent or a pharmaceutical composition containing the compound represented by the formula (I) or the compound of the present invention as an active ingredient is useful for preventing and / or treating diseases associated with endothelial cell damage.
  • the composition is a pharmaceutical composition for a disease involving Z or a therapeutic agent or endothelial cell damage.
  • the compound represented by the formula (I) or the compound of the present invention which is an active ingredient of the pharmaceutical composition, the prophylactic or therapeutic agent of the present invention, is ineffective for the steroid used as a therapeutic agent for sepsis.
  • the efficacy was demonstrated in a mouse cecal ligation puncture peritonitis model, a sepsis model of persistent infection with live bacteria.
  • the cecal ligation and puncture peritonitis model in rodents is similar to sepsis caused by peritonitis in humans who cause sepsis due to persistent infection by viable bacteria leaking from the puncture of the cecum (Journal of Surgical Research 1980 29 , ⁇ ⁇ 189-201), which is considered to be the most useful model for sepsis. That is, in the above experimental examples, the therapeutic agent or the pharmaceutical composition for preventing Z containing the compound represented by the formula (I) or the compound of the present invention as an active ingredient is extremely highly effective as compared with the current therapeutic agent. This is an example showing that it is a preventive and / or therapeutic agent for sepsis by a mechanism of inhibiting vascular endothelial damage, or a pharmaceutical composition for sepsis.
  • the compound represented by the formula (I) or the compound of the present invention which is an active ingredient of a pharmaceutical composition, a prophylactic or therapeutic agent of the present invention, also inhibits a signal mediated by TLR4 and a signal mediated by TLR2. And signal inhibition via TLR9. It has been shown that a plurality of endotoxins inhibit endotoxin-dependent TLR-mediated signaling, respectively. Therefore, a prophylactic Z therapeutic agent comprising a compound represented by the formula (I) or a compound of the present invention as an active ingredient or This is an example showing that the pharmaceutical composition is effective as a prophylactic and / or therapeutic agent for a disease associated with a signal mediated by TLR, or as an inhibitor of the signal.
  • Methylprednisolone which was used as a comparison, was significantly more susceptible to intravenous administration of 1 O mg Z kg compared to the control group. Decreased thymus weight, reduced spleen weight, increased total blood cholesterol, and decreased blood glucose. This indicates that the compound which is an active ingredient of the pharmaceutical composition and the prophylactic / therapeutic agent of the present invention has no toxicity at a concentration showing sufficient efficacy in vivo.
  • NMR NMR was measured with J EOL JNM-EX270 (manufactured by JEOL Ltd.) or J EOL JNM-LA300 (manufactured by JEOL Ltd.), and TMS (tetramethylsilane) was used as an internal standard and expressed in (ppm).
  • TMS tetramethylsilane
  • Example 2 The same reaction as in Example 1 was carried out using 2,5-dichrolic benzonitrile to obtain the target compound as a white powder. '
  • Example 2 The same reaction as in Example 1 was performed using 2,5-dibromobenzonitrile to obtain the target compound as a white powder.
  • Example 2 The same reaction as in Example 1 was carried out using 2,5-difluorobenzonitrile to obtain a target compound as a white powder.
  • Example 2 The same reaction as in Example 1 was performed using 2-chloro-5-trifluoromethylbenzonitrile to obtain the target compound as a yellow powder.
  • Example 2 The same reaction as in Example 1 was carried out using 2-fluoro-5-hydroxymethylbenzonitrile to obtain the desired compound as a pale yellow powder.
  • Example 2 The same reaction as in Example 1 was carried out using 2-promo 5-methoxybenzonitrile to obtain the target compound as a beige powder.
  • aqueous ammonia (18 ml) was added to a mixture of 2_mercapto-1-methoxybenzonitrile (2.0 g) and an aqueous solution of IN-sodium hydroxide (12 ml). At a temperature of 5 to 0 ° C, 5% sodium hypochlorite (13.4 ml) was added dropwise over 30 minutes. After standing at room temperature overnight, water and ethyl acetate were added to the reaction solution, and the insoluble matter was removed by filtration. The filtrate was separated, and the organic layer was dried over anhydrous sodium sulfate and then dried under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate Z hexane) to obtain the desired compound (1.46 g) as a white powder.
  • Example 2 The same reaction as in Example 1 was carried out using 4-benzyloxy-2-fluorobenzonitrile to obtain the desired compound as a white powder.
  • Example 13 The same reaction as in Example 13 was carried out using 3-amino-16-hydroxy-1,2-benzoisothiazole obtained in Example 16 and methane, to obtain the target compound as a pale yellow powder.
  • Example 13 The same reaction as in Example 13 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole and 3-chloromethylpyridine hydrochloride obtained in Example 16, and the target compound was converted to beige powder. As obtained.
  • Example 16 Using 3-amino-16-hydroxy-1,2-benzoisothiazole and 3-bromo-1-propanol obtained in Example 16, the same reaction as in Example 13 was carried out, and the target compound was light beige. Obtained as a powder.
  • Example 20 The same procedure as in Example 20 (Step 4) was carried out, using 5-amino-1,3-di-t-butoxycarboxylamine 1,2-benzoisothiazole synthesized in Example 20 (Step 2), to obtain the desired compound Was obtained as a dark brown powder.
  • Example 22 The same operation as in Example 22 was performed using acid monohydrate to obtain the desired compound. Obtained as a white powder.
  • Example 26 The same operation as in Example 22 was carried out using 3-amino-1,2-benzoisothiazole obtained in Example 1 and maleic acid, to obtain the desired compound as a white powder.
  • Example 30 The same reaction as in Example 30 was carried out using 3_amino-6-1-1-1,2-benzoisothiazole obtained in Example 28 to obtain a target compound.
  • Example 14 The same reaction as in Example 14 was carried out using 2_mercapto-5-acetylacetylbenzonitrile to obtain the target compound as a yellow powder.
  • Example 38 The same reaction as in Example 36 was carried out using 6-acetyl-3-amino-1,2-benzisothiazole obtained in Example 36 to obtain a target compound as a pale yellow powder.
  • Example 40 The same reaction as in Example 40 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole and methylpropargyl ether obtained in Example 28 to obtain the target compound as a yellow powder.
  • Example 40 The same reaction as in Example 26 was carried out using 3-amino-6- (3-hydroxy-1-propyne-11-yl) 1-1,2-benzoisothiazole obtained in Example 40 to obtain the desired compound Was obtained as a white powder.
  • Example 43 The same reaction as in Example 43 was carried out using 3-amino-6-iod_1,2-benzisothiazole obtained in Example 28 to obtain the target compound as a white powder.
  • Example 43 The same reaction as in Example 43 was carried out using 3_amino-5-hydroxy-1,2-benzoisothiazole and 4-methoxyphenylboronic acid obtained in Example 27, and the target compound was obtained as a white powder. Obtained.
  • Example 43 The same reaction as in Example 43 was carried out using 3-amino-6-iodo-1,2-benzoisothiazole and 2-nitrophenylboric acid obtained in Example 28, and the target compound was obtained as a dark yellow powder. As obtained.
  • Example 16 The same reaction as in Example 13 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole and cloethylmethyl ether obtained in Example 16 to obtain the target compound as a pale beige powder Obtained.
  • Example 16 The same reaction as in Example 13 was performed using 3-amino-16-hydroxy-1,2-benzoisothiazole and 2- (dimethylamino) ethyl chloride hydrochloride obtained in Example 16 to obtain the desired compound was obtained as a light gray powder.
  • Example 13 The same reaction as in Example 13 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole and 6-cyclohexanol obtained in Example 16 to obtain a target compound.
  • Example 13 The same reaction as in Example 13 was carried out using 3-amino-5-hydroxy_1,2-benzoisothiazole and 2-benzene benzene obtained in Example 12 to obtain the target compound as a yellow powder. .
  • Example 13 The same reaction as in Example 13 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole and 2-fluoronitrobenzene obtained in Example 16, to obtain the target compound as a yellow powder. ;, 11 ⁇
  • Example 53 The same reaction as in Example 52 was carried out using 3-amino-6- (2-nitrophenoxy) -1,2-benzoisothiazole obtained in Example 53 to obtain the desired compound as an orange powder.
  • Example 13 The same reaction as in Example 13 was carried out using 3-amino-6- (2-nitrophenoxy) -1,1,2-benzoisothiazole and methane obtained in Example 53 to obtain the desired compound as a yellow powder.
  • Example 53 The same reaction as in Example 13 was carried out using 3-amino-6- (2-nitrophenoxy) -1,1,2-benzoisothiazole and methane obtained in Example 53 to obtain the desired compound as a yellow powder.
  • Example 52 The same reaction as in Example 52 was carried out using 3-methylamino-1- (2-diphenoxy) -11,2-benzoisothiazole obtained in Example 55, to obtain the desired compound as a white powder.
  • Example 16 3-amino-6-hydroxy-1,2-benzoisothia obtained in Example 16 The same reaction as in Example 13 was carried out using sol and 3-fluoronitrobenzene to obtain the desired compound as a yellow powder.
  • Example 52 The same reaction as in Example 52 was carried out using 3-amino-6- (3-nitrophenoxy) 1-1,2-benzoisothiazole obtained in Example 57 to obtain a target compound as a pale gray powder.
  • Example 13 The same reaction as in Example 13 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole and 4-fluoronitrobenzene obtained in Example 16 to obtain the target compound as a yellow powder. As obtained.
  • Example 59 Using 3-amino-6- (4-nitrophenoxy) -11,2-benzoisothiazole obtained in Example 59, the same reaction as in Example 52 was carried out to obtain the target compound as a pale gray powder.
  • Example 16 Using 3_amino-6-hydroxy-11,2-benzoisothiazole and 2-fluorobenzonitrile obtained in Example 16, the same reaction as in Example 13 was carried out, and the target compound was obtained as a white powder. Obtained.
  • Example 13 The same reaction as in Example 13 was carried out using 3-amino-16-hydroxy-1,2-benzoisothiazole and 2-fluoropyridine obtained in Example 16 to obtain a target compound as a pale gray powder.
  • Example 16 The same reaction as in Example 13 was carried out using 3-amino-16-hydroxy-1,2-benzoisothiazole and 2-fluoropyridine obtained in Example 16 to obtain a target compound as a pale gray powder.
  • Example 13 The same reaction as in Example 13 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole obtained in Example 16 and pyridine monohydrochloride to give the desired compound.
  • Example 16 The same reaction as in Example 13 was performed using 3-amino-6-hydroxy-1,2-benzoisothiazole and 2-nitrobenzil bromide obtained in Example 16. To the obtained crude product was added 4M-hydrogen chloride / ethyl acetate, and the mixture was stirred at room temperature for 5 minutes and concentrated under reduced pressure. To this, getyl ether was added, filtered and dried to obtain the target compound.
  • Example 16 Using 3-amino-6-hydroxy-1,2-benzoisothiazole and 4-chloromethylpyridine hydrochloride obtained in Example 16, the same reaction as in Example 13 was carried out, and the target compound was white. Obtained as a powder.
  • Example 66 The same reaction as in Example 66 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole and 2-pyridylmethyl alcohol obtained in Example 16 to obtain the target compound as a white powder Was.
  • Example 14 The same reaction as in Example 14 was carried out using 2-mercapto-141-trobenzonitrile to obtain the target compound as a yellow powder.
  • Example 75 Was used to carry out the same reaction as in Example 72 to obtain the target compound as a white powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-16-hydroxymethyl-1,2-benzoisothiazole obtained in Example 34 to obtain the target compound as a white powder.
  • Negation R (* CDC1 3); 7.83 (1H, s), 7.84-7.77 (1H, m), 7.42-7.33 (1H, m), 4. 63 (2H, s), 3.45 (3H, s), 3.42 (3H, s), 1.41 (9H, s)
  • Example 37 Using 3-amino-6- (1-hydroxy-1-methylethyl) 1-1,2-benzoisothiazole obtained in Example 37, the same reaction as in Example 72 was carried out, and the target compound was pale yellow. Obtained as a powder.
  • Example 3 Synthesis of 3-amino-6-benzoyl-1,2-benzoisothiazol hydrochloride
  • Example 7 Using 3-amino-6-benzoyl-1,2,2-benzoisothiazole obtained in Example 38. By performing the same reaction as in 2, the target compound was obtained as a pale yellow powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (3-hydroxy-1-propyne-111-yl) -1,2-benzoisothiazol obtained in Example 40.
  • the target compound was obtained as a white powder.
  • Example 41 The same reaction as in Example 72 was carried out using 3-amino-6- (3-methoxy-11-propyn-1-yl) _1,2-benzoisothiazol obtained in Example 1. The compound was obtained as a white powder. 8
  • Example 72 The same reaction as in Example 72 was carried out using 3-methylamino-1 6- (3-methoxy-11-propyne-11-yl) 1-1,2-benzoisothiazol obtained in Example 42 to obtain the desired compound Was obtained as a white powder.
  • Step 1 Synthesis of 3-amino-6- (3- (N, N-di-tert-butoxycarbonylamino) -11-propyne-11-yl) 1-1,2-benzoisothiazole
  • Step 1 Synthesis of 3-amino-6- (3- (N-t-butoxycarporinyl N-methylamino) -11-propyne-11-yl) 1-1,2-benzoisothiazole
  • Example 28 The same reaction as in Example 40 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole and N-t-butoxycarporinyl N-methyl-propargylamine obtained in the above, The desired compound was obtained.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (2-ditrophenyl) -1,2-benzoisothiazole obtained in Example 46, and the target compound was converted into a pale yellow powder. Obtained.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (4-aminophenyl) 1-1,2-benzoisothiazole obtained in Example 47, and the target compound was converted into a white powder. Obtained.
  • Example 72 The same reaction as in Example 72 was performed using 3_amino-6- (2-methoxyethoxy) -1,2-benzoisothiazole obtained in Example 48 to obtain the target compound as a white powder. .
  • Example 49 Using the 3-amino-6- (2-dimethylaminoethoxy) -1,2-benzoisothiazole obtained in Example 49, the same reaction as in Example 72 was carried out to obtain the target compound as a white powder. Obtained.
  • Example 16 Using the 3-amino-6-hydroxy-1,2, -benzoisothiazole obtained in Example 16 and N-t-butoxycarbonylpiperidin-1-ol, The same reaction as in Example 66 was carried out to obtain the desired compound as a pale yellow powder.
  • Example 78 The same reaction as in Example 78 (Step 4) was carried out using 3-amino-6- (N-t-butoxycarbonylpiperidine-1_4-yloxy) 1-1,2-benzoisothiazole obtained in Step 1;
  • the target compound was obtained as a white powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3_amino-5_ (2-ditrophenoxy) -l, 2-benzoisothiazole obtained in Example 51 to obtain the target compound as a white powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-5_ (2-aminophenoxy) 1-1,2-benzoisothiazole obtained in Example 52 to obtain the target compound as a white powder.
  • Example 53 The same reaction as in Example 72 was carried out using 3-amino-6- (2-ditrophenoxy) 1-1,2-benzoisothiazole obtained in 3 to obtain the target compound as a white powder.
  • Example 53 The same reaction as in Example 72 was carried out using 3-amino-6- (2-ditrophenoxy) 1-1,2-benzoisothiazole obtained in 3 to obtain the target compound as a white powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-16- (2-aminophenoxy) -11,2-benzoisothiazole obtained in Example 54 to obtain the target compound as a white powder. .
  • Example 55 Using 3-methylamino-6- (2-nitrophenoxy) -1,2-benzoisothiazole obtained in Example 55, the same reaction as in Example 72 was carried out to obtain a target compound.
  • Example 56 The same reaction as in Example 72 was carried out using 6- (2-aminophenoxy) -13-methylamino-1,2,2-benzoisothiazole obtained in Example 6 to obtain the desired compound Was obtained as a white powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3_amino-6- (3-aminophenoxy) 1-1,2-benzoisothiazole obtained in Example 58 to obtain the target compound as a pale gray powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (412-trophenoxy) -1,2-benzoisothiazole obtained in Example 59 to obtain the desired compound as a pale yellow powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (4-aminophenoxy) -1,1,2-benzoisothiazole obtained in Example 60 to obtain the target compound as a pale yellow powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (2-cyanophenoxy) -1,2-benzoisothiazole obtained in Example 61 to obtain the target compound as a pale gray powder.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (2-pyridyloxy) -1,2-benzoisothiazole obtained in Example 62, to obtain the desired compound as a pale gray powder .
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (4-pyridyloxy) -1,2-benzoisothiazole obtained in Example 63 to obtain the desired compound
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (2-aminobenzyloxy) 1-1,2-benzoisothiazole obtained in Example 65, and the target compound was converted into a pale yellow powder. As obtained.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-6- (ethoxycarbonyl (phenyl) methoxy) 1-1,2-benzoisothiazole obtained in Example 66 to give the target compound as white Obtained as a powder.
  • Example 15 Using 3-amino-6-benzyloxy-1,1,2-benzoisothiazole obtained in Example 15, the same reaction as in Example 72 was carried out to obtain a target compound.
  • Example 66 The same reaction as in Example 66 was carried out using 3-amino-6-hydroxy-1,2-benzoisothiazole and 4-t-butoxycarbonylaminobenzyl alcohol obtained in Example 16 to obtain the desired compound. Obtained as a pale yellow powder.
  • Step 2 3-Amino-6- (4-aminobenzyloxy) -1,2-benzoy Synthesis of sothiazole dihydrochloride
  • Example 69 Using 3-amino-6- (2-pyridylmethoxy) 1-1,2-benzoisothiazole obtained in Example 69, the same reaction as in Example 72 was carried out to obtain a target compound.
  • Example 72 The same reaction as in Example 72 was carried out using 3-amino-16-methanesulfonyl 1,2-benzoisothiazole obtained in Example 71 to obtain a target compound.
  • Table 4 shows the structures of the compounds of the present invention synthesized in Examples 1 to 110 described above.
  • Table 5 shows the IR spectrum, NMR spectrum and physical property data of the melting point of these examples.
  • Me represents a methyl group
  • Et represents an ethyl group.
  • Example 9 Example 10 -HGI 1 3 shift
  • Example 15 Example 16 Example 17 Example Example 19 Example 20
  • Example 27 NH 2 NH, (Part 3) Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27
  • Example 29 Example 30 (Part 4) Example 31
  • Example 32 Example 33
  • Example 37 Example 38 Example 39 Example 40 Table 4 (Part 5) Example 41 Example 42 Example
  • Example 67 Example 68
  • Example 69 Example 70 tar
  • Example 105 Example 106
  • the pharmaceutical composition of the present invention provides a novel agent for preventing and / or treating a disease associated with endothelial cell damage.
  • it provides an agent for preventing and / or treating sepsis, severe sepsis or septic shock. This is effective even in cases where conventional antibacterial agents and steroids are ineffective, due to a novel mechanism that suppresses endothelial cell damage and suppresses the induction of various media.
  • composition of the present invention provides a preventive and / or therapeutic agent for a disease associated with a signal mediated by TLR, or an agent for inhibiting the signal.
  • the present invention also provides novel compounds.
  • the compounds are useful as active ingredients in the above-mentioned pharmaceutical compositions.

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Abstract

L'invention concerne un agent de prévention et/ou de thérapie de maladies associées à des troubles endothéliaux, de sepsie, de sepsie grave, de chocs septiques ou de maladies associées à des signaux de récepteurs TLR. L'agent selon l'invention contient, en tant que principe actif, un composé 3-amino-1,2-benzisothiazole de formule (I) ou un dérivé de ce composé, R1, R2, R3 et R4 représentant hydrogène ou un substituant.
PCT/JP2003/004108 2002-03-29 2003-03-31 Agent therapeutique destine a des troubles endotheliaux WO2003087072A1 (fr)

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WO2004113304A1 (fr) * 2003-05-22 2004-12-29 Abbott Laboratories Inhibiteurs de kinases de type indazole, benzisoxazole et benzisothiazole
WO2005007635A3 (fr) * 2003-07-18 2005-08-11 Sigma Tau Ind Farmaceuti Derives de la combretastatine a action cytotoxique
EP1606283A4 (fr) * 2003-03-03 2007-05-23 Array Biopharma Inc Inhibiteurs de la p 38 et leurs procedes d'utilisation
US7297709B2 (en) 2003-05-22 2007-11-20 Abbott Laboratories Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
WO2008090048A2 (fr) 2007-01-26 2008-07-31 Basf Se Composés de 3-amino-1,2-benzisothiazole utilisés contre les animaux nuisibles ii
JP2008545008A (ja) * 2005-06-30 2008-12-11 プロシディオン・リミテッド Ｇｐｃｒアゴニスト
EP2123159A1 (fr) 2008-05-21 2009-11-25 Bayer CropScience AG (1,2-benzisothiazol-3-yl)(thio)carbamate et (1,2-benzisothiazol-3-yl)(thio)oxamate et leurs formes d'oxydation en tant que pesticides
US7799782B2 (en) 2003-03-03 2010-09-21 Array Biopharma Inc. P38 inhibitors and methods of use thereof
US8017554B2 (en) 2006-03-31 2011-09-13 Basf Se 3-amino-1,2-benzisothiazole compounds for combating animal pest
US8039639B2 (en) 2006-01-31 2011-10-18 Array Biopharma Inc. Kinase inhibitors and methods of use thereof
CN105669588A (zh) * 2016-03-16 2016-06-15 天津大学 苯并异噻唑类衍生物的制备方法

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EP2246333A1 (fr) * 2003-05-22 2010-11-03 Abbott Laboratories Nhibiteurs de kinases de type indazole, benzisoxazole et benzisothiazole
JP2011088918A (ja) * 2003-05-22 2011-05-06 Abbott Lab インダゾール、ベンズイソオキサゾールおよびベンズイソチアゾールキナーゼ阻害剤
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WO2009141065A3 (fr) * 2008-05-21 2010-10-07 Bayer Cropscience Ag (1,2-benzisothiazol-3-yl)(thio)carbamate et (1,2-benzisothiazol-3-yl)(thio)oxamate et leur formes d'oxydation utilisés comme pesticides
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