WO2001055121A1 - Dérivés d'azépine - Google Patents

Dérivés d'azépine Download PDF

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WO2001055121A1
WO2001055121A1 PCT/JP2001/000521 JP0100521W WO0155121A1 WO 2001055121 A1 WO2001055121 A1 WO 2001055121A1 JP 0100521 W JP0100521 W JP 0100521W WO 0155121 A1 WO0155121 A1 WO 0155121A1
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group
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ring
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atom
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PCT/JP2001/000521
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Japanese (ja)
Inventor
Satoru Ikegami
Kiyoshi Inoguchi
Hideto Fukui
Yuji Sumita
Tatsuya Maruyama
Mitsuru Watanuki
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Kaken Pharmaceutical Co., Ltd.
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Priority to AU28828/01A priority Critical patent/AU2882801A/en
Publication of WO2001055121A1 publication Critical patent/WO2001055121A1/fr

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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
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    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
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    • C08L53/00—Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
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    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/08—Polyethers derived from hydroxy compounds or from their metallic derivatives
    • C08L71/10—Polyethers derived from hydroxy compounds or from their metallic derivatives from phenols
    • C08L71/12—Polyphenylene oxides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel azepine-derived ⁇ pine or a salt thereof, a medicament containing them as an active ingredient, and a VL ⁇ -4 antagonist.
  • Cell adhesion is indispensable for complex life phenomena caused by cell-cell interactions such as cell activation, migration, proliferation, and differentiation.
  • cell-cell or cell-cell extracellular matrix interactions involve cell adhesion molecules classified as integrins, immunoglobulins, selectins, and force-dherins.
  • Integrins have a ct3-heterodimer structure and are classified into three main groups, ⁇ 1, 2, and ⁇ 3 subfamilies.
  • VLA protein one of which is integrin VLA-4 ( ⁇ 4) 31), which is expressed on lymphocytes, eosinophils, basophils and monocytes, and 1 and fibronectin are ligands.
  • VLA-4 is a / 31 integrin that plays an important role in cell-cell and cell-extracellular matrix interactions via VCAM-1 and fibronectin.
  • the leukocytes circulating in the blood must pass through vascular endothelial cells and infiltrate the site of inflammation.
  • VLA-4 and VCAM-1 The binding between VLA-4 and VCAM-1 is one of the most important mechanisms for strong adhesion and adhesion between leukocytes and vascular endothelium.
  • Inflammatory cells such as T lymphocytes, B lymphocytes, monocytes, and eosinophils, express VLA-4, and the VLA-4 / VCAM-1 mechanism is strongly involved in infiltrating these cells into inflammatory foci.
  • Adhesion molecules also play an important role in cell activation through cell-cell interactions, and the VCAM-1 ZVL A-4 mechanism activates eosinophils to cause degranulation. It has been shown that signals mediated by VLA-4 are also involved in antigen-specific proliferation activation of limbocytes.
  • an anti-VLA-4 monoclonal antibody inhibits the adhesion of VLA-4 expressing Ramos cells to human umbilical vein vascular endothelial cells (HUVEC) and VCAM-1 transgenic C ⁇ S cells.
  • the antibody has shown efficacy in both treatment and prevention.
  • rat adjuvant arthritis model Barbadillo et al., Arthr. Rheuma., 1993, 36, 95
  • contact hypersensitivity e.g., contact hypersensitivity
  • delayed type hypersensitivity modenole e.g., contact hypersensitivity
  • mice autoimmune encephalomyelitis (Yednock, Nature, 1992, 356, 63), asthma modenole (Abraham et al., J. Clin. Invest., 1993, 93, 776), inflammatory bowel disease (IBD)
  • the effects of antibodies were also evaluated in a model (Podolsky et al., J. Clin. Invest., 1993, 92, 372).
  • VLA-4 cell adhesion by VLA-4 plays a role in rheumatoid arthritis, nephritis, diabetes, systemic lupus erythematosus, late-onset allergy, multiple sclerosis, arteriosclerosis, organ transplantation and various malignancies. It was shown to fulfill.
  • blockade of VLA-4 by a suitable antagonist is effective for treatment of the above-mentioned various diseases including inflammatory diseases.
  • the extracellular domain of VCAM-1 is composed of six immunoglobulin-like structures, and the amino acid sequences of domains 4, 5, and 6 are highly homologous to the amino acid sequences of domains 1, 2, and 3, respectively.
  • the binding region for —4 is known to be domains 1 and 4 (Osborn et al., J. Exp. Med., 1992, 176, 99). From the X-ray crystallographic analysis of domains 1 and 2 of VCAM-1, the binding domain to VLA-4 is estimated to be the CD loop of the first domain (Q38 IDSPL) (Jones et al., Nature, 1995, 373, 539).
  • VLA-4 antagonists include cyclic peptides and peptide-like compounds (W096 / 22966, W098 / 42656) based on the LDV sequence of CS-1 peptide, which is the VLA-4 recognition site of fibronectin. Reported:
  • the present invention has been made in view of the treatment and prevention of such a disease mediated by VL II-4, and an object of the present invention is to provide a VL A-4 excellent in oral absorption and in vivo kinetics.
  • An object of the present invention is to provide a novel compound having an antagonistic activity or a salt thereof, and to provide a medicament containing these as an active ingredient. Disclosure of the invention
  • the present inventors used the X-ray crystal structure of VCAM-1 to ascertain the relative positional relationship of side chains important for activity expression from its CD loop, Translated as pharmacophore, and a compound database search was performed. Based on the results, the present inventors have conducted intensive research and found that the azepine derivative has an excellent VLA-4 antagonistic action, thereby completing the present invention.
  • the present invention provides a compound represented by the formula (I):
  • R 1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an arylalkyl group having 7 to 11 carbon atoms, Represents an aryl group or a heterocyclic group having 6 to 10 carbon atoms, R 2 represents a hydrogen atom or a carboxyl protecting group, R 3 represents an alkylene group having 1 to 6 carbon atoms, and an alkyl group having 2 to 6 carbon atoms.
  • R 4 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, which represents a benzene group, a cycloalkylene group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a divalent heterocyclic group.
  • R 4 may combine with R 3 to form a ring, and the ring may further contain an oxygen atom, a nitrogen atom, or a sulfur atom as a constituent, and a double bond is formed in the ring. .
  • X represents a hetero ring Ariru ring or to, m is; • L ⁇ 3 integer Represents, gamma nitrogen atom, an oxygen atom, a sulfur atom, in one N (R 5) i (wherein, R 5 independently represents the same meaning as R 4, also the R 5 combines with R 1 ring Or one S (O) n— (where n represents an integer of 1 to 2), and when Y is a nitrogen atom, the broken line in the formula is doubled.
  • Z represents the formula
  • a 1 represents a methylene group, a snolephoninole group, a carbonyl group or a thiocarbonyl group
  • R 6 represents an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms, and a carbon number of 3 to 6.
  • aryl represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and an alkyl group having 7 to 11 carbon atoms.
  • Reel represents an alkyl group, an aryl alkenyl group having 8 to 12 carbon atoms, an aryl group or a heterocyclic group having 6 to 10 carbon atoms, and R 8 may be combined with R 6 to form a ring. Les ,.
  • R 7 is the formula
  • R 9 and R 1 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a hydroxyl group, and R 9 is bonded to R 6 or R 8 to form a ring.
  • a 3 represents a methylene group, a carbonyl group, a thiocarbonyl group, an oxygen atom or —S (0) P- (where p represents an integer of 0 to 2)
  • Represents J) 3 represents any of 3 ).
  • the present invention relates to a medicine and a VLA-4 antagonist containing the azepine derivative represented by the formula (I) or a salt thereof as an active ingredient.
  • alkyl group having 1 to 6 carbon atoms include a methyl group, a nityl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec_butyl group, Examples thereof include a linear or branched alkyl group such as an n-pentyl group, a tert-amyl group, a 3-methylbutyl group, a neopentyl group, and an n-hexyl group. These may be substituted.
  • alkenyl group having 2 to 6 carbon atoms include a linear or branched alkenyl group such as a vinyl group, a propenyl group, and an isopropenyl group. Further, they may be substituted.
  • cycloalkyl group having 3 to 7 carbon atoms include a cyclopropyl group, a cyclobutyl group, a pentyl group, a hexyl group, and a heptyl group. These may be substituted.
  • arylalkyl group having 7 to 11 carbon atoms include a benzyl group, a phenylethyl group and a phenylpropyl group. These may be substituted.
  • aryl alkenyl group having 8 to 12 carbon atoms include a styryl group and a cinnamyl group. These may be substituted.
  • aryl group having 6 to 10 carbon atoms include a phenyl group, an 11-naphthyl group, and a 2-naphthyl group. These may be substituted, and the same applies to “aryl ring”.
  • Heterocyclic group refers to a 5- to 7-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom in the ring, and specific examples thereof include: Examples thereof include a furyl group, a phenyl group, an imidazolyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, a birazinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a mopiperazinyl group, a morpholinyl group, and a dioxanyl group.
  • a bicyclic or tricyclic condensed heterocyclic ring in which the monocyclic heterocyclic ring and the benzene ring or the monocyclic heterocyclic ring are condensed and specific examples thereof include a benzofuranyl group, a benzochenyl group, an indolyl group, and a benzyl group.
  • examples include an imidazolyl group, a quinolyl group, a tetrahydroquinolyl group, a chromanyl group, a piperonyl group, a pyrido [4,3-d] pyrimidinyl group, and an isoxazo port [4,5_c] pyridinyl group. They may also be substituted: the same applies to “heterocycle”.
  • alkylene group having 1 to 6 carbon atoms include linear or branched alkylene groups such as a methylene group, an ethylene group, a propylene group, and a butylene group. They may also be substituted:
  • alkenylene group having 26 carbon atoms include straight-chain or branched-chain alkenylene groups such as a vinylene group and a bronylene group. These may be substituted.
  • cycloalkylene group having 37 carbon atoms examples include a 1,1-cyclopropylene group, a 12-cyclopropylene group, and a 1,3-cyclohexylene group. These may be substituted.
  • substituents in the case of “optionally substituted” include an alkyl group having 16 carbon atoms, a cycloalkyl group having 37 carbon atoms, an aryl group having 6 10 carbon atoms, and a heterocyclic ring.
  • Group halogen atom, hydroxyl group, alkoxy group having 16 carbon atoms, aliphatic acryl group having 15 carbon atoms, aromatic acyl group having 711 carbon atoms, aliphatic sulfonyl group having 14 carbon atoms, 27 carbon atoms
  • Examples include a sulfonyl group, an aliphatic sulfamoyl group having 14 carbon atoms, a cyano group, a nitro group, an amino group, a substituted amino group, and a carboxyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • alkoxy group having 16 carbon atoms examples include methoxy group, ethoxy group, ⁇ -propoxy group, isopropoxy group, ⁇ -butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group And linear or branched alkoxy groups such as n-pentyloxy group, tert-aminooxy group, 3-methylbutoxy group, neopentyloxy group and n-xyloxy group.
  • ⁇ aliphatic acryl group having 15 carbon atoms '' include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a norrenyl group, an isovaleryl group, and a pivaloyl group.
  • a chain aliphatic acyl group may include:
  • aromatic acyl group having 7 11 carbon atoms for example, benzoyl group, toluoi And the like.
  • alkoxycarbonyl group having 2 to 7 carbon atoms examples include methoxycarbonyl, ethoxycarbonyl, ⁇ -propoxycarbonyl, isopropoxycarbonyl, ⁇ -butoxycarbonyl, isobutoxycarbonyl, tert — Straight or branched alkoxycarbonyl groups such as butoxycarbonyl, sec-butoxycarbonyl, benzyloxycarbonyl, etc .:
  • alkyl amide group having 2 to 5 carbon atoms include a methyl amide group, an ethyl amide group, an n-propyl amide group, an isopropyl amide group, an n-butyl amide group, an isobutyl amide group, and a tert butyl group.
  • Examples thereof include linear or branched alkynoleamide groups such as —butylamide group, sec-butylamide group, n-pentylamide group and tert-amylamide group.
  • alkylthio group having 1 to 4 carbon atoms include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a tert-butylthio group, and a sec-butylthio group. And straight-chain or branched alkylthio groups.
  • aliphatic sulfonyl group having 1 to 4 carbon atoms include straight-chain or branched groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-butylsulfonyl, and 2-butylsulfonyl. And a branched aliphatic sulfonyl group.
  • aromatic sulfonyl group having 6 to 10 carbon atoms include a phenylsulfonyl group and a tolylsulfonyl group.
  • aliphatic sulfamoyl group having 1 to 4 carbon atoms include a methylsulfamoyl group, an ethylsulfamoyl group, and n-phenyl.
  • n-butylsulfamoyl group isobutylsulfanyl group
  • examples thereof include straight-chain or branched aliphatic sulfamoyl groups such as tert-butyl, tinolenorefamoyl group and sec-butylsulfamoyl group.
  • substituent of the “substituted amino group” include a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aliphatic acyl group having 1 to 5 carbon atoms, an aromatic acyl group, C4 to C4 aliphatic sulfonyl group, C2 to C7 alkoxycarbonyl group, C2 to C5 alkylamide group, C1 to C4 aliphatic sulfonyl group, aromatic sulfonyl group, carbon number And 1-4 aliphatic sulfamoyl groups.
  • ring when “R 3 and R combine to form a ring” include an azetidine ring, a pyrroline ring, a pyrrolidine ring, a piperidine ring, a tetrahydropyridine ring, a morpholine ring, a thiomorpholine ring, and a piperazine ring. can give. These may be substituted.
  • RS and R 6 combine to form a ring include a fluorene ring. These may be substituted.
  • R 9 and R 6 combine to form a ring include a pyrrolidine ring and a piperidine ring. They may also be substituted:
  • ring when “R 9 and R 8 combine to form a ring” include a pyrrolidine ring, a piperidine ring, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, and the like. These may be substituted.
  • carboxyl protecting group refers to a residue of the alcohol portion of a carboxylic acid ester which is relatively easily cleaved to generate a corresponding free carboxy group, and specific examples thereof include a methyl group, an ethyl group, and an n-propyl group.
  • Alkyl group having 1 to 6 carbon atoms such as tert-butyl group, lower alkenyl group having 2 to 6 carbon atoms such as aryl group, benzyl group, arylalkyl group such as p-methoxybenzyl group or phenyl group
  • Treatment under mild conditions such as hydrolysis, catalytic reduction or cleavage with a transition metal catalyst. And the group which is eliminated.
  • Table 1 shows preferred examples of Z in the present invention. It should be noted that in the table, the Me-mele group is shown. table 1
  • R 1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, Represents a cycloalkyl group, an aryl group or a heterocyclic group having 6 to 10 carbon atoms, represents a hydrogen atom
  • R 3 represents an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms
  • R " 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • R 4 may be bonded to R 3 to form a ring, the ring may further contain an oxygen atom as a constituent, may contain a double bond in the ring, and may be substituted.
  • X represents an aryl ring or a hetero ring
  • m represents 1 or 2
  • Y represents a nitrogen atom, oxygen Atom, sulfur atom, —N (R 5 ) — (wherein, R 5 independently represents the same meaning as, and R 5 may be combined with R 1 to form a ring.)
  • R 5 independently represents the same meaning as, and R 5 may be combined with R 1 to form a ring.
  • A represents a sulfonyl group or a carbonyl group
  • R 6 is an aropenylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms, and a divalent carbon number of 7 to 11
  • R 8 has 1 to 1 carbon atoms.
  • R 7 is a group represented by the formula
  • R y and R 1Q each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a hydroxyl group, and R y is bonded to R 6 or R :: to form ⁇ .
  • a represents an oxygen radicals
  • a 3 is methylene group, carboxyalkyl group
  • an oxygen atom or - represents either represents a) -.
  • S_ ⁇ represents either represents a) -.
  • the group or ring representing R 1 , X, R 6 or R 8 may be substituted.
  • Or a salt thereof is preferred.
  • the salt of the compound of the present invention represented by the formula (I) is not particularly limited as long as it is a pharmacologically acceptable salt.
  • a salt with an inorganic base a salt with an organic base, a salt with an inorganic acid And salts with organic acids and salts with amino acids.
  • the salt with an inorganic base include sodium salts, potassium salts such as potassium salts, ammonium salts and the like.
  • the salt with an organic base include a triethylamine salt, a pyridine salt, an ethanolamine salt, a cyclohexylamine salt, and a dicyclohexylamine salt.
  • salts with inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates and the like.
  • salts with organic acids include formate, acetate, tartrate, maleate, succinate, methanesulfonate and the like.
  • salt with an amino acid include a glycine salt, an alanine salt, an arginine salt, a glutamine salt and an asbalaginate salt.
  • the compound of the present invention represented by the formula (I) can be produced by the following method in a row.
  • a halogen atom, a methylsulfonyl group, a compound of the formula (II-11) can be produced by a known method, and a compound of the formula (III-11), (III-2) and (III — 3) Compounds are available as commercially available reagents or easily derived therefrom by conventional chemical reactions.
  • the compound of the formula (1-1) can be produced by the reaction of the following steps 1 and 2.
  • the compound of the formula (II-11) can be produced by reacting the compound of the formula (II-11) with the compound of the formula (III-11).
  • the reaction is carried out in the presence of an organic base, and is carried out using 1 to 5 equivalents of the compound of the formula (III-11) based on 1 equivalent of the compound of the formula (II-11):
  • Preferred inorganic bases include sodium hydrogencarbonate, Examples include sodium carbonate, carbonated carbonate, sodium hydroxide, hydroxylated phosphate, sodium hydride, and the like.
  • Preferred organic bases are triethylamine, pyriamine, and the like.
  • the amount of the inorganic or organic base used varies depending on the amount of the compound of the formula (II-11), and is usually 1 to 7 equivalents to 1 equivalent of the compound of the formula (II-11).
  • the reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include ethynole acid, acetone, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide and the like.
  • the reaction can be performed in a mixed solvent thereof.
  • the reaction temperature is not particularly limited, and the reaction is usually carried out at 0 to 100 ° C, and the reaction time is usually 30 minutes to 24 hours.
  • Step 2 In this step, after reducing the nitro group of the compound of the formula (II-12) under ordinary conditions such as hydrogenation, the compound is reacted with the compound of the formula (III-12) or the compound of the formula (III-13) Thereby, the compound of the formula (I-11) can be produced.
  • the reaction is performed using 1 to 5 equivalents of the compound of the formula (III-12) or the compound of the formula (III-13) based on 1 equivalent of the compound of the formula ( ⁇ -2).
  • the reaction is generally carried out in the presence of a condensing agent.
  • condensing agents include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethinoleamino Propyl) carbodiimide, N, N'-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolinium chloride, benzotriazolyl-N-hydroxytrisdimethylaminophosphonium hexafluorophosphoride, diphenylphosphoryl azide And so on.
  • the amount of the condensing agent to be used varies depending on the amount of the compound of formula (III-2), and is usually 1 to 7 equivalents relative to 1 equivalent of the compound of formula (II-12). If necessary, an activator such as 1-hydroxybenzotriazole or N-hydroxysuccinimide can be used. The amount of the activator used is usually 1 to 7 equivalents per equivalent of the compound of the formula ( ⁇ -2).
  • the reaction is usually carried out in the presence of an inorganic or organic base.
  • Preferred inorganic bases are sodium hydrogencarbonate, sodium carbonate, carbonated lime, sodium hydroxide, and sodium hydroxide. And the like.
  • Preferred organic bases are triethylamine, pyridine and N-methylmorpho. Phosphorus, 1,8-diazabicyclo [5,4,0] pentaca 7-ene, potassium tert-butoxide, etc .:>
  • the amount of inorganic or organic base used depends on the amount of the compound of formula (III-13): Thus, it usually varies from 1 to 7 equivalents to 1 equivalent of the compound of the formula (II-II) II). .
  • the reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction. Examples include ethynole, acetate, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. It is also preferable to carry out the reaction in a mixed solvent thereof.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at 0 to 100 ° C., and the reaction time is usually 30 minutes to 72 hours.
  • Examples of the leaving group for W 3 and W 4 include a halogen atom, a methylsulfonyl group, and a thio group.
  • Examples of the amino protecting group for P include an acetyl group and tert-buto. And a benzyloxy group and a benzyloxycarbonyl group.
  • the compound of the formula ⁇ -2) can be produced by the reaction of the following steps 1 and 2.
  • Step 1 the compound of the formula (II-3) can be produced by the same reaction as in the step 1 of the production method 1 for the compound of the formula (II-II) and the compound of the formula (III-14).
  • Step 2 In this step, after removing the amino protecting group of the compound of the formula ( ⁇ —) under ordinary conditions, the compound of the formula ( ⁇ -2) or the compound of the formula (III-13) is prepared in the same manner as in step 2 of the production method 1. By a similar reaction, the compound of the formula (1-2) can be produced.
  • R 1 R 2 , R 3 , R 4 , X, ⁇ , ⁇ , and m have the same meanings as described above, and W 5 represents a leaving group.
  • the leaving group of W 5, a halogen atom can be obtained by induced readily methylsulfonyl group, tosyl group Nadogaa formula (III one 5) compounds or from it as commercial reagents by conventional chemical reactions
  • the compound of the formula (I-12) can be produced by reacting the compound of the formula ( ⁇ -1) and the compound of the formula ( ⁇ -5) in the same manner as in Step 1 of Production Method 1.
  • R 2 is a hydrogen atom— ⁇ , 0 Production method of compound of formula (I)
  • the compound of the formula (I-14) can be prepared by the method described in the literature (for example, TW Greene and PGM Wuts, Protective Liroupy in Organic synthesis, John Wiley & Sons, New York, 1991).
  • the compound of the present invention produced by the above-mentioned production method is isolated and purified as a free compound, a salt thereof, a solvate such as a hydrate or an ethanol solvate thereof, or a polymorphic substance.
  • a pharmacologically acceptable salt of the compound of the present invention can be produced by a usual salt formation reaction. Isolation and purification are performed by applying chemical operations such as extraction fractionation, crystallization, and various types of fractionation chromatography. Further, the optical isomer can be derived into an isomer (a book in a chemically unlimited manner) by selecting an appropriate starting compound or by a racemic compound racemic resolution method.
  • the azepine derivative of the present invention has an excellent VLII-4 antagonistic activity, and is used for treatment or prevention of a disease caused by leukocyte adhesion and infiltration or a disease in which a VLA-4 dependent adhesion process plays a role. It is useful as a medicine, for example, rheumatoid arthritis, nephritis, inflammatory bowel disease, systemic lupus erythematosus, inflammatory diseases of the central nervous system, asthma, allergies (such as late-onset tire allergy), multiple sclerosis, cardiac vascular diseases, arterial sclerosis, diabetes, various malignant tumors, injury prevention of transplanted organs, 3 such as tumor growth or metastasis inhibiting the like
  • the compound of the present invention can be administered systemically or locally, orally, intravenously, subcutaneously, or rectally. Oral administration is preferable, and the dosage form can be appropriately selected according to the administration route.
  • Oral administration is preferable, and the dosage form can be appropriately selected according to the administration route.
  • examples include tablets, troches, sublingual tablets, dragees, capsules, and pills. , Powders, granules, solutions, emulsions, syrups, inhalants, eye drops, nasal drops, injections, suppositories and the like.
  • these preparations can be prepared by incorporating a vehicle, a preservative, a wetting agent, an emulsifier, a stabilizer, a solubilizing agent, and the like:
  • the dose of the compound of the present invention may be appropriately determined depending on conditions such as the administration subject, administration route, and symptoms.For example, when orally administered to an adult patient, the compound of the present invention, which is the active ingredient, is usually administered in a single dose.
  • the dose may be in the range of about 0.1 to 10 Omg / kg, preferably 1 to 3 Omg / kg, and is preferably administered once to three times a day.
  • the proton nuclear magnetic resonance spectrum was measured with a J NM-EX 270 spectrometer (270 MHz, manufactured by JEOL Ltd.) using tetramethylsilane as the internal standard, and the ⁇ The values are shown in ppm.
  • the fast atom bombardment mass spectrum was measured with a JMS-HX110A type spectrometer (manufactured by JEOL).
  • Optical rotation was measured with a SEPA-300 type spectrometer (manufactured by Horiba).
  • Me represents a methyl group
  • Et represents an ethyl group.
  • the compound (54 mg, 0.90 mmo1) obtained in (2) was dissolved in a mixed solvent of methanol (2 m) and tetrahydrofuran (l ml), and 2N sodium hydroxide was added.
  • Example 8 to 154 The compounds shown in Examples 8 to 154 were produced in the same manner as in Example 1.
  • the physical properties of the obtained compound are shown in Tables 2 to 10 below.
  • the column of Z corresponds to Table 1 described above.
  • the title compound was obtained as a yellow powder (two kinds of isomers! 'The mixture) in the same manner as in Example 15-55.
  • Example 158 In the same manner as in Example 155, the compounds shown in Examples 158 to 193 were produced. The physical properties of the obtained compound are shown in Tables 11 and 12 below. The column of Z corresponds to Table 1 described above. N—R 31
  • Inhibitory activity of the compounds of the present invention on adhesion between Chinese hamster ovary cells (CHO cells) transfected with human VCAM-1 gene and human promyelocytic cell line HL-60 cells expressing VLA-4 was evaluated using the following method.
  • VCAM- 1 expression CH0 cells 9 6 well culture plates 1 and 7 X 1 0 3 or added pressure per hole until confluent state 1 0% ⁇ Shi calf serum (FCS) containing Ham 's F- After culturing for 3 days in 12 medium, HL-60 cells were resuspended in Hanks solution containing 0.4% serum albumin (BSA), and 5 / M of 2, -bis- (carbooxyethyl) -o, r -Add carboxy-fluorescein-Penta acetoxy methyl ester (BCECF-AM) to label.
  • FCS Shi calf serum
  • BSA serum albumin
  • BCECF-AM carboxy-fluorescein-Penta acetoxy methyl ester
  • the BCECF label the HL- 60 cell suspension 1 8 0 ⁇ 1 was resuspended in 4 X 1 0 6 cells / ml in FCS-free RPMI 1640 medium, the test substance solution at various concentrations 2 0, u 1 Dzu' added And pre-treat at 37 ° C for 15 minutes.
  • the pretreated HL-60 cells are layered on a 96-well plate in which VCAM-1 expressing CH0 cells have been cultured, 2 ⁇ 10 5 per well and adhered at 37 ° C. for 5 minutes.
  • the plate is then filled with 0.4% BSA Hank's solution, and the plate is turned upside down with a plate sealer, and the plate is incubated for another 15 minutes.
  • the cells are destroyed by adding PBS containing 1% NP-40, and the fluorescence intensity of the resulting supernatant is measured using a cytoFluor 2300 fluorescence measurement system (Millipore).
  • the fluorescence intensity of PBS containing 1% NP-40 was added. Fluorescent labels the HL- 60 suspension of 2 X 1 0 5, 1 0 5, 2 X 1 0 ⁇ 1 0 1 cells / ml and made as: the addition to the two 1% NP- 40 containing PBS, the cells disrupted line ' The fluorescence intensity of the obtained supernatant is measured. The test results are based on the calibration curve created from the standard measurement, and the number of cells adhering to VCAM-1 expressing CH0 cells by adding control and test substances. Is measured, and the cell adhesion inhibition rate (%) is calculated by the following equation.
  • the azepine derivative of the present invention has an excellent VLA-4 antagonist action, and plays a role in a disease mediated by cell adhesion, particularly a disease caused by leukocyte adhesion and infiltration, or a VL 4-4-dependent adhesion process. It is useful as a medicament for treating or preventing VL4-mediated diseases such as diseases.

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Abstract

Cette invention, qui a trait à des dérivés d'azépine correspondant à la formule générale (I) ou à leurs sels, concerne également des médicaments contenant ces dérivés ou ces sels en tant qu'ingrédients actifs. Dans cette formule, R1 représente un hydrogène, un alkyle, un aryle ou analogue, R2 représente un hydrogène ou un groupe de protection carboxyle, R3 représente un alcoylène, un groupe hydrocarbure divalent ou analogue, R4 représente un hydrogène, un alkyle ou analogue, X représente un groupe carbocyclique aromatique ou un groupe hétérocyclique, m représente un nombre entier dont la valeur est comprise entre 1 et 3, Y représente un azote, un oxygène ou analogue et Z représente un groupe correspondant à la formule générale (II): R?8 - R7 - R6 - A1¿ -.. Dans cette formule, A1 représente un méthylène, un sulfonyle ou analogue, R6 représente un alcoylène, un groupe divalent dérivé d'un arylalcane ou analogue, R7 représente un méthylène, un carbonyle ou analogue et R8 représente un alkyle, un arylalkyle ou analogue. Ces médicaments, qui font montre de remarquables qualités d'absorbabilité pérorale et de comportement in vivo, se révèlent être des antagonistes de VLA-4 (activation très tardive).
PCT/JP2001/000521 2000-01-28 2001-01-26 Dérivés d'azépine WO2001055121A1 (fr)

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WO2004067008A1 (fr) * 2003-01-28 2004-08-12 Takeda Pharmaceutical Company Limited Agonistes de recepteurs
WO2004091628A1 (fr) * 2003-04-18 2004-10-28 Takeda Pharmaceutical Company Limited Antagoniste de récepteur
JP2004331659A (ja) * 2003-04-18 2004-11-25 Takeda Chem Ind Ltd 受容体拮抗剤
JP2004346059A (ja) * 2003-01-28 2004-12-09 Takeda Chem Ind Ltd 受容体作動薬
JP2005509005A (ja) * 2001-11-13 2005-04-07 ３−ディメンショナル ファーマシューティカルズ， インコーポレイテッド 置換１，４−ベンゾジアゼピンおよび癌の処置のためのその使用
JPWO2010016552A1 (ja) * 2008-08-07 2012-01-26 武田薬品工業株式会社 過敏性腸症候群治療薬
US8629274B2 (en) 2011-12-21 2014-01-14 Novira Therapeutics, Inc. Hepatitis B antiviral agents
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WO2004067008A1 (fr) * 2003-01-28 2004-08-12 Takeda Pharmaceutical Company Limited Agonistes de recepteurs
JP2004346059A (ja) * 2003-01-28 2004-12-09 Takeda Chem Ind Ltd 受容体作動薬
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US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

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