WO2001055121A1 - Azepine derivatives - Google Patents

Azepine derivatives Download PDF

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Publication number
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
carbon atoms
ring
formula
atom
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PCT/JP2001/000521
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French (fr)
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/en

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    • 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
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    • 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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    • C07D243/14—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
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    • 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

Azepine derivatives of the general formula (I) or salts thereof, and drugs containing the derivatives or the salts as the active ingredient. In said Formula, R1 is hydrogen, alkyl, aryl, or the like; R2 is hydrogen or a carboxyl-protecting group; R3 is alkylene, a divalent aromatic hydrocarbon group, or the like; R4 is hydrogen, alkyl, or the like; X is an aromatic carbocycle or a heterocycle; m is an integer of 1 to 3; Y is nitrogen, oxygen, or the like; and Z is a group of the general formula (II): R?8 - R7 - R6 - A1¿ -, (wherein A1 is methylene, sulfonyl, or the like; R6 is alkylene, a divalent group derived from an arylalkane, or the like; R7 is methylene, carbonyl, or the like; and R8 is alkyl, arylalkyl, or the like). The drugs are excellent in peroral absorbability and in vivo fate and exhibit VLA-4 antagonism.

Description

明 細 書  Specification
ァゼピン誘導体  Azepine derivative
技術分野 Technical field
本発明は、新規なァゼピン誘導 ί本またはその塩並びにそれらを有効成分として含 有する医薬および V L Α— 4アンタゴニス トに関する。 背景技術  TECHNICAL FIELD The present invention relates to a novel azepine-derived ίpine or a salt thereof, a medicament containing them as an active ingredient, and a VLΑ-4 antagonist. Background art
細胞の接着現象は、 細胞の活性化、 移動、 増殖、 分化などの細胞間相互作用によ つてもたらされる複雑な生命現象に不可欠である。 そして、 このような細胞一細胞 または細胞一細胞外マ ト リ ックスの相互作用には、インテグリ ン、免疫グ口ブリ ン、 セレクチン、 力 ドヘリンなどに分類される細胞接着分子が関与している。 インテグ リ ンは、 ct 3—へテロダイマー構造を有し、 3種の主要グループ β 1、 2およ び β 3のサブフアミリーに分類される。  Cell adhesion is indispensable for complex life phenomena caused by cell-cell interactions such as cell activation, migration, proliferation, and differentiation. In addition, such 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, β1, 2, and β3 subfamilies.
β 1インテグリンは、 VLAタンパク質とも呼ばれ、 その一つであるインテグリ ン VLA— 4 (α 4 )3 1 ) は、 リンパ球、 好酸球、 好塩基球、 単球に発現し、 VC AM— 1とフイブロネクチンがリガンドである。 すなわち、 VLA— 4は、 VCA M— 1およびフイブロネクチンを介して細胞一細胞相互作用および細胞一細胞外 マトリックス相互作用において重要な役割を果たす /3 1インテグリ ンである。 白血球が炎症組織で機能するためには、血液中を循環している白血球が血管内皮 細胞をくぐり抜けて炎症部位へと浸潤しなければならなレ、。  β1 integrin is also called VLA protein, one of which is integrin VLA-4 (α4) 31), which is expressed on lymphocytes, eosinophils, basophils and monocytes, and 1 and fibronectin are ligands. Thus, VLA-4 is a / 31 integrin that plays an important role in cell-cell and cell-extracellular matrix interactions via VCAM-1 and fibronectin. In order for leukocytes to function in inflamed tissues, the leukocytes circulating in the blood must pass through vascular endothelial cells and infiltrate the site of inflammation.
VL A- 4と VC AM— 1の結合は、 白血球と血管内皮との強レ、接着に最も重要 な機構の一つである。 Tリ ンパ球、 Bリ ンパ球、 単球および好酸球などの炎症性細 胞は V L A— 4を発現し、 これらの細胞の炎症病巣への浸潤に V L A— 4 /V C A M— 1機構は強く関与している。 そして、 接着分子は、 細胞間相互作用を介する細 胞の活性化にも重要な役割を果たし、 V CAM— 1 ZVL A— 4機構が好酸球を活 性化させ脱顆粒を引き起こすこと、 また、 VLA— 4を介するシグナルは、 リンバ 球の抗原特異的な増殖活性化にも関与することが明らかにされている。 炎症などにおける VCAM— 1 /VL A— 4機構の役割を解明するために、モノ クローナル抗体によるこれら分子間の結合の阻害が試みられてきた。 例えば、 抗 V L A— 4モノクローナル抗 ί本は、 ヒ ト臍帯静脈血管内皮細胞 （HUVEC) および VC AM— 1遺伝子導入 C〇 S細胞への VLA— 4発現性 Ramos 細胞の接着を阻 害する。 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. Are involved. 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. In order to elucidate the role of the VCAM-1 / VLA-4 mechanism in inflammation and the like, attempts have been made to inhibit the binding between these molecules using a monoclonal antibody. For example, 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〇S cells.
そして、 いくつかの動物モデルで、 抗体により治療または予防両方で効果が示さ れた。 例えば、 ラッ トアジュバン ト関節炎モデル（Barbadillo et al. , Arthr. Rheuma.， 1993, 36, 95)、接触性過敏症、遅延型過敏症モデノレ（Ferguson and Kupper, J. Immunol. , 1993, 150， 1172； Chisholm et al, , Eur. J. Immunol. , 1993， 23, 682) で有意な効果が示された。 また、 実験的自己免疫脳脊髄炎（Yednock, Nature, 1992, 356, 63)、 喘息モデノレ（Abraham et al. , J. Clin. Invest. , 1993, 93， 776)、 炎症性腸疾患 ( I BD) モデル（Podolsky et al.， J. Clin. Invest. , 1993， 92， 372) でも抗体の作用が評価された。  In some animal models, the antibody has shown efficacy in both treatment and prevention. For example, rat adjuvant arthritis model (Barbadillo et al., Arthr. Rheuma., 1993, 36, 95), contact hypersensitivity, delayed type hypersensitivity modenole (Ferguson and Kupper, J. Immunol., 1993, 150, 1172). Chisholm et al,, Eur. J. Immunol., 1993, 23, 682) showed a significant effect. Experimental 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).
さらに、 VLA— 4による細胞接着が、 リウマチ性関節炎、 腎炎、 糖尿病、 全身 性エリテマトーデス、 遅発性タイプのアレルギー、 多発性硬化症、 動脈硬化、 臓器 移植および種々の悪性腫瘍におレ、て役割を果たすことが示された。  In addition, 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.
したがって、 適当なアンタゴニストによる VL A— 4遮断は、 炎症疾患をはじめ とする上記の種々疾患の治療に関して有効である。  Therefore, blockade of VLA-4 by a suitable antagonist is effective for treatment of the above-mentioned various diseases including inflammatory diseases.
一方、 VCAM— 1の細胞外ドメインは、 6つの免疫グロブリン様構造からなり、 ドメイン 4, 5および 6のアミノ酸配列は、 それぞれドメイン 1 , 2および 3のァ ミノ酸配列と相同性が高く、 V L A— 4との結合領域はドメイン 1および 4である ことが知られている（Osborn et al.， J. Exp. Med. , 1992, 176, 99)。 VCAM— 1のドメイン 1および 2の X線結晶構造解析から、 V L A— 4との結合部分が第 1 ドメインの CDループ部分 （Q 3 8 I D S P L) と推定されている（Jones et al.， Nature, 1995, 373, 539)。 また、 V C AM— 1の変異解析の報告から、 VLA— 4の認識部位は、 第 1 ドメィン及び第 4 ドメインの Q I D S P L配列であり、 特に 第 40番目のァスパラギン酸が重要であることが知られている（Staunton et al. , J. Cell. Biol. , 1994. 125， 215； Osborn et al. , J. Cell. Biol. , 1994, 125, 601):On the other hand, 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). In addition, reports of mutation analysis of VCAM-1 show that the recognition site of VLA-4 is the QIDSPL sequence of the 1st domain and 4th domain, and it is known that the 40th aspartic acid is particularly important. (Staunton et al., J. Cell. Biol., 1994. 125, 215; Osborn et al., J. Cell. Biol., 1994, 125, 601):
V LA— 4アンタゴニス トとしては、 フイブロネクチンの VLA— 4認識部位で ある C S— 1ぺプチドの L D V配列をもとにした環状べプチドやべブチド様化合 物 (W096/22966, W098/42656)が報告されてレ、る: 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:
また、 RGD配列をもとにした GPIIbZlIIa受容体アンタゴニストを転用し、 必須官能基などを置き換え VLA— 4アンタゴニストを創製している報告もある (W098/04247) D その中には、 ベンゾジァゼピンを有する G P II b ΖΠΙ a受容 ί本ァ ンタゴニス 卜のグァニジノ官能基を置き換えた化合物がある。 There is also a report that diverts GPIIbZlIIa receptor antagonist based on RGD sequence and replaces essential functional groups etc. to create VLA-4 antagonist (W098 / 04247) D Among them, GP with benzodiazepine II b ΖΠΙa receptor が あ る Some compounds have replaced the guanidino functional group of this antagonist.
しかしながら、 これらの化合物いずれにおいても、 経口投与におけるバイオアベ イラビリティ一の欠如、 生体内での容易な分解性などの問題点が残されている。 そ れ故に治療および予防での使用に好ましいプロファイルを有する V LA— 4アン タゴニス トが必要となる。  However, all of these compounds have problems such as lack of bioavailability in oral administration and easy degradability in vivo. Therefore, there is a need for a VLA-4 antagonist with a favorable profile for therapeutic and prophylactic use.
本発明は、 このような VL Α— 4を介する疾患の治療および予防を鑑みて成され たものであり、 本発明の目的は、 経口吸収性および生体内での動態に優れた VL A —4アンタゴニスト作用を有する新規化合物またはその塩を提供すること、 さらに これらを有効成分とする医薬を提供することにある。 発明の開示  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
本発明者らはこれらの目的を達成するために、 VCAM— 1の X線結晶構造をも とに、 その C Dループ部分から活性発現に重要な側鎖の相対的位置関係を把握後、 それをファーマコファーとして翻訳し、 化合物データべ一ス検索を行った。 その結 果をもとに鋭意研究を行い、ァゼピン誘導体が優れた V L A— 4アンタゴニス ト作 用を有することを見出して本発明を完成した。  To achieve these objectives, 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.
すなわち、 本発明は、 式 （ I )
Figure imgf000006_0001
That is, the present invention provides a compound represented by the formula (I):
Figure imgf000006_0001
(式中、 R 1は水素原子、 炭素数 1〜 6のアルキル基、 炭素数 2〜 6のアルケニル 基、 炭素数 3〜 7のシクロアルキル基、 炭素数 7〜 1 1のァリールアルキル基、 炭 素数 6〜 1 0のァリール基またはへテロ環基を表し、 R2は水素原子またはカルボ キシル保護基を表し、 R3は炭素数 1〜 6のアルキレン基、 炭素数 2〜 6のァルケ 二レン基、 炭素数 3〜 7のシクロアルキレン基、 2価の炭素数 6〜 1 0のァリール 基または 2価のへテロ環基を表し、 R4は水素原子または炭素数 1〜 6のアルキル 基を表し、また、 R4は R3と結合し環を形成していてもよく、環はさらに酸素原子、 窒素原子、 硫黄原子を構成成分として含んでいてもよく、 環内に二重結合を含んで いてもよく、 置換されていてもよい。 Xはァリール環またはへテロ環を表し、 mは ;L〜 3の整数を表し、 γは窒素原子、 酸素原子、 硫黄原子、 一 N ( R 5) 一 （式中、 R5は独立して R4と同じ意味を表し、 また、 R5は R 1と結合し環を形成していても よレ、。） または一 S ( O) n— (式中、 nは 1〜2の整数を表す。） を表し、 Yが窒 素原子の時には式中の破線は二重結合を表す。 Zは式 (In the formula, 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. And 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. . it may also comprise, optionally substituted 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
R 8 — R 7 — R 6 — A 1 — R 8 — R 7 — R 6 — A 1 —
(式中、 A1は、 メチレン基、 スノレホニノレ基、 カルボニル基またはチォカルボニル 基を表し、 R6は炭素数 1〜6のアルキレン基、 炭素数 2〜 6のァルケ二レン基、 炭素数 3〜 7のシクロアルキレン基、 2価の炭素数 7〜 1 1のァリールアルキル基、 2価の炭素数 8〜1 2のァリールアルケニル基、 2価の炭素数 6〜 1 0のァリ ール 基または 2価のへテロ環基を表し、 は炭素数 1〜6のアルキル基、 炭素数 2〜 6のアルケニル基、 炭素数 3〜 7のシク口アルキル基、 炭素数 7〜 1 1のァリ ール アルキル基、 炭素数 8 〜 1 2のァリールアルケニル基、 炭素数 6 〜 1 0のァリール 基またはへテロ環基を表し、 また、 R8は R6と結合し環を形成していてもよレ、。 (In the formula, A 1 represents a methylene group, a snolephoninole group, a carbonyl group or a thiocarbonyl group, and 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. 7 cycloalkylene group, divalent carbon number 7 to 11 arylalkyl group, divalent carbon number 8 to 12 arylylalkenyl group, divalent carbon number 6 to 10 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 ,.
R7は式 R 7 is the formula
A A
Ry R y
A  A
N人 N N'  N N '
、A \  , A \
1 0  Ten
R R  R R
Figure imgf000007_0001
Figure imgf000007_0001
(式中、 R9および R1()はそれぞれ独立して水素原子、炭素数 1 〜 6のアルキル基ま たは水酸基を表し、 R9は R6または R8と結合し環を形成していてもよい。 は酸 素原子または硫黄原子を表し、 A3はメチレン基、 カルボニル基、 チォカルボニル 基、 酸素原子または— S ( 0 ) P- (式中、 pは 0 〜 2の整数を表す J を表す。） のいずれかを表す 3 ) を表す。） で表されるァゼピン誘導体またはその塩に関する。 また、 本発明は式 （ I ) で表されるァゼピン誘導体またはその塩を有効成分として 含有する医薬および V L A— 4アンタゴニストに関する。 発明の詳細な説明 (In 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. Represents an oxygen atom or a sulfur atom, and 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 ). ) Or a salt thereof. In addition, 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. Detailed description of the invention
前記式 （ I ) における置換基について説明する。  The substituent in the formula (I) will be described.
「炭素数 1 〜 6のアルキル基」 の具体例としては、 メチル基、 ニチル基、 n—プ 口ピル基、 イソプロピル基、 n—ブチル基、 イソブチル基、 t e r t—ブチル基、 s e c _ブチル基、 n—ペンチル基、 t e r tーァミル基、 3—メチルブチル基、 ネオペンチル基、 n —へキシル基などの直鎖または分枝鎖状のアルキル基があげら れる。 またこれらは置換されていてもよい。 「炭素数 2〜 6のアルケニル基」 の具体例としては、 ビニル基、 プロぺニ'レ基、 ィソプロぺニル基などの直鎖または分枝鎖状のアルケニル基があげられる。 また二 れらは置換されていてもよい。 Specific examples of the “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. Specific examples of the "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.
「炭素数 3〜 7のシクロアルキル基」 の具体例としては、 シクロプロピル基、 シ クロブチル基、 シク口ペンチル基、 シク口へキシル基、 シク口へプチル基など あ げられる。 またこれらは置換されていてもよい。  Specific examples of the “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.
「炭素数 7〜1 1のァリールアルキル基」 の具体例としては、 ベンジル基、 フニ ネチル基、 フエニルプロピル基などがあげられる。 またこれらは置換されていても よい。  Specific examples of the "arylalkyl group having 7 to 11 carbon atoms" include a benzyl group, a phenylethyl group and a phenylpropyl group. These may be substituted.
「炭素数 8〜 1 2のァリールアルケニル基」 の具体例としては、 スチリル基、 シ ンナミル基などがあげられる。 またこれらは置換されていてもよレ、。  Specific examples of the "aryl alkenyl group having 8 to 12 carbon atoms" include a styryl group and a cinnamyl group. These may be substituted.
「炭素数 6〜1 0のァリール基」 の具体例としては、 フエ二ル基、 1一ナフチル 基、 2—ナフチル基などがあげられる。 またこれらは置換されていてもよレ、： 「ァ リール環」 についても同様のものがあげられる。  Specific examples of the "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”.
「ヘテロ環基」 とは、 環中に窒素原子、 酸素原子または硫黄原子から選択される 1ないし 3個の複素原子を含む 5〜 7員の単環性複素環を表し、 具体例としては、 フリル基、 チェニル基、 イミダゾリル基、 チアゾリル基、 ォキサゾリル基、 ピリジ ル基、 ビラジニル基、 ピロリジニル基、 ピペリジニル基、 ピペラジニル基、 モピ ペラジニル基、 モルホリニル基、 ジォキサニル基などがあげられる。 または前記単 環性複素環とベンゼン環もしくは前記単環性複素環が縮合した 2または 3環性縮 合複素環を表し、 具体例としては、 ベンゾフラニル基、 ベンゾチェ二ル基、 インド リル基、 ベンズイミダゾリル基、 キノリル基、 テトラヒ ドロキノリル基、 クロマ二 ル基、 ピぺロニル基、 ピリ ド [ 4， 3 - d ] ピリ ミジニル基、 イソキサゾ口 [ 4， 5 _ c ]ピリジニル基などがあげられる。またこれらは置換されていてもよい： 「へ テロ環」 についても同様のものがあげられる。  "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. Or 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”.
「炭素数 1〜6のアルキレン基」 の具体例としては、 メチレン基、 エチレン基、 プロピレン基、プチレン基などの直鎖または分枝鎖状のアルキレン基があげられる。 またこれらは置換されていてもよレ、： Specific examples of the “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:
「炭素数 2 6のァルケ二レン基」 の具体例としては、 ビニレン基、 ブロぺニレ ン基などの直鎖または分枝鎖状のァルケ二'ノ ン基があげられる。 またこれらは置換 されていてもよレ、。  Specific examples of the “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.
「炭素数 3 7のシクロアルキレン基」 の具体 ί列としては、 1 , 1ーシクロア口 ピレン基、 1 2—シクロプロピレン基、 1 , 3 —シクロへキシレン基などがあげ られる。 またこれらは置換されていてもよい。  Specific examples of the “cycloalkylene group having 37 carbon atoms” include a 1,1-cyclopropylene group, a 12-cyclopropylene group, and a 1,3-cyclohexylene group. These may be substituted.
「置換されていてもよい」 場合の置換基の具体例としては、 炭素数 1 6のアル キル基、 炭素数 3 7のシクロアルキル基、 炭素数 6 1 0のァリ一ル基、 ヘテロ 環基、 ハロゲン原子、 水酸基、 炭素数 1 6のアルコキシ基、 炭素数 1 5の脂肪 族ァシル基、 炭素数 7 1 1の芳香族ァシル基、 炭素数 1 4の脂肪族スルホニル 基、 炭素数 2 7のアルコキシカルボニル基、 炭素数 2 5のアルキルアミ ド基、 炭素数 1 4のアルキルチオ基、 炭素数 1 4の脂肪族スルフィニル基、 炭素数 1 4の脂肪族スルホニル基、 炭素数 6 1 0の芳香族スルホニル基、 炭素数 1 4 の脂肪族スルファモイル基、 シァノ基、 ニ ロ基、 アミノ基、 置換アミノ基、 カル ボキシル基などがあげられる。  Specific examples of the substituent 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 An alkoxycarbonyl group having 25 carbon atoms, an alkylamide group having 25 carbon atoms, an alkylthio group having 14 carbon atoms, an aliphatic sulfinyl group having 14 carbon atoms, an aliphatic sulfonyl group having 14 carbon atoms, and an aromatic group having 6 10 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.
「ハロゲン原子」 の具体例としては、 フッ素原子、 塩素原子、 臭素原子またはョ ゥ素原子などがあげられる。  Specific examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
「炭素数 1 6のアルコキシ基」 の具体 ί列としては、 メ トキシ基、 エ トキシ基、 η—プロボキシ基、 イソプロポキシ基、 η—ブトキシ基、 イソブトキシ基、 t e r t 一ブトキシ基、 s e c —ブトキシ基、 n—ペンチルォキシ基、 t e r t —アミノレ ォキシ基、 3—メチルブトキシ基、 ネオペンチルォキシ基、 n キシルォキシ基 などの直鎖または分枝鎖状のアルコキシ基があげられる。  Specific examples of the “alkoxy group having 16 carbon atoms” include methoxy group, ethoxy group, η-propoxy group, isopropoxy group, η-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.
「炭素数 1 5の脂肪族ァシル基」の具体例としては、ホルミル基、ァセチル基、 プロピオニル基、 ブチリル基、 イソブチリル基、 ノくレリル基、 イソバレリル基、 ピ バロィル基などの直鎖または分枝鎖状の脂肪族ァシル基があげられる:  Specific examples of the `` 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:
「炭素数 7 1 1の芳香族ァシル基」 の具 (本例としてはべンゾィル基、 トルオイ ル基などがあげられる。 Tool for "aromatic acyl group having 7 11 carbon atoms" (for example, benzoyl group, toluoi And the like.
「炭素数 2〜 7のアルコキシカルボニル基」 の具 ί本例としては、 メ トキシカルボ ニル基、 エトキシカルボニル基、 η—プロポキシカルボニル基、 イソプロボキシカ ルボニル基、 η—ブトキシカルボニル基、 イソブトキシカルボニル基、 t e r t— ブトキシカルボ二ノレ基、 s e cーブトキシカルボニル基、 ベンジルォキシカルボ二 ル基などの直鎖または分枝鎖状のアルコキシカルボニル基があげられる：  Examples of “alkoxycarbonyl group having 2 to 7 carbon atoms” と し て Examples include methoxycarbonyl, ethoxycarbonyl, η-propoxycarbonyl, isopropoxycarbonyl, η-butoxycarbonyl, isobutoxycarbonyl, tert — Straight or branched alkoxycarbonyl groups such as butoxycarbonyl, sec-butoxycarbonyl, benzyloxycarbonyl, etc .:
「炭素数 2〜 5のアルキルアミ ド基」 の具体例としては、 メチルアミ ド基、 ェチ ルァミ ド基、 n—プロピルァミ ド基、イソプロピルァミ ド基、 n—ブチルァミ ド基、 ィソブチルアミ ド基、 t e r t —ブチルアミ ド基、 s e c一ブチルアミ ド基、 n— ペンチルアミ ド基、 t e r tーァミルアミ ド基などの直鎖または分技鎖状のアルキ ノレアミ ド基があげられる。  Specific examples of the “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.
「炭素数 1〜4のアルキルチオ基」 の具体例としては、 メチルチオ基、 ェチルチ ォ基、 n—プロピルチオ基、 イソプロピルチオ基、 n—ブチルチオ基、 イソブチル チォ基、 t e r t一プチルチオ基、 s e c一プチルチオ基などの直鎖または分枝鎖 状のアルキルチオ基があげられる。  Specific examples of the "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.
「炭素数 1〜 4の脂肪族スルフィニル基」 の具 (本例としてはメチルスルフィニル 基、ェチルスルフィ二ノレ基、プロピノレスノレフィニル基、 1ーブチルスノレフィニル基、 2一ブチルスルフィニル基などの直鎖または分枝鎖状の脂肪族スルフィニル基が  (Caliphatic sulfinyl group having 1 to 4 carbon atoms) (Examples include methylsulfinyl group, ethylsulfininole group, propinolesnorefinyl group, 1-butylsnorefinyl group, and 2-butylsulfinyl group. Is a linear or branched aliphatic sulfinyl group
「炭素数 1〜 4の脂肪族スルホニル基」の具体例としては、メチルスルホニル基、 ェチルスルホニル基、 ブロピルスルホニル基、 1ーブチルスルホニル基、 2—ブチ ルスルホニル基などの直鎖または分枝鎖状の脂肪族スルホ二ル基があげられる。 Specific examples of the "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.
「炭素数 6〜 1 0の芳香族スルホニル基」 の具体例としてはフエニルスルホニル 基、 トリルスルホニル基などがあげられる。  Specific examples of the "aromatic sulfonyl group having 6 to 10 carbon atoms" include a phenylsulfonyl group and a tolylsulfonyl group.
「炭素数 1〜4の脂肪族スルファモイル基」 の具体例としては、 メチルスルファ モイノレ基、 ェチルスノレファモイノレ基、 n—フ。ロピルスルファモィル基、 イソフ。ロピ  Specific examples of the “aliphatic sulfamoyl group having 1 to 4 carbon atoms” include a methylsulfamoyl group, an ethylsulfamoyl group, and n-phenyl. Ropylsulfamoyl group, Isof. Ropi
'基、 n—ブチルスルファモイル基、ィソブチルスルファ二 t e r tーブ、チノレスノレファモイル基、 s e c —ブチルスルファモイル基などの直鎖 または分枝鎖状の脂肪族スルファモイル基があげられる。 'Group, 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.
「置換ァミノ基」 の置換基の具体例としては、 水酸基、 炭素数 1〜 6のアルキル 基、 炭素数 1〜6のアルコキシ基、 炭素数 1〜5の脂肪族ァシル基、 芳香族ァシル 基、炭素数丄〜 4の脂肪族スルホニル基、炭素数 2〜 7のアルコキシカルポニル基、 炭素数 2〜 5のアルキルアミ ド基、 炭素数 1〜4の脂肪族スルホニル基、 芳香族ス ルホニル基、 炭素数 1〜 4の脂肪族スルファモイル基などがあげられる。  Specific examples of the 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.
「R 3 と が結合し環を形成」 する場合の環の具体例としては、 ァゼチジン環、 ピロリン環、 ピロリジン環、 ピペリジン環、 テトラヒ ドロピリジン環、 モルホリン 環、 チオモルホリン環、 ピべラジン環などがあげられる。 またこれらは置換されて いてもよレ、。 Specific examples of the 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.
「R5と R 1が結合し環を形成」 する場合の環の具体例としては、 ピロール環、 ィ ミダゾ一ル環、 トリァゾ一ル環などがあげられる。 またこれらは置換されていても よい。 Specific examples of the ring in the case of "R 5 and R 1 is attached form a ring", a pyrrole ring, I Midazo Ichiru ring, such Toriazo Ichiru ring. These may be substituted.
「RSと R6が結合し環を形成」 する場合の環の具体例としては、 フルオレン環な どがあげられる。 またこれらは置換されていてもよレ、。 Specific examples of the ring in the case where “ RS and R 6 combine to form a ring” include a fluorene ring. These may be substituted.
「R 9 と R6が結合し環を形成」 する場合の環の具体例としては、 ピロリジン環、 ピペリジン環などがあげられる。 またこれらは置換されていてもよレ、： Specific examples of the ring in the case where “R 9 and R 6 combine to form a ring” include a pyrrolidine ring and a piperidine ring. They may also be substituted:
「R9と R8が結合し環を形成」 する場合の環の具体例としては、 ピロリジン環、 ピペリジン環、 テトラヒ ドロキノリン環、 テトラヒ ドロイソキノリン環などがあげ られる。 またこれらは置換されていてもよい。 Specific examples of the 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.
「カルボキシル保護基」 とは、 比較的容易に開裂して対応する遊離のカルボキシ ル基を生じるカルボン酸エステルのアルコール部残基を表し、その具体咧としては、 メチル基、 ェチル基、 n—プロピル基、 t e r t —ブチル基などの炭素数 1〜 6の アルキル基、 ァリル基などの炭素数 2〜 6の低級アルケニル基、 ベンジル基、 p 一 メ トキシベンジル基などのァリ—ルアルキル基またはフエニル基などの加水分解、 接触還元あるいは遷移金属触媒による開裂などの温和な条件で処理十ることによ り脱離する基があげられる。 The term “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.
本発明における好ましい Zの例を表 1に示す。 なお、 表において、 M e メ 'レ 基を表す。 表 1  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
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000012_0001
Figure imgf000013_0001
N  N
x N 03 T3 x N 03 T3
^ ^
Figure imgf000014_0001
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0002
OM OMee OM OMee
\〇Λ ϊ/ιο \ 〇Λ ϊ / ιο
N N
CO CO CO CO CO CO
ω O CO CO  ω O CO CO
X 寸  X dimension
N  N
Ν Ν
CO COCO CO
CO, CO CO CO CO, CO CO CO
匚 〇 Q_ cr CO 匚 〇 Q_ cr CO
また、 式 （ I ) で表される本発明化合物の好ましい範囲は以下のとおりである- 式 （ I ) において、 R1は水素原子、 炭素数 1〜 6のアルキル基、 炭素数 3〜 7 のシクロアルキル基、 炭素数 6〜 1 0のァリール基またはへテロ環基を表し、 は水素原子を表し、 R3は炭素数 1〜 6のアルキレン基、 炭素数 2〜 6のァルケ二 レン基、 炭素数 3〜 7のシクロアルキレン基、 2価の炭素数 6〜 1 0のァリール基 または 2価のへテロ環基を表し、 R"1は水素原子または炭素数 1〜6のアルキル基 を表し、 また、 R4は R3と結合し環を形成していてもよく、 環はさらに酸素原子を 構成成分として含んでいてもよく、 環内に二重結合を含んでいてもよく、 置換され ていてもよレ、。 Xはァリール環またはへテロ環を表し、 mは 1または 2を表し、 Y は窒素原子、 酸素原子、 硫黄原子、 — N (R5) ― (式中、 R5は独立して と同じ 意味を表し、 また、 R5は R 1 と結合し環を形成していてもよレ、。） を表し、 Yが窒 素原子の時には式中の破線は二重結合を表す。 Zは式 The preferred range of the compound of the present invention represented by the formula (I) is as follows: In the formula (I), 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, Represents a cycloalkylene group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms or a divalent heterocyclic group, and 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.) When Y is a nitrogen atom, the broken line in the formula represents a double bond.
R 8 — R 7 — R 6 _ A 1 — R 8 — R 7 — R 6 _ A 1 —
(式中、 A ま、 スルホニル基またはカルボ二ル基を表し、 R6は炭素数 1〜6のァ ノレキレン基、 炭素数 2〜 6のァルケ二レン基、 2価の炭素数 7〜 1 1のァリールァ ルキル基、 2価の炭素数 8〜 1 2のァリールアルケニル基、 2価の炭素数 6〜 1 0 のァリール基または 2価のへテロ環基を表し、 R8は炭素数 1〜6のアルキル基、 炭素数 7〜 1 1のァリ—ルアルキル基、 炭素数 8〜 1 2のァリ—ルアルケニル基、 炭素数 6〜 1 0のァリール基またはへテロ環基を表し、 また、 R8は R6と結合し環 を形成していてもよい。 R7は式 (In the formula, A represents a sulfonyl group or a carbonyl group, and 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 Represents an arylalkyl group having 8 to 12 carbon atoms, an arylalkyl group having 8 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms or a divalent heterocyclic group, and R 8 has 1 to 1 carbon atoms. 6, an alkyl group having 6 to 11 carbon atoms, an arylalkyl group having 7 to 11 carbon atoms, 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 combine with R 6 to form a ring R 7 is a group represented by the formula
A A
R9 R 9
A A
N人 N'  N people N '
10 ヽ 3  10 ヽ 3
R R、 R  R R, R
\ (式中、 Ryおよび R 1Qはそれぞれ独立して水素原子、炭素数 1〜6のアルキル基ま たは水酸基を表し、 Ryは R6または R::と結合し澴を形成していてもよレ、。 A」は酸 素原子を表し、 A 3はメチレン基、カルボ二ル基、酸素原子または— S〇.」—を表す。） のいずれかを表す。） を表す。 また、 R 1 , X， R 6または R 8を表す基または環は 置換されていてもよい。） で表されるァゼピン誘導 ί本またはその塩が好ましいつ 式 （ I ) で表される本発明化合物において、 不斉炭素が存在する場合には、 その ラセミ体、 ジァステレオ異性体および個々の光学活性体のいずれも本発明に含まれ るものであり、 また幾何異性体が存在する場合には （Ε ) 体、 ( Ζ ) ί本およびその 混合物のいずれも本発明に含まれるものである： \ (Wherein, 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 澴. Moyore, a "represents an oxygen radicals, a 3 is methylene group, carboxyalkyl group, an oxygen atom or - represents either represents a) -. S_〇".. ). Further, the group or ring representing R 1 , X, R 6 or R 8 may be substituted. ) Or a salt thereof is preferred. In the compound of the present invention represented by the formula (I), when an asymmetric carbon is present, its racemic form, diastereoisomer and individual optical activity Any of the isomers are included in the present invention, and when a geometric isomer is present, the (Ε) isomer, (Ζ) ί and any mixture thereof are also included in the present invention:
式 （ I ) で表される本発明化合物の塩として 、 薬理学的に許容される塩であれ ば特に制限されず、 例えば、 無機塩基との塩、 有機塩基との塩、 無機酸との塩、 有 機酸との塩およびアミノ酸との塩などがあげられる。無機塩基との塩の例としては、 ナトリゥム塩、力リゥム塩などのアル力リ金属塩およびアンモニゥム塩などがあげ られる。 有機塩基との塩の例としては、 トリェチルァミン塩、 ピリジン塩、 ェタノ ーノレアミン塩、 シクロへキシルァミン塩、 ジシクロへキシルァミン塩などがあげら れる。 無機酸との塩の例としては、 塩酸塩、 臭化水素酸塩、 硫酸塩、 硝酸塩などが あげられる。 有機酸との塩の例としては、 ギ酸塩、 酢酸塩、 酒石酸塩、 マレイン酸 塩、 コハク酸塩、 メタンスルホン酸塩などがあげられる。 また、 アミノ酸との塩の 例としては、 グリシン塩、 ァラニン塩、 アルギニン塩、 グルタミン塩、 ァスバラギ ン酸塩などがあげられる。  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. For example, 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. Examples of the salt with an inorganic base include sodium salts, potassium salts such as potassium salts, ammonium salts and the like. Examples of the salt with an organic base include a triethylamine salt, a pyridine salt, an ethanolamine salt, a cyclohexylamine salt, and a dicyclohexylamine salt. Examples of salts with inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates and the like. Examples of salts with organic acids include formate, acetate, tartrate, maleate, succinate, methanesulfonate and the like. Examples of the salt with an amino acid include a glycine salt, an alanine salt, an arginine salt, a glutamine salt and an asbalaginate salt.
式 （ I ) で表される本発明化合物は、 ί列えば以下に示す方法により製造すること ができる。  The compound of the present invention represented by the formula (I) can be produced by the following method in a row.
[製造法 1 ] R4が水素である式 （ 1〕 化合物の製造法 (I I I - 1 ) [Production method 1] Production method of compound of formula (1) wherein R 4 is hydrogen (III-1)
Figure imgf000018_0001
Figure imgf000018_0001
Z - OH ( I I I 2) Z-OH (I I I 2)
還兀 Return
Figure imgf000018_0002
Figure imgf000018_0002
(式中、 R R2、 R3、 X、 Y、 Zおよび mは前記と同じ意味を表し、 W1および W2は脱離基を表す。） (Wherein, RR 2 , R 3 , X, Y, Z and m represent the same meaning as described above, and W 1 and W 2 represent a leaving group.)
W1および W2の脱離基としては、 ハロゲン原子、 メチルスルホニル基、 式（II一 1)化合物は公知の方法により製造でき、 また式（III一 1 )、 (III- 2) および （ΠΙ— 3) 化合物は市販の試薬としてまたはそれから通常の化学反応によ り容易に誘導することにより入手できる。 As the leaving group for W 1 and W 2 , 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.
式 （ 1— 1) 化合物は、 以下の工程 1および 2の反応により製造することができ る。  The compound of the formula (1-1) can be produced by the reaction of the following steps 1 and 2.
(工程 1) 本工程では、 式 （II一 1 化合物と式 （III一 1 ) 化合物を反応するこ とにより式 （II一 2) 化合物を製造することができる。 この反応は通常、 無機また は有機塩基の存在下で行われ、 式 （II一 1) 化合物 1当量に対して式 （III一 1) 化合物を 1〜5当量用いて行われる： 好ましい無機塩基としては、 炭酸水素ナトリ ゥム、 炭酸ナトリゥム、 炭酸力リゥム、 水酸化ナトリゥム、 水酸化力リゥム、 水素 化ナトリウムなどがあげられ、 好ましい有機塩基としてはトリエチルァミン、 ピリ ジン、 N—メチルモルホリン、 1 , 8—ジァザビシクロ [ 5 , 4 , 0 ] ゥンデ力一 7—ェン、 カリウム t e r t —ブトキシドなどがあげられる。 用いる無機または有 機塩基の量は、 式 （II I一 1 ) 化合物の量によって変動し、 通常、 式 （II一 1 ) 化 合物 1当量に対し 1〜 7当量である。 (Step 1) In this step, 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. Gin, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] indene-7-ene, potassium tert-butoxide 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).
反応溶媒としては、 反応を著しく阻害しないものであれば特に限定されないが、 酉乍酸ェチノレ、 アセトン、 ジクロロメタン、 ジクロロェタン、 テトラヒ ドロフラン、 ァセトニトリル、 N , N—ジメチルホルムアミ ド、 ジメチルスルホキシドなどが子 ましく、またこれらの混合溶媒中で行うこともできる。反応温度は特に限定されず、 通常、 0〜 1 0 0 °Cで行われ、 反応時間は通常、 3 0分〜 2 4時間である。  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. Alternatively, 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.
(工程 2 ) 本工程では、 式 （II一 2 ) 化合物のニトロ基を水素添加などの通常の条 件で還元した後、 式 （III一 2 ) 化合物または式 （III一 3 ) 化合物と反応すること により式（ I 一 1 )化合物を製造できる。式（Π— 2 )化合物 1当量に対して式（III 一 2 ) 化合物または式 （II I一 3 ) 化合物を 1〜5当量用いて行われる。  (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 (Π-2).
式 （III一 2 ) 化合物を用いる場合は、 通常、 縮合剤の存在下で行われ、 好まし い縮合剤としては、 ジシクロへキシルカルボジイミ ド、 1ーェチルー 3— （3—ジ メチノレアミノプロピル） カルボジイ ミ ド、 N， N ' 一カルボニルジイミダゾール、 塩化 2—クロロー 1， 3—ジメチルイ ミダゾリニゥム、 ベンゾトリアゾリル一 N— ヒ ドロキシトリスジメチルアミノホスホニゥムへキサフルォロリン化物塩、 ジフエ ニルホスホリルアジドなどがあげられる。 用いる縮合剤の量は、 式 （III— 2 ) ィ匕 合物の量によって変動し、 通常、 式 （II一 2 ) 化合物 1当量に対し 1〜 7当量であ る。 また、 必要に応じて 1ーヒ ドロキシベンゾトリァゾ一ルまたは N—ヒ ドロキシ スクシンィミ ドなどの活性化剤を用 、ることもできる。 用いる活性化剤の量は、 通 常、 式 （Π— 2 ) 化合物 1当量に対し 1〜 7当量である。  When the compound of the formula (III-12) is used, the reaction is generally carried out in the presence of a condensing agent. Preferred 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 (Π-2).
また、 式 （III一 3 ) 化合物を用いる場合は、 通常、 無機または有機塩基の存在 下で行われ、 好ましい無機塩基としては、 炭酸水素ナトリウム、 炭酸ナトリウム、 炭酸力リゥム、 水酸化ナトリゥム、 水酸化力リゥム、 水素化ナトリゥムなどがあげ られ、 好ましい有機塩基としてはトリエチルァミン、 ピリジン、 N—メチルモルホ リン、 1， 8—ジァザビシクロ [5, 4 , 0] ゥンデカー 7—ェン、 カリ ウム t e r t一ブトキシドなどがあげられる： > 用いる無機または有機塩基の量は、 式 （III 一 3) 化合物の量:こよって変動し、 通常式 （II一 2) 化合物 1当量に対し 1〜 7当 量で ¾)。。 When the compound of the formula (III-13) is used, 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). .
反応溶媒としては、 反応を著しく阻害しないものであれば特に限定されないが、 酌酸ェチノレ、 アセ トン、 ジクロロメタン、 ジクロロェタン、 テトラヒ ドロフラン、 ァセ トニ トリル、 N， N—ジメチルホルムアミ ド、 ジメチルスルホキシドなどが好 ましく、またこれらの混合溶媒中で行うこともできる。反応温度は特に限定されず、 通常 0〜 1 00°Cで行われ、 反応時間は通常 30分〜 7 2時間である。  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.
[製造法 2 ]  [Production method 2]
Figure imgf000020_0001
Figure imgf000020_0001
Z - OH ( I 1 1 -2) Z-OH (I 1 1 -2)
脱保護  Deprotection
Figure imgf000020_0002
Figure imgf000020_0002
(式中、 R R2、 R3、 R\ X、 Y、 Zおよび mは前記と同じ意味を表し、 W3お よ W4は脱離基を表し、 Pはァミノ保護基を表す 3 ) (Wherein, RR 2 , R 3 , R \ X, Y, Z and m represent the same meaning as described above, W 3 and W 4 represent a leaving group, and P represents an amino protecting group 3 )
W3および W4の脱離基としては、 ハロゲン原子、 メチルスルホニル基、 ト などがあげられる， Pのァミノ保護基としては、 ァセチル基、 t e r t—ブト 力ルボニル基、 ベンジルォキシカルボ二ル基などがあげられる。 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.
式 （III一 4) 化合物は市販の試薬としてまたはそれから通常の化学反応により 容易に誘導することにより入手できる：  Compounds of formula (III-14) are available as commercially available reagents or readily derived therefrom by conventional chemical reactions:
式 Π— 2 ) 化合物は、 以下の工程 1および 2の反応により製造することができ る。  The compound of the formula Π-2) can be produced by the reaction of the following steps 1 and 2.
(工程 1) 本工程では、 式 （IIー丄 化合物と式 （III一 4) 化合物を製造法 1の 工程 1 と同様の反応によって、 式 （II— 3) 化合物を製造することができる。  (Step 1) In this step, 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).
(工程 2) 本工程では、 式 （Π— 化合物のァミノ保護基を通常の条件で除去し た後、 式 （ΙΠ— 2) 化合物または式 （III一 3) 化合物を製造法 1の工程 2と同様 の反応によって、 式 （ 1—2) 化合物を製造することができる。  (Step 2) In this step, after removing the amino protecting group of the compound of the formula (Π—) under ordinary conditions, the compound of the formula (ΙΠ-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.
[製造法 3 ]  [Production method 3]
( I I 1—5) (I I 1—5)
W5 W 5
I  I
Figure imgf000021_0001
Figure imgf000021_0001
(式中、 R1 R2、 R3、 R4、 X、 Υ、 Ζおよび mは前記と同じ意味を表し、 W5は 脱離基を表す。） (Wherein, R 1 R 2 , R 3 , R 4 , X, Υ, Ζ, and m have the same meanings as described above, and W 5 represents a leaving group.)
W5の脱離基としては、 ハロゲン原子、 メチルスルホニル基、 トシル基などがあ 式 （III一 5) 化合物は市販の試薬としてまたはそれから通常の化学反応により 容易に誘導することにより入手できる 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
式 （ I一 2) 化合物は、 式 （Π— 1 ) 化合物と式 （ΙΠ— 5) 化合物を製造法 1 の工程 1と同様の反応によって、 製造することができる。 [製造法 4 ] R2が水素原子— ■■ ,0式 （ I ) 化合物の製造法 The compound of the formula (I-12) can be produced by reacting the compound of the formula (Π-1) and the compound of the formula (ΙΠ-5) in the same manner as in Step 1 of Production Method 1. [Production method 4] R 2 is a hydrogen atom— ■■, 0 Production method of compound of formula (I)
Figure imgf000022_0001
Figure imgf000022_0001
(式中、 R R3、 R\ X、 Υ、 Ζおよび mは前記と同じ意味を表し、 R 2aはカル' ボキシル保護基を表す。） (Wherein, RR 3 , R \ X, Υ, Ζ, and m represent the same meaning as described above, and R 2a represents a carboxyl protecting group.)
式（ I 一 4 )化合物は、式（ I 一 3 ) ίヒ合物を文献記載の方法（例えば、 T. W. Greene and P. G. M. Wuts, Protect ive Liroupy i n Organic synthesi s, John Wi ley & Sons, New York, 1991 ) で処理することにより製造することができる。  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).
前述した製法で製造される本発明化合物は、 遊離化合物、 その塩、 その水和物も しくはェタノール和物などの各種溶媒和物または結晶多形の物質として単離精製 される。本発明化合物の薬理学的に許容される塩は通常の造塩反応により製造する ことができる。 単離精製は抽出分別、 結晶化、 各種分画ク口マトグラフィ一などの 化学操作を適用して行われる。 ま 、 光学異性体は適当な原料化合物を選択するこ とにより、 またはラセミ化合物 ラセミ分割法により立 ί本化学的に钝枠な異性 (本に 導くことができる。  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.
本発明のァゼピン誘導体は、 優れた V L Α— 4アンタゴニスト作用を有し、 白血 球の接着および浸潤により惹起される疾患または V L A— 4依存性接着過程があ る役割を果たす疾患の治療または予防用医薬として有用であり、 例えば、 リゥマチ 性関節炎、 腎炎、 炎症性腸疾患、 全身性エリテマトーデス、 中枢神経系の炎症性疾 患、 喘息、 アレルギー （遅発性タイアのアレルギーなど）、 多発性硬化症、 心臓血 管性疾患、 動脈硬化症、 糖尿病、 種々の悪性腫瘍、 移植臓器の損傷予防、 腫瘍増殖 または転移阻止などがあげられる 3 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
本発明化合物は、 全身的また 局所的に、 経口、 静脈内注射、 皮下注射、 直腸内 投与などの方法で投与されるが、 中でも経口投与が望ましいつ また剤型は投与経路 に応じて適宜選択することができ、 例えば、 錠剤、 トローチ剤、 舌下錠、 糖衣錠、 カプセル剤、 丸剤、 散剤、 顆粒剤、 液剤、 乳剤、 シロップ剤、 吸入剤、 点眼剤、 点 鼻剤、 注射剤、 座剤などがあげられる。 またこれらの製剤は陚形剤、 防腐剤、 浸潤 剤、 乳化剤、 安定化剤、 溶解補助剤などを配合し製造することができる： 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.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. In addition, these preparations can be prepared by incorporating a vehicle, a preservative, a wetting agent, an emulsifier, a stabilizer, a solubilizing agent, and the like:
本発明化合物の投与量は、 投与対象、 投与ルート、 症状などの条件によって適宜 決定すればよく、 例えば、 成人の患者に対して経口投与する場合、 有効成分である 本発明化合物を通常 1回量として、 約 0. 1〜1 0 Omgノ k g、 好ましくは 1〜 3 Omg/k gの範囲であればよく、 1 日 1〜3回投与するのが好ましい。  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.
以下に実施例を挙げて本発明の特徴をさらに具 ί本的に説明する。以下の実施例に 示す材料、 使用量、 割合、 処理内容、 処理手順等は、 本発明の趣旨を逸脱しない限 り適宜変更することができる。 したがって、 本発明の範囲は以下に示す具体例によ り限定的に解釈されるべきものではない。  Hereinafter, the features of the present invention will be described more specifically with reference to examples. Materials, used amounts, ratios, treatment details, treatment procedures, and the like shown in the following examples can be appropriately changed without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the specific examples described below.
なお、 プロ トン核磁気共鳴スぺク トル — NMR) は、 テトラメチルシラン を内部標準とし、 J NM-EX 2 70型スぺク トロメーター （2 70MH z、 日本 電子製） で測定し、 δ 値は p pmで示した。 高速原子衝撃質量スペク トル （FA BMS) は、 JMS— HX 1 1 0 A型スぺク トロメーター （日本電子製） で測定し た。 旋光度は S E P A— 3 00型スぺク トロメータ一 （堀場製） で測定した。 また、以下の構造式および表において、 Meはメチル基、 E tはェチル基を表す。 〔実施例 1〕 トランス一 7—クロロー 1， 2, 3, 5—テトラヒ ドロー 2—ォキソ ― 5一フエ二ルー 1 一 [3— [[4— （ 3— o— トリルウレイ ド） フ-ニル] ァセ チルァミノ] ベンジル] 一 4, 1—ベンゾォキサゼピン一 3—酢酸の製造
Figure imgf000024_0001
The proton nuclear magnetic resonance spectrum (NMR) was measured with a J NM-EX 270 spectrometer (270 MHz, manufactured by JEOL Ltd.) using tetramethylsilane as the internal standard, and the δ The values are shown in ppm. The fast atom bombardment mass spectrum (FA BMS) was measured with a JMS-HX110A type spectrometer (manufactured by JEOL). Optical rotation was measured with a SEPA-300 type spectrometer (manufactured by Horiba). In the following structural formulas and tables, Me represents a methyl group and Et represents an ethyl group. [Example 1] trans-7-chloro-1,2,3,5-tetrahydro 2-oxo-5-1-Fe-N-1-1 [3 -— [[4- (3-o-tolyl ureido) funyl] Preparation of [acetylamino] benzyl] 1,4,1-benzoxazepine-13-acetic acid
Figure imgf000024_0001
( 1 ) トランス一 7—クロロー 1 , 2， 3, 5—テトラヒ ドロー 1一 （3—二トコ ベンジル） 一 2—ォキソ一 5—フエ二ルー 4, 1—ベンゾォキサゼピン一 3—酢酸 ェチノレエステノレ (1) Trans-7-chloro-1,2,3,5-tetrahydro-1- (3-ditobenzyl) -12-oxo-5-phenyl-4,1-benzoxazepine-13-acetic acid Echinorestenore
トランス一 7—クロ口一 1 , 2, 3, 5—テトラヒ ドロ一 2—ォキソ一 5—フニ ニノレー 4, 1—ベンゾォキサゼピン一 3—醉酸ェチルエステノレ （ 1 8 0mg、 0. 5 0 mm o 1 ) のアセ トン溶液 （4m l ) に、 3—二トロベンジルブロミ ド (1 6 2mg、 0. 7 5mmo l )、 炭酸力リウム （1 3 8mg、 1. 00 mm o 1 ) およびヨウ化ナトリウム （ 1 5 m g、 0. l Ommo l ) を加えて、 5時間カロ 熱還流する。 反応後、 溶媒を減圧濃縮し、 残留物にジェチルエーテルを加えて水お よび飽和食塩水で洗浄後、 無水硫酸マグネシウムで乾燥し、 溶媒を減圧濃縮する。 残留物をシリカゲルカラムクロマトグラフィー （n—へキサン：酢酸ェチル = 5 : 1 ) で精製し、 無色固体 （24 5mg、 9 9%) を得た。  Trans 7-chloro-1,2,3,5-tetrahydro 2-oxo-5-funininoleic 4,1-benzoxazepine-3-3-ethylestenole (180 mg, 0.50 mmo1) in acetone solution (4 ml), 3-nitrobenzylbromide (162 mg, 0.75 mmol), potassium carbonate (138 mg, 1.00 mmo1) and Add sodium iodide (15 mg, 0.1 l Ommol) and heat to reflux for 5 hours. After the reaction, the solvent is concentrated under reduced pressure, getyl ether is added to the residue, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain a colorless solid (245 mg, 99%).
FABMS (m/z) ： 495 (MH+) . FABMS (m / z): 495 (MH + ).
¾一 NMR (CDC13) δ ： 8.19-8.1δ(2Η,ηι),7.72 (1Η, d, J=7.6Hz) , 7.64-7.19(8H,mj, 6.59 (1H, d, J=2.3Hz), 5.58 (1H, s) , 5.37 (1H, d, J=15.2Hz), 5.15(1H, d, J=15.2Hz) , 4.54 (1H, dd, J=8.6， 5.3Hz)， 4.15 (2H， q, J=6.9Hz) , 3.15 (1H， dd， J=16.8， 8.6Hz)， 2.79 (1H, dd, J=16.8， 5.3Hz) , 1.25 (3H， t, J=6.9Hz) . ¾ one NMR (CDC1 3) δ: 8.19-8.1δ (2Η, ηι), 7.72 (1Η, d, J = 7.6Hz), 7.64-7.19 (8H, mj, 6.59 (1H, d, J = 2.3Hz) , 5.58 (1H, s), 5.37 (1H, d, J = 15.2Hz), 5.15 (1H, d, J = 15.2Hz), 4.54 (1H, dd, J = 8.6, 5.3Hz), 4.15 (2H, q, J = 6.9Hz), 3.15 (1H, dd, J = 16.8, 8.6Hz), 2.79 (1H, dd, J = 16.8, 5.3Hz), 1.25 (3H, t, J = 6.9Hz).
(2) トランス一 7—クロ口一 1 , 2, 3, 5—テトラヒ ドロ一 2—ォキソ一 5— フエ二ルー 1一 [3— [[4一 （3— o— トリノレウレイ ド） フエニル] ァセチルァ ミノ] ベンジル] —4， 1一べンゾォキサゼピン一 3—酢酸ェチルエステル ( 1 ) で得た化合物 （ 9 6 0 m g 、 1 . 9 4 mm o 1 ) をメタノール （ 1 0 0 m 1 ) に溶解し、 1◦%パラジウム炭素 ( 1 δ Omg) を加えて、 3 0分間水素添 加する- 反応後、 触媒を濾去し、 溶媒を减圧濃縮して残留物をシリカゲルカラムク ロマ卜グラフィー （n—へキサン： ジニチルエーテル = 1 ： 1 ) で精製し、 無色個 体 （7 8 6 m g、 8 7 %) を得た: こ うち 5 0 m gを N , N—ジメチルホルムァ ミ ド （ 2 m U に溶解し、 [ 4— ( 3— ϋ一 トリルウレイ ド） フェニル] 酢酸(2) Trans-7-Black 1,2,3,5-Tetrahydro 2-oxo-1 5-Feniru1-1 [3 — [[4- (3-o—Trinoleureido) phenyl] acetyla Mino] benzyl] —4,1 Benzoxazepine-13-ethyl acetate The compound (960 mg, 1.94 mmo 1) obtained in (1) was dissolved in methanol (100 m 1), and 1 °% palladium carbon (1δOmg) was added thereto. Hydrogenation for 1 minute-After the reaction, the catalyst is removed by filtration, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane: dinityl ether = 1: 1), and colorless An individual (786 mg, 87%) was obtained: 50 mg of this was dissolved in N, N-dimethylformamide (dissolved in 2 mU, and [4- (3-tri-triureide)) was obtained. Phenyl] acetic acid
( 3 1 m g、 0. 1 1 mm o 1 )、 1ーヒ ドロキ、ンベンゾトリァゾール （ 2 5 m g、 0. 1 7 mm o 1 ) および 1一ェチル一 3— （ 3—ジメチルァミノプロピル） カル ボジィミ ド塩酸塩 （3 2 mg、 0. 1 7 mm o 1 ) を加えて室温で 4 2時間撹拌す る。 反応後、 酢酸ェチルで抽出し、 1 X塩酸および飽和食塩水で順次洗浄後、 無水 硫酸マグネシウムで乾燥し、 溶媒を減圧濃縮する。 残留物を分取薄層クロマトグラ フィー （n—へキサン ：酢酸ェチル = 1 ： 2 ) で精製し、 無色固体 （6 4m g、 8 1 %) を得た。 (31 mg, 0.11 mmo1), 1-hydroxy, benzotriazole (25 mg, 0.17 mmo1) and 1-ethyl-3- (3-dimethylaminopropyl) ) Add carbodimid hydrochloride (32 mg, 0.17 mmo 1) and stir at room temperature for 42 hours. After the reaction, the reaction solution is extracted with ethyl acetate, washed successively with 1X hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (n-hexane: ethyl acetate = 1: 2) to give a colorless solid (64 mg, 81%).
FABMS (m/ z) ： 731 (MH+). FABMS (m / z): 731 (MH + ).
¾-NMR (CDC13) δ ： 8.10 (IH, s), 7.6δ-6.87(21H, m), 6.54(1H, d, J=2.3Hz), 5.55 (IH, s), 5.06 (IH, d， J=15.5Hz), 4.96 (IH, d, J=15.5Hz), 4.50 (IH, dd, J=8.9, 5.3Hz) , 4.16-4.02 (2H, ra) , 3.48 (2H, a , 3.11 (1H， dd, J=16.5, 8.9Hz)， 2.76(1H， dd, J=16.5, 5.3Hz)， 2.13 (3H, s)， 1.20 (3H, t, J=6.9Hz) . ¾-NMR (CDC1 3) δ : 8.10 (IH, s), 7.6δ-6.87 (21H, m), 6.54 (1H, d, J = 2.3Hz), 5.55 (IH, s), 5.06 (IH, d , J = 15.5Hz), 4.96 (IH, d, J = 15.5Hz), 4.50 (IH, dd, J = 8.9, 5.3Hz), 4.16-4.02 (2H, ra), 3.48 (2H, a, 3.11 ( 1H, dd, J = 16.5, 8.9Hz), 2.76 (1H, dd, J = 16.5, 5.3Hz), 2.13 (3H, s), 1.20 (3H, t, J = 6.9Hz).
( 3) トランス一 7—クロロ ー 1， 2 , 3 , 5—テ トラヒ ドロー 2—ォキソ一 5— フエ二ルー 1— [3— [[4一 （ 3— o— トリノレウレイ ド） フエニル] ァセチルァ  (3) Trans-7-chloro-1,2,3,5—Tetrahidro 2-oxo-5-Feuniru 1— [3 — [[4-1 (3-o—trinoureido) phenyl] acetyla
4 1一べ: 'サゼピン一 3—酢酉;  4 1 all: 'one zezepin 3-vinegar rooster;
( 2 ) で得た化合物 （ 54 m g、 0. 9 0 mm o 1 ) をメタノール （ 2 m】） と テトラヒ ドロフラン （l m l ) の混合溶媒に溶解し、 2 N水酸化ナトリウム  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.
( l m l ) を加えて室温で 1 . 5時間撹拌する。 反応後、 2 N塩酸で酸性にして溶 媒を減圧濃縮し、 残留物に水を加えて濾取し、 無色固体 （4 l m g、 7 1 %) を得 た。  (lml) and stirred at room temperature for 1.5 hours. After the reaction, the mixture was acidified with 2N hydrochloric acid, the solvent was concentrated under reduced pressure, water was added to the residue, and the mixture was collected by filtration to obtain a colorless solid (4 lmg, 71%).
FABMS(ra/z) ： 703 (ΜΗ') . Ή-N R (DMS0-d6) 0 ： 10.21 (IH, a), 9.28(1H, s) , 8.16(1H, s .7.83-6.90 (19H， m)， 6.29 (IH, d, J=2.3Hz) , 5.58 ( 1H， s)， 5.42 (IH, d, J=15.2Hz .4.91 (IH, d， J=15.2Hz), 4.35(1H， dd, J=7.9， 5.6Hz)， 3.54 (2H， s), 2.83 (IH, dd, j = 16.2, 7.9Hz)， 2.57 (IH, dd, J=16.2， 5.6Hz)， 2.2 (3Ii s) . FABMS (ra / z): 703 (ΜΗ '). Ή-NR (DMS0-d 6 ) 0: 10.21 (IH, a), 9.28 (1H, s), 8.16 (1H, s .7.83-6.90 (19H, m), 6.29 (IH, d, J = 2.3Hz ), 5.58 (1H, s), 5.42 (IH, d, J = 15.2Hz) 4.91 (IH, d, J = 15.2Hz), 4.35 (1H, dd, J = 7.9, 5.6Hz), 3.54 (2H, s), 2.83 (IH, dd, j = 16.2, 7.9 Hz), 2.57 (IH, dd, J = 16.2, 5.6 Hz), 2.2 (3Ii s).
〔実施例 2〕 （土） 一 トランス一 7—クロロー 1— [2—クロロー 5— [[3—メ ト キシー 4一 （3— o— トリルゥレイ ド） フエニル] ァセチルアミ '] ベンジル] 一 1 , 2, 3, 5—テ トラヒ ドロー 2—ォキソ一 5—フエ二ルー 4. 1一ベンゾォキ サゼピン一 3—酢酸  [Example 2] (Sat) 1-trans-7-chloro-1-[2-chloro-5-[[3-methoxyl 4- (3-o-tolyl perido) phenyl] acetylami '] benzyl] 1-1,2 , 3,5-Tetrahi Draw 2-oxo-5-Feuniru 4.1 Benzoxazezepine-1-3-acetic acid
Figure imgf000026_0001
実施例 1と同様にして、 表題化合物を無色粉末として得た。
Figure imgf000026_0001
The title compound was obtained as a colorless powder in the same manner as in Example 1.
FABMS (ra/z) ： 767 (MH+) . FABMS (ra / z): 767 (MH + ).
'H-NMR (CDC13) δ ： 8.03 (IH, s), 7.87-7.81 (2H, ra) , 7.47-7. I0(12H, m) , 7.02 (1H， d, J=l.7Hz), 6.94 (IH, d， J=8.6Hz)， 6.38 (IH, s),6.72-6.62 (3H. m) , 5.80 (IH, s) , 5.56 (1H， d, J=16.8Hz)， 4.65 (IH, d， J=16.8Hz) , 4.56 (IH, dd, J=10.6.3.3Hz) , 3.58 (3H， s)， 3.50 (2H， s)， 3.26(1H, dd, J=17.5, 10.6)， 2.77 (IH, dd, J=17.5, 3.3Hz)， 2.22 (3H, s). 'H-NMR (CDC1 3) δ:. 8.03 (IH, s), 7.87-7.81 (2H, ra), 7.47-7 I0 (12H, m), 7.02 (1H, d, J = l.7Hz), 6.94 (IH, d, J = 8.6Hz), 6.38 (IH, s), 6.72-6.62 (3H.m), 5.80 (IH, s), 5.56 (1H, d, J = 16.8Hz), 4.65 (IH , d, J = 16.8Hz), 4.56 (IH, dd, J = 10.6.3.3Hz), 3.58 (3H, s), 3.50 (2H, s), 3.26 (1H, dd, J = 17.5, 10.6), 2.77 (IH, dd, J = 17.5, 3.3Hz), 2.22 (3H, s).
〔実施例 3〕 （ + ) — トランス一 7—クロ口一 1一 [2—クロ口一 5— [[3 -メ ト キシ一 4一 （3— o—トリノレゥレイ ド） フエニル] ァセチルァミノ] ベンジル] 一 1 , 2, 3, 5—テトラヒ ドロ一 2—ォキソ一 5—フエ二ルー 4， 1—ベンゾォキ サゼピン一 3—酢酸  [Example 3] (+) — Trans 7-chloro 1- 11 [2-cyclo 1- 5-([3-Methoxy 1-41 (3-o-trinorelide) phenyl] acetylamino] benzyl] 1,1,2,3,5-tetratetrahydro-2-oxo-5-phenyl-4,1-benzoxazezepine-13-acetic acid
実施例 1と同様にして、 表題化合物を微黄色粉末として得た,： 9 ^M- ε -. ^,3- ^ -- ' Τ 一 Η Τ— The title compound was obtained as a slightly yellow powder, as in Example 1, 9 ^ M- ε-. ^, 3- ^-'Τ 一 Η Τ—
[/ ^^ [ ί--^Δ. し 4 ri、1 一 0— ε ) —^]] 一 ε] - τ - ([/ ^^ [ί-^ Δ. then 4 ri, 1 1 0 — ε) — ^]] 1 ε]-τ-(
-ェ — S一 ^ 一 2— ε ' Z - n n l - (S S) [ 9 fli}¾¾] -E — S one ^ one 2— ε 'Z-n n l-(S S) [9 fli} ¾¾]
• (ζΗε
Figure imgf000027_0001
• ( ζ Ηε
Figure imgf000027_0001
'PP ¾T)C9 ' '(ΖΗ9 ·0ΐ 'Ζ " ΐ=Γ 'ΡΡ 'Ηΐ) ΙΖ 'Ζ ' (s 'Η2) 19 'ε '(s 'HC)69 Έ '(ZHS "8 '9 Όΐ=Γ 'PP ¾T)Ze ' (8 '9Τ=Γ 'P ¾I)TS 'f (ZHS ·9=Γ 'b 'HT) 98 ' ' (ZH8 ·9ΐ=Γ 'P 'HT)ZS "9 '(ra'HS)S9 "9-96 ·9 '(ω'Η6)ΐΐ ' - ^ 'Ζ ' (™ Ήε) 6Z - -26 Ί ： 9 (εΐつ (D) 画一 Ητ 'PP ¾T) C9''(ΖΗ9 · 0ΐ' Ζ "ΐ = Γ 'ΡΡ' Ηΐ) ΙΖ 'Ζ' ( s 'Η2) 19' ε '( s ' HC) 69 Έ '( Z HS"8' 9 Όΐ = Γ 'PP ¾T) Ze' (8 '9Τ = Γ' P ¾I) TS 'f ( Z HS9 = Γ'b'HT) 98 '' ( Z H89ΐ = Γ 'P' HT) ZS "9 '( ra ' HS) S9" 9-96 · 9 '(ω'Η6) ΐΐ'-^ 'Ζ' (™ Ήε) 6Z--26 ：: 9 ( ε ΐ つ (D) Uniform Η τ
'(+顯） U9： (z/m) swavd '(+ Hen) U9: ( z / m) swavd
Figure imgf000027_0002
ε一べ ^ >,_ I ' ー ^^ー Z - ^ ~ G ^Δ^ ^-ο 'ς ' z ' T - [ ^, .^ [, /^^ [_Λ(-^ {
Figure imgf000027_0002
ε all ^>, _ I 'ー ^^ ー Z-^ ~ G ^ Δ ^ ^ -ο' ς 'z' T-[^,. ^ [, / ^^ [_Λ (-^ {
- o - 2 ) 一^一 ^ H — ε]] - I [S .¾牽〕  -o-2) One ^ one ^ H — ε]]-I [S.
'、へ（ -- ί "、0S '0=つ） 。9 '9S— : n ["]', To (-ί ", 0S' 0 =). 9 '9S—: n ["]
。:· っ ^^^ ^ ^m 、 つ 對^? τm . : ^^^ ^ ^ m, vs ^? Τm
^ /、ベ — ΐ ' ^ - Ι-^ Δ- - -^ - ~- 6 -- a ^ ^ S ' ε 'S ' Τ 一
Figure imgf000027_0003
- o - 8) — ー 、^ 4 ー S]] - — ΐ一 a a 一 Z— 'く 4 — (-) [fr ¾g¾] ^ /, Ba — ΐ '^-Ι- ^ Δ---^-~-6-a ^ ^ S' ε 'S' Τ 一
Figure imgf000027_0003
-o-8) — ー, ^ 4 ー S]]-— ΐ 一 aa 一 Z— 'く 4 — (-) [fr ¾g¾]
'、へ （ ε ·ο=つ） 。9 '6S+ : (' ["] S00/I0df/X3d UISS/IO O .
Figure imgf000028_0001
実施例 1と同様にして、 表題化合物を固体として得た。 ', To (ε · ο = tsu). 9 '6S +: ('["] S00 / I0df / X3d UISS / IO O.
Figure imgf000028_0001
The title compound was obtained as a solid in the same manner as in Example 1.
FABMS z) ： 700 (MH+) . FABMS z): 700 (MH + ).
一匪 R (DMS0— d6) S ： 10.08 (IH, s) , 9.98 (IH, s)， 8.94 (IH, s) , 7.73— 7.67 (2H, ra ， 7.57 (IH, dd, J=8.6， 2.3Hz)， 7.49-7.41 (4H, ra)， 7. 34-7.29 (2H, ra) , 7.25-7.20 (3H， ra) , 7. 13-7.06 (5H, m)， 6.97(1H, t, J=7.6Hz) , 6.90 (IH, t， J-7.6Hz) , 6.60 (1H， d, J=7.6Hz)， 5.39 (IH, d, J=15.5Hz) , 4.85 (IH, d, J=15.5Hz) , 4. 11 (IH, dd, J=7.9, 5.6Hz)， 3.41 (2H, s) , 3. 11 (IH, dd, J=15.8, 7.9Hz)， 2.73 (IH, dd, J=15.8， 5.6Hz) , 2.21 (3H， s) . 〔実施例 7〕 ( 3 S) 一 1一 [2 —クロ口 _ 5— [[ 3 —メ トキシ一 4— ( 3 - o - トリノレウレイ ド） フエニル] ァセチルァミノ] ベンジル] — 2 , 3—ジヒ ドロ一 5 —メチル一 2—ォキソ一 1 H—ピリ ド [ 3， 2— e ] [ l， 4] ジァゼピン一 3 — 酢酸 Ichi匪R (DMS0- d 6) S: 10.08 (IH, s), 9.98 (IH, s), 8.94 (IH, s), 7.73- 7.67 (2H, ra, 7.57 (IH, dd, J = 8.6, 2.3Hz), 7.49-7.41 (4H, ra), 7.34-7.29 (2H, ra), 7.25-7.20 (3H, ra), 7.13-7.06 (5H, m), 6.97 (1H, t, J = 7.6Hz), 6.90 (IH, t, J-7.6Hz), 6.60 (1H, d, J = 7.6Hz), 5.39 (IH, d, J = 15.5Hz), 4.85 (IH, d, J = 15.5Hz), 4.11 (IH, dd, J = 7.9, 5.6Hz), 3.41 (2H, s), 3.11 (IH, dd, J = 15.8, 7.9Hz), 2.73 (IH, dd, J = 15.8, 5.6Hz), 2.21 (3H, s). [Example 7] (3S) 1 1 1 [2—Black mouth _ 5 — [[3—Methoxy 1 4— (3-o-Trinoleureido ) Phenyl] acetylamino] benzyl] — 2,3-dihydro-5-methyl-1-oxo-1H-pyrido [3,2-e] [l, 4] dazepine-13—acetic acid
Figure imgf000028_0002
実施例 1と同様にして、 表題化合物を黄色粉末として得た。
Figure imgf000028_0002
The title compound was obtained as a yellow powder in the same manner as in Example 1.
FABMS z) ： 669画.  FABMS z): 669 strokes.
¾一 NMR (CD30D) δ ： 8.66 (IH, d, J=4.3Hz) , 8.07 (IH, d, J=8.2Hz) , 7.99 (IH, d. J=8.2Hz), 7.75 (IH, dd, J=8.6, 4.3Hz) , 7.64 (IH, s), 7.58 (IH, d, J=7.9Hz) , 7.2S-6.99 (8H, ra) , 6.95 (IH, s)， 6.84(1H， d， J=8.6Hz)， 5.48(1H， d, J=16.5Hz) .5.16 (IH. d. J二 16.5Hz), 4.64-4.58(1H， ra)， 3.91 (3H， s), 3.59(2H， s), 3.36(1H， dd, J=17.5, 7.3Hz) , 3.18 (1H， dd, J=17.5， 6.6Hz) , 2.29 (3H, s) . ¾ one NMR (CD 3 0D) δ: 8.66 (IH, d, J = 4.3Hz), 8.07 (IH, d, J = 8.2Hz), 7.99 (IH, d. J = 8.2Hz), 7.75 (IH, dd, J = 8.6, 4.3Hz), 7.64 (IH, s), 7.58 (IH, d, J = 7.9Hz), 7.2S-6.99 (8H, ra), 6.95 (IH, s), 6.84 (1H, d, J = 8.6 Hz), 5.48 (1H, d, J = 16.5 Hz) .5.16 (IH. D. J 26.5 Hz), 4.64-4.58 (1H, ra) , 3.91 (3H, s), 3.59 (2H, s), 3.36 (1H, dd, J = 17.5, 7.3 Hz), 3.18 (1H, dd, J = 17.5, 6.6 Hz), 2.29 (3H, s).
実施例 1と同様にして、 実施例 8〜 1 54に示す化合物を製造した。 得られた化 合物の物性値を以下の表 2〜表 10に示す。 なお、 Zの欄は前記表 1に対^する。 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.
表 2 Table 2
Figure imgf000030_0001
実施例 Z FABMS {m/z)
Figure imgf000030_0001
Example Z FABMS (m / z)
8 a1 703 (MH+)8 a1 703 (MH + )
(+)-体 (+)-Body
9 a1 703 (MH+)9 a1 703 (MH + )
H-体 H-body
10 b1 719 (MH+)10 b1 719 (MH + )
11 d 707 (MH+)11 d 707 (MH + )
12 d1 733 (MH+)12 d1 733 (MH + )
13 e1 795 (MH十）13 e1 795 (MH10)
14 f1 719 (MH+)14 f1 719 (MH + )
15 hi 703 (MH+)15 hi 703 (MH + )
16 i1 655 (MH+)16 i1 655 (MH + )
17 j1 669 (MH+)17 j1 669 (MH + )
18 k1 689 (MhT)18 k1 689 (MhT)
19 11 717 (MH+)19 11 717 (MH + )
20 pi 705 (MH+)20 pi 705 (MH + )
21 Π 717 ( H+)21 Π 717 (H + )
22 s1 681 (MH+)22 s1 681 (MH + )
23 t1 681 (MH+)23 t1 681 (MH + )
24 u1 643 (MH+)24 u1 643 (MH + )
25 v1 645 (MHT)25 v1 645 (MHT)
26 w1 659 (MH÷) 続き 実施例 Z FAB MS (m/z)26 w1 659 (MH ÷ ) Continued Example Z FAB MS (m / z)
27 x1 583 (MH+)27 x1 583 (MH + )
28 yi 625 (MH+)28 yi 625 (MH + )
29 z 1 645 (MH+)29 z 1 645 (MH + )
30 a2 673 (MH+)30 a2 673 (MH + )
31 b2 646 (MH÷)31 b2 646 (MH ÷ )
32 c2 646 (MH+)32 c2 646 (MH + )
33 d2 675 (MH+)33 d2 675 (MH + )
34 e2 663 (MH+)34 e2 663 (MH + )
35 †2 675 (MH+)35 † 2 675 (MH + )
36 g2 663 (MH+)36 g2 663 (MH + )
37 h2 661 (MH+)37 h2 661 (MH + )
38 i2 661 (MH+)38 i2 661 (MH + )
39 j2 658 (MH+)39 j2 658 (MH + )
40 k2 675 (MH+)40 k2 675 (MH + )
41 I2 661 (MH+)41 I2 661 (MH + )
42 m2 684 ( H+)42 m2 684 (H + )
43 Iつ 2 684 (MH+)43 I 2 684 (MH + )
44 02 684 (MH+)44 02 684 (MH + )
45 p2 615 (MH+)45 p2 615 (MH + )
46 q2 609 (MH+)46 q2 609 (MH + )
47 r2 595 (MH+)47 r2 595 (MH + )
48 s2 625 (MH+)48 s2 625 (MH + )
49 t2 613 (MH+)49 t2 613 (MH + )
50 U2 671 iMH+) 続き 実施例 z FAB MS {m/z)50 U 2 671 iMH + ) Continued Example z FAB MS (m / z)
51 x2 718 ( H÷)51 x2 718 (H ÷ )
52 y2 742 (MH+)52 y2 742 (MH + )
53 z2 674 (ΜΗΊ53 z2 674 (ΜΗΊ
54 702 (MH+)54 702 (MH + )
-J J -J J
7^1 fMH 1 j y°  7 ^ 1 fMH 1 j y °
58 700 MH+ 58 700 MH +
Oc7 I / U ou DOO い ， JOc7 I / U ou DOO I, J
61 k3 688 ( H+)61 k3 688 (H + )
62 I3 736 (MH+)62 I3 736 (MH + )
63 m3 650 ( H+)63 m3 650 (H + )
64 n3 664 (MH+)64 n3 664 (MH + )
65 t3 656 (MH")65 t3 656 (MH ")
66 u3 672 ( H+)66 u3 672 (H + )
67 v3 716 (MH+)67 v3 716 (MH + )
68 w3 633 (MH+) 68 w3 633 (MH + )
Figure imgf000033_0001
Figure imgf000033_0001
— H— R3—— — H— R 3 ——
実施例 z FABMS ifv./z)Example z FABMS ifv./z)
69 a1 721 (MH÷)69 a1 721 (MH ÷ )
70 f1 737 ( H+)70 f1 737 (H + )
71 a1 737 (MH^)71 a1 737 (MH ^)
72 f1 753 (MH72 f1 753 (MH
73 ml 759 (MH+)73 ml 759 (MH + )
74 n1 759 (MH+) 74 n1 759 (MH + )
き Come
Figure imgf000034_0001
表 4
Figure imgf000034_0001
Table 4
Figure imgf000035_0001
Figure imgf000035_0001
実施例 Z FABMS {m/z)Example Z FABMS (m / z)
85 a1 593 (MH+)85 a1 593 (MH + )
86 hi 593 (MH+)86 hi 593 (MH + )
87 k1 579 (MH+)87 k1 579 (MH + )
88 11 607 (MH+)88 11 607 (MH + )
89 u1 533 (MH+)89 u1 533 (MH + )
90 v1 561 ( H+)90 v1 561 (H + )
91 x3 511 (MH+)91 x3 511 (MH + )
92 y3 519 (MH+)92 y3 519 (MH + )
93 z3 473 (MH+)93 z3 473 (MH + )
94 a4 512 (MH+)94 a4 512 (MH + )
95 b4 479 (MH+) 95 b4 479 (MH + )
\ \ \ \
12：χ.,ζ •- 12 ： χ., Ζ •-
2：ェ ζェ ,
Figure imgf000036_0001
\ λ o、 o o 2: ζ ζ,
Figure imgf000036_0001
\ λ o, oo
一 N— R3— One N—R3—
実施例 I Z FAB MS (m/z) Example I Z FAB MS (m / z)
96 a1 627 (MH+) 96 a1 627 (MH + )
97 a1 623 (MH+) 97 a1 623 (MH + )
98 f 1 639 (MH+) 98 f 1 639 (MH + )
99 gi 657 (MH+) 99 gi 657 (MH + )
100 a1 593 (MH+) 100 a1 593 (MH + )
101 e1 607 (MH+) 101 e1 607 (MH + )
Figure imgf000037_0001
Figure imgf000037_0001
\一 N— R3一 \ One N—R three
実施例 I z FABMS ( /z) Example Iz FABMS (/ z)
H  H
102 s- a1 607 (MH >  102 s-a1 607 (MH>
H  H
103 gi 637 (MH— ;  103 gi 637 (MH—;
104 f1 657 (MhT) 104 f1 657 (MhT)
105 ml 663 (MH+) 105 ml 663 (MH + )
106 n1 663 (MH o1 627 (ΜΗ106 n1 663 (MH o1 627 (ΜΗ
107 107
627 (MH627 (MH
108 X q1 108 X q1
109 f1 666 (MH f1 692 (MH109 f1 666 (MH f1 692 (MH
110 110
111 f1 694 (MHT) 111 f1 694 (MHT)
112 112
a1 641 (MH")  a1 641 (MH ")
113 113
f1 657 ( H~) 表 7f1 657 (H ~) Table 7
Figure imgf000038_0001
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0002
;>6 続き ;> 6 Continued
H  H
125 。 . u rr 〇 a1 737 (MH+) 125. u rr 〇 a1 737 (MH + )
H H
Me  Me
Meへ Me0JX 〇 a1 695 (MH+) To Me Me0 JX 〇 a1 695 (MH + )
H H
Me  Me
127 Me人 び 0 a1 695 ( H+) 127 Me 0 a1 695 (H + )
H H
Me  Me
128 Me人. び 〇 v1 637 (MH+) 128 Me people. 〇 v1 637 (MH + )
H H
Me Me
29 0 v1 637 (MH+) 29 0 v1 637 (MH + )
Me人  Me people
H  H
130 Meヽ く XX 0 a1 651 (MH+) 130 Me ヽ XX 0 a1 651 (MH + )
Figure imgf000040_0001
Figure imgf000040_0001
続き
Figure imgf000041_0003
Continued
Figure imgf000041_0003
表 9 Table 9
Figure imgf000041_0001
Figure imgf000041_0002
o
Figure imgf000041_0001
Figure imgf000041_0002
o
Figure imgf000042_0001
Figure imgf000042_0001
Figure imgf000042_0002
Figure imgf000042_0002
lり 〔実施例 1 5 5〕 1 , 2, 3, 5—テトラヒ ドロー 1一 [ 1一 [3—メ トキシ一 4 一 （3— o— ト リ ルウレイ ド） フエ二ノレ] ァセチルー 3—ピペリジニル] メチルー 5ーメチルー 2一ォキソ一 4， 1一べンゾォキサゼピン一 3—酢酸の製造 l [Example 15 55] 1,2,3,5-tetrahydrau l- [11- [3-methoxyl-4-1 (3-o-triureido) pheninole] acetyl-3-piperidinyl] methyl- Production of 5-methyl-2-oxo-1,4,1-benzoxazepine-13-acetic acid
Figure imgf000043_0001
Figure imgf000043_0001
( l) l - ( l - t e r t—ブトキシカルボ二ルー 3—ピペリジニル）メチルー 1 , 2 , 3 , 5—テ トラヒ ドロ一 5—メチル一 2—ォキソ一 4， 1—ベンゾォキサゼピ ンー 3—酢酸ェチルエステル (l) l-(l-tert e-tert-butoxycarbonyl 3-piperidinyl) methyl-1,2,3,5-tetrahydro-5-methyl-12-oxo-1,4,1-benzoxazepin-3-acetyl acetate
1， 2, 3, 5—テトラヒ ドロー 5—メチル一 2—ォキソ一4, 1—ベンゾォキ サゼピン— 3—酢酸ェチルエステル （ 6 34m g、 2. 40mmo l ) の N, N— ジメチルホルムァミ ド溶液 （6m l ) に、 氷冷下、 6 0。/。水素化ナトリウム 1,2,3,5-tetrahydro-5-methyl-1-oxo-1,4-benzoxazezepine-3-acetic acid ethyl ester (634 mg, 2.40 mmol) in N, N-dimethylformamide (6ml) under ice cooling, 60. /. Sodium hydride
(1 1 6mg、 2. 8 8mmo 1 ) を加えて 1 5分撹拌した後、 N— t e r t—ブ トキシカノレボニル一 3—ブロモメチノレピペリジン （ 1. 0 0 g、 3. 6 0 mm o 1 ) を加えて、 室温で 7. 5時間撹拌する。 反応後、 水を加えて酢酸ェチルで 2回抽出 し、 有機層を水および飽和食塩水で洗浄後、 無水硫酸マグネシウムで乾燥し、 溶媒 を減圧濃縮する。 残留物をシリカゲルカラムクロマトグラフィー （n—へキサン： ジェチルエーテル = 2 ： 1) で精製し、 無色アモルファス （8 1 9mg、 74%) を 2種の異性体混合物として得た。 (116 mg, 2.88 mmo 1) and stirred for 15 minutes, and then N-tert-butoxycanolebonyl-3-bromomethinolepiperidine (1.00 g, 3.60 mmo 1) Add 1) and stir at room temperature for 7.5 hours. After the reaction, water is added and the mixture is extracted twice with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: getyl ether = 2: 1) to give a colorless amorphous (81 mg, 74%) as a mixture of two isomers.
FABMS (m/z) ： 461 (MH+) . FABMS (m / z): 461 (MH + ).
¾-NMR (CDC13) δ ： (異性体 A) 7.47-7.29 (4H, m) , 4.89 (1Η, q, J=6.3Hz) , 4.36-3.37 (4H, m)， 4.21 (1H， dd, J=8.6, 5.0Hz)， 4.07 (2H, q, J=7.3Hz)， 3.01 (1H， dd, J=16.8， 8.6Hz)， 2.89-2.39 (2H， m)， 2.60 (1H， dd, J=16.8, 5.0Hz) , 1.98-1.56 (2H， m)， 1.63 (3H, d， J=6.3Hz), 1.39 (9H, s) , 1.33-1.08 (3H, m) , 1.20 (3H, t, J=7.3Hz)； (異性 ί本 B ) 7.47-7.27 (4H， ra)， 4.98— 4.84 (1H, m)， 4.21 (1H， dd， J=8.6, 5.0Hz)， 4.07 (1H, q, J=7.3Hz),4.00— 3, 40 (4H, ra) , 3.01 (1H, dd, J=16.8, 8.6Hz), 2.89-2.40 (2H， ra), 2.59 (1H, dd, J=16.8, 5.0Hz)， 1.94— 1.02 (5H, m) , 1.63 (3H, d, J=6.3Hz), 1.420H, s), 1.21 (3H, t, J=7.3Hz). ¾-NMR (CDC1 3) δ : ( isomer A) 7.47-7.29 (4H, m) , 4.89 (1Η, q, J = 6.3Hz), 4.36-3.37 (4H, m), 4.21 (1H, dd, J = 8.6, 5.0Hz), 4.07 (2H, q, J = 7.3Hz), 3.01 (1H, dd, J = 16.8, 8.6Hz), 2.89-2.39 (2H, m), 2.60 (1H, dd, J = 16.8, 5.0Hz), 1.98-1.56 (2H, m), 1.63 (3H, d, J = 6.3Hz), 1.39 (9H, s), 1.33-1.08 (3H, m), 1.20 (3H, t, J = 7.3Hz); (Homomeric B) 7.47-7.27 (4H, ra), 4.98-4.84 (1H, m), 4.21 (1H, dd, J = 8.6, 5.0Hz), 4.07 (1H, q, J = 7.3Hz), 4.00— 3, 40 (4H, ra), 3.01 (1H, dd, J = 16.8, 8.6Hz), 2.89-2.40 (2H, ra), 2.59 (1H, dd, J = 16.8, 5.0Hz), 1.94— 1.02 (5H, m), 1.63 (3H, d, J = 6.3Hz), 1.420H, s), 1.21 (3H, t, J = 7.3Hz).
(2) 1 , 2, 3, 5—テトラヒ ドロ一 1一 [1一 [3—メ トキシ一 4一 （3— o 一 トリノレゥレイ ド） フエ二ノレ] ァセチルー 3—ピぺリジニル] メチル一 5—メチル 一 2—ォキソ一 4, 1—ベンゾォキサゼピン一 3—酢酸ェチルエステル  (2) 1,2,3,5-tetrahydro-1- [1- [3-methoxy-4-41 (3-o-trinorelide) pheninole] acetyl-3-3-pyridinyl] methyl-1-5- Methyl 1,2-oxo-1,4,1-benzoxazepine-13-ethyl acetate
( 1 ) で得た化合物 （ 5 1 m g、 0. 1 1 mm o 1 ) の酢酸ェチル （ 0. 5m l ) 溶液に、 4 N塩酸一酢酸ェチル溶液（ 1. 5 m 1 ) をカ卩え、室温で 50分撹拌した。 反応後、 溶媒を減圧濃縮して得られる黄色油状物を N， N—ジメチルホルムアミ ド To a solution of the compound obtained in (1) (51 mg, 0.11 mmo 1) in ethyl acetate (0.5 ml) was added a 4 N solution of ethyl acetate monohydrochloride (1.5 ml) to a solution. And stirred at room temperature for 50 minutes. After the reaction, the solvent is concentrated under reduced pressure, and the yellow oil obtained is N, N-dimethylformamide
(0. 5m l ) に溶角 し、 [3—メ トキシ一 4— (3— o—トリノレウレイ ド） フエ 二ノレ] 酢酸 （ 42 m g、 0. 1 3 mm o 1 )、 1ーヒ ドロキシベンゾトリアゾーノレ(0.5 ml), [3-Methoxy-14- (3-o-trinolureido) pheninole] acetic acid (42 mg, 0.13 mmo1), 1-hydroxyl Benzotriazonole
( 1 8mg、 0. 1 3 mm 0 1 ) および 1ーェチルー 3— （3—ジメチルアミノプ 口ピル） カルボジィミ ド塩酸塩 （ 2 5 m g、 0. 1 3 mm o 1 )、 N—メチルモル ホリン（3 7 1、 0. 3 31111110 1 ) を加えて室温で 1 5時間撹拌する。反応後、 1 0%クェン酸を加えて酢酸ェチルで 2回抽出し、 有機層を水、 飽和炭酸水素ナト リゥム水、 飽和食塩水で順次洗浄後、 無水硫酸マグネシウムで乾燥し、 溶媒を減圧 濃縮する。 残留物を分取薄層クロマトグラフィー （n—へキサン：酢酸ニチル = 1 : 3) で精製し、 無色油状物 （6 2mg、 8 5%) を 2種の異性体混合物として 得た。 (18 mg, 0.13 mm 0 1) and 1-ethyl-3- (3-dimethylaminopropyl pill) carbodiimide hydrochloride (25 mg, 0.13 mmo 1), N-methylmorpholine (3 7 1 and 0.331111110 1) are added and stirred at room temperature for 15 hours. After the reaction, add 10% citrate and extract twice with ethyl acetate.The organic layer is washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. I do. The residue was purified by preparative thin-layer chromatography (n-hexane: nityl acetate = 1: 3) to give a colorless oil (62 mg, 85%) as a mixture of two isomers.
FABMS(m/z) ： 657 (MH+). FABMS (m / z): 657 (MH + ).
¾一 NMR (CDC13) δ (異性体 A： 2種の回転異性 ί本混合物） 8.06 _8.01 (1H， m) , 7.63— 6.94 (10H, ra)， 6.75— 6.61 (2H, m)， 4.94-4.74(1H, m)， 4.39-4.01 (5H, ra) , 3.80-3.37(7H, m) , 3.14-2.22 (7H, ra)， 1.96— 1.16(11H, ra)； ¾ one NMR (CDC1 3) δ (isomer A: 2 kinds of rotamers ί The mixture) 8.06 _8.01 (1H, m) , 7.63- 6.94 (10H, ra), 6.75- 6.61 (2H, m), 4.94-4.74 (1H, m), 4.39-4.01 (5H, ra), 3.80-3.37 (7H, m), 3.14-2.22 (7H, ra), 1.96—1.16 (11H, ra);
(異性体 B ： 2種の回転異性体混合物） 8.06— 8.00(lH，m)， 7.61— 7.06(9H，m), 6.89— 6.63 (3H， ra)， 5.04-4.13 (3H, m) , 4.08 (2Η, q, J=7.3Hz)， 3.95-3.47 (5H, ra) , 3.60 (3H， s)， 3.10-2.43 (4H， ra) , 2.22 (3H, s)， 2.05— 1.03 (8H， m)， 1.20 (3H， t, J=7.3Hz). (Isomer B: mixture of two rotamers) 8.06-8.00 (lH, m), 7.61—7.06 (9H, m), 6.89—6.63 (3H, ra), 5.04-4.13 (3H, m), 4.08 (2Η, q, J = 7.3Hz), 3.95-3.47 (5H, ra), 3.60 (3H, s), 3.10-2.43 (4H, ra), 2.22 (3H, s), 2.05-1.03 (8H, m ), 1.20 (3H, t, J = 7.3Hz).
(3) 1 , 2, 3， 5—テ 卜ラヒ ドロー 1一 [ 1一 [ 3—メ トキシ一 4一 （ 3— — トリノレウレイ ド） フエニル] ァセチル一 3—ピベリジニル] メ^ " 'レー 5— 一 2一ォキソ一 4 , 1 一べンゾォキサゼピン一 3—酢酸  (3) 1, 2, 3, 5—Tetrahi Draw 1-1 [1- [3-Methoxy-1-41 (3-—trinoureido) phenyl] Acetyl-1 3-Piberidinyl] 1,2-oxo-4,1,1-benzoxazepine-13-acetic acid
(2) で得た化合物 （4 7mg、 0. 0 8mmo 1 ) を先の実施 」 1 (3) と同 様に処理して無色粉末 （ 4 2 m g、 9 3%) を 2種の異性体混合 ¾として得た。  The compound obtained in (2) (47 mg, 0.08 mmo 1) was treated in the same manner as in 1) (3) to give a colorless powder (42 mg, 93%) in two isomers. Obtained as mixture ¾.
FABMS (m/z) ： 629 (MH+) . FABMS (m / z): 629 (MH + ).
¾一 NMR (CDC13) δ： (異性体 A: 2種の回転異性体混合物） 8.01— .93 (lH，ra), 7.52 -7.06(10H, ra), 6.70-6.57 (2H, ra) , 4.85— 4.62 (1H, ra), 4.47-2.56 14H， m), 2.21 (3H, s), 1.67— 1.21(8H， m)； ¾ one NMR (CDC1 3) δ: (isomer A: 2 rotamers mixture) 8.01- .93 (lH, ra) , 7.52 -7.06 (10H, ra), 6.70-6.57 (2H, ra), 4.85—4.62 (1H, ra), 4.47-2.56 14H, m), 2.21 (3H, s), 1.67—1.21 (8H, m);
(異性体 B： 2種の回転異性 ί本混合物） 8.02-7.89 (1H, m)， 7.52-6. 5(10H, ra) , 6.67 一 6· 61 (2H， ra)， 4.95— 4.73 (1H， ra)， 4.41一 4.36 (1H, m)， 4.20— 4.11 ' 1H, m) ,  (Isomer B: Two kinds of rotamers: This mixture) 8.02-7.89 (1H, m), 7.52-6.5 (10H, ra), 6.67-61 (2H, ra), 4.95—4.73 (1H , Ra), 4.41-4.36 (1H, m), 4.20-4.11 '1H, m),
4.00-3.26 (8H, ra), 3.17-2.19 (7H, ra) , 2.12-0.95 (8H, m) . 4.00-3.26 (8H, ra), 3.17-2.19 (7H, ra), 2.12-0.95 (8H, m).
〔実施例 1 5 6〕 1 , 2, 3， 5—テトラヒ ドロー 1— [1一 [3—メ トキシ一 4 ― (3— o— トリノレウレイ ド） フエニル] ァセチル一 3—ピペリジニル] メチルー 2—ォキソ一 4， 1一べンゾォキサゼピン一 3—酢酸  [Example 1556] 1,2,3,5-tetrahydro 1- [1- [3-methoxy-14- (3-o-trinoureido) phenyl] acetyl-1-3-piperidinyl] methyl-2-oxo 1,4,1 Benzoxazepine-13-acetic acid
Figure imgf000045_0001
実施例 1 5 5と同様にして、 表題化合物を黄色粉末 （ 2種の異性！'本混合物） とし て得た。
Figure imgf000045_0001
The title compound was obtained as a yellow powder (two kinds of isomers! 'The mixture) in the same manner as in Example 15-55.
FABMS (ra/z) ： 615 (MH+).  FABMS (ra / z): 615 (MH +).
— NMR (CDC13) δ ： 8.04-7.92 (1H, ra) , 7.53-6.96 (10Η, m) , 6.77-6.65 (2H, ra) , .86-3.27 (12H, ra) , 3.22-2.25 (7H, m) , 2.16— 0.97 (5H, m) · 〔実施例 1 5 7〕 (3 S) 一 2, 3—ジヒ ドロ一 1— [1— [3—メ トキシー 4— (3— o— ト リノレゥレイ ド） フエニル] ァセチルー 3一ピペリジニル] メチ /レー 5 - NMR (CDC1 3) δ: 8.04-7.92 (1H, ra), 7.53-6.96 (10Η, m), 6.77-6.65 (2H, ra), .86-3.27 (12H, ra), 3.22-2.25 (7H , m), 2.16— 0.97 (5H, m) [Example 1557] (3S) -1,2,3-dihydro-1- [1- [3-methoxy 4- (3-o-trinoleide) phenyl] acetyl-31-piperidinyl] methyl / leh Five
—メチルー 2—ォキソ一 1 H—ピリ ド [3, 2 - e ] [1， 4] ジァゼピン一 3— 酢酸 —Methyl-2-oxo-1-H-pyrido [3,2-e] [1,4] diazepine-3-acetic acid
Figure imgf000046_0001
実施例 1 5 5と同様にして、 表題化合物を黄色粉末 （2種の異性 (本混合物） とし て得た。
Figure imgf000046_0001
The title compound was obtained as a yellow powder (two types of isomers (this mixture)) in the same manner as in Example 15 55.
FABMS (m/z) ： 627 (MH+) . FABMS (m / z): 627 (MH + ).
ー讀 (CD30D) 6 ： (異性体 A： 2種の回転異性体混合物) 8, 77— 8.63(lH,m)， 8, 16-7.57(4H, m), 7.20— 6.64 (5H, m) , 4.60-4.18 (2H, ra), 3.96— 2.29(18H, m)， 1.90-1.05 (5H, m)； Over讀(CD 3 0D) 6: (isomer A: 2 rotamers mixture) 8, 77- 8.63 (lH, m), 8, 16-7.57 (4H, m), 7.20- 6.64 (5H, m), 4.60-4.18 (2H, ra), 3.96-2.29 (18H, m), 1.90-1.05 (5H, m);
(異性体 B ： 2種の回転異性体混合物） 8.79 (IH, d， J=4. OHz)， 8.24 (1H, d， J=8.3Hz)， .98 (IH, d, J=8.2Hz), 7.94— 7.86 (IH, m) , 7.59 (IH, d, J=7.3Hz), 7.20— 7.13 (2H, ra) , .03 (IH, d, J=7.3Hz) , 6.81 (IH, s)， 6.63 (1H， d, 1=7.9Hz) , 4.60— 4.40 (2H, ra) , .86 (3H, s), 3.83-3.50 (5H, m), 3.40— 3, 00 (6H, m), 2.62 (IH, dd， J=12.9, 7.9Hz), .29 (3H, s), 1.87-1.03 (5H， m).  (Isomer B: mixture of two rotamers) 8.79 (IH, d, J = 4. OHz), 8.24 (1H, d, J = 8.3 Hz), .98 (IH, d, J = 8.2 Hz) , 7.94- 7.86 (IH, m), 7.59 (IH, d, J = 7.3 Hz), 7.20- 7.13 (2H, ra), .03 (IH, d, J = 7.3 Hz), 6.81 (IH, s) , 6.63 (1H, d, 1 = 7.9Hz), 4.60—4.40 (2H, ra), .86 (3H, s), 3.83-3.50 (5H, m), 3.40—3,00 (6H, m), 2.62 (IH, dd, J = 12.9, 7.9Hz), .29 (3H, s), 1.87-1.03 (5H, m).
実施例 1 5 5と同様にして、 実施例 1 5 8〜 1 9 3に示す化合物を製造した。 得 られた化合物の物性値を以下の表 1 1および表 1 2に示す。 なお、 Zの欄は前記表 1に対応する。
Figure imgf000047_0001
N— R3一 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.
Figure imgf000047_0001
N—R 31
実施例 I Ζ FABMS (m/z)  Example I Ζ FABMS (m / z)
158 、び †1 615 (MH+) 158, † 1 615 (MH + )
159 、び gi 629 (MH+) 異性体 A 159, and gi 629 (MH +) isomer A
160 、び gi 629 (MH+) 異性体 B 160, gi 629 (MH + ) isomer B
161 29 (MH+) 異性体 A 、び gi 6 161 29 (MH + ) isomer A, gi 6
162 g 162 g
異性体 B 、び 629 (MH+) Isomer B, 629 (MH + )
163 、σ u2 567 (MH+) 163, σ u2 567 (MH + )
164 、び v2 628 (MH+) 164, v2 628 (MH + )
165 、び w2 644 (MH+) 165, w2 644 (MH +)
166 、び f3 634 (MH+) 続き 166, f3 634 (MH + ) Continued
167 、び d3 634 (MH+) 167, d3 634 (MH + )
168 、 f3 609 (MH+) 168, f3 609 (MH + )
169 ヽび o3 596 ( H+) 169 Pavilion o3 596 (H + )
170 、び P3 596 (MH+) 170, P3 596 (MH + )
171 、び 93 576 ( H+) 171 and 93 576 (H + )
172 、び r3 576 (MH+) 73 172, r3 576 (MH + ) 73
ヽ C S3 612 (MH+) ヽ C S3 612 (MH + )
174 、び t3 551 (MH+) 174, t3 551 (MH + )
175 、 a1 597 (MH+) 175, a1 597 (MH + )
176 、び gi 627 (MH+) 176, gi 627 (MH + )
177 a1 611 ( H+) 177 a1 611 (H + )
178 、Ο gi 641 (MH+) 178, Ο gi 641 (MH + )
、 ,
179 Ν 179 Ν
gi 669 (MH+)gi 669 (MH + )
Me Me
180 gi 695 (MH+)180 gi 695 (MH + )
、 ,
181 631 (MH+) 181 631 (MH + )
Figure imgf000049_0001
Figure imgf000049_0001
― N— 3― ― N― 3 ―
実施例 I z FAB MS {m/∑)  Example Iz FAB MS (m / ∑)
H H
182 a1 641 (MH ）  182 a1 641 (MH)
183 H a1 656 (MH+) 183 H a1 656 (MH + )
H H
184 a1 670 (MH")  184 a1 670 (MH ")
185 f1 714 (MH+) 異性体 A 185 f1 714 (MH + ) isomer A
Me  Me
186 f1 714 (MH— ) 異性体 B 186 f1 714 (MH—) isomer B
Me  Me
187 f1 714 (MH ) 異性体 A Me 187 f1 714 (MH) isomer A Me
188  188
異性体 B f1 714 (MH^) Isomer B f1 714 (MH ^)
Me  Me
189 f1 726 (ΜΗή 異性体 A  189 f1 726 (ΜΗή isomer A
190 f1 726 (MH ； 異性体 B 191 - r ί1 698 (MH+) 190 f1 726 (MH; isomer B 191-r ί1 698 (MH + )
192 192
異性体 A 、び g 726 (MH+) Isomer A and g 726 (MH + )
193 、び g 726 (MH+) 異性体 B 193, g 726 (MH + ) isomer B
〔試験例 1〕 V L A— 4 V C AM— 1接着阻害試験 [Test Example 1] V L A—4 V CAM—1 Adhesion Inhibition Test
ヒ ト VCAM— 1 遺伝子をトランスフエク 卜したチャイニーズハムスター卵巣細胞 (CHO細胞） と、 VLA— 4を発現するヒ ト前骨髄球様細胞株 HL— 60細胞間の接着に 対する本発明化合物の阻害活性を下記の方法を用いて評価した。  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.
上記の VCAM— 1発現 CH0細胞を 9 6穴培養プレートに 1穴あたり 7 X 1 03個添 加し、 コンフレントな状態になるまで 1 0 %ゥシ胎児血清 （FCS) 含 Ham' s F— 12 培地で 3 日間培養し、 HL— 60細胞を 0 . 4 %ゥシ血清アルブミン （BSA) 含ハンク ス液に再浮遊し、 5 / M の 2 , —bis— (carbooxy ethyl)— o ，り ― carboxy― fluorescein— Penta acetoxy Methyl ester (BCECF- AM)を添加してラベルする。 FCS 不含 RPMI 1640培地で 4 X 1 06個/ mlに再浮遊した BCECFラベル HL— 60細胞縣濁液 1 8 0 μ 1 に、 種々の濃度の試験物質溶液を 2 0 ,u 1づっ添加して 3 7 °Cで 1 5分 間前処置する。 そして、 前処置した HL— 60細胞を、 VCAM— 1発現 CH0細胞を培養 した 9 6穴プレートに、 1穴あたり 2 X 1 05個重層して、 3 7 °Cで 5分間接着さ せる。 その後プレートを 0 . 4 %BSAハンクス液で満たし、 プレートシ一ラーで力 バーしてプレートを逆さにして、 更に 1 5分間培養する。 洗浄後、 1 %NP— 40 含 PBSを添加して細胞を破壊し、 得られた上清の蛍光強度を cyto Fluor 2300蛍光測 定システム （ミ リポア製） で測定する。 Additional 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. The BCECF label the HL- 60 cell suspension 1 8 0 μ 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. Then, 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. After washing, 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).
またブランクとして、 1 %NP— 40含 PBSの蛍光強度、更にスタンダードとして、 蛍光標識 HL— 60浮遊液を 2 X 1 0 5、 1 0 5, 2 X 1 0 \ 1 0 1個/ ml となるよう：二 1 %NP— 40含 PBSに添加、細胞破壊を行し '、、得られた上清の蛍光強度を測定する： 試験結果は、 スタンダ— ドの測定から作成される検量線により、 コン トロールお よび試験物質添加による VCAM— 1発現 CH0細胞に接着した細胞数を測定し、次式に より細胞接着抑制率 （％) を算出する。 As a blank, 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.
試験物質添加群の接着細胞数 細胞接着抑制率 （％) = 1 0 0 X [ 1 一 J コ ト口ール群の接着細胞数 本試験により得られた本発明化合物の 5 0。/。阻害濃度を表 1 3に示す。 表 Ί 3  Number of adherent cells in the test substance-added group Cell adhesion inhibition rate (%) = 100 X [110 J Number of adherent cells in the control group] 50 of the compound of the present invention obtained by this test. /. The inhibitory concentrations are shown in Table 13. Table Ί 3
Figure imgf000051_0001
産業上の利用の可能性
Figure imgf000051_0001
Industrial applicability
本発明のァゼピン誘導体は、 優れた V L A— 4アンタゴニス ト作用を有し、 細胞 接着を介する疾患、特に白血球の接着および浸潤により惹起される疾患または V L Α— 4依存性接着過程がある役割を果たす疾患などの V L 4を介する疾患の 治療または予防用医薬として有用である。  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.

Claims

5冃 求 の  5 冃
1. 式 （ I)  1. Formula (I)
Figure imgf000052_0001
Figure imgf000052_0001
(式中、 R1は水素原子、 炭素数 1〜 6のアルキル基、 炭素数 2〜 6のアルケニル 基、 炭素数 3〜 7のシクロアルキル基、 炭素数 7〜1 1のァリールアルキル基、 炭 素数 6〜10のァリール基またはへテロ環基を表し、 R2は水素原子またはカルボ キシル保護基を表し、 R3は炭素数 1〜 6のアルキレン基、 炭素数 2〜 6のァルケ 二レン基、 炭素数 3〜 7のシク口アルキレン基、 2価の炭素数 6〜 1 0のァリール 基または 2価のへテロ環基を表し、 R4は水素原子または炭素数 1〜6のアルキル 基を表し、また、 R4は と結合し環を形成していてもよく、環はさらに酸素原子、 窒素原子、 硫黄原子を構成成分として含んでいてもよく、 環内に二重結合を含んで いてもよく、 置換されていてもよい。 Xはァリール環またはへテロ環を表し、 mは 1〜3の整数を表し、 Yは窒素原子、 酸素原子、 硫黄原子、 一 N (R5) 一 （式中、 R5は独立して R4と同じ意味を表し、 また、 R5は R1と結合し環を形成していても よレ、。） または一 S (O) n— （式中、 nは 1〜2の整数を表す。） を表し、 Yが窒 素原子の時には式中の破線は二重結合を表す。 Zは式 (Wherein, 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 alkenylene having 2 to 6 carbon atoms. Represents a cycloalkylene group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms or a divalent heterocyclic group, and R 4 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. And R 4 may be bonded to and form a ring, and the ring may further contain an oxygen atom, a nitrogen atom, or a sulfur atom as a constituent, and contains a double bond in the ring. X represents an aryl ring or a hetero ring, and m represents an integer of 1 to 3 Y is a nitrogen atom, an oxygen atom, a sulfur atom, in one N (R 5) i (wherein, R 5 independently are as defined R 4, also, R 5 forms a bond with ring with R 1 ) Or one S (O) n— (where n represents an integer of 1 to 2), and when Y is a nitrogen atom, the dashed line in the formula represents a double bond. Z is the formula
R8 — R7 — R6 — A1 — R 8 — R 7 — R 6 — A 1 —
(式中、 A1は、 メチレン基、 スルホニル基、 カルボニル基またはチォカルボニル 基を表し、 R6は炭素数 1〜 6のアルキレン基、 炭素数 2〜 6のァルケニンン基、 炭素数 3〜 7のシクロアルキレン基、 2価の炭素数 7〜1 1のァリールアルキル基、 2価の炭素数 8〜1 2のァリ—ルァノレケニル基、 2価の炭素数 6〜1 0のァリ—ノレ 基または 2価のへテロ環基を表し、 Rsは炭素数 1〜6のアルキル基、 炭素数 2〜 6のアルケニル基、 炭素数 3〜 7のシクロアルキル基、 炭素数 7〜 1 1のァリール アルキル基、 炭素数 8〜 1 2のァリ ールアルケニル基、 炭素数 6〜 1 0のァリー/レ 基またはへテロ環基を表し、 また、 R8は R6と結合し環を形成していてもよレ、。 R 7は式 R NI (In the formula, A 1 represents a methylene group, a sulfonyl group, a carbonyl group or a thiocarbonyl group, and R 6 is an alkylene group having 1 to 6 carbon atoms, an alkenin group having 2 to 6 carbon atoms, and a carbon atom having 3 to 7 carbon atoms. Cycloalkylene group, divalent C7-C11 arylalkyl group, divalent C8-C12 arylalkenyl group, divalent C6-C10 arylene group R s 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, or a 7 to 11 carbon atoms. Represents an arylalkyl group, an arylalkenyl group having 8 to 12 carbon atoms, an aryl / le group having 6 to 10 carbon atoms or a heterocyclic group, and R 8 is bonded to R 6 to form a ring. You can. R 7 is the formula R NI
c、  c,
A A
N人 ノ \ 、N ゝ、  N people \, N ゝ,
10 、A、  10, A,
R FT  R FT
Figure imgf000053_0001
Figure imgf000053_0001
(式中、 R9および R"1はそれぞれ独立して水素原子、炭素数 1〜6 (Wherein R 9 and R ″ 1 are each independently a hydrogen atom, a carbon number of 1 to 6
たは水酸基を表し、 R9は R6または Rsと結合し環を形成していてもよい。 は酸 素原子または硫黄原子を表し、 A3はメチレン基、 カルボニル基、 チォカルボニル 基、 酸素原子または一 S ( O ) P- (式中、 pは 0〜2の整数を表す。） を表す J のいずれかを表す。） を表す。） で表されるァゼピン誘導体またはその塩。 Or R 9 represents a hydroxyl group, and R 9 may combine with R 6 or R s to form a ring. Represents a oxygen atom or a sulfur atom, A 3 is methylene group, a carbonyl group, Chio carbonyl group, (wherein, p is expressed. An integer of 0 to 2) oxygen atom or a S (O) P- represent the Represents one of J. ). Or a salt thereof.
2. 式 （ I ) 2. Formula (I)
Figure imgf000054_0001
Figure imgf000054_0001
(式中、 R1は水素原子、 炭素数 1〜6のアルキル基、 炭素数 3〜 7のシクロアル キル基、 炭素数 6〜 1 0のァリール基またはへテロ環基を表し、 R2は水素原子を 表し、 R3は炭素数 1〜6のアルキレン基、 炭素数 2〜 6のァルケ二レン基、 炭素 数 3〜 7のシクロアルキレン基、 2価の炭素数 6〜 1 0のァリール基または 2価の ヘテロ環基を表し、 R4は水素原子または炭素数 1〜 6のアルキル基を表し、また、 R4は R3と結合し環を形成していてもよく、 環はさらに酸素原子を構成成分として 含んでいてもよく、 環内に二重結合を含んでいてもよく、 置換されていてもよレ、。 (In the formula, R 1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group or a heterocyclic group having 6 to 10 carbon atoms, and R 2 represents hydrogen. R 3 represents an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms, a cycloalkylene group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, or Represents a divalent heterocyclic group, R 4 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R 4 may be bonded to R 3 to form a ring, and the ring further comprises an oxygen atom May be included as a constituent, may contain a double bond in the ring, and may be substituted.
Xはァリール環またはへテロ環を表し、 mは 1または 2を表し、 Yは窒素原子、 酸 素原子、 硫黄原子、 一 N (R5) 一 （式中、 R5は独立して R4と同じ意味を表し、 ま た、 R5は R1 と結合し環を形成していてもよい。） を表し、 Yが窒素原子の時には 式中の破線は二重結合を表す。 Zは式 X represents an aryl ring or a hetero ring, m represents 1 or 2, Y represents a nitrogen atom, an oxygen atom, a sulfur atom, one N (R 5 ) 1 (wherein R 5 is independently R 4 And R 5 may combine with R 1 to form a ring.), And when Y is a nitrogen atom, the broken line in the formula represents a double bond. Z is the expression
R8 — R7 — R6 — A1 — R 8 — R 7 — R 6 — A 1 —
(式中、 A1は、 スルホニル基またはカルボ二ル基を表し、 R6は炭素数 1〜6のァ ルキレン基、 炭素数 2〜 6のァルケ二レン基、 2価の炭素数 7〜 1 1のァリールァ ルキル基、 2価の炭素数 8〜 1 2のァリールアルケニル基、 2価の炭素数 6〜 1 0 のァリール基または 2価のへテロ環基を表し、 R8は炭素数 1〜 6のアルキル基、 炭素数 7〜 1 1のァリ ールアルキル基、 炭素数 8〜 1 2のァリールアルケニル基、 炭素数 6〜 1 0のァリール基またはへテロ環基を表し、 また、 R8は R6と結合し環 を形成していてもよいつ R7は式 A2 (In the formula, A 1 represents a sulfonyl group or a carbonyl group, R 6 is an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms, and a divalent carbon atom having 7 to 1 carbon atoms. 1 represents an arylalkyl group, a divalent carbon atom having 8 to 12 carbon atoms, a divalent aryl group having 6 to 10 carbon atoms or a divalent heterocyclic group, and R 8 represents 1 carbon atom. Represents an alkyl group having 6 to 6 carbon atoms, an arylalkyl group having 7 to 11 carbon atoms, an arylarylalkenyl group having 8 to 12 carbon atoms, an aryl group or a heterocyclic group having 6 to 10 carbon atoms, and R 8 R 7 where one may combine to form a ring with R 6 of the formula A 2
R9 R 9
Ai  Ai
N人 T 、A N、 \N people T, A N, \
1。 ή9 FT 1. ή 9 FT
A3 A 3
(式中、 R9および R "1はそれぞれ独立して水素原子、炭素数 1〜6のアルキル基ま たは水酸基を表し、 R9は R6または R8と結合し環を形成していてもよい。 A2は酸 素原子を表し、 A3はメチレン基、カルボニル基、酸素原子または一 S 0 2—を表す。） のいずれかを表す。） を表す。 また、 R 1 , X , R 6または R 8を表す基または環は 置換されていてもよい。） で表されるァゼピン誘導体またはその塩。 (Wherein, 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 2 represents an oxygen atom, and A 3 represents any one of a methylene group, a carbonyl group, an oxygen atom or 1 S 0 2 —), and R 1 , X, The group or ring representing R 6 or R 8 may be substituted.) Or a salt thereof.
3 . 請求の範囲第 1項または第 2項：こ記載 誘導体またはその塩を 有効成分として含有する医薬。 3. Claims 1 or 2: A medicament comprising the derivative or a salt thereof as an active ingredient.
4 . 請求の範囲第 1項または第 2項に記載のァゼピン誘導体またはその塩を 有効成分として含有する V L A— 4アンタゴニスト。 4. A VLA-4 antagonist containing the azepine derivative or a salt thereof according to claim 1 or 2 as an active ingredient.
5 . 請求の範囲第 1項または第 2項に記載のァゼピン誘導体またはその塩を 哺乳類に投与することを含む、 細胞接着を介する疾患の治療または予防方法。 5. A method for treating or preventing a disease mediated by cell adhesion, which comprises administering the azepine derivative or a salt thereof according to claim 1 or 2 to a mammal.
6 . 請求の範囲第 1項または第 2項に記載のァゼピン誘導体またはその塩を 哺乳類に投与することを含む、 V L A— 4を介する疾患の治療または予防方法。 6. A method for treating or preventing a disease mediated by VLA-4, comprising administering the azepine derivative or a salt thereof according to claim 1 or 2 to a mammal.
7 . 請求の範囲第 1項または第 2項に記載のァゼピン誘導体またはその塩を 哺乳類に投与することを含む、 リウマチ性関節炎、 腎炎、 炎症性腸疾患、 全身性二 リテマトーデス、 中枢神経系の炎症性疾患、 喘息、 アレルギー （遅発性タイプのァ レルギ一など）、 多発性硬化症、 心臓血管性疾患、 動脈硬化症、 糖尿病もしくは悪 性腫瘍の治療または予防方法、 移植臓器の損傷予防方法、 または腫瘍増殖もしくは 転移阻止方法。 7. The azepine derivative or a salt thereof according to claim 1 or 2 Including administration to mammals, including rheumatoid arthritis, nephritis, inflammatory bowel disease, systemic erythematosus, inflammatory diseases of the central nervous system, asthma, allergies (such as late-onset allergies), multiple sclerosis To treat or prevent disease, cardiovascular disease, arteriosclerosis, diabetes or malignant tumors, to prevent transplanted organ damage, or to prevent tumor growth or metastasis.
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