WO2014034719A1 - Dérivé de quinoline possédant une activité inhibitrice de tlr - Google Patents

Dérivé de quinoline possédant une activité inhibitrice de tlr Download PDF

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WO2014034719A1
WO2014034719A1 PCT/JP2013/072999 JP2013072999W WO2014034719A1 WO 2014034719 A1 WO2014034719 A1 WO 2014034719A1 JP 2013072999 W JP2013072999 W JP 2013072999W WO 2014034719 A1 WO2014034719 A1 WO 2014034719A1
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methylpiperazin
methyl
quinolin
amino
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俊司 竹村
祥元 三宅
章泰 纐纈
宙久 徳田
正教 芦川
達明 西山
哲 合田
裕一朗 天竺桂
正毅 山火
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興和株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention has a nucleic acid receptor inhibitory action and is caused by inhibition of a signal downstream of the nucleic acid receptor, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis ( MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis cardiomyopathy
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • SS Sjogren's syndrome
  • MS multiple sclerosis
  • IBD inflammatory bowel disease
  • Behcet's syndrome autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis cardiomyopathy
  • the immune system When the pathogen enters the living body, the immune system immediately identifies and eliminates the pathogen.
  • the immune system can be broadly divided into innate immunity and acquired immunity.
  • acquired immunity a myriad of receptors having different antigen specificities are expressed on the surface of T cells and B cells by a method called gene rearrangement, and deal with any unknown foreign antigen (Non-patent Document 1).
  • TLR Toll-like receptor
  • Non-patent Document 2 In that sense, induction of gene expression of cytokines and chemokines such as type I interferon and the group of molecules involved in antigen presentation induced by activation of the innate immune system known so far, and subsequent activity of the adaptive immune system It has become clear that the pathway leads to activation of specific immune responses by coordinating with the development (Non-patent Document 2).
  • TLR3 recognizes virus-derived double-stranded RNA
  • TLR7 similarly recognizes virus-derived single-stranded RNA
  • TLR9 recognizes and activates bacterial CpG DNA.
  • CpG DNA repeats at a certain frequency with a characteristic sequence of bacterial genomic DNA that is not methylated. In mammalian genomic DNA, the frequency of CpG sequences is low and methylated frequently, so there is no immunostimulatory effect (Non-patent Document 3).
  • TLRs 7 and 9 function as receptors that recognize extracellular RNA and DNA in endosomes and lysosomes, and induce gene expression of type I interferons and inflammatory cytokines. Both are mediated by a MyD88-dependent signal transduction pathway, whereas the former involves IRAK1 / IKK ⁇ -IRF-7, while the latter involves MyD88, which involves NF- ⁇ B, IRF-5, and MAP kinase pathways.
  • Is known to associate with IRF-1 and IRF-4 in addition to IRF-7 and IRF-5 Non-Patent Documents 4, 5, and 6
  • IRF transcription factors involved downstream of TLR9 The type and role differ depending on the cell type.
  • the nucleic acid receptor recognizes RNA or DNA as a ligand, but under normal conditions, the self-nucleic acid is not recognized as a ligand and does not activate innate immunity. This is because the self-nucleic acid released by cell death is degraded before being recognized by the nucleic acid receptor by a nuclease in the serum.
  • intracellular localization not in the cell surfaces of TLR3, 7 and 9 but in endosomes is considered as a mechanism that does not recognize self-nucleic acids.
  • a defense mechanism may be disrupted, forming a complex with an endogenous protein and activating a nucleic acid receptor signal (Non-Patent Document). 7).
  • RA nucleic acid receptor
  • SLE SLE
  • SS SS
  • MS psoriatic arthritis
  • Behcet's syndrome autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or It is considered possible to improve cardiomyopathy due to sepsis.
  • these several diseases have a specific relationship with TLR.
  • Non-patent Document 8 hydroxychloroquine, an antimalarial drug, is known to have an inhibitory action on TLR7 and 9 by suppressing acidification of endosomes, and is approved as a therapeutic drug for RA and SLE in most countries except Japan ( Non-patent document 9).
  • Non-patent Document 10 the attenuation of antinuclear antibodies observed in SLE-like pathogens in TLR9 knockout mice has been reported (Non-patent Document 10), and similar results have been reported in experiments using TLR9-inhibiting nucleic acids.
  • Non-Patent Document 11 the attenuation of antinuclear antibodies observed in SLE-like pathogens in TLR9 knockout mice has been reported (Non-patent Document 10), and similar results have been reported in experiments using TLR9-inhibiting nucleic acids.
  • Non-Patent Document 11 Furthermore, a low molecular weight compound having the same action has also been reported (CPG 52364: Patent Document 1).
  • TLR7 knockout mice MRL / lpr mice that spontaneously develop SLE-like symptoms
  • SLE-like symptoms such as a decrease in urinary protein and blood IgG
  • Non-patent Document 11 suppression of SLE-like symptoms has also been reported by administering an inhibitory nucleic acid
  • TLR7 is also very useful as a target of SLE.
  • EAE model which is a model of MS in mice
  • the pathogenesis of the disease is weak in TLR2 and TLR9 knockout mice, and the involvement of TLR has been shown (Non-patent Document 14).
  • Non-patent Document 15 It has been reported that salivary gland epithelial cells of SS patients are highly sensitive to apoptosis due to activation of TLR3, and TLR is considered to be involved.
  • TLR inhibition acts on a diseased body
  • TLR activation is suppressed on the diseased body.
  • Non-patent Document 17 There has been a report that the contractility of cardiomyocytes has been lost by inflammatory cytokines produced by the ligand CpG-B DNA, and its action was attenuated in TLR9 knockout mice. From these facts, it is considered to be involved in cardiomyopathy due to sepsis.
  • Hydroxychloroquine is known to have a TLR9 inhibitory action and is already used in clinical practice, but it is not so strong as a TLR9 inhibitory action, and a drug having a stronger TLR9 inhibitory action has a stronger drug effect. I can expect. Hydroxychloroquine has concerns about side effects such as chloroquine retinopathy, but there is a possibility that such side effects may be eliminated by compounds having different skeletons.
  • a low molecular weight drug that exhibits a strong nucleic acid receptor inhibitory action and can be administered orally will be used in future RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, vasculitis and other autoimmune diseases, inflammation It is considered useful in the treatment of cardiomyopathy due to allergies, asthma, graft rejection, GvHD or sepsis.
  • NK-3 receptor modulator characterized by having an aryl or heteroarylalkylcarbamoyl group at the 4-position of quinoline
  • MCH melanin-concentrating hormone
  • Non-Patent Document 6 has the ability to inhibit VLA-4 (Patent Document 6) and the effect of suppressing immunostimulatory action by oligodeoxynucleotides having a CpG motif.
  • Non-Patent Documents 18 and 19, and Patent Documents 7 and 8) differ from the group of compounds contained in the present invention in terms of the substitution mode.
  • An object of the present invention is to provide a novel compound having a low molecular weight nucleic acid receptor inhibitory action. More particularly, RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis prevention and / or cardiomyopathy. Another object is to provide a medicament useful for treatment.
  • the present inventors have found that the quinoline derivative represented by the following general formula (1) expresses human TLR3 endogenously.
  • Test using ECV304 derived from human vascular endothelial cells test using HEK293 cells derived from human fetal kidney cells expressing human TLR7, HEK293 cells derived from human fetal kidney cells expressing human TLR9 And the present invention has been completed.
  • Ring A represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group
  • ring A is a C 1-6 alkyl group, a phenyl group, a hydroxy C 1-3 alkyl group, an amino C 1-6 alkyl group, a C 1-3 alkylamino C 1-6 alkyl group, or a C 1-3 alkyl.
  • C 1-3 alkylcarbamoyl C 1-6 alkyl group, C 1-6 alkyloxycarbonyl group, benzyloxy C 1-6 alkyl group and benzyloxycarbonyl C 1-6 alkyl group May have 1 to 3 substituents selected from the group consisting of Y represents a bond or a phenylene group; Z represents a bond, a C 1-6 alkylene group, a N—R 7 group or an oxygen atom, R 7 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group, Either R 2 or R 4 represents an R 8 group and the other is represented by formula (2):
  • Ring B represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group
  • ring B is a halogen atom, a C 1-6 alkyl group, a C 1-3 alkyloxy group, a C 3-8 cycloalkyl C 1-3 alkyl group, and formula (3):
  • T represents a bond, an N—R 9 group, an NH—C 1-6 alkylene group or a C 1-6 alkylene group
  • R 9 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group
  • Ring C represents a C 3-8 cycloalkyl group, a C 6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group
  • ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a C 1-3 alkyloxy group and an NH—R 10 group
  • R 10 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group
  • Ring B represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group
  • ring B is a halogen atom, a C 1-6 alkyl group, a C 1-3 alkyloxy group, a C 3-8 cycloalkyl C 1-3 alkyl group, and formula (5):
  • R 9 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group
  • Ring C represents a C 3-8 cycloalkyl group, a C 6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group
  • ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a C 1-3 alkyloxy group and an NH—R 10 group
  • R 10 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group
  • Ring A is a piperazinyl group, piperidinyl group or morpholinyl group
  • Ring B is a piperazinyl group, piperidinyl group, morpholinyl group, pyridyl group or quinolyl group
  • Ring C is a cyclopropyl group, phenyl group, piperidinyl group or piperazinyl group The compound or a salt thereof, or a solvate thereof according to the above [1], which is a group.
  • Ring A represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group
  • ring A is a C 1-6 alkyl group, a phenyl group, a hydroxy C 1-3 alkyl group, an amino C 1-6 alkyl group, a C 1-3 alkylamino C 1-6 alkyl group, or a C 1-3 alkyl.
  • C 1-3 alkylcarbamoyl C 1-6 alkyl group, C 1-6 alkyloxycarbonyl group, benzyloxy C 1-6 alkyl group and benzyloxycarbonyl C 1-6 alkyl group May have 1 to 3 substituents selected from the group consisting of Y represents a bond or a phenylene group; Z represents a bond, a C 1-6 alkylene group, a N—R 7 group or an oxygen atom, R 7 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group, Either R 2 or R 4 represents an R 8 group and the other is represented by formula (2):
  • Ring B represents a C 6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group
  • ring B is a halogen atom, a C 1-6 alkyl group, a C 1-3 alkyloxy group, a C 3-8 cycloalkyl C 1-3 alkyl group, and formula (3):
  • T represents a bond, an N—R 9 group, an NH—C 1-6 alkylene group or a C 1-6 alkylene group
  • R 9 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group
  • Ring C represents a C 3-8 cycloalkyl group, a C 6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group
  • ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a C 1-3 alkyloxy group and an NH—R 10 group
  • R 10 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group
  • ring B represents a C 6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group
  • ring B is a halogen atom, a C 1-6 alkyl group, a C 1-3 alkyloxy group, a C 3-8 cycloalkyl C 1-3 alkyl group, and formula (5):
  • R 9 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group
  • Ring C represents a C 3-8 cycloalkyl group, a C 6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group
  • ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a C 1-3 alkyloxy group and an NH—R 10 group
  • R 10 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group
  • Ring A is a piperazinyl group, piperidinyl group or morpholinyl group
  • Ring B is a phenyl group, piperazinyl group, piperidinyl group, morpholinyl group, pyridyl group or quinolyl group
  • Ring C is a cyclopropyl group, phenyl group, piperidinyl group
  • autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, inflammatory bowel disease, psoriatic arthritis, Behcet's syndrome or vasculitis .
  • the present invention also relates to a disease caused by activation of at least one signal selected from the group consisting of TLR3, TLR7 and TLR9, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS). ), Multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, vasculitis and other autoimmune diseases, inflammation, allergy, asthma, graft rejection and graft-versus-host disease (GvHD) And the like, or a salt thereof, or a solvate thereof, for the manufacture of a preventive and / or therapeutic agent.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • SS Sjogren's syndrome
  • MS Multiple sclerosis
  • IBD inflammatory bowel disease
  • Behcet's syndrome psoriatic arthritis
  • Behcet's syndrome
  • the present invention provides a TLR3, characterized by administering an effective amount of the compound according to any one of the above [4] to [6], or a salt thereof, or a solvate thereof, Diseases resulting from activation of at least one signal selected from the group consisting of TLR7 and TLR9, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS) , Prevention and / or treatment methods for inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection and graft-versus-host disease (GvHD) About.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • SS Sjogren's syndrome
  • MS multiple sclerosis
  • IBD inflammatory bowel disease
  • the present invention also relates to the compound according to any one of the above [4] to [6], or a salt thereof, or a solvate thereof for use as a medicine.
  • the present invention also relates to a disease caused by activation of at least one signal selected from the group consisting of TLR3, TLR7 and TLR9, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) , Multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD)
  • the present invention relates to the compound according to any one of [4] to [6] above, or a salt thereof, or a solvate thereof for use in prevention and / or treatment of cardiomyopathy due to sepsis.
  • the quinoline derivative of the present invention, or a salt thereof, or a solvate thereof, which is an active ingredient of a TLR3, 7, and / or 9 inhibitor, is RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, It is useful as an agent for preventing and / or treating autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or cardiomyopathy due to sepsis.
  • FIG. 14 shows the anti-type 2 collagen IgG antibody titer 15 days after additional sensitization with the compound of Example 19.
  • ** indicates that the risk rate is less than 1% (p ⁇ 0.01) in Steel's multiple comparison test using the control group as a comparison control.
  • ** indicates that the time-dependent change of the arthritis score by the compound of Example 39.
  • ** indicates that the risk rate is less than 1% (p ⁇ 0.01) in Steel's multiple comparison test using the control group as a comparison control.
  • 5- or 6-membered saturated nitrogen-containing heterocyclic group refers to a monocyclic 5- or 6-membered saturated cyclic group containing one or more nitrogen atoms. Specifically, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, etc. are mentioned, for example.
  • C 6-10 aryl group means an aryl group having 6 to 10 carbon atoms. Specifically, a phenyl group, an azulenyl group, a naphthyl group, etc. are mentioned, for example.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • C 1-6 alkyl group means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group.
  • C 1-3 alkyl group means a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl groups and the like.
  • amino C 1-6 alkyl group means the above C 1-6 alkyl group substituted with an amino group. Specifically, for example, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminoisobutyl, amino-sec-butyl, amino-tert-butyl, aminopentyl, aminoisopentyl, amino-2- Methylbutyl, aminoneopentyl, amino-1-ethylpropyl, aminohexyl, aminoisohexyl, amino-4-methylpentyl, amino-3-methylpentyl, amino-2-methylpentyl, amino-1-methylpentyl, amino- 3,3-dimethylbutyl, amino-2,2-dimethylbutyl, amino-1,1-dimethylbutyl, amino-1,2-dimethylbutyl, amino-1,3-dimethylbutyl, amino-2,3-dimethyl Butyl, amino-1-1,1-dimethylbut
  • C 1-3 alkylamino C 1-6 alkyl group means the above amino C 1-6 alkyl group in which a C 1-3 alkyl group is substituted at the amino group site. Specifically, for example, methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminoisopropyl, methylaminobutyl, methylaminoisobutyl, methylamino-sec-butyl, methylamino-tert-butyl, methylaminopentyl, methylamino Isopentyl, methylamino-2-methylbutyl, methylaminoneopentyl, methylamino-1-ethylpropyl, methylaminohexyl, methylaminoisohexyl, methylamino-4-methylpentyl, methylamino-3-methylpentyl, methylamino -2-methylpent
  • hydroxy C 1-3 alkyl group means the above C 1-3 alkyl group substituted with a hydroxyl group. Specific examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl groups and the like.
  • C 1-6 alkyloxy group means a group to which the C 1-6 alkyl group is bonded via an oxygen atom. Specifically, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, hexyl Oxy, isohexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 1-ethylbutoxy or 2-ethylbutoxy group.
  • C 1-6 alkyloxycarbonyl group means a group in which the C 1-6 alkyloxy group is bonded to a carbonyl group. Specifically, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxy Carbonyl, neopentyloxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylmethylmethylbutoxycarbony
  • benzyloxy C 1-6 alkyl group means the C 1-6 alkyl group substituted with a benzyloxy group. Specifically, for example, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxyisopropyl, benzyloxybutyl, benzyloxyisobutyl, benzyloxy-sec-butyl, benzyloxy-tert-butyl, benzyloxypentyl, benzyl Oxyisopentyl, benzyloxy-2-methylbutyl, benzyloxyneopentyl, benzyloxy-1-ethylpropyl, benzyloxyhexyl, benzyloxyisohexyl, benzyloxy-4-methylpentyl, benzyloxy-3-methylpentyl, benzyl Oxy-2-methylpentyl, benzyloxymethylpentyl
  • benzyloxycarbonyl C 1-6 alkyl group means the C 1-6 alkyl group substituted with a benzyloxycarbonyl group. Specifically, for example, benzyloxycarbonylmethyl, benzyloxycarbonylethyl, benzyloxycarbonylpropyl, benzyloxycarbonylsopropyl, benzyloxycarbonylbutyl, benzyloxycarbonylsobutyl, benzyloxycarbonyl sec-butyl, benzyloxycarbonyl tert -Butyl, benzyloxycarbonylpentyl, benzyloxycarbonylsopentyl, benzyloxycarbonyl 2-methylbutyl, benzyloxycarbonylneopentyl, benzyloxycarbonyl 1-ethylpropyl, benzyloxycarbonylhexyl, benzyloxycarbonylsohexyl
  • C 1-3 alkylcarbamoyl group means a carbamoyl group substituted with the C 1-3 alkyl group. Specific examples include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl groups and the like.
  • C 1-3 alkylcarbamoyl C 1-6 alkyl group means the C 1-6 alkyl group substituted with the C 1-3 alkylcarbamoyl group. Specifically, for example, methylcarbamoylmethyl, ethylcarbamoylmethyl, propylcarbamoylmethyl, isopropylcarbamoylmethyl, methylcarbamoylethyl, ethylcarbamoylethyl, propylcarbamoylethyl, isopropylcarbamoylethyl, methylcarbamoyl-n-propyl, ethylcarbamoyl-n -Propyl, propylcarbamoyl-n-propyl, isopropylcarbamoyl-n-propyl, methylcarbamoylisopropyl, ethylcarbamoyl
  • C 1-3 alkylcarbamoyl C 1-6 alkylcarbonyl group means a group in which a carbonyl group is bonded to the C 1-3 alkylcarbamoyl C 1-6 alkyl group.
  • C 1-3 alkyloxy C 1-3 alkyl group a hydroxyl group means said hydroxy C 1-3 alkyl group substituted with a C 1-3 alkyl group.
  • methoxymethyl, ethoxymethyl, propoxymethyl isopropoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, isopropoxypropyl, methoxyisopropyl, ethoxy
  • Examples include isopropyl, propoxyisopropyl, isopropoxyisopropyl groups and the like.
  • C 3-8 cycloalkyl group means a monocyclic 3- to 8-membered saturated cyclic group in which all of the atoms constituting the ring are carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
  • C 3-8 cycloalkyl C 1-3 alkyl group means the above C 1-3 alkyl group substituted with the above C 3-8 cycloalkyl group. Specific examples include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethyl group, and a cyclooctylmethyl group.
  • C 6-10 aryl C 1-3 alkyl group means the above C 1-3 alkyl group substituted with a C 6-10 aryl group.
  • Specific examples include benzyl, phenylethyl, phenylpropyl, phenylisopropyl, azulenylmethyl, azulenylethyl, azulenylpropyl, azulenylisopropyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylisopropyl and the like.
  • C 6-10 aryloxy C 1-3 alkyl group means the above hydroxy C 1-3 alkyl group in which the hydroxyl group is substituted with a C 6-10 aryl group.
  • the “5- to 10-membered aromatic nitrogen-containing heterocyclic group” includes at least one nitrogen atom and may contain one or more heteroatoms other than nitrogen atoms. A good monocyclic, polycyclic or condensed aromatic heterocyclic group is shown.
  • pyridyl group pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, pyrrolyl group, pyrazolyl group, isoxazolyl group, oxazolyl group, isothiazolyl group, thiazolyl group, oxadiazolyl group, thiadiazolyl group, indolyl Group, indazolyl group, purinyl group, benzoxazolyl group, benzothiazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group and the like.
  • 5- or 6-membered saturated heterocyclic group refers to a 5- or 6-membered saturated cyclic group containing one or more heteroatoms.
  • C 1-3 alkyloxy group means a group to which the C 1-3 alkyl group is bonded via an oxygen atom. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group.
  • C 1-6 alkylene group means a divalent straight chain or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Specifically, for example, methylene group, ethylene group, trimethylene group, isopropylene group, n-butylene group, isobutylene group, tert-butylene group, n-pentylene group, 2-methylbutylene group, 2,2-dimethyltrimethyl group. Examples include a methylene group and an n-hexylene group.
  • C 2-6 alkenylene group means a divalent, linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms having one double bond.
  • vinylene group 1-propenylene group, 2-propenylene group, 1-butenylene group, 2-butenylene group, 3-butenylene group, 1-pentenylene group, 2-pentenylene group, 3-pentenylene group
  • Examples include 4-pentenylene group, 4-methyl-3-pentenylene group, 1-hexenylene group, 2-hexenylene group, 3-hexenylene group, 4-hexenylene group, 5-hexenylene group, and the like.
  • the 5- or 6-membered saturated nitrogen-containing heterocyclic group is preferably a piperazinyl group, a piperidinyl group or a morpholinyl group.
  • the 5- to 10-membered aromatic nitrogen-containing heterocyclic group is preferably a pyridyl group or a quinolyl group.
  • the C 6-10 aryl group is preferably a phenyl group.
  • the halogen atom is preferably a fluorine atom or a chlorine atom.
  • the C 1-6 alkyl group is preferably a methyl group.
  • the C 1-3 alkyl group is preferably a methyl group.
  • the amino C 1-6 alkyl group is preferably an aminobutyl group or an aminohexyl group.
  • the C 1-3 alkylamino C 1-6 alkyl group is preferably a methylaminobutyl group or a methylaminohexyl group.
  • the hydroxy C 1-3 alkyl group is preferably a hydroxyethyl group.
  • the C 1-3 alkyloxy group is preferably a methoxy group.
  • the C 1-6 alkyloxycarbonyl group is preferably a tert-butoxycarbonyl group.
  • the benzyloxy C 1-6 alkyl group is preferably a benzyloxyethyl group.
  • the benzyloxycarbonyl C 1-6 alkyl group is preferably a benzyloxycarbonylpentyl group.
  • the C 1-3 alkylcarbamoyl C 1-6 alkyl group is preferably a methylcarbamoylpentyl group.
  • the C 1-3 alkylcarbamoyl C 1-6 alkylcarbonyl group is preferably a methylcarbamoylethylcarbonyl group.
  • the C 3-8 cycloalkyl group is preferably a cyclopropyl group.
  • the C 6-10 aryl C 1-3 alkyl group is preferably a benzyl group.
  • the saturated heterocyclic group of C 1-3 alkyl may also be 5 or 6 membered substituted with group may piperazinyl group is preferable be substituted with C 1-3 alkyl groups, a methyl group A substituted piperazinyl group is more preferred.
  • the C 1-6 alkylene group is preferably a methylene group, an ethylene group, a trimethylene group or a pentylene group.
  • the C 2-6 alkenylene group is preferably a vinylene group or a 1-propenylene group.
  • ring A a piperazinyl group, a piperidinyl group and a morpholinyl group are preferable.
  • Ring A may have include a C 1-6 alkyl group, a phenyl group, a hydroxy C 1-3 alkyl group, a C 1-3 alkylcarbamoyl C 1-6 alkylcarbonyl group, and a C 1-3 alkyl.
  • a carbamoyl C 1-6 alkyl group, a C 1-6 alkyloxycarbonyl group, a benzyloxy C 1-6 alkyl group, a benzyloxycarbonyl C 1-6 alkyl group and a C 6-10 aryl C 1-3 alkyl group are preferred, More preferred are methyl, phenyl, hydroxyethyl, methylcarbamoylethylcarbonyl, methylcarbamoylpentyl, tert-butoxycarbonyl, benzyloxyethyl, benzyloxycarbonylpentyl and benzyl.
  • ring B a phenyl group, a piperazinyl group, a piperidinyl group, a morpholinyl group, a pyridyl group and a quinolyl group are preferable.
  • the substituent that the ring B may have, a C 1-6 alkyl group, a C 3-8 cycloalkyl C 1-3 alkyl group and a group represented by the formula (3) are preferable, and a methyl group, cyclopropylmethyl, The group and the group represented by the formula (3) are more preferable.
  • the ring C is preferably a C 3-8 cycloalkyl group, a C 6-10 aryl group, and a 5- or 6-membered saturated nitrogen-containing heterocyclic group, a cyclopropyl group, a phenyl group, piperidinyl More preferred are groups and piperazinyl groups.
  • the substituent that the ring C may have, a halogen atom, a C 1-6 alkyl group and a C 1-3 alkyloxy group are preferable, and a fluorine atom, a chlorine atom, a methyl group and a methoxy group are more preferable.
  • Z is preferably a bond, a C 1-6 alkylene group and an oxygen atom, and more preferably a bond, a trimethylene group and an oxygen atom.
  • Z is preferably a bond and N—R 7 (wherein R 7 represents a hydrogen atom, a C 1-6 alkyl group or a 2-nitrobenzenesulfonyl group), Bonds and NH groups are more preferred.
  • T is preferably a bond, a C 1-6 alkylene group or an NH alkylene group, more preferably a bond, a methylene group or an NHCH 2 group.
  • the combination of X, W, V and U is preferably the following.
  • N 1 - (-4- 1- benzyl-yl) -N 4 - (quinolin-6-yl) succinamide N 1 - (-4- 1- benzyl-yl) -N 4 - [2- (4- methylpiperazin-1-yl) quinolin-6-yl] succinamide, N 1 - (-4- 1- benzyl-yl) -N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide, N 1 - (-4- 1- benzyl-yl) -N 4 - (2-morpholino-6-yl) succinamide, N 1 - (-4- 1- benzyl-yl) -N 4 - [2- (4- phenyl-piperidin-1-yl) quinolin-6-yl] succinamide, N 1 - [1- (2- chlorobenzyl) piperidin-4-yl] -N
  • N 1 - (-4- 1- benzyl-yl) -N 4 - (quinolin-6-yl) succinamide N 1 - (-4- 1- benzyl-yl) -N 4 - [2- (4- methylpiperazin-1-yl) quinolin-6-yl] succinamide, N 1 - (-4- 1- benzyl-yl) -N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide, N 1 - (-4- 1- benzyl-yl) -N 4 - (2-morpholino-6-yl) succinamide, N 1 - (-4- 1- benzyl-yl) -N 4 - [2- (4- phenyl-piperidin-1-yl) quinolin-6-yl] succinamide, N 1 - [1
  • the quinoline derivative of the present invention, or a salt thereof, or a solvate thereof includes not only the quinoline derivative of the present invention but also a pharmaceutically acceptable salt thereof, various hydrates and solvates thereof, Substances having a form, and substances that are prodrugs of these substances are included.
  • acceptable salts in the quinoline derivative of the present invention include inorganic acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (eg, methane). And acid addition salts with sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.
  • solvates of the quinoline derivative of the present invention and pharmaceutically acceptable salts thereof include hydrates and various solvates (for example, solvates with alcohols such as ethanol).
  • the quinoline derivative of the present invention can be produced by combining known methods. Although the manufacturing method of a quinoline derivative is shown in the following reaction process drawing, a manufacturing method is not limited to this. Moreover, you may perform each reaction, protecting a functional group as needed. The protection and deprotection conditions can be performed with reference to generally used methods (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the quinoline derivative of the present invention can be produced by combining known methods. Although the manufacturing method of a quinoline derivative is shown in the following reaction process drawing, a manufacturing method is not limited to this.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W, V, U, A, B, Y, and Z are the same as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown. ]
  • the quinoline derivative (8) can be produced by reacting the quinoline derivative (6) with the amine derivative (7). If necessary, sodium iodide or potassium iodide may be added and reacted.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction.
  • alcohol solvents such as methanol, ethanol and isopropanol
  • amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide Ether solvents such as diethyl ether, tetrahydrofuran and dioxane
  • sulfoxide solvents such as dimethyl sulfoxide and sulfolane
  • halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane
  • the reaction temperature is room temperature to 120 ° C., preferably 50 ° C. to 100 ° C.
  • the reaction time is 1 hour to 3 days, preferably 3 hours to 24 hours.
  • the amine derivative (7) used in the above reaction a commercially available one can be used as it is, or it can be suitably produced by a known method, but is not limited thereto.
  • Step 2 The nitro group of the quinoline derivative (8) can be reacted in a solvent in the presence of a reducing agent to produce the quinoline derivative (9).
  • This reduction reaction may be performed by (a) catalytic hydrogenation in which a nitro group is reduced using a catalytic hydrogen reduction catalyst in a suitable inert solvent under a hydrogen atmosphere, or (b) a metal or metal salt in a suitable inert solvent. It is carried out by metal reduction in which the nitro group is reduced using a mixture of acid, metal, metal or metal salt and alkali metal hydroxide, sulfide or ammonium salt as a reducing agent.
  • examples of the solvent include water; organic acid solvents such as acetic acid; alcohol solvents such as methanol, ethanol and isopropanol; hydrocarbon solvents such as n-hexane and cyclohexane; dioxane and tetrahydrofuran.
  • Ether solvents such as diethyl ether and diethylene glycol dimethyl ether; ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N, N-dimethylformamide or a mixed solvent thereof.
  • the reaction temperature is ⁇ 20 to 150 ° C., preferably 0 to 100 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
  • the solvent examples include water; organic acid solvents such as acetic acid; alcohol solvents such as methanol or ethanol; ether solvents such as tetrahydrofuran and dioxane.
  • the reaction temperature is, for example, 0 to 150 ° C., preferably 50 to 120 ° C. when zinc and acetic acid are used as the reducing agent.
  • the reaction time is 1 minute to 12 hours, preferably 1 minute to 6 hours.
  • Step 3 The dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (10) is performed using a condensing agent in the presence or absence of a base in the solvent and in the presence or absence of a condensation accelerator.
  • a condensing agent in the presence or absence of a base in the solvent and in the presence or absence of a condensation accelerator.
  • the solvent is not particularly limited.
  • halogen hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; ester solvents such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; tetrahydrofuran And ethers such as dioxane; nitriles such as acetonitrile and propionitrile; amides such as N, N-dimethylformamide and N-methylpyrrolidone; water and the like can be used alone or in combination.
  • the base is not particularly limited.
  • pyridine 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 Organic bases such as diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine , Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate Alkali carbonates such as sodium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.
  • DMAP dimethylaminopyridine
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • the reaction temperature is ⁇ 20 to 100 ° C., preferably 0 to 40 ° C.
  • the reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.
  • the compound (1) of the present invention can also be produced by performing a condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (11) in the presence of a base in a solvent.
  • the solvent is not particularly limited.
  • halogen hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane
  • ester solvents such as ethyl acetate and isopropyl acetate
  • aromatic hydrocarbons such as toluene and benzene
  • tetrahydrofuran And ethers such as dioxane
  • nitriles such as acetonitrile and propionitrile
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone; water and the like can be used alone or in combination.
  • the base is not particularly limited.
  • organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine, lithium hydride, sodium hydride, hydrogenated Alkali metal hydrides such as potassium, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate, An alkali metal bicarbonate such as potassium bicarbonate can be used.
  • the reaction temperature is ⁇ 20 to 100 ° C., preferably 0 to 40 ° C.
  • the reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.
  • R 2 represents R 8
  • R 8 represents a C 1-3 alkyl group
  • R 4 represents the formula (2)
  • R 1 , R 3 , R 5 , R 6 , A, Y, and Z are the same as defined above, and E is independently a leaving group such as a halogen atom or a triflate group.
  • R 12 represents a C 1-3 alkyl group.
  • the quinoline derivative (13) can be produced by reacting the quinoline derivative (12) having a leaving group with the amine derivative (7). It can be carried out in the same manner as the above-mentioned step 1.
  • the quinoline derivative (8) can be produced by reacting the quinoline derivative (13) with the alcohol derivative (14). If necessary, a quaternary ammonium salt such as tetrabutylammonium sulfate may be added and reacted.
  • the base is not particularly limited.
  • pyridine 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 -Organic bases such as diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine; sodium methoxide, potassium Alcoholates such as methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide; inorganics such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate Bases, preferably sodium hydroxide, sodium methoxide That.
  • DMAP dimethylaminopyridine
  • collidine lutidine
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction.
  • alcohol solvents such as methanol, ethanol and isopropanol
  • amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide Ether solvents such as diethyl ether, tetrahydrofuran and dioxane
  • sulfoxide solvents such as dimethyl sulfoxide and sulfolane
  • halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane
  • water and mixed solvents thereof The reaction temperature is room temperature to 120 ° C., preferably 50 ° C.
  • reaction time is 1 hour to 3 days, preferably 3 hours to 24 hours.
  • the alcohol derivative (14) used in the above reaction a commercially available product can be used as it is or can be appropriately produced by a known method, but is not limited thereto.
  • R 2 represents R 8
  • R 8 represents a saturated heterocyclic group may 5 or 6 membered substituted by a C 1-3 alkyl group
  • Ring A is a 5 or 6-membered
  • R 4 represents formula (2)
  • Y and Z represent a bond
  • the quinoline derivative (8) can be produced from the quinoline derivative (12).
  • R 1 , R 3 , R 5 , R 6 , and A are the same as defined above, and E independently represents a leaving group such as a halogen atom or a triflate group.
  • the quinoline derivative (8) can be produced by reacting the quinoline derivative (12) with the amine derivative (7). It can be carried out in the same manner as the above-mentioned step 1.
  • R 2 represents R 8
  • R 4 represents the formula (2)
  • X represents N-R 11
  • R 11 represents a C 1-6 alkyl group
  • X and W When the bond is an amide bond, the compound (1) of the present invention can be produced from the quinoline derivative (9).
  • R 1 , R 3 , R 5 , R 6 , R 11 , A, B, Y, Z, W, V, and U are as defined above.
  • the quinoline derivative (13) can be produced by 2-nitrobenzenesulfonyl (Ns) reaction of the amino group of the quinoline derivative (9). It can be performed with reference to commonly used methods (Protective Groups Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the quinoline derivative (15) can be produced by Mitsunobu reaction between the quinoline derivative (13) and the alcohol derivative (14).
  • Reagents, bases and reaction conditions used are not particularly limited as long as they are usually used for Mitsunobu reaction. For example, as described in Swamy, KCK et al., Chem. Rev. 2009, 109, 2551, etc. Can be used.
  • the solvent used in this step is not particularly limited as long as it does not inhibit the reaction.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether; aromatic hydrocarbons such as toluene Halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile;
  • reaction temperature in this step varies depending on the raw materials and solvent to be used, it is generally ⁇ 20 to 120 ° C., preferably 0 ° C. to 60 ° C., and the reaction time is usually 10 minutes to 1 day, preferably 10 minutes. ⁇ 6 hours.
  • the alcohol derivative (14) used in the above reaction a commercially available one can be used as it is, or it can be suitably produced by a known method, but is not limited thereto.
  • the quinoline derivative (16) can be produced by deprotecting the Ns group of the quinoline derivative (15). It can be performed with reference to commonly used methods (Protective Groups Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (16) and the carboxylic acid derivative (10) or a condensation reaction of the carboxylic acid derivative (11). It can be performed in the same manner as in the above-described step 3.
  • R 2 represents R 8
  • R 4 represents formula (2)
  • X represents a NHC (O) group
  • Z represents a N—R 7 group
  • V represents a N—R
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, W, and U represent the same as defined above, and P represents a protecting group. . ]
  • the compound (1) of the present invention can be produced by deprotecting the quinoline derivative (17). It can be performed with reference to commonly used methods (Protective Groups Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • E represents a leaving group such as a halogen atom or a triflate group.
  • the quinoline derivative (19) can be produced by a dehydration condensation reaction of the quinoline derivative (18) and the carboxylic acid derivative (10) or a condensation reaction of the carboxylic acid derivative (11). It can be performed in the same manner as in the above-described step 3.
  • the compound (1) of the present invention can be produced by an amino coupling reaction of the quinoline derivative (19) and the amine derivative (20).
  • the metal catalyst, ligand, base, and reaction conditions are not particularly limited as long as they are reagents and conditions that are usually used in amination reactions. For example, A. R. Muci, S. L. Buchwald, Top. Curr. Chem ., 219, 131-209, (2002) etc. can be used. It is also possible to apply a method of an amination reaction performed in a solvent or without a solvent, in the presence or absence of a base, and in the presence of a metal catalyst. In that case, microwave irradiation may be performed.
  • the metal catalyst is not particularly limited.
  • palladium (II) acetate palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0 ), Tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium (0), etc.
  • Monovalent copper reagents such as cuprous iodide, cuprous bromide, cuprous cyanide may be used alone, but (2-biphenyl) di-tert-butylphosphine, (2- Biphenyl) dicyclohexylphosphine, tricyclohexylphosphine, 1,3-bis (phenyl) Suphono) propane, 2,2'-bis (diphenylphosphanyl) -1,1'-binaphthyl, 2- (dicyclohexylphosphono) biphenyl, 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl , Tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine and the like can also be used in combination.
  • Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metals, such as metallic lithium, metallic sodium, metallic potassium; Lithium hydroxide, Hydroxide Alkali metal hydroxides such as sodium and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.
  • the solvent is not particularly limited.
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone
  • dimethyl sulfoxide amides such as N, N-dimethylformamide and N-methylpyrrolidone
  • ethers such as dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as toluene; water alone Or they can be used in combination.
  • the reaction temperature is preferably 0 to 200 ° C, more preferably 100 ° C to 150 ° C.
  • the reaction time is preferably 1 minute to 5 days, more preferably 30 minutes to 6 hours.
  • the compound (1) of the present invention can be produced from the quinoline derivative (19). .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, Y, and Z are the same as defined above, and E is elimination of a halogen atom or a triflate group, etc.
  • R 13 and R 14 represent a hydrogen atom or a C 1-6 alkyl group, and R 13 and R 14 may be combined to form a ring.
  • the compound (1) of the present invention can be produced by the Suzuki-Miyaura coupling reaction of the quinoline derivative (19) and the borane compound (21).
  • the metal catalyst, base and reaction conditions used are not particularly limited as long as they are reagents and conditions used for the Suzuki-Miyaura coupling reaction. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, (1995), etc. can be used.
  • the metal catalyst to be used is not particularly limited.
  • the base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium, and tert-butoxy potassium. Sodium carbonate and cesium carbonate.
  • the solvent is not particularly limited. For example, ethers such as tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as toluene; amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide Water or the like can be used alone or in combination.
  • the reaction temperature is 0 to 200 ° C, preferably 60 ° C to 150 ° C.
  • the reaction time is 1 hour to 48 hours, preferably 30 minutes to 20 hours.
  • the borane compound (21) used in the above reaction a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, W, and U represent the same as defined above, and P represents a protecting group. . ]
  • the quinoline derivative (24) can be produced by a dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (22) or a condensation reaction of the carboxylic acid derivative (23). It can be performed in the same manner as in the above-described step 3.
  • the quinoline derivative (25) can be produced by deprotecting the quinoline derivative (24).
  • the deprotection reaction can be performed with reference to commonly used methods (Protective Groups Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the compound (1) of the present invention can be produced by a dehydration condensation reaction between the quinoline derivative (25) and the amine derivative (26) or amine derivative (27). It can be performed in the same manner as in the above-described step 3.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, W, and U represent the same as defined above, and P represents a protecting group. . ]
  • the quinoline derivative (30) can be produced by a dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (28) or a condensation reaction of the carboxylic acid derivative (29). It can be performed in the same manner as in the above-described step 3.
  • the quinoline derivative (31) can be produced by deprotecting the quinoline derivative (30). It can be performed with reference to commonly used methods (Protective Groups Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (31) and the carboxylic acid derivative (32). It can be performed in the same manner as in the above-described step 3.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, and W are the same as defined above, and E is a halogen atom or a triflate group. And the like. ]
  • the quinoline derivative (35) can be produced by a dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (33) or a condensation reaction of the carboxylic acid derivative (34). It can be performed in the same manner as in the above-described step 3.
  • the compound (1) of the present invention can be produced by an alkylation reaction of the quinoline derivative (35) with the amine derivative (26) or the amine derivative (27).
  • Alkylation can be performed in a solvent in the presence of a base.
  • the solvent is not particularly limited.
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide; ethers such as dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile alone or
  • the base can be used in combination, and is not particularly limited.
  • alkali metals such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium metal Metals, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, lithium diisopropylamide, sodium diisopropylamide and potassium dioxide Isop Use pyramide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxysodium, tert-butoxypotassium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.
  • the reaction temperature is ⁇ 10 to 200 ° C., and varies depending on the reaction conditions, but is preferably 0 ° C. to 120 ° C.
  • the reaction time varies from 1 hour to 72 hours depending on the reaction conditions, but is preferably 1 hour to 36 hours.
  • the amine derivative (24) used in the above reaction a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, W, V, and U are as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown.
  • the quinoline derivative (36) can be produced by Sandmeyer reaction of the quinoline derivative (9) (Chem. Rev., 40, 251-277, 1947). Diazotization can be carried out by reacting sodium nitrite, amyl nitrite or the like under acidic conditions. As the acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like can be used. A quinoline derivative (36) can be obtained by allowing a halogenating agent to act on the obtained diazonium salt. As the halogenating agent, copper chloride, copper bromide, potassium iodide, iodine or the like can be used.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, and ester solvents such as ethyl acetate and isopropyl acetate; ether solvents such as diethyl ether, tetrahydrofuran and dioxane, water and the like can be used alone or in combination. Preferably it is water.
  • the reaction temperature is generally ⁇ 10 to 100 ° C., preferably 0 to 40 ° C.
  • the reaction time is 5 minutes to 1 day, preferably 1 to 12 hours.
  • the quinoline derivative (36) can be lithiated and then reacted with carbon dioxide to produce the carboxylic acid derivative (37).
  • the lithiation reagent n-butyllithium, sec-butyllithium, tert-butyllithium, lithium hexamethyldisilazide, or the like can be used.
  • the solvent is not particularly limited as long as it does not inhibit the reaction.
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether can be used alone or in combination. Tetrahydrofuran is preferred.
  • the reaction temperature is ⁇ 100 to 30 ° C., preferably ⁇ 80 ° C. to 0 ° C.
  • the reaction time is 1 hour to 48 hours, preferably 30 minutes to 20 hours.
  • the compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (37) and the amine derivative (38). It can be performed in the same manner as in the above-described step 3.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, W, V, and U are as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown.
  • the compound (1) of the present invention can be produced by an alkylation reaction of the quinoline derivative (9) and the alkyl derivative (39). This can be performed in the same manner as in step 22 described above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, X, W, and U are the same as defined above; Independently, a protecting group is shown. ]
  • the quinoline derivative (41) can be produced by Mitsunobu reaction between the quinoline derivative (13) and the carboxylic acid derivative (40). It can be performed in the same manner as in the above-described step 8.
  • the quinoline derivative (42) can be produced by deprotecting the protecting group of the quinoline derivative (41). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the quinoline derivative (44) can be produced by a dehydration condensation reaction between the quinoline derivative (42) and the amine derivative (43). It can be performed in the same manner as in the above-described step 3.
  • the compound (1) of the present invention can be produced by deprotecting the protecting group of the quinoline derivative (44). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, X, W, and U are the same as defined above, and P is a protecting group Indicates.
  • the quinoline derivative (46) can be produced by Mitsunobu reaction of the quinoline derivative (13) and the alcohol derivative (45). It can be performed in the same manner as in the above-described step 8.
  • the compound (1) of the present invention can be produced by deprotecting the quinoline derivative (46). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • R 2 represents R 8
  • R 4 represents formula (2)
  • Y and Z represent a bond
  • X represents an oxygen atom
  • V represents a N—R 11 group
  • U represents a bond
  • the compound (1) of the present invention can be produced from the quinoline derivative (47).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, X, W, and U are as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown.
  • the quinoline derivative (51) can be produced by Mitsunobu reaction of the quinoline derivative (47) and the alcohol derivative (50). It can be performed in the same manner as in the above-described step 8.
  • the alcohol derivative (50) can be produced by Mitsunobu reaction of the amine derivative (48) and the alcohol derivative (49). It can be performed in the same manner as in the above-described step 8.
  • the compound (1) of the present invention can be produced by reacting the quinoline derivative (51) with the amine derivative (7). It can be carried out in the same manner as the above-mentioned step 1.
  • R 2 represents R 8
  • R 4 represents formula (2)
  • X represents an NHC (O) group
  • Y represents a bond
  • Z represents a C 1-6 alkylene group.
  • the compound (1) of the present invention can be prepared from the quinoline derivative (6).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, W, V, and U are as defined above, and E is a halogen atom Or, it represents a leaving group such as a triflate group, and n represents an integer of 1 to 4. ]
  • the quinoline derivative (53) can be produced by the Sonogashira reaction of the quinoline derivative (6) and the alkyne derivative (52).
  • the palladium catalyst, the copper catalyst, the base, and the reaction conditions are not particularly limited as long as they are reagents and conditions used in a normal Sonogashira reaction. For example, Heravi, Majid M .; 7761-7775, Sakai (2009) and the like can be used.
  • the palladium catalyst is not particularly limited.
  • bis (triphenylphosphine) palladium (II) dichloride, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), Bis (tri-tert-butylphosphine) palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (Triphenylphosphine) palladium (0) or the like can be used.
  • the copper catalyst is not particularly limited, but copper (I) iodide is preferable.
  • the base is not particularly limited, but pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo Use organic bases such as [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine be able to.
  • the solvent is not particularly limited.
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as toluene; water alone Or they can be used in combination.
  • the reaction temperature is preferably 0 to 120 ° C, more preferably 0 ° C to 60 ° C.
  • the reaction time is preferably 1 minute to 3 days, more preferably 1 hour to 24 hours.
  • the alkyne derivative (52) used in the above reaction a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.
  • the quinoline derivative (54) can be produced by the methanesulfonyl (Ms) reaction of the hydroxyl group of the quinoline derivative (53). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the quinoline derivative (55) can be produced by an alkylation reaction of the quinoline derivative (54) and the amine derivative (7). This can be performed in the same manner as in step 22 described above.
  • the quinoline derivative (56) can be produced by the reduction reaction of the quinoline derivative (55). It can be performed in the same manner as in Step 2 described above.
  • the compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (56) and the carboxylic acid derivative (10) or a condensation reaction of the carboxylic acid derivative (11). It can be performed in the same manner as in the above-described step 3.
  • R 2 represents R 8
  • R 4 represents formula (2)
  • X represents a bond
  • W represents a C 2-6 alkenylene group
  • V represents a C (O) NH group.
  • the present compound (1) can be produced from the quinoline derivative (36).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, and U are as defined above, and E is a halogen atom or a triflate group. And n represents an integer of 0 to 4. ]
  • the quinoline derivative (58) can be produced by the Heck reaction of the quinoline derivative (36) and the alkene derivative (57).
  • the palladium catalyst, ligand, base, and reaction conditions are not particularly limited as long as they are reagents and conditions used in a normal Hecking reaction. For example, McCartney, Dennis; Guiry, Patrick J. ), 5122-5150, (2011) etc. can be used. Microwave irradiation may be performed.
  • the palladium catalyst is not particularly limited.
  • the base is not particularly limited, but pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo Use organic bases such as [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine be able to.
  • DMAP 4-dimethylaminopyridine
  • collidine lutidine
  • DBU 1,5-diazabicyclo
  • Use organic bases such as [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropyle
  • the ligand is not particularly limited, but tri-o-tolylphosphine, (2-biphenyl) di-tert-butylphosphine, (2-biphenyl) dicyclohexylphosphine, tricyclohexylphosphine, 1,3-bis (phenylphosphones) C) Propane, 2,2'-bis (diphenylphosphanyl) -1,1'-binaphthyl, 2- (dicyclohexylphosphono) biphenyl, 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl , Tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine, and other ligands can be used.
  • the solvent is not particularly limited.
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as toluene; water alone Or they can be used in combination.
  • the reaction temperature is preferably 0 to 200 ° C, more preferably 100 ° C to 150 ° C.
  • the reaction time is preferably 1 minute to 5 days, more preferably 30 minutes to 6 hours.
  • the alkene derivative (57) used in the above reaction a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.
  • the quinoline derivative (59) can be produced by deprotecting the quinoline derivative (58). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (59) and the amine derivative (26). It can be performed in the same manner as in the above-described step 3.
  • R 2 represents R 8
  • R 4 represents formula (2)
  • X represents a bond
  • W represents a C 2-6 alkenylene group
  • V represents an NR 11 group.
  • U represents a bond
  • the compound (1) of the present invention can be produced from the quinoline derivative (36).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, and U are as defined above, and E is a halogen atom or a triflate group.
  • P represents a protecting group, and n represents an integer of 0-4.
  • the quinoline derivative (62) can be produced by the Heck reaction of the quinoline derivative (36) and the alkene derivative (61). This can be performed in the same manner as in the above-described step 41.
  • the alkene derivative (61) can be produced by the protection reaction of the alkene derivative (60). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the compound (1) of the present invention can be produced by deprotecting the protecting group of the quinoline derivative (62). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the compound (1) of the present invention is It can be produced from the quinoline derivative (63).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, V, and U are the same as defined above, and n is 0 to 4] Indicates an integer. ]
  • the compound (1) of the present invention can be produced by a catalytic hydrogen reduction reaction of the quinoline derivative (63).
  • the solvent include water; organic acid solvents such as acetic acid; alcohol solvents such as methanol, ethanol and isopropanol; hydrocarbon solvents such as n-hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether.
  • System solvents ; ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N, N-dimethylformamide, etc., or a mixed solvent thereof can be used.
  • the catalyst for example, palladium, palladium-black, palladium-carbon, platinum-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like can be used alone or in combination.
  • the reaction temperature is ⁇ 20 to 150 ° C., preferably 0 to 100 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
  • the compound (1) of the present invention is derived from the isatin derivative (64). Can be manufactured.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, W, V, and U are as defined above.
  • the quinoline derivative (66) can be produced by reacting the isatin derivative (64) with the ketone derivative (65).
  • the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.
  • An alkali metal bicarbonate or the like can be used.
  • the solvent is not particularly limited as long as it does not inhibit the reaction.
  • alcohol solvents such as methanol, ethanol and isopropyl alcohol: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and ethylene glycol dimethyl ether Etc .; Aromatic hydrocarbons such as toluene; amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide, water and the like can be used alone or in combination.
  • the reaction temperature is usually ⁇ 0 to 120 ° C., preferably 60 ° C. to 120 ° C., and the reaction time is usually 10 minutes to 3 days, preferably 12 hours to 24 hours.
  • isatin derivative (64) and the ketone derivative (65) used in the above reaction commercially available ones can be used as they are or can be appropriately produced by known methods, but are not limited thereto.
  • the compound (1) of the present invention can be produced by a dehydration condensation reaction between the quinoline derivative (66) and the amine derivative (38). It can be performed in the same manner as in the above-described step 3.
  • the quinoline derivative (66) can be produced by reacting the aniline derivative (67) with the aldehyde derivative (68) and the ⁇ -ketocarboxylic acid derivative (69).
  • the solvent is not particularly limited as long as it does not inhibit the reaction.
  • alcohol solvents such as methanol, ethanol and isopropyl alcohol: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and ethylene glycol dimethyl ether Etc .; Aromatic hydrocarbons such as toluene; amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide, water and the like can be used alone or in combination.
  • the reaction temperature is usually ⁇ 0 to 120 ° C., preferably 40 ° C. to 100 ° C.
  • the reaction time is usually 10 minutes to 1 day, preferably 10 minutes to 6 hours.
  • aniline derivative (67), aldehyde derivative (68) and ⁇ -ketocarboxylic acid derivative (69) used in the above reaction commercially available ones can be used as they are, or they can be appropriately produced by known methods. It is not limited to.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, Y, Z, W, V, and U are as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown.
  • the quinoline derivative (71) can be produced by reacting the quinoline derivative (70) with the amine derivative (7). It can be carried out in the same manner as the above-mentioned step 1.
  • the quinoline derivative (72) can be produced by deprotecting the protecting group of the quinoline derivative (71). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (72) and the amine derivative (38). It can be performed in the same manner as in the above-described step 3.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, W, V, U, Y and Z are the same as defined above, and E is a halogen atom or A leaving group such as a triflate group is shown.
  • the quinoline derivative (8) can be produced by reacting the quinoline derivative (6) with the alcohol derivative (73). It can be carried out in the same manner as the above-mentioned step 1.
  • the quinoline derivative (9) can be produced by the reduction reaction of the quinoline derivative (8). It can be performed in the same manner as in Step 2 described above.
  • the compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (10) or a condensation reaction of the carboxylic acid derivative (11). It can be performed in the same manner as in the above-described step 3.
  • ring A may be converted as follows.
  • R 15 represents hydrogen or a C 1-5 alkyl group
  • P represents a protecting group
  • the amine derivative (75) can be produced by deprotecting the protecting group of the protected amine (74). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the amine derivative (77) can be produced by reductive alkylation of the amine derivative (75) and the aldehyde derivative (76).
  • the reductive alkylation reaction can be performed using a reducing reagent in a solvent in the presence or absence of an acid.
  • the dehydration operation may be performed using a Dean-Stark apparatus or the like.
  • the solvent is not particularly limited.
  • 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol, acetic acid, Fluoroacetic acid or the like can be used alone or in combination.
  • Lewis acids such as proton acids, such as propionic acid and benzoic acid, titanium tetrachloride, boron trifluoride, and stannic chloride, can be used.
  • a reducing reagent for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride,
  • borohydride reagents such as lithium triethylborohydride, lithium hydride lithium, diisopropylaluminum hydride, aluminum hydride reagents such as sodium bis (2-methoxyethoxy) aluminum hydride, metal catalyst and hydrogen source Reduction can be used.
  • a hydrogen source for catalytic reduction for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide, Raney nickel, platinum dioxide, platinum Black etc. can be used.
  • a metal catalyst for example, palladium carbon, palladium black, palladium hydroxide, Raney nickel, platinum dioxide, platinum Black etc.
  • the aldehyde derivative (76) used in the above reaction a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.
  • ring A may be converted as follows.
  • R 16 represents a C 1-6 alkyl group
  • E represents a leaving group such as a halogen atom or a triflate group.
  • the ring A derivative (79) can be produced by an alkylation reaction between the ring A derivative (75) and the alkyl halide derivative (78). This can be performed in the same manner as in step 22 described above.
  • ring A may be converted as follows.
  • R 17 and R 18 represent a C 1-3 alkyl group, and n represents an integer of 1 to 6.
  • Carboxylic acid derivative (81) can be produced by reacting ring A derivative (75) with acid anhydride (80).
  • the solvent is not particularly limited as long as it does not inhibit the reaction.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether; N, N-dimethylformamide, N-methyl Amides such as pyrrolidone; dimethyl sulfoxide and the like can be used alone or in combination.
  • the reaction temperature is usually 0 ° C. to 120 ° C., preferably 40 ° C. to 100 ° C., and the reaction time is usually 10 minutes to 3 days, preferably 12 hours to 24 hours.
  • the ring A derivative (83) can be produced by a dehydration condensation reaction between the carboxylic acid derivative (81) and the amine derivative (82). It can be performed in the same manner as in the above-described step 3.
  • ring B may be converted as follows.
  • R 19 represents hydrogen, a C 1-5 alkyl group, or the same ring C as defined above, and P represents a protecting group.
  • An amine derivative (85) can be produced by deprotecting the ring B derivative (84). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • the ring B derivative (87) can be produced by a reductive alkylation reaction between the amine derivative (85) and the aldehyde derivative (86). This can be performed in the same manner as in step 58 described above.
  • amine derivative (38) used in the above production method a commercially available one can be used as it is, or it can be suitably produced by a known method, and when V represents an NHC (O) group and U represents a bond, For example, it can be produced by the following method, but is not limited thereto.
  • the amide derivative (90) can be produced by a dehydration condensation reaction between the carboxylic acid derivative (88) and the amine derivative (89). It can be performed in the same manner as in the above-described step 3.
  • the amine derivative (38) can be produced by deprotecting the protecting group of the amine derivative (90). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • carboxylic acid derivative (11) used in the above production method a commercially available one can be used as it is, or it can be suitably produced by a known method, and for example, it can be produced by the following method.
  • Carboxylic acid derivative (11) can be produced by acid chloride reaction of carboxylic acid derivative (10).
  • the solvent is not particularly limited.
  • halogen hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane
  • aromatic hydrocarbons such as toluene and benzene
  • ethers such as tetrahydrofuran and dioxane
  • acetonitrile and propio Nitriles such as nitriles
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone can be used alone or in combination.
  • the reaction temperature is ⁇ 20 to 100 ° C., preferably ⁇ 20 to 60 ° C.
  • the reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.
  • carboxylic acid derivative (10) is used in the production method as they use a commercial available or can be suitably prepared by a known method, V represents N-R 11, R 11 is 2-nitro-sulfonyl When a group is represented and U represents a bond, it can be produced, for example, by the following method.
  • P represents a protecting group
  • E represents a leaving group such as a halogen atom or a triflate group.
  • An amine derivative (95) can be produced by a reductive alkylation reaction between a ketone derivative (91) and an amine derivative (92). This can be performed in the same manner as in step 58 described above.
  • the amine derivative (95) can be produced by an alkylation reaction of the amine derivative (93) and the carboxylic acid derivative (94). This can be performed in the same manner as in step 22 described above.
  • the amine derivative (96) can be produced by 2-nitrobenzenesulfonyl (Ns) reaction of the amino group of the amine derivative (95). This can be carried out in the same manner as in step 7 described above.
  • Carboxylic acid derivative (10) can be produced by deprotecting the protecting group of amine derivative (96). It can be performed with reference to commonly used methods (Protective Group Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • carboxylic acid derivative (96) a commercially available product can be used as it is, or it can be appropriately produced by a known method. For example, it can also be produced by the following method, but it is limited thereto. It is not a thing.
  • Amine derivative (97) can be produced by 2-nitrobenzenesulfonyl (Ns) reaction of amine derivative (93). This can be carried out in the same manner as in step 7 described above.
  • Carboxylic acid derivative (96) can be produced by Mitsunobu reaction of amine derivative (97) and alcohol derivative (98). It can be performed in the same manner as in the above-described step 8.
  • Substituents and the like in the above general formula are oxidized, reduced, alkylated, amidated, esterified, hydrolyzed with reference to methods generally used as necessary (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.), The desired product can be obtained by appropriate conversion by reductive amination or the like.
  • the protecting group is not particularly limited, but those that can be introduced by a generally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) can be used as appropriate.
  • the present invention is not limited to this.
  • various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between isomers.
  • a racemic mixture is obtained by a general racemic resolution method such as a method of optically resolving a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography.
  • a general racemic resolution method such as a method of optically resolving a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography.
  • the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography.
  • An optically active compound can also be produced by using an appropriate optically active raw material.
  • the TLR3, 7 and / or 9 inhibitor of the present invention and the preventive and / or therapeutic agent for cardiomyopathy due to autoimmune disease, inflammation, allergy, asthma, graft rejection, GvHD or sepsis are represented by the general formula (1). Containing a quinoline derivative, a salt thereof, or a solvate thereof as an active ingredient, and can be used as a pharmaceutical composition. In that case, the compound of the present invention may be used alone, but it is usually used in combination with a pharmaceutically acceptable carrier and / or diluent.
  • the administration route is not particularly limited, but can be appropriately selected depending on the purpose of treatment.
  • any of oral preparations, injections, suppositories, inhalants and the like may be used.
  • Pharmaceutical compositions suitable for these dosage forms can be produced by utilizing known preparation methods.
  • the compound represented by the general formula (1) is a pharmaceutically acceptable excipient, and further, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, and a corrigent.
  • a flavoring agent After adding a flavoring agent, tablets, coated tablets, granules, powders, capsules and the like can be produced using conventional methods.
  • the additive may be one commonly used in the art.
  • excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like.
  • binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like.
  • disintegrant examples include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • lubricant examples include purified talc, stearate, borax, and polyethylene glycol.
  • corrigent examples include sucrose, orange peel, citric acid, tartaric acid and the like.
  • an oral solution, syrup, etc. are added to the compound represented by the general formula (1) by adding a corrigent, a buffer, a stabilizer, a corrigent and the like using a conventional method.
  • An elixir or the like can be produced.
  • the flavoring agent include those listed above.
  • the buffering agent include sodium citrate
  • examples of the stabilizing agent include tragacanth, gum arabic, and gelatin.
  • a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the compound represented by the general formula (1), and subcutaneously using a conventional method.
  • Intramuscular and intravenous injections can be manufactured.
  • the pH adjusting agent and the buffering agent include sodium citrate, sodium acetate, sodium phosphate and the like.
  • the stabilizer include sodium pyrosulfite, EDTA (sodium edetate), thioglycolic acid, and thiolactic acid.
  • the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.
  • the isotonic agent include sodium chloride and glucose.
  • a known suppository carrier such as polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride, etc., and a surfactant (for example, , Tween (registered trademark)) and the like can be added and then manufactured using a conventional method.
  • a surfactant for example, , Tween (registered trademark)
  • the dose of the quinoline derivative represented by the general formula (1) of the present invention varies depending on age, body weight, symptom, dosage form, number of administrations, etc., but is usually a compound represented by the general formula (1) for adults.
  • 0.1 mg to 1000 mg, preferably 1 mg to 1000 mg, more preferably 1 mg to 500 mg per day is orally or parenterally administered in one or several divided doses.
  • Example 1 N 1 - (1-benzyl-piperidin-4-yl) -N 4 - (quinolin-6-yl) succinamide manufacturing 4-oxo-4- (quinolin-6-ylamino) butyric acid (70 mg, 0.27 mmol), 1 -Benzylpiperidin-4-amine (77 mg, 0.41 mmol), WSC ⁇ HCl (78 mg, 0.41 mmol), HOBT ⁇ H 2 O (62 mg, 0.41 mmol) dissolved in methylene chloride (3 mL) at room temperature Stir overnight. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform.
  • Example 6 N 1 - [1- (2- chlorobenzyl) piperidin-4-yl] -N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 4- Performed using ⁇ [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino ⁇ -4-oxobutyric acid and 1- (2-chlorobenzyl) piperidin-4-amine In the same manner as in Example 1, the title compound (26%) was obtained as a yellow solid.
  • Example 7 N 1 - [1- (3- chlorobenzyl) piperidin-4-yl] -N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 4- Performed using ⁇ [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino ⁇ -4-oxobutyric acid and 1- (3-chlorobenzyl) piperidin-4-amine In the same manner as in Example 1, the title compound (27%) was obtained as a yellow solid.
  • Example 8 N 1 - [1- (4- chlorobenzyl) piperidin-4-yl] -N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 4- Performed using ⁇ [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino ⁇ -4-oxobutyric acid and 1- (4-chlorobenzyl) piperidin-4-amine In the same manner as in Example 1, the title compound (6%) was obtained as a yellow solid.
  • Example 9 N 1 - [1- (4- methoxybenzyl) piperidin-4-yl] -N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 4- Performed using ⁇ [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino ⁇ -4-oxobutyric acid and 1- (4-methoxybenzyl) piperidin-4-amine In the same manner as in Example 1, the title compound (9%) was obtained as a yellow solid.
  • Example 10 N 1 - [1- (2,4- difluorobenzyl) piperidin-4-yl] -N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] Production of succinamide 4- ⁇ [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino ⁇ -4-oxobutyric acid and 1- (2,4-difluorobenzyl) piperidin-4-amine Used to give the title compound (24%) as a yellow solid as in Example 1.
  • Example 11 Process for producing 4- [4- (benzylamino) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -4-oxobutanamide 1 Preparation of tert-butyl 4- (N-benzyl-2,2,2-trifluoroacetamido) piperidine-1-carboxylate
  • Example 15 Preparation of N- (1-benzylpiperidin-4-yl) -6- ⁇ [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino ⁇ hexanamide 4-methyl-2
  • Step 2 of Example 14 using-(4-methylpiperazin-1-yl) quinolin-6-amine and N- (1-benzylpiperidin-4-yl) -6-bromohexanamide
  • the title compound (32%) was obtained as a brown amorphous.
  • Example 16 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide 4-Methyl- Similar to Example 1 using 2- (4-methylpiperazin-1-yl) quinoline-6-carboxylic acid and 3-([1,4′-bipiperidin] -1′-yl) propan-1-amine To give the title compound (52%) as a yellow oil.
  • reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Example 21 N 1 - (1-benzyl-piperidin-4-yl) -N 3 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine of the manufacturing process 1 N- (3-hydroxypropyl) -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide, and N, N ′-(propane- 1,3-diyl) bis ⁇ N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide ⁇
  • N- (3-hydroxypropyl) -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide and N- (1-benzylpiperidine-4 -Il) -2-Nitrobenzenesulfonamide was used in the same manner as in Step 2 of Example 20 to obtain the title compound (52%) as a yellow amorphous.
  • Example 22 Preparation of N 1 , N 3 -bis [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine N, N ′-(propane-1,3 -Diyl) bis ⁇ N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide ⁇ in the same manner as in Example 19 The compound (70%) was obtained as a yellow solid.
  • Example 23 Process for producing N- ⁇ 3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl ⁇ -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide 1 Preparation of 2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxylic acid
  • Example 25 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide 2- [ Example 1 using 4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxylic acid and 3-([1,4′-bipiperidin] -1′-yl) propan-1-amine In the same manner as described above, the title compound (2 step yield: 44%) was obtained as a yellow amorphous substance. Maleic acid (90 mg, 0.69 mmol) was added to an ethanol (1 mL) solution of the obtained title compound (125 mg, 0.23 mmol), recrystallized, and the title compound trimaleate (158 mg, 73% )
  • Example 26 Preparation of N- ⁇ 3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl ⁇ -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide 2- (4-Methyl).
  • the title compound (2-step yield) was obtained in the same manner as in Example 1 using piperazin-1-yl) quinoline-4-carboxylic acid and 3-amino-N- (1-benzylpiperidin-4-yl) propionamide. 50%) was obtained as a slightly yellow solid.
  • Example 28 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- (4-methylpiperazin-1-yl) quinolin-4-carboxamide 2- (4-Methylpiperazine- Using 1-yl) quinoline-4-carboxylic acid and 3-([1,4′-bipiperidin] -1′-yl) propan-1-amine in the same manner as in Example 1, the title compound (2 steps) Yield 52%) was obtained as a yellow amorphous.
  • Example 30 N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4- Preparation of carboxamide 6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxylic acid and 3-([1,4′-bipiperidin] -1′-yl) The title compound (71%) was obtained as a pale yellow solid in the same manner as in Example 1 using propan-1-amine.
  • N 1 (-4-1-benzyl-piperidin-yl) -N 4 - producing N 1 of ⁇ 4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl ⁇ succinamide - (1-benzyl-piperidin-4-yl) -N 4 - (2-chloro-4-methyl-6-yl) succinamide (100 mg, 0.22 mmol), tetrakis (triphenylphosphine) palladium (0) (25 mg, 0.02 mmol), 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine (98 mg, 0.32 mmol), 2M aqueous sodium carbonate solution (2 mL) was mixed with THF (4 mL), and the mixture was stirred at reflux for 5 hours.
  • Example 34 Process for producing 2-[(1-benzylpiperidin-4-yl) amino] -N- ⁇ 4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl ⁇ acetamide 1
  • Example 35 N 1 - (1-benzyl-piperidin-4-yl) -N 4 - (4-methyl-2 - ⁇ [4- (4-methylpiperazin-1-yl) phenyl] amino ⁇ quinolin-6-yl) succinamide of producing N 1 - (4-1-benzyl-piperidin-yl) -N 4 - (2-chloro-4-methyl-6-yl) succinamide (100 mg, 0.22 mmol), 4- (4- methylpiperazin -1 -Il) aniline (49 mg, 0.26 mmol), palladium (II) acetate (5 mg, 0.02 mmol), BINAP (27 mg, 0.04 mmol), cesium carbonate (140 mg, 0.43 mmol) in dioxane (2 mL) Mix and stir overnight with reflux.
  • Example 40 Preparation of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [4- (4-methylpiperazin-1-yl) phenyl] acetamide 4-Methyl- In the same manner as in Example 1 using 2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2- [4- (4-methylpiperazin-1-yl) phenyl] acetic acid, the title compound (30%) was obtained as a light brown solid.
  • Methyl 2- ⁇ N- [1- (cyclopropylmethyl) piperidin-4-yl] -2-nitrophenylsulfonamide ⁇ acetate is used to produce the title compound (crude) in the same manner as in Step 2 of Example 2. Obtained as a pale yellow solid.
  • Example 1 using 4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2- [2-nitro-N- (pyridin-4-ylmethyl) phenylsulfonamido] acetic acid In the same manner as above, the title compound (crude) was obtained as a light brown amorphous.
  • Example 43 4- [4- (6- ⁇ 2-[(1-Benzylpiperidin-4-yl) amino] acetamido ⁇ -4-methylquinolin-2-yl) piperazin-1-yl] -N-methyl-4-oxo Butanamide production process 1 tert-Butyl 4- (6- ⁇ 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido ⁇ -4-methylquinolin-2-yl) piperazine-1-carboxylate Manufacturing of
  • Example 45 Preparation of 2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide
  • 2- [N- (1-benzyl) Piperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide was used in the same manner as in Example 19, The title compound (78%) was obtained as a brown amorphous.
  • Example 46 Preparation of 2-[(1-benzylpiperidin-4-yl) (methyl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide 4-methyl Step 1 and step of Example 38 using 2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2-[(1-benzylpiperidin-4-yl) (methyl) amino] acetic acid. Similar to 2, the title compound (42%) was obtained as a tan oil.
  • Example 49 Process for producing N- ⁇ 2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl ⁇ -2-[(1-methylpiperidin-4-yl) amino] acetamide 1 tert-Butyl 4- (4-methyl-6- ⁇ 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido ⁇ quinolin-2-yl) piperazine-1-carboxylate Manufacturing of
  • Step 6 Preparation of N- ⁇ 4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl ⁇ -2-[(1-methylpiperidin-4-yl) amino] acetamide N- ⁇ 4-Methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl ⁇ -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide In the same manner as in Example 19, the title compound (3 step yield: 41%) was obtained as a pale yellow amorphous.
  • Example 54 Process for producing 3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide 1 Preparation of (E) -tert-butyl 3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acrylate
  • 6-iodo-4-methyl-2- (4-methylpiperazin-1-yl) quinoline 400 mg, 1.08 mmol
  • tert-butyl acrylate (0.78 mL, 5.4 mmol)
  • tris (dibenzylideneacetone) dipalladium 104 mg, 0.108 mmol
  • tri (o-tolyl) phosphine (191 mg, 0.65 mmol)
  • diisopropylethylamine (0.73 mL, 4.32 mmol
  • Example 55 Preparation of 3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) propionamide (E) -3- [4 Using -methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide in the same manner as in Step 2 of Example 5, The title compound (46%) was obtained as a pale yellow solid.
  • N-allyl-1-methylpiperidin-4-amine 800 mg, 5.16 mmol
  • Boc 2 O 1.12 g, 5.16 mmol
  • THF 10 mL
  • Example 58 Preparation of 1-methyl-N- ⁇ 3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propyl ⁇ piperidin-4-amine (E) -1-Methyl-N In the same manner as in Step 2 of Example 5, using — ⁇ 3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl ⁇ piperidin-4-amine, The compound (64%) was obtained as a pale yellow oil.
  • Example 60 Preparation of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) oxy] acetamide 4-Methyl-2- In the same manner as in Step 1 and Step 2 of Example 38, using (4-methylpiperazin-1-yl) quinolin-6-amine and 2-[(1-methylpiperidin-4-yl) oxy] acetic acid, The title compound (95%) was obtained as a pale yellow solid.
  • Example 61 Preparation of 2- ⁇ [1- (cyclopropylmethyl) piperidin-4-yl] oxy ⁇ -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide N- Using [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide and cyclopropanecarboxaldehyde, step 1 of Example 36 and Similarly, the title compound (87%) was obtained as a pale yellow solid.
  • Step 6 Preparation of N-methyl-6- [4- (4-methyl-6- ⁇ 2-[(1-methylpiperidin-4-yl) amino] acetamido ⁇ quinolin-2-yl) piperazin-1-yl] hexanamide N-methyl-6- [4- (4-methyl-6- ⁇ 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido ⁇ quinolin-2-yl ) Piperazin-1-yl] hexanamide was used in the same manner as in Step 4 of Example 11 to obtain the title compound (77%) as a brown amorphous.
  • Example 64 (N 1 - (1-benzyl-piperidin-4-yl) -N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide) of Preparation 4 - ⁇ [4 -Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino ⁇ -4-oxobutyric acid and 1-benzylpiperidin-4-amine are prepared in the same manner as in Example 1. be able to. It can also be purchased from Aurora Fine Chemical.
  • Example 65 N 1 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N 4 - (2-morpholinoethyl) succinamide manufacturing 4 - ⁇ [4-methyl-2- ( 4-methylpiperazin-1-yl) quinolin-6-yl] amino ⁇ -4-oxobutyric acid and 2-morpholinoethanamine can be used in the same manner as in Example 1. It can also be purchased from Aurora Fine Chemical.
  • Example 68 Preparation of N, 2-bis [4- (4-methylpiperazin-1-yl) phenyl] quinolin-4-amine 4-chloro-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline ( 50 mg, 0.15 mmol) in toluene (1.5 mL) was added 4- (4-methylpiperazin-1-yl) aniline (34 mg, 0.18 mmol), tri-tert-butylphosphine (13.4 mg, 0.045 mmol), tris (Dibenzylideneacetone) dipalladium (0) (9 mg, 0.015 mmol) and tert-butoxy sodium (29 mg, 0.30 mmol) were added, and the mixture was stirred at 60 ° C.
  • TLR9 activation inhibition test using TLR9-expressing reporter cells 1) Establishment of TLR9-expressing reporter cells Human TLR9-expressing cells were obtained by expressing cells expressing human TLR9 in HEK293, a human fetal kidney cell line, from Invivogen. (HTLR9 / 293xL). hTLR9 / 293xL was subcultured using Dulbecco's modified Eagle medium (DMEM (sigma)) containing 10% fetal bovine serum, penicillin, and streptomycin. PGL4.28 (Promega) in which a firefly luciferase gene was linked to the NF ⁇ B recognition sequence 4 times was introduced by lipofection using Fugene6 (Roche).
  • DMEM Dulbecco's modified Eagle medium
  • Hygromycin and blasticidin resistant cell clones were selected and used as TLR9 expression reporter cells (hTLR9 NF ⁇ B-luc / 293xL). 2) TLR9 plated at activation inhibition test hTLR9 NF ⁇ B-luc / 96 well-white 293xL microtiter plate 1.0 ⁇ 10 4 / 80 ⁇ L, 37 °C in CO 2 incubator, and cultured overnight. A test compound (10 ⁇ L) diluted with DMEM was added to a final concentration of 0.01, 0.03, 0.1, 0.3, 1 ⁇ M. One hour later, CpG-B DNA (ODN2006) (Invivogen) as a TLR9 ligand was added to a final concentration of 1 ⁇ M (10 ⁇ L).
  • Luciferase activity was measured as TLR9 activity after incubation in a CO 2 incubator for a total of 100 ⁇ L for 4 hours. Luciferase activity was measured by adding 60 ⁇ L of Bright Glo (Promega) and measuring the amount of luminescence with a multi-microplate reader ARVO (Perkin Elmer). The 50% inhibitory concentration (IC 50 value) of each test compound was calculated with the luciferase activity when no test compound was added as 100%.
  • the compound of the present invention has a strong TLR9 inhibitory action. Therefore, the quinoline derivative represented by the general formula (1) of the present invention is used as a TLR9 inhibitor as a disease associated with activation of TLR9 signal, such as RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet. It has been found useful as an active ingredient of a prophylactic and / or therapeutic agent for cardiomyopathy due to syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis.
  • autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis.
  • TLR7 activation inhibition test using TLR7-expressing reporter cells 1) Establishment of TLR7-expressing reporter cells Human TLR7-expressing cells are cells obtained by expressing human TLR7 in a human fetal kidney cell line, Invivogen. (HTLR7 / 293xL). hTLR7 / 293xL was subcultured using Dulbecco's modified Eagle medium (DMEM (sigma)) containing 10% fetal bovine serum, penicillin, and streptomycin. PGL4.28 (Promega) in which a firefly luciferase gene was linked to the NF ⁇ B recognition sequence 4 times was introduced by lipofection using Fugene6 (Roche).
  • DMEM Dulbecco's modified Eagle medium
  • Hygromycin and blasticidin resistant cell clones were selected and used as TLR7 expression reporter cells (hTLR7 NF ⁇ B-luc / 293 ⁇ L). 2) The TLR7 activation Inhibition Test hTLR7 NF ⁇ B-luc / 293xL plated at 1.0 ⁇ 10 4 / 80 ⁇ L in a 96 well white microtiter plate, 37 ° C. in a CO 2 incubator, and cultured overnight. A test compound (10 ⁇ L) diluted with DMEM was added to a final concentration of 0.03, 0.1, 0.3, 1, 3, 10 ⁇ M. One hour later, Imiquimod (Invivogen), a TLR7 ligand, was added to a final concentration of 10 ⁇ M (10 ⁇ L).
  • Luciferase activity was measured as TLR7 activity after incubation in a CO 2 incubator for a total of 100 ⁇ L for 4 hours. Luciferase activity was measured by adding 60 ⁇ L of Bright Glo (Promega) and measuring the amount of luminescence with a multi-microplate reader ARVO (Perkin Elmer). The 50% inhibitory concentration (IC 50 value) of each test compound was calculated with the luciferase activity when no test compound was added as 100%. 3) Results Table 2 shows the activity values (IC 50 values) of the compounds obtained in the above examples.
  • the compound of the present invention has a strong TLR7 inhibitory action. Therefore, the quinoline derivative represented by the general formula (1) of the present invention is used as a TLR7 inhibitor for diseases associated with activation of TLR7 signal such as RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet. It was found to be useful as an active ingredient of a prophylactic and / or therapeutic agent for cardiomyopathy caused by syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis.
  • diseases associated with activation of TLR7 signal such as RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet. It was found to be useful as an active ingredient of a prophylactic and / or therapeutic agent for cardiomyopathy caused by syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis.
  • mice Male DBA / 1J mice (Nippon Charles River Co., Ltd.) were used. The body weight of 7-week-old DBA / 1J mice was measured, and grouping was performed using a single-block blocking assignment using this as an index.
  • the group composition is as follows: control group (administration medium (0.5% hydroxymethylpropylcellulose aqueous solution) administration group), Example 19 or 39 compound 25 mg / kg administration group, Example 19 or 39 compound 50 mg / kg administration Grouped.
  • test method A 0.2% type 2 collagen solution is prepared by mixing 0.3% type 2 collagen solution (collagen technical workshop) and physiological saline (Otsuka Pharmaceutical) in a ratio of 2: 1. did. Next, an equal amount of 0.2% type 2 collagen solution and Adjuvant Complete Freund (DIFCO) were mixed, and a first-sensitized emulsion was prepared with a handy microhomogenizer NS-310E (Microtech Nithion) under ice cooling. After shaving the ridges of the animals with clippers, 0.05 mL each of the first sensitizing emulsion was intradermally administered to the left and right sides of the ridges. After the completion of the first sensitization, the drug solution was orally administered once a day until 34 days after the first sensitization (14 days after the additional sensitization).
  • DIFCO Adjuvant Complete Freund
  • the additional sensitization was performed in the following procedure 20 days after the first sensitization.
  • a 0.2% type 2 collagen solution was prepared by mixing 0.3% type 2 collagen solution and physiological saline at a ratio of 2: 1.
  • an equal amount of 0.2% type 2 collagen solution and Adjuvant Incomplete Freund (DIFCO) were mixed, and an additional sensitive emulsion was prepared with a handy microhomogenizer NS-310E under ice cooling.
  • Additional sensitization was performed by administering 0.1 mL of the prepared additional sensitizing emulsion into the ridge skin, and arthritis was induced.
  • the primary endpoint, limb swelling, was determined by arthritis by three judges in a blinded manner, 3 times: initial assessment 7 days after additional sensitization, intermediate assessment 10 or 11 days later, and final assessment 14 days later.
  • the score was determined.
  • As the evaluation criteria for swelling the following four criteria were applied to each limb, and the total of the limbs was used as the individual arthritis score.
  • plasma anti-type 2 collagen IgG antibody titer was measured by ELISA using an orbital blood sample 15 days after additional sensitization.
  • FIG. 15 is a graph showing changes over time in arthritis scores of a mouse collagen-induced arthritis model in a control group (drug non-administered group), a compound of Example 19 administered with a 25 mg / kg compound and a 50 mg / kg administered group
  • a control group drug non-administered group
  • a compound of Example 19 administered with a 25 mg / kg compound
  • a 50 mg / kg administered group In the control group, an increase in the arthritis score was observed after 7 days from the additional sensitization.
  • the administration group of the compound of Example 19 exhibited a significant inhibitory effect suggesting dose dependency at a dose of 50 mg / kg.
  • ** and *** indicate a risk rate of less than 1% (p ⁇ 0.01) and less than 0.1% (p ⁇ 0.01), respectively, in Steel's multiple comparison test using the control group as a comparative control. 0.001).
  • FIG. 2 shows the average value of anti-type 2 collagen IgG antibody titer 15 days after the additional sensitization.
  • ** indicates that the risk rate is less than 1% (p ⁇ 0.01) in Steel's multiple comparison test using the control group as a comparison control.
  • FIG. 3 shows the change over time in the arthritis score as an average value.
  • FIG. 4 is a graph showing changes over time in arthritis scores of a mouse collagen-induced arthritis model in a control group (drug non-administered group), a compound of Example 39 administered with 25 mg / kg and a group administered with 50 mg / kg.
  • the control group an increase in the arthritis score was observed after 7 days from the additional sensitization.
  • the administration group of the compound of Example 39 showed a significant inhibitory effect at a dose of 50 mg / kg, suggesting dose dependency.
  • ** indicates that the risk rate is less than 1% (p ⁇ 0.01) in Steel's multiple comparison test using the control group as a comparison control.
  • FIG. 4 shows the average value of anti-type 2 collagen IgG antibody titer 15 days after the additional sensitization.
  • * in a figure shows that a risk rate is less than 5% (p ⁇ 0.05) in Steel multiple comparison test which made the control group the comparison control.
  • the compounds of Examples 19 and 39 are effective as a therapeutic agent for rheumatoid arthritis.
  • the quinoline derivative of the present invention or a salt thereof, or a solvate thereof has an excellent TLR3, 7 and / or 9 inhibitory action, and is an autoimmune disease, inflammation, allergy, asthma, graft rejection or GvHD.
  • Useful for prophylactic and / or therapeutic agents Useful for prophylactic and / or therapeutic agents.
  • the present invention provides a preventive and / or therapeutic agent for cardiomyopathy due to autoimmune disease, inflammation, allergy, asthma, graft rejection, GvHD or sepsis, and is useful in the pharmaceutical industry and has industrial applicability. is doing.

Abstract

La présente invention concerne un composé représenté par la formule générale (1), un sel du composé ou un solvate du composé ou du sel, pouvant inhiber TLR3, 7 et/ou 9 et possédant un excellent effet prophylactique et/ou thérapeutique sur les maladies auto-immunes, les inflammations, les allergies, l'asthme, le rejet d'une greffe, GvHD ou une cardiomyopathie associée à une sepsie. A : un cycle hétérocyclique azoté saturé à 5 ou 6 chaînons (substitué) ; Y : une liaison ou un groupe phénylène ; Z : une liaison, un groupe alkylène en C1 à C6, N-R7 ou O ; R1, R3 et R5 à R8 : H, un groupe alkyle en C1 à C3 ou un groupe équivalent ; R7 : H, un groupe alkyle en C1 à C6 ou un groupe 2-nitrobenzènesulfonyle ; et R2 et R4 : un représente R8 et l'autre représente un groupe représenté par la formule (2) (où B : un cycle carbocyclique/hétérocyclique (substitué), W : un groupe alcénylène en C2 à C6 ou un groupe équivalent, X, V : une liaison, C(O)NH, NHC(O) ou un groupe équivalent, et U : une liaison ou un groupe alkylène en C1 à C6 ; le cas dans lequel X, V et U représentent tous des liaisons est exclu).
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US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains
US10954233B2 (en) 2016-09-09 2021-03-23 Novartis Ag Compounds and compositions as inhibitors of endosomal toll-like receptors

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