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    • 专利摘要:
    A therapeutic agent for kidney disease containing the compound or optically active isomer represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient: [Wherein X represents an oxygen atom or a group represented by the following general formula (2): (Wherein n represents an integer of 0 to 2), R 1 represents a hydrogen atom or an acyl group, R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group, R 3 represents a lower alkyl group, R 4 , R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted aryl group, and R 6 is also a formyl group , Carboxyl group, lower alkoxycarbonyl group or optionally substituted carbamoyl group, R 3 and R 4 together may form a 5-membered ring, or R 5 and R 6 may form a saturated heterocyclic group or a cycloalkyl group containing one or more oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms, Provided that the 5-membered ring formed by R 3 and R 4 and the benzene ring together are benzofuran, benzo [b] thiophene, benzo [b] thiophene-1-oxide or benzo [b] thiophene-1,1-diox When seeding, there is no R 6 ].
    公开号:KR20000022211A
    申请号:KR1019980710630
    申请日:1997-05-23
    公开日:2000-04-25
    发明作者:오사무 신시；요시아끼 다까시마；구니오 다무라；아끼라 이시까와；요시아끼 가또
    申请人:나가야마 오사무；쥬가이 세이야쿠 가부시키가이샤；
    IPC主号:
    专利说明:

    Kidney Disease Therapeutics and Organ Preservatives
    The kidney is one of the organs associated with potential oxidative stress in humans. Various kidney diseases, such as acute renal failure, drug-induced nephropathy, glomerular nephropathy, diabetic nephropathy, chronic renal failure, and the importance of radical injury by free radicals or free radicals in the formation and progression of kidney transplantation It has been pointed out for a long time. Recently, the role of lipids in cellular injury is of particular interest (Keane WF, Lipids and Kidney. Kidney Int., 46: 910-920, 1994; Higuchi and Sanaka, "Renal Disease", Antioxidants-Free radicals and biological defense) (Niki, Shimazaki and Mino, eds.) Gakkai Shuppan Center, 223-229,1994; Aoyagi "Therapy with Antioxidants / Scavenger, No. 3, Renal Diseases", Biomedicine & Therapeutics, 26: 592-596, 1992). However, the effects of antioxidants, particularly inhibitors of lipid peroxidation, fh, have not been able to explain kidney disease well, and no useful compounds have been reported that inhibit lipid peroxidation as a therapeutic or preservative or long term preservative.
    Vitamin E (α-tocopherol) is a natural potent inhibitor of lipid peroxidation and its use in kidney transplantation and renal ischemia models has been reported (Marubayashi, Dohi and Kawasaki "Renal maintenance and active oxygen species", Kidney and Dialysis, 24: 785-790, 1988; Takenaka M., Tatsukawa Y., Dohi K., Ezaki H., Matsukawa K., Kawasaki T., Transplantation, 32: 137-141, 1981). Not. This is because vitamin E acts only on the surface of membranes and lipids and does not inhibit lipid peroxidation inside membranes and lipids (Niki E., Chem. Phys. Lipids, 44: 227-253, 1987). ). Because vitamin E is present in sufficient amounts endogenously (Nakamura "Absorption, Distribution and Excretion of Vitamin E", Vitamin E-Basic and Clinical Study (Igarashi, eds.), Ishiyaku Shuppan, 33-58, 1985), E is expected to have an inhibitory effect on lipid peroxidation close to the surface of the membrane and lipids. On the other hand, since the membrane and lipids exhibit insufficient defense against lipid peroxidation, it is considered that inhibiting lipid peroxidation in the membrane and lipids is important for the treatment and prevention of kidney disease. In addition, the effect of probucol, a type of fat-soluble antioxidant, has been reported on various kidney disease models (Modi KS, Schreiner GF, Purkerson ML, J. Lab. Clin. Med., 120: 310-317, 1992; Bird JE, Milhoan K., Wilson CB, Young SG, Mundy CA, Partha sarathy S., Blantz RC, J. Clin.Invest., 81: 1630-1638, 1988; Hirano T., Mamo JCL, Nagano S., Sugisaki T., Nephron, 58: 95-100, 1991). However, simple phenolic compounds such as probucol and butylated hydroxytoluene have a 10 or 100 times lower reactivity to α-tocopherols in lipid peroxy radicals (Gotoh N., Shimizu K., Komuro E., Tsuchiya J.). , Noguchi N., Niki E., Biochem.Biophys.Acta, 1128: 147-154, 1992; Burton GW, Ingold KU, J. Am. Chem. Soc., 103: 6472-6477, 1981). Thus, probucol did not show a sufficient protective effect on kidney function.
    Thus, potent cytoprotectants that inhibit lipid peroxidation, which are hardly inhibited by vitamin E, are expected to be effective in the prevention and treatment of various kidney diseases and in the preservation of organs, but such agents have not been reported yet.
    The present invention relates to a therapeutic agent or organ preservative for kidney disease. More specifically, the present invention relates to nephropathy caused by chronic renal failure, diabetic nephropathy, glomerulonephritis, immunocomplex nephritis, acute renal failure, platinum complexes such as cisplatin or other drugs such as gentamicin, para The present invention relates to therapeutic agents and long-term preservatives containing 2,5-di-t-butylphenol derivatives as active ingredients in various kidney diseases such as nephropathy and uremia due to pesticides such as Paracort.
    As a result of intense research to solve the above problems, not only the compound represented by the following formula (1) or the optically active isomer or pharmaceutically acceptable salt thereof shows a strong cytoprotective effect on the cells induced in the kidney, It has been found to exhibit a powerfully improved effect on renal function in puromycin-induced nephropathy and ischemic active renal failure models, thus completing the present invention:

    [Wherein X represents an oxygen atom or a group represented by the following general formula (2):

    (Wherein n represents an integer of 0 to 2),
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 3 represents a lower alkyl group,
    R 4 , R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted aryl group, and R 6 is also a formyl group , Carboxyl group, lower alkoxycarbonyl group or optionally substituted carbamoyl group,
    R 3 and R 4 together may form a 5-membered ring, or
    R 5 and R 6 may form a saturated heterocyclic group or a cycloalkyl group containing one or more oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms,
    Provided that the 5-membered ring formed by R 3 and R 4 and the benzene ring together are benzofuran, benzo [b] thiophene, benzo [b] thiophene-1-oxide or benzo [b] thiophene-1,1-diox When forming a seed, there is no R 6 ].
    Some of the compounds represented by formula (1) have already been disclosed in patent publications (JP 6-206842, WO94 / 08930, JP 7-330759 / 95, WO95 / 27710).
    Preferred Embodiments of the Invention
    In the definition of the compound represented by the formula (1), acyl groups in R 1 include acetyl, formyl, propionyl, benzoyl, benzyloxycarbonyl, aminoacetyl, N-methylaminoacetyl and N, N-dimethylamino It includes an acetyl group. Lower alkyl group in R 2 means a C 1-6 straight or branched chain alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group. Lower alkenyl group means a C 2-6 straight or branched alkenyl group such as a vinyl, allyl, butenyl, or phenethyl group.
    R 4 , R 5 and R 6 are C 1-20 straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, heptyl , Octyl, nonyl or decyl group. Alkenyl group refers to a C 2-20 straight or branched alkenyl group such as a vinyl, allyl, butenyl, pentenyl, geranyl or farnesyl group. Alkynyl group means a C 2-20 straight or branched alkynyl group such as ethynyl, propynyl or butynyl group. Aryl group means a monovalent substituent obtained by removing a hydrogen atom from an aromatic hydrocarbon, such as a phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl or phenanthryl group.
    Substituents of an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group and an optionally substituted aryl group include a halogen atom, a lower alkyl group, a lower alkenyl group, a hydroxyl group, an amino group, a substituted amino group such as dimethylamino, and an alkoxy group And acyloxy groups such as 3,5-di-t-butyl-4-hydroxy-2-methylphenoxy, nitro groups, trifluoromethyl groups, phenyl groups and acetoxy groups. Halogen atoms include chlorine, bromine, fluorine and iodine. Lower alkyl and lower alkenyl groups include those described above for R 2 . Alkoxy groups include alkyloxy groups derived from the alkyl groups described in R 4 , R 5, and R 6 above.
    Five-membered rings formed of R 3 and R 4 include furan rings, dihydrofuran rings, thiophene rings, and dihydrothiophene rings, each of which is a dihydrobenzofuran ring with a benzene ring in formula (1), To form a benzo [b] thiophene ring and a dihydrobenzothiophene ring.
    The cycloalkyl group formed from R 5 and R 6 means a C 3-8 cycloalkyl group, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooxyl group. Saturated heterocyclic groups containing at least one oxygen atom, sulfur atom or alkyl-substituted nitrogen atom include tetrahydropyranyl, tetrahydrothiopyranyl and N-methylpiperidyl groups.
    R 6 also represents formyl, carboxyl, lower alkoxycarbonyl or optionally substituted carbamoyl group. Lower alkoxycarbonyl groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and t-butoxycarbonyl groups. Optionally substituted carbamoyl groups include mono- or di-lower alkyl-substituted carbamoyl groups, as well as cyclic aminocarbonyl groups. Mono- or di-lower alkyl-substituted carbamoyl groups mean carbamoyl groups substituted with one or more lower alkyl groups such as methyl and ethyl, for example N-methylcarbamoyl, N-ethylcarbamoyl, N , N-dimethylcarbamoyl and N, N-diethylcarbamoyl groups. The cyclic aminocarbamoyl group is a di- which forms a ring in which two organic groups attached to a nitrogen atom, such as pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl and morpholinocarbonyl groups, are formed. By lower alkyl-substituted carbamoyl groups are meant.
    When X is an oxygen atom in the formula (1), the following substituents are preferable.
    R 1 is preferably a hydrogen atom, acetyl, benzyloxycarbonyl, aminoacetyl, N-methylaminoacetyl or N, N-dimethylaminoacetyl group, in particular a hydrogen atom, acetyl or N, N-dimethylaminoacetyl group.
    R 2 is preferably a hydrogen atom, a methyl or n-propyl group, in particular a hydrogen atom.
    Preferably, R 3 and R 4 together form a furan or dihydrofuran ring, in particular a dihydrofuran ring.
    R 5 is preferably hydrogen atom or methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, benzyl, hydroxymethyl, aminomethyl or N, N-dimethylaminomethyl groups, in particular hydrogen atoms or methyl, n-pentyl, benzyl, hydroxymethyl, aminomethyl or N, N-dimethylaminomethyl groups.
    R 6 is preferably a hydrogen atom or methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, benzyl, cyanomethyl, methoxycarb Carbonyl, pyrrolidinocarbonyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylethenyl, 3-aminoguanidinomethyl or N-guanidinoaminomethyl groups, especially hydrogen atoms or methyl, n-pentyl , Benzyl, methoxycarbonyl, pyrrolidinocarbonyl, 3-aminoguanidinomethyl or N-guanidinoaminomethyl group.
    The ring formed of R 5 and R 6 is preferably cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, tetrahydrothiopyranyl or N-methylpiperidyl group, in particular cyclopentyl, cyclohexyl, Cycloheptyl or tetrahydropyranyl groups.
    When X in formula (1) is a group of formula (2)

    (Wherein n is an integer of 0 to 2)
    The following substituents are preferred.
    R 1 is preferably a hydrogen atom or an acetyl, benzyloxycarbonyl, aminoacetyl, N-methylaminoacetyl or N, N-dimethylaminoacetyl group, in particular hydrogen or acetyl or N, N-dimethylaminoacetyl group.
    R 2 is preferably a hydrogen atom or a methyl or n-propyl group, in particular a hydrogen atom.
    Preferably, R 3 and R 4 together form a thiophene or dihydrothiophene ring, in particular a dihydrothiophene ring.
    R 5 is preferably hydrogen atom or methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, hydroxymethyl, aminomethyl or N, N-dimethylaminomethyl group, in particular hydrogen atom or methyl, hydroxymethyl, aminomethyl or N, N-dimethylaminomethyl group.
    R 6 is preferably a hydrogen atom or methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, benzyl, cyanomethyl, methoxycarb Carbonyl, pyrrolidinocarbonyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylethenyl, 3-aminoguanidinomethyl or N-guanidinoaminomethyl groups, especially hydrogen atoms or methyl or n-penes Til group.
    The ring formed of R 5 and R 6 is preferably cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, tetrahydrothiopyranyl or N-methylpiperidyl group, in particular cyanopentyl, cyclohexyl And a cycloheptyl or tetrahydropyranyl group.
    n is preferably 0 or 1, in particular 0.
    Preferred examples of the compound represented by the formula (1) are represented by the formula (3):

    [Wherein X represents an oxygen atom or a group represented by the formula (2):

    (Wherein n represents an integer of 0 to 2),
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 5 and R 6 may be the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted aryl group, R 6 is also a formyl group, A carboxyl group, a lower alkoxycarbonyl group or an optionally substituted carbamoyl group, or
    R 5 and R 6 may together form a saturated heterocyclic group or cycloalkyl group containing one or more oxygen atoms, sulfur atoms or alkyl substituted nitrogen atoms,
    Provided that the bicyclic ring containing X represents benzofuran, benzo [b] thiophene, benzo [b] thiophen-1-oxide or benzo [b] thiophene-1,1-dioxide, 6 is missing.
    The definition and preferable example of each substituent in general formula (3) are the same as that of the said general formula (1).
    Another preferred example of a compound represented by formula (1) is represented by formula (4):

    [Wherein X represents an oxygen atom or a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 5 and R 6 are the same or different and each is a hydrogen atom, a C 1-20 optionally substituted alkyl group, a C 2-20 optionally substituted alkenyl group, a C 2-20 optionally substituted alkynyl group or an optionally substituted aryl group R 6 also represents a formyl group, a carboxyl group, a lower alkoxycarbonyl group or an optionally substituted carbamoyl group, or
    R 5 and R 6 may together form a saturated heterocyclic group or cycloalkyl group containing one or more oxygen atoms, sulfur atoms or alkyl substituted nitrogen atoms.
    Definitions and preferred examples of each substituent in the formula (4) are the same as those mentioned in the formula (1). In addition, R 6 is (i) formyl, carboxyl, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl-substituted carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, pipepe A lazinocarbonyl or morpholinocarbonyl group; (ii) cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl-substituted carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl and mor A C 1-20 alkyl group substituted with one or more substituents selected from the group consisting of polynocarbonyl groups; Or (iii) cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl-substituted carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl and C 2-20 alkenyl groups substituted with one or more substituents selected from the group consisting of morpholinocarbonyl groups. Moreover, R 6 constitutes (i) thioureido, 3-aminoguanidino, N-guanidinoamino, 4-guanidinophenoxy and 4- (N-guanidinoaminomethyl) phenoxy group C 1-20 alkyl group substituted with one or more substituents selected from the group consisting of; Or (ii) thioureido, 3-aminoguanidino, N-guanidinoamino, 4-guanidinophenoxy and 4- (N-guanidinoaminomethyl) phenoxy group Or a C 2-20 alkenyl group substituted with one or more substituents.
    Compounds of formula (1) of the present invention may have an asymmetric center and thus may be optically active. The present invention includes racemic forms as well as optically active forms.
    The compound of formula (1) may form an acid or base addition salt, depending on its substituents. Accordingly, the present invention includes pharmaceutically acceptable salts of compounds of formula (1). Examples of acid addition salts of compounds of formula (1) include inorganic acid salts such as hydrochlorides, sulfates, nitrates and phosphates, as well as acetates, lactates, oxalates, citrates, tartrates and p-toluenesulfonates Contains organic acid salts. Examples of base addition salts of compounds of formula (1) include inorganic base salts such as sodium, potassium, calcium, aluminum and ammonium salts, as well as amine salts.
    Suitable compounds for the purposes of the present invention are as follows:
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2,2-diethyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2,2-di-n-propyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2,2-di-n-butyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2-n-octylbenzofuran;
    4,6-di-t-butyl-5-hydroxy-2-n-octyl-2,3-dihydrobenzofuran;
    2,4,6-tri-t-butyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2,2-di-i-propyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2,2-diphenyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2,2-dibenzyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2-chloromethyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclohexane;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1'-cycloheptane;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclooctane;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-4'-tetrahydropyran;
    5-hydroxy-4,6-di-t-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxybenzofuran;
    4,6-di-t-butyl-5-hydroxy-2-methylbenzofuran;
    2,4,6-tri-t-butyl-5-hydroxybenzofuran;
    2,6-di-t-butyl-3-methyl-4-propyloxyphenol;
    4-allyloxy-2,6-di-t-butyl-3-methylphenol;
    1,3-bis (3,5-di-t-butyl-4-hydroxy-2-methylphenoxy) propane;
    4,6-di-t-butyl-2,2-di-n-pentyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2,2-di-n-octyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2,2-di-n-heptyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2,2-di-n-hexyl-5-hydroxy-2,3-dihydrobenzofuran;
    2,2-di-i-amyl-4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8,12-trimethyltrideca-3 (E), 7 (E), 11-trienyl) -2 , 3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4 ', 8', 12'-trimethyltridecyl) -2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2- (5-hydroxy-4-methyl-3 (E) -pentenyl) -2-methyl-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxybenzo [b] thiophene;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-diethyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-di-n-propyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-di-i-propyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-di-n-butyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-di-i-amyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-di-n-hexyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-di-n-heptyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-di-n-octyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-diphenyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-dibenzyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8,12-trimethyltrideca-3 (E), 7 (E), 11-trienyl) -2 , 3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8,12-trimethyltridecyl) -2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2-n-octyl-2,3-dihydrobenzothiophene;
    2,4,6-tri-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-7-n-propyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-1'-cyclopentane;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-1'-cyclohexane;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-1'-cycloheptane;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-1'-cyclooctane;
    4,6-di-t-butyl-2-methyl-5-hydroxybenzo [b] thiophene;
    2,4,6-tri-t-butyl-5-hydroxybenzo [b] thiophene;
    4,6-di-t-butyl-2-n-octyl-5-hydroxybenzo [b] thiophene;
    4,6-di-t-butyl-5-hydroxy-2- (N, N-dimethylaminomethyl) -2-methyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8-dimethylnona-3 (E), 7-dienyl) -2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8-dimethylnonyl) -2,3-dihydrobenzothiophene;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-4'-tetrahydrothiopyran;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-4'-tetrahydropyran;
    2-aminomethyl-4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-2-cyanomethyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-carboxylic acid;
    4,6-di-t-butyl-5-hydroxy-2-methoxycarbonyl-2-methyl-2,3-dihydrobenzofuran;
    1- (4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-carbonyl) pyrrolidine;
    Ethyl 3- (4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) -2-propenoate;
    Ethyl 3- (4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) propanoate;
    6- (4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) -5-hexenoic acid;
    6- (4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) hexanoic acid;
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-4 '-(1'-methylpiperidine);
    1-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] thiourea;
    1-amino-3-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] guanidine;
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4-nitrophenoxymethyl) -2,3-dihydrobenzofuran;
    2- (4-aminophenoxymethyl) -4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran;
    1- (4-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] phenyl) guanidine;
    1- {4-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzylideneamino) guanidine;
    1- {4-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzylamino) guanidine; And
    1-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methylamino] guanidine.
    Some compounds represented by the general formula (1) used in the present invention can be synthesized according to the procedures described in, for example, JP 6-206842 / 94 and 7-330759 / 95.
    Some compounds of the present invention can be synthesized according to the following scheme.
    Scheme A

    Wherein R 1 represents a hydrogen atom or an acyl group, R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group, and R 5 , R 7 and R 8 may be the same or different and each represents a hydrogen atom, optionally substituted. A substituted alkyl group or an optionally substituted alkenyl group, R 9 and R 10 may be the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkenyl group, and R 9 and R 10 collectively contain one or more nitrogen atoms and May form a 5-8 membered heterocyclic ring which may further contain one or more heteroatoms such as oxygen and sulfur atoms, and R 11 represents a hydrogen atom, an acyl group, a lower alkyl group, a lower alkenyl group or any Substituted aryl groups.)
    Scheme B

    (Wherein R 1 , R 2 , R 5 , R 9 and R 10 are as defined above, A represents a protecting group such as trimethylsilyl, X represents an oxygen atom or a sulfur atom, R 12 represents an optionally substituted alkyl group, An optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted aryl group, R 13 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted aryl group, m Represents an integer of 0 to 18.)
    In Scheme A, the reaction to produce the compound of formula (4) is carried out by treating the compound of formula (1) obtained according to the method described in JP 7-330759 / 95 in the presence of a base such as sodium bicarbonate and iodine, The reaction is carried out in a mixed solvent such as diethyl ether. Alternatively, the compound of formula (4) reacts the compound of formula (1) with m-chloroperbenzoic acid in a solvent such as chloroform and then methanesulfonyl chloride in a solvent such as dichloromethane in the presence of a base such as triethylamine. Can be obtained by reaction with sodium iodide in a solvent such as N, N-dimethylformamide.
    Various derivatives can be obtained from compounds of formula (4) according to the following three methods:
    1. A compound of formula (4) is reacted with alkylamine or ammonia, such as primary amine or secondary amine, in a solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate at room temperature, or potassium phthal Reaction with imide to yield the compound of formula (5);
    2. reacting the compound of formula (4) with potassium cyanide or the like in a solvent such as N, N-dimethylformamide or dimethyl sulfoxide to give the compound of formula (6); And
    3. The compound of formula (4) is reacted with an alkali metal carboxylate such as sodium acetate in a solvent such as N, N-dimethylformamide, dimethyl sulfoxide or hexamethyl phosphate triamide, or a base such as sodium hydride Reaction with alkyl alcohol or phenol in the presence of gives a compound of formula (7).
    In Scheme B, the compound of formula (9) is a compound of formula (8) obtained by the method described in Scheme A or JP 7-330759 / 95 above in a solvent such as tetrahydrofuran or hexane diisobutylaluminum hydride Or by reacting with lithium aluminum hydride. Compounds of formula (10) can be obtained by reacting compounds of formula (9) with trimethylsilyl trifluoromethanesulfonate in the presence of a base such as 2,6-lutidine. The compound of formula (11) can be obtained by oxidizing the compound of formula (10) with a combination of dimethyl sulfoxide, oxalyl chloride and the like. Various derivatives can be obtained from compounds of formula (11) according to the following five methods:
    1. The compound of formula (11) is oxidized with sodium chlorite in a mixture of t-butyl alcohol and the like, an aqueous solution of sodium dihydrogen phosphate to give a compound of formula (12), which is then added in a solvent such as tetrahydrofuran. deprotecting with n-butylammonium fluoride or the like to obtain a compound of formula (15);
    2. A process for reacting a compound of formula (12) with a catalytic amount of hydrogen chloride in an alkyl alcohol to give a compound of formula (14). Alternatively, the compound of formula (12) is reacted with an alkyl halide in a solvent such as N, N-dimethylformamide, dimethyl sulfoxide or hexamethylphosphate triamide in the presence of a base such as sodium hydride to give the compound of formula (13) Obtaining, followed by deprotection with tetra-n-butylammonium fluoride or the like in a solvent such as tetrahydrofuran to give the compound of formula (14);
    3. The compound of formula (12) is reacted with a primary or secondary amine in a solvent such as dichloromethane in the presence of a condensing agent such as benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature. Reacting with the same alkyl amine to give a compound of formula (16), which is then deprotected with tetra-n-butylammonium fluoride or the like in a solvent such as tetrahydrofuran to obtain a compound of formula (17);
    4. The compound of formula (11) is reacted with a Witting reagent or Hornner-Emons reagent in a solvent such as tetrahydrofuran to give a compound of formula (18), which is tetrahydrofuran Deprotecting with tetra-n-butylammonium fluoride or the like in a solvent such as to obtain a compound of formula (19); And
    5. Catalytic reduction of the compound of formula (18) in a solvent such as ethyl acetate in the presence of a transition metal catalyst such as palladium yields the compound of formula (20), which is then tetra-n-butyl in a solvent such as tetrahydrofuran Deprotection with ammonium fluoride or the like to give the compound of formula (21).
    The therapeutic agent for nephropathy of the present invention can be used as various pharmaceutical compositions comprising a physiologically nontoxic physiologically or liquid pharmaceutical carrier together with the compound of formula (1) as an active ingredient. These pharmaceutical compositions are formulated and used in various dosage forms depending on the route of administration. Dosage forms include tablets, granules, pills, capsules, solutions, syrups, suspensions, emulsions and injections. Suitable pharmaceutical carriers include conventional excipients, binders, disintegrants, lubricants, coatings, dissolution aids, emulsifiers, suspending agents, stabilizers and solvents. The amount of the active ingredient represented by the formula (1) contained in the pharmaceutical composition of the present invention is generally 0.01 to 99% by weight, preferably 0.1 to 90% by weight.
    The compound represented by the formula (1) or the pharmaceutical composition of the present invention can be used through oral administration, parenteral administration such as intravenous injection, continuous administration in a sustained release formulation and the like.
    Kidney caused by agrochemicals such as para-coat, nephropathy caused by chronic renal failure, diabetic nephropathy, glomerulonephritis, immunocomplex nephritis, acute renal failure, platinum complexes such as cisplatin or other drugs such as gentamicin The actual requirement of the compound represented by the formula (1) for treating various kidney diseases such as pathology, uremia, or preserving the organs varies depending on the age of the patient, the severity of the condition, the route of administration or other factors. However, it will be in an amount of 1-1000 mg, preferably 10-500 mg per day. In patients in need of such treatment, this amount is preferably administered 1-3 times.
    Organ preservatives of the present invention are used for any organ of humans and animals, such as brain, heart, kidney, pancreas, lung, liver and bone marrow cells. Kidneys are the more preferred organ. The compounds of the present invention may be added to organ perfusate or preservatives to minimize organ injury while preserving organs extracted from organ transplant donors. The organ preservation agent of the present invention can also function to maintain the organ after transplantation by inhibiting the injury of the extracted organ.
    Normally acceptable effective amounts of the compound represented by the formula (1) for use as a preservative to maintain the organs are, for example, 1-1000 mg, which is, for example, at a concentration of 0.1-10000 mg / L. Can be used in preservatives.
    The following Examples and Test Examples 1-4 further illustrate the invention, but are not intended to limit the invention.
    Example
    Following the procedure described in JP 6-206842 / 94, the compounds of the following Examples 1-46 are synthesized.
    Example 1
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 2
    4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran
    Example 3
    5-acetoxy-4,6-di-t-butyl-2,2-dimethyl-2,3-dihydrobenzofuran
    Example 4
    4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran
    Example 5
    5-acetoxy-4,6-di-t-butyl-2,2-diethyl-2,3-dihydrobenzofuran
    Example 6
    4,6-di-t-butyl-2,2-diethyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 7
    4,6-di-t-butyl-2,2-di-n-propyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 8
    4,6-di-t-butyl-2,2-di-n-butyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 9
    5-acetoxy-4,6-di-t-butyl-2- (1-octenyl) benzofuran
    Example 10
    5-acetoxy-4,6-di-t-butyl-2-n-octylbenzofuran
    Example 11
    4,6-di-t-butyl-5-hydroxy-2-n-octylbenzofuran
    Example 12
    4,6-di-t-butyl-5-hydroxy-2-n-octyl-2,3-dihydrobenzofuran
    Example 13
    2,4,6-tri-t-butyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 14
    4,6-di-t-butyl-2,2-di-i-propyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 15
    4,6-di-t-butyl-2,2-diphenyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 16
    4,6-di-t-butyl-2,2-dibenzyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 17
    4,6-di-t-butyl-2-chloromethyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 18
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane
    Example 19
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclohexane
    Example 20
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1'-cycloheptane
    Example 21
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclooctane
    Example 22
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-4'-tetrahydropyran
    Example 23
    4-acetoxy-3,5-di-t-butyl-1- (2-methyl-2-propenyloxy) -2-propylbenzene
    Example 24
    5-acetoxy-4,6-di-t-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran
    Example 25
    5-hydroxy-4,6-di-t-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran
    Example 26
    5-acetoxy-4,6-di-t-butylbenzofuran
    Example 27
    4,6-di-t-butyl-5-hydroxybenzofuran
    Example 28
    4,6-di-t-butyl-5-hydroxy-2-methylbenzofuran
    Example 29
    2,4,6-tri-t-butyl-5-hydroxybenzofuran
    Example 30
    1-acetoxy-2,6-di-t-butyl-3-methyl-4-propyloxybenzene
    Example 31
    2,6-di-t-butyl-3-methyl-4-propyloxyphenol
    Example 32
    1-acetoxy-4-allyloxy-2,6-di-t-butyl-3-methylbenzene
    Example 33
    4-allyloxy-2,6-di-t-butyl-3-methylphenol
    Example 34
    1,3-bis (4-acetoxy-3,5-di-t-butyl-2-methylphenoxy) propane
    Example 35
    1,3-bis (3,5-di-t-butyl-4-hydroxy-2-methylphenoxy) propane
    Example 36
    4,6-di-t-butyl-2,2-di-n-pentyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 37
    4,6-di-t-butyl-2,2-di-n-octyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 38
    4,6-di-t-butyl-2,2-di-n-heptyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 39
    4,6-di-t-butyl-2,2-di-n-hexyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 40
    5-acetoxy-2,2-di-i-amyl-4,6-di-t-butyl-2,3-dihydrobenzofuran
    Example 41
    2,2-di-i-amyl-4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran
    Example 42
    5-acetoxy-4,6-di-t-butyl-2-methyl-2- (4,8,12-trimethyltrideca-3 (E), 7 (E), 11-trienyl) -2 , 3-dihydrobenzofuran
    Example 43
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8,12-trimethyltrideca-3 (E), 7 (E), 11-trienyl) -2 , 3-dihydrobenzofuran
    Example 44
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4 ', 8', 12'-trimethyltridecyl) -2,3-dihydrobenzofuran
    Example 45
    5-acetoxy-4,6-di-t-butyl-2- (5-hydroxy-4-methyl-3 (E) -pentenyl) -2-methyl-2,3-dihydrobenzofuran
    Example 46
    4,6-di-t-butyl-5-hydroxy-2- (5-hydroxy-4-methyl-3 (E) -pentenyl) -2-methyl-2,3-dihydrobenzofuran
    Example 47
    5-acetoxy-4,6-di-t-butyl-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran
    Dissolve 10.0 g of 4-acetoxy-3,5-di-t-butyl-2- (2-methyl-2-propenyl) phenol synthesized according to JP 7-330759 / 95 in 200 ml of chloroform, m- 11.0 g of chloroperbenzoic acid are added and the mixture is heated at reflux for 24 h. After cooling, the reaction solution is combined with saturated aqueous sodium thiosulfate solution and extracted with chloroform. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 25% ethyl acetate to give 5-acetoxy-4,6-di-t-butyl-2-hydroxymethyl-2-methyl- 7.3 g of 2,3-dihydrobenzofuran (rostereomeric mixture) are obtained as colorless oil (yield 70%).
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 1.30 (s, 9H), 1.37 (s, 9H), 1.38 (s, 1.5H), 1.45 (s, 1.5H), 2.30 (s, 3H), 3.06 (d, 0.5H, J = 15.5 Hz), 3.16 (d, 0.5H, J = 15.5 Hz), 3.38 (d, 0.5H, J = 15.5 Hz), 3.52 (d, 0.5H, J = 15.5 Hz ), 3.58-3.72 (m, 2H), 6.75 (s, 0.5H), 6.76 (s, 0.5H).
    Mass: 334 (M + ).
    Example 48
    4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran
    Under a nitrogen atmosphere, a solution of 500 mg of 5-acetoxy-4,6-di-t-butyl-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran in 17 ml of tetrahydrofuran was dissolved in tetra To a suspension of 114 mg of lithium aluminum hydride in 3 ml of hydrofuran is added dropwise. The mixture is heated at reflux for 2 hours and then cooled to room temperature. Ethyl acetate is added dropwise, followed by 10% hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and then concentrated, and the concentrate is purified by silica gel column chromatography, eluting with n-hexane containing 20% ethyl acetate to give 4,6-di-t-butyl-5-. 320 mg of hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran are obtained as a white solid (yield 73%).
    m.p. : 126-128 ° C.
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 1.38 (s, 3H), 1.40 (s, 9H), 1.49 (s, 9H), 2.04 (bs, 1H), 3.14 (d, 1H, J = 15.5 Hz), 3.45 (d, 1H, J = 15.5 Hz), 3.59 (d, 2H, J = 1.65 Hz), 4.74 (s, 1H), 6.65 (s, 1H).
    IR (cm- 1 ): 3648, 3448, 2960.
    Mass: 292 (M + ).
    Following the procedure described in JP 7-330759 / 95, the compounds of the following Examples 49-67 are synthesized.
    Example 49
    5-acetoxy-4,6-di-t-butyl-2,2-di-n-pentyl-2,3-dihydrobenzothiophene
    Example 50
    4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzothiophene
    Example 51
    4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzothiophene
    Example 52
    4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzothiophene
    Example 53
    5-acetoxy-4,6-di-t-butylbenzo [b] thiophene
    Example 54
    4,6-di-t-butyl-5-hydroxybenzo [b] thiophene
    Example 55
    5-acetoxy-4,6-di-t-butylbenzo [b] thiophene-1,1-dioxide
    Example 56
    5-acetoxy-4,6-di-t-butyl-2,3-dihydrobenzothiophene-1,1-dioxide
    Example 57
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene
    Example 58
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-1'-cyclohexane
    Example 59
    5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzothiophene
    Example 60
    5-acetoxy-4,6-di-t-butyl-2- (N, N-dimethylaminomethyl) -2-methyl-2,3-dihydrobenzothiophene
    Example 61
    4,6-di-t-butyl-5-hydroxy-2- (N, N-dimethylaminomethyl) -2-methyl-2,3-dihydrobenzothiophene
    Example 62
    5-acetoxy-2-acetoxymethyl-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzothiophene
    Example 63
    4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzothiophene
    Example 64
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8-dimethylnona-3 (E), 7-dienyl) -2,3-dihydrobenzothiophene
    Example 65
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8-dimethylnonyl) -2,3-dihydrobenzothiophene
    Example 66
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8,12-trimethyltrideca-3 (E), 7 (E), 11-trienyl) -2 , 3-dihydrobenzothiophene
    Example 67
    4,6-di-t-butyl-5-hydroxy-2-methyl-2- (4,8,12-trimethyltridecyl) -2,3-dihydrobenzothiophene
    Example 68
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-4'-tetrahydrothiopyran
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-4'-tetrahydrothiopyran is synthesized according to the procedure described in JP 6-206842 / 94.
    m.p. : 209.2 ° C.
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 1.41 (s, 9H), 1.48 (s, 9H), 1.77-1.94 (m, 2H), 2.09-2.21 (m, 2H), 2.45-2.58 (m , 2H), 2.98-3.12 (m, 2H), 3.18 (s, 2H), 4.73 (s, 1H), 6.66 (s, 1H).
    IR (cm- 1 ): 3628, 2936.
    Mass: 334 (M + ).
    Example 69
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-4'-tetrahydropyran
    4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-4'-tetrahydropyran is synthesized according to the procedure described in JP 7-330759 / 95.
    1 H NMR (270 MHz, CDCl 3 ) δ PPM: 1.40 (s, 9H), 1.53 (s, 9H), 1.87-1.92 (m, 4H), 3.38 (s, 2H), 3.61-3.70 (m, 2H ), 3.86-3.91 (m, 2H), 5.15 (s, 1H), 6.98 (s, 1H).
    Mass: 334 (M + ).
    Example 70
    2-aminomethyl-4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran
    1) Synthesis of 5-acetoxy-4,6-di-t-butyl-2-methanesulfonyloxymethyl-2-methyl-2,3-dihydrobenzofuran
    0.5 g of 5-acetoxy-4,6-di-t-butyl-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 47 was dissolved in 50 ml of dichloromethane, Combine with 0.18 g of triethylamine and 0.2 g of methanesulfonyl chloride and stir the mixture at room temperature for 24 hours. The reaction mixture is then combined with water and extracted with ethyl acetate, and the organic layer is washed with 10% hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 33% ethyl acetate to give 5-acetoxy-4,6-di-t-butyl-2-methanesulfonyloxymethyl-2-methyl 0.55 g of -2,3-dihydrobenzofuran (rostereomeric mixture) are obtained as colorless oil (yield 89%).
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 1.29 (s, 4.5H), 1.30 (s, 4.5H), 1.37 (s, 9H), 1.48 (s, 1.5H), 1.54 (s, 1.5H ), 2.30 (s, 1.5H), 2.31 (s, 1.5H), 2.92 (s, 1.5H), 3.04 (s, 1.5H), 3.16 (d, 0.5H, J = 15.8 Hz), 3.27 (d , 0.5H, J = 15.8Hz), 3.42 (d, 0.5H, J = 15.8Hz), 3.49 (d, 0.5H, J = 15.8Hz), 4.16-4.30 (m, 2H), 6.74 (s, 0.5 H), 6.76 (s, 0.5 H).
    Mass: 412 (M + ).
    2) Synthesis of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran
    0.55 g of 5-acetoxy-4,6-di-t-butyl-2-methanesulfonyloxymethyl-2-methyl-2,3-dihydrobenzofuran is dissolved in 10 ml of N, N-dimethylformamide And 3.0 g of sodium iodide, and the mixture is heated to reflux for 24 hours. After cooling, water is added and the mixture is extracted with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 10% ethyl acetate to give 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2. , 3-dihydrobenzofuran (rotary isomer mixture) is obtained as a colorless oil (yield 68%).
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 1.30 (s, 9H), 1.38 (s, 9H), 1.61 (s, 1.5H), 1.67 (s, 1.5H), 2.30 (s, 3H), 3.22 (d, 0.5H, J = 15.8 Hz), 3.34 (d, 0.5H, J = 15.8 Hz), 3.40 (dd, 2H, J = 16.5 Hz, J = 13.5 Hz), 3.52 (d, 0.5H, J = 15.8 Hz), 3.58 (d, 0.5H, J = 15.8 Hz), 6.76 (s, 0.5H), 6.77 (s, 0.5H).
    Mass: 444 (M + ).
    3) Other Synthesis of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran
    10.0 g of 4-acetoxy-3,5-di-t-butyl-2- (2-methyl-2-propenyl) phenol synthesized according to the procedure described in JP 7-330759 / 95 was diluted with diethylether-water ( 3: 1) It is dissolved in 200 ml of the mixed solvent, combined with 5.3 g of sodium bicarbonate and 12.0 g of iodine, and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is then combined with saturated aqueous sodium thiosulfate solution, extracted with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to 5-acetoxy-4,6-di-t-butyl 13.2 g of 2-iodomethyl-2-methyl-2,3-dihydrobenzofuran (rostereomeric mixture) are obtained as colorless oil (yield 95%).
    4) Synthesis of 5-acetoxy-4,6-di-t-butyl-2-methyl-2-phthalimidemethyl-2,3-dihydrobenzofuran
    14.2 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran and 7.0 g of potassium phthalimide were added to 150 ml of dimethylformamide. Suspension and the mixture is heated at 140 ° C. under stirring for 14 hours. After the reaction, the mixture is cooled to room temperature, combined with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 20% ethyl acetate to give 5-acetoxy-4,6-di-t-butyl-2-methyl-2-phthalimidemethyl-. 13.4 g of 2,3-dihydrobenzofuran (rostereomeric mixture) are obtained as white crystals (yield 92%).
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 1.215 (s, 4.5H), 1.220 (s, 4.5H), 1.335 (s, 4.5H), 1.343 (s, 4.5H), 1.49 (s, 1.5 H), 1.53 (s, 1.5H), 2.23 (s, 1.5H), 2.27 (s, 1.5H), 3.13-3.26 (m, 1H), 3.59-3.70 (m, 1H), 3.91-3.94 (m , 2H), 6.71 (s, 1H), 7.66-7.71 (m, 2H), 7.78-7.84 (m, 2H).
    Mass: 463 (M + ).
    5) Synthesis of 5-acetoxy-2-aminomethyl-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran
    1.24 g of hydrazine monohydrate was added to a suspension of 9.5 g of 5-acetoxy-4,6-di-t-butyl-2-methyl-2-phthalimidemethyl-2,3-dihydrobenzofuran in 150 ml of ethanol at room temperature. And the mixture is heated at reflux for 1 h. After the reaction, the mixture is cooled to room temperature and combined with 50 ml of 6N hydrochloric acid solution and again heated under reflux for 30 minutes. After cooling to room temperature, the mixture is neutralized with 2N aqueous sodium hydroxide solution and the chloroforms are combined to form an insoluble material. The mixture is filtered to remove insoluble matters and the mother liquor is liquid-liquid separated. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 5-acetoxy-2-aminomethyl-4,6-di-t-butyl-2-methyl-2,3-di. 6.85 g of hydrobenzofuran (rostereomeric mixture) are obtained as colorless oil (quantitative).
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 1.25 (s, 12H), 1.33 (s, 9H), 2.247 (s, 1.5H), 2.250 (s, 1.5H), 2.75-3.33 (m, 4H ), 6.70 (s, 1 H).
    Mass: 333 (M + ).
    6) Synthesis of 2-aminomethyl-4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran
    Under nitrogen atmosphere, 13.2 ml of a 1M diisobutylaluminum hydride solution in toluene and 5-acetoxy-2-aminomethyl-4,6-di-t-butyl-2-methyl-2,3-di in 30 ml of toluene To a solution of 1.0 g of hydrobenzofuran is added dropwise at room temperature. After stirring for 14 hours at room temperature, the mixture is combined with water and extracted with ethyl acetate, and the obtained organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified from a mixed solvent of ethyl acetate and hexane by recrystallization to give 2-aminomethyl-4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran 0.62 g is obtained as white crystals (yield 71%).
    1 H NMR (270 MHz, CDCl 3 ) δ PPM: 1.40 (s, 3H), 1.43 (s, 9H), 1.52 (s, 9H), 2.83 (s, 2H), 3.17 (d, 1H, J = 15.7 Hz), 3.37 (d, 1H, J = 15.7 Hz), 4.74 (s, 1H), 6.67 (s, 1H).
    Mass: 291 (M + ).
    Example 71
    4,6-di-t-butyl-2-cyanomethyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran
    1.00 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 70-2) and 0.36 g of potassium cyanide were added Dissolve in 5 ml of dimethyl sulfoxide and the mixture is heated and stirred overnight at 140 ° C. under nitrogen. After cooling to room temperature, the reaction solution is poured into water, extracted with ether, the mixed organic layers are washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane containing 9-13% ethyl acetate to give 4,6-di-t-butyl-2-cyanomethyl-5-hydroxy-2-methyl. 0.09 g of -2,3-dihydrobenzofuran is obtained as a colorless solid (yield 13%).
    1 H NMR (270 MHz, CDCl 3 ) δ PPM: 1.40 (s, 9H), 1.49 (s, 9H), 1.61 (s, 3H), 2.68 (d, 2H, J = 2.3 Hz), 3.32 (d, 1H, J = 15.8 Hz), 3.44 (d, 1H, J = 15.8 Hz), 4.80 (s, 1H), 6.67 (s, 1H).
    Mass: 301 (M + ).
    Example 72
    4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-carboxylic acid
    1) Synthesis of 4,6-di-t-butyl-2-hydroxymethyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran
    1.17 ml of 2,6-lutidine in 5 ml of dichloromethane and 4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-di synthesized in Example 48 A solution of 0.59 g of hydrobenzofuran is cooled to 0 ° C. under nitrogen, combined with 1.25 ml of trimethylsilyl trifluoromethanesulfonate and stirred. After 30 minutes, the reaction solution is poured into water, extracted with ether and the mixed organic layers are concentrated. The residue is dissolved in 10 ml of THF, 5% hydrochloric acid is added and the solution is stirred for 1 hour, after which the reaction mixture is concentrated and extracted with water and ether. The mixed organic layer is washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane containing 9% ethyl acetate to give 4,6-di-t-butyl-2-hydroxymethyl-2-methyl-5-trimethylsilyloxy- 0.62 g of 2,3-dihydrobenzofuran is obtained as a colorless oil (yield 84%).
    1 H NMR (270 MHz, CDCl 3 ) δ PPM: 0.30 (s, 9H), 1.38 (s, 12H), 1.45 (s, 9H), 3.07 (d, 1H, J = 15.5 Hz), 3.41 (d, 1H, J = 15.5HZ), 3.58 (bs, 2H), 6.69 (s, 1H).
    Mass: 365 (M + +1).
    2) Synthesis of 4,6-di-t-butyl-2-formyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran
    0.26 ml of oxalyl chloride is added dropwise to a solution of 0.43 ml of dimethyl sulfoxide in 12 ml of dichloromethane cooled to −78 ° C. under nitrogen. After 15 minutes, a solution of 4,6-di-t-butyl-2-hydroxymethyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran in 5 ml of dichloromethane is added dropwise. After 15 minutes more, 1.91 ml of triethylamine are added dropwise, and the mixture is then slowly warmed to room temperature. After one hour, the reaction solution is poured into water and extracted with dichloromethane, the mixed organic layers are extracted with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by eluting with n-hexane containing 9% ethyl acetate on a short column of silica gel to contain 4,6-di-t-butyl-2-formyl-2-methyl-5-trimethylsilyl containing impurities. 1.04 g of oxy-2,3-dihydrobenzofuran is obtained.
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 0.28 (s, 9H), 1.37 (s, 9H), 1.42 (s, 9H), 1.50 (s, 3H), 3.19 (d, 1H, J = 15.5 Hz), 3.64 (d, 1H, J = 15.5 Hz), 6.78 (s, 1H), 9.71 (s, 1H).
    Mass: 363 (M + +1).
    3) Synthesis of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid
    Sodium dihydrogen phosphate saturated in 0.5 g solution of 4,6-di-t-butyl-2-formyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran in 5 ml of t-butyl alcohol 5 ml of aqueous solution and 0.73 ml of 2-methyl-2-butene are added and the mixture is cooled to -5 ° C. To this solution, a solution of 0.14 g of sodium chlorite in 5 ml of distilled water is added dropwise, the mixture is stirred for 20 minutes, and then further stirred at room temperature for 15 minutes. The reaction solution is extracted with diethyl ether and the mixed organic layers are washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue is recrystallized from hexane to give 0.38 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid as colorless powder ( Yield 73%).
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 0.28 (s, 9H), 1.37 (s, 9H), 1.42 (s, 9H), 1.69 (s, 3H), 3.36 (d, 1H, J = 15.8 Hz), 3.84 (d, 1H, J = 15.8 Hz), 6.80 (s, 1H).
    Mass: 378 (M + ).
    4) Synthesis of 4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-carboxylic acid
    Under a nitrogen atmosphere, a solution of 0.19 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid in 1 ml of THF was brought to 0 ° C. After cooling, 1 ml of tetra-n-butylammonium fluoride (1.0 mmol / ml THF solution) is added dropwise to this solution, and the mixture is stirred for 1 hour. After stopping the reaction by adding saturated aqueous ammonium chloride solution, the mixture was extracted with water and diethyl ether, the mixed organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to 4,6-di-t-butyl 0.14 g of -5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-carboxylic acid is obtained as a colorless solid (yield 91%).
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 1.43 (s, 9H), 1.48 (s, 9H), 1.70 (s, 3H), 3.39 (d, 1H, J = 16.2 Hz), 3.92 (d, 1H, J = 16.2 Hz), 6.77 (s, 1H).
    Mass: 306 (M + ).
    Example 73
    4,6-di-t-butyl-5-hydroxy-2-methoxycarbonyl-2-methyl-2,3-dihydrobenzofuran
    0.20 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid was dissolved in 5 ml of saturated hydrogen chloride solution in methanol at room temperature, The mixture is stirred for 3 hours, then the reaction solution is concentrated. The residue was purified by eluting with n-hexane containing 16% ethyl acetate on a silica gel short column to give 4,6-di-t-butyl-5-hydroxy-2-methoxycarbonyl-2-methyl-2, 0.15 g of 3-dihydrobenzofuran is obtained as a colorless powder.
    1 H NMR (270 MHz, CDCl 3 ) δ ppm: 1.41 (s, 9H), 1.49 (s, 9H), 1.66 (s, 3H), 3.36 (d, 1H, J = 16.OHz), 3.78 (s , 3H), 3.91 (d, 1H, J = 16.OHz), 4.79 (s, 1H), 6.78 (s, 1H).
    Mass: 321 (M + +1).
    Example 74
    1- (4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-carbonyl) pyrrolidine
    1) Synthesis of 1- (4,6-di-tert-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carbonyl) pyrrolidine
    0.20 g of 4,6-di-tert-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid, 0.20 ml of triethylamine and 0.06 ml of pyrroli Dean was dissolved in 3 ml of dichloromethane at room temperature, 0.35 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate was added and the mixture was stirred for 4 hours. The mixture was extracted with water and diethyl ether and the combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluent: n-hexane containing 33% ethyl acetate) to give 0.21 g of 1- (4,6-di-tert-butyl-2-methyl-5 Trimethylsilyloxy-2,3-dihydrobenzofuran-2-carbonyl) pyrrolidine was obtained as a colorless solid (yield: 92%).

    2) Synthesis of 1- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-carbonyl) pyrrolidine
    1- (4,6-di-tert-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carbonyl) pyrrolidine same as in Example 72-4) Process to yield 0.11 g of 1- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-carbonyl) pyrrolidine as a colorless solid Obtained (yield 63%).

    Example 75
    Ethyl 3- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)-2-propenoate
    1) Synthesis of ethyl 3- (4,6-di-tert-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-yl) -2-propenoate
    Under a nitrogen stream, a suspension of 0.17 g sodium hydride dissolved in 12 ml of THF was cooled to 0 ° C. and 0.68 ml of triethyl phosphonoacetate was added dropwise. After stirring for 15 minutes, the solution was allowed to warm to room temperature and cooled to 0 ° C., and then 4,6-di-tert-butyl-2-formyl synthesized in Example 72-2) dissolved in 5 ml of THF. A solution of -2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran was added dropwise. After 1 hour, the reaction was stopped by addition of saturated aqueous ammonium chloride solution. The reaction solution was extracted with water and diethyl ether, and the combined organic layers were washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane containing 1.5 to 2% ethyl acetate) to give 0.54 g of ethyl 3- (4,6-di-tert-butyl-2-methyl-5 Trimethylsilyloxy-2,3-dihydrobenzofuran-2-yl) -2-propenoate was obtained as a colorless liquid (yield: 91%).

    2) Synthesis of ethyl 3- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) -2-propenoate
    0.14 g of ethyl 3- (4,6-di-tert-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-yl) -2-propenoate was prepared in Example 72 -4) 0.09 g of ethyl 3- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)- 2-propenoate was obtained as a colorless viscous liquid (yield: 77%).

    Example 76
    Ethyl 3- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) propanoate
    1) Synthesis of ethyl 3- (4,6-di-tert-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-yl) propanoate
    Ethyl 3- (4,6-di-tert-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzo synthesized in 0.27 g of Example 75-1) dissolved in 20 ml of ethanol A catalytic amount of 10% palladium-carbon was added to a solution of furan-2-yl) -2-propenoate and the mixture was stirred for 48 hours under hydrogen stream. After the catalyst was filtered off, the filtrate was concentrated and the residue was purified by a short silica gel column (eluent: n-hexane containing 9% ethyl acetate) to 0.27 g of ethyl 3- (4,6-di-tert- Butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-yl) propanoate was obtained as a colorless viscous liquid.

    2) Synthesis of ethyl 3- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) propanoate
    0.12 g of ethyl 3- (4,6-di-tert-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-yl) -2-propanoate was prepared in Example 72 -4) 0.09 g of ethyl 3- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)- 2-propanoate was obtained as a colorless viscous liquid (yield: 90%).

    Example 77
    6- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) -5-hexenoic acid
    Under a stream of nitrogen, a solution of 0.92 g of tert-butoxylated potassium dissolved in 10 ml of THF was added dropwise to a suspension of 0.46 g of 5-carboxypentyltriphenylphosphonium bromide dissolved in 5 ml of THF at 0 ° C. The mixture was stirred for 30 minutes. 4,6-di-tert-butyl-2-formyl-2-methyl-5-trimethylsilyloxy-2,3-di synthesized in Example 72--2) dissolved in 10 ml of THF in the reaction mixture A solution of hydrobenzofuran was added dropwise and the mixture was stirred overnight while slowly warming to room temperature. The reaction solution was extracted with water and diethyl ether, and the combined aqueous layers were acidified with concentrated hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane containing 50% ethyl acetate) to give 0.22 g of 6- (4,6-di-tert-butyl-5-hydroxy-2-methyl -2,3-dihydrobenzofuran-2-yl) -5-hexenoic acid was obtained as a colorless viscous liquid (yield: 43%).

    Example 78
    6- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) hexanoic acid
    6- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2- synthesized in 0.11 g of Example 77 dissolved in 10 ml of ethyl acetate A catalytic amount of 10% palladium-carbon was added to a solution of il) -5-hexenoic acid, and the mixture was stirred for 24 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated to 0.10 g of 6- (4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) hexenoic acid Was obtained as a colorless viscous liquid (yield 90%).

    Example 79
    4,6-di-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-4 '-(1'-methylpiperidine)
    4,6-di-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-4 '-(1'-methylpy, according to the method described in JP 6-206842 / 94 Ferridine) was synthesized.

    Example 80
    1-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] thiourea
    1) Synthesis of (5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl isothiocyanate
    Synthesized from 6.18 g of Example 70-5) dissolved in 20 ml of tetrahydrofuran in an ice-cold suspension of 4.56 g of dicyclohexylcarbodiimide and 8 ml of carbon disulfide dissolved in 20 ml of tetrahydrofuran. A solution of acetoxy-2-aminomethyl-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran was added dropwise. The mixture was stirred at 0 ° C. for 2 hours and then at room temperature for 24 hours. After the reaction, carbon disulfide and tetrahydrofuran were removed using an evaporator, and the precipitated dicyclohexylthiourea was filtered off. Water was then added to the filtrate and the solution extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: n-hexane containing 10% ethyl acetate) to give 5.15 g of (5-acetoxy-4,6-di-tert-butyl-2-methyl-2 , 3-dihydrobenzofuran-2-yl) methyl isothiocyanate (rotary isomer mixture) was obtained as a colorless oil (yield 74%).

    2) Synthesis of 1-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] thiourea
    5.15 g of (5-acetoxy-4,6-di-tert-butyl-2-methyl-2, dissolved in 20 ml of ethanol in a solution of 4.16 g of 28% aqueous ammonia in 10 ml of ethanol at room temperature A solution of 3-dihydrobenzofuran-2-yl) methyl isothiocyanate was added dropwise. The mixture was stirred at rt for 2 h and then heated at reflux for 1 h. After cooling, ethanol was removed using an evaporator and the mixture was mixed with water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform containing 10% methanol) to give 5.3 g of 1-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2 , 3-dihydrobenzofuran-2-yl) methyl] thiourea (rotary isomer mixture) was obtained as a white solid (yield 99%).

    3) Synthesis of 1-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] thiourea
    30 ml of 1.0 g of 1-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] thiourea under a nitrogen stream In toluene. To this solution was added 10.2 ml of hydrogenated diisobutyl aluminum (1.0 M in toluene) and the mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was mixed with saturated aqueous ammonium chloride solution and 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: n-hexane containing 33% ethyl acetate) to give 0.89 g of 1-[(4,6-di-tert-butyl-5-hydroxy-2- Methyl-2,3-dihydrobenzofuran-2-yl) methyl] thiourea was obtained as white crystals (yield 100%).

    Example 81
    1-amino-3-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] guanidine
    1) Synthesis of 1-amino-3-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] guanidine
    1.0 g of 1-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] thiourea was added 3.62 g of methyl iodide. The mixture was stirred for 30 minutes at room temperature. After the reaction, excess methyl iodide was removed using an evaporator. The resulting concentrate was dissolved in 10 ml of methanol and the solution was stirred with 0.3 g of hydrazine monohydrate at room temperature for 2 hours. The reaction solution was mixed with water and saturated aqueous sodium carbonate solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform containing 10% methanol) to give 0.98 g of 1-amino-3-[(5-acetoxy-4,6-di-tert-butyl-2 -Methyl-2,3-dihydrobenzofuran-2-yl) methyl] guanidine (rotary isomer mixture) was obtained (yield 99%).

    2) Synthesis of 1-amino-3-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] guanidine
    0.98 g of 1-amino-3-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methyl] guanidine under a nitrogen stream Was dissolved in 50 ml of toluene. 10 ml of hydrogenated diisobutyl aluminum (1.0 M in toluene) was added to this solution, and the mixture was stirred at room temperature for 1 hour. After the reaction, saturated aqueous ammonium chloride solution was added and the insoluble material was filtered off over celite. The filtrate was extracted with ethyl acetate and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform containing 10% methanol) to give 0.32 g of 1-amino-3-[(4,6-di-tert-butyl-5-hydroxy-2 -Methyl-2,3-dihydrobenzofuran-2-yl) methyl] guanidine was obtained as white crystals (yield 37%).

    Example 82
    4,6-di-tert-butyl-5-hydroxy-2-methyl-2- (4-nitrophenoxymethyl) -2,3-dihydrobenzofuran
    1) Synthesis of 5-acetoxy-4,6-di-tert-butyl-5-hydroxy-2-methyl-2- (4-nitrophenoxymethyl) -2,3-dihydrobenzofuran
    Under nitrogen stream, ice-cooled 1.08 g of 60% oily sodium hydride dissolved in 50 ml of N, N-dimethylformamide in a solution of 3.76 g of 4-nitrophenol dissolved in 25 ml of N, N-dimethylformamide. To the suspension was added dropwise and the mixture was stirred at rt for 1 h. The reaction solution was then cooled to 0 ° C. and 5-acetoxy-4,6-di-tert- synthesized in 10.2 g of Example 70-2) dissolved in 25 ml of N, N-dimethylformamide. A solution of butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran was added dropwise and the mixture was heated at reflux for 14 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (eluent: n-hexane containing 20% ethyl acetate) to give 6.57 g of 5-acetoxy-4,6-di-tert-butyl-2-methyl-2- (4-nitrophenoxymethyl) -2,3-dihydrobenzofuran (rotary isomer mixture) was obtained as a pale yellow oil (yield 64%).

    2) Synthesis of 4,6-di-tert-butyl-5-hydroxy-2-methyl-2- (4-nitrophenoxymethyl) -2,3-dihydrobenzofuran
    Under nitrogen stream, 30 ml of toluene was added with 1.0 g of 5-acetoxy-4,6-di-tert-butyl-2-methyl-2- (4-nitrophenoxymethyl) -2,3-dihydrobenzofuran. Dissolved in. 5.5 ml of hydrogenated diisobutyl aluminum (1.0 M in toluene) was added to this solution, and the mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride solution and 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: n-hexane containing 5% ethyl acetate) to give 0.33 g of 4,6-di-tert-butyl-5-hydroxy-2-methyl-2- (4-nitrophenoxymethyl) -2,3-dihydrobenzofuran was obtained as a pale yellow oil (yield 36%).

    Example 83
    2- (4-aminophenoxymethyl) -4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran
    1) Synthesis of 5-acetoxy-2- (4-aminophenoxymethyl) -4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran
    Under hydrogen stream, 5.5 g of 5-acetoxy-4,6-di-tert-butyl-2-methyl-2- (4-nitrophenoxymethyl) -2,3-di dissolved in 50 ml of ethyl acetate The solution of hydrobenzofuran was catalytically reduced over 1.1 g of 10% palladium-carbon over 14 hours. After the reaction, 10% palladium-carbon was filtered off and the solvent was distilled off to remove 5.14 g of 5-acetoxy-2- (4-aminophenoxymethyl) -4,6-di-tert-butyl-2-methyl -2,3-dihydrobenzofuran (rotary isomer mixture) was obtained as a colorless oil (yield 100%).

    2) Synthesis of 2- (4-aminophenoxymethyl) -4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran
    Under nitrogen stream, 30 g of toluene was added with 1.2 g of 5-acetoxy-2- (4-aminophenoxymethyl) -4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran. Dissolved in. To this solution was added 11.3 ml of hydrogenated diisobutyl aluminum (1.0 M in toluene) and the mixture was stirred at room temperature for 2 hours. After the reaction, saturated aqueous ammonium chloride solution was added, the insoluble material was filtered off over celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: n-hexane containing 33% ethyl acetate) to give 0.63 g of 2- (4-aminophenoxymethyl) -4,6-di-tert-butyl- 5-hydroxy-2-methyl-2,3-dihydrobenzofuran was obtained as a pale yellow oil (yield 59%).

    Example 84
    1- {4-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] phenyl} guanidine
    1) Synthesis of 1- {4-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] phenyl} guanidine
    A solution of 3.0 g of 5-acetoxy-2- (4-aminophenoxymethyl) -4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran dissolved in 30 ml of ethanol 30 ml of ethanol saturated hydrogen chloride was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. Excess hydrogen chloride and ethanol were then distilled off using an evaporator to yield hydrochloride. The hydrochloride obtained was again dissolved in 100 ml of ethanol, 10.65 ml of 50% cyanamide was added dropwise at room temperature, and the mixture was heated at reflux for 14 hours. After the reaction, ethanol was distilled off using an evaporator, and the reaction solution was mixed with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform containing 10% methanol) to yield 1.41 g of 1- {4-[(5-acetoxy-4,6-di-tert-butyl-2- Methyl-2,3-dihydrobenzofuran-2-yl) methoxy] phenyl} guanidine (rotary isomer mixture) was obtained as a colorless oil (yield 43%).

    2) Synthesis of 1- {4-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] phenyl} guanidine
    Under nitrogen stream, 1.4 g of 1- {4-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] phenyl } Guanidine was dissolved in 50 ml of toluene. To this solution was added 12 ml of hydrogenated diisobutyl aluminum (1.0 M in toluene) and the mixture was stirred at room temperature for 14 hours. 6 ml of hydrogenated diisobutyl aluminum (1.0 M in toluene) was further added at room temperature, and then the mixture was heated at reflux for 2 hours. After the reaction, saturated aqueous ammonium chloride solution was added, the insoluble material was filtered off over celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform containing 10% methanol) to give 0.67 g of 1- {4-[(4,6-di-tert-butyl-5-hydroxy-2- Methyl-2,3-dihydrobenzofuran-2-yl) methoxy] phenyl} guanidine was obtained as a pale yellow oil (yield 52%).

    Example 85
    1- {4-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzylideneamino} guanidine
    1) Synthesis of 5-acetoxy-4,6-di-tert-butyl-2- (4-formylphenoxymethyl) -2-methyl-2,3-dihydrobenzofuran
    Under nitrogen stream, a solution of 4.57 g of 4-hydroxybenzaldehyde dissolved in 70 ml of N, N-dimethylformamide was dissolved in 1.5 g of 60% oily sodium hydride dissolved in 50 ml of N, N-dimethylformamide. To the ice cold suspension was added dropwise and the mixture was stirred at room temperature for 30 minutes. The reaction solution was then cooled to 0 ° C. and 5-acetoxy-4,6-di-tert- synthesized in 13.2 g of Example 70-2) dissolved in 100 ml of N, N-dimethylformamide. A solution of butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran was added dropwise and the mixture was heated at reflux for 6 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (eluent: n-hexane containing 20% ethyl acetate) to give 6.4 g of 5-acetoxy-4,6-di-tert-butyl-2- (4-form Milphenoxymethyl) -2-methyl-2,3-dihydrobenzofuran (rotary isomer mixture) was obtained as a colorless oil (yield 48%).

    2) of 1- {4-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzylideneamino} guanidine synthesis
    8.54 g of 5-acetoxy-4,6-di-tert-butyl-2- (4-formylphenoxymethyl) -2-methyl-2,3 in a mixed solvent of 40 ml ethanol and 16 ml pyridine -Dihydrobenzofuran was dissolved and 2.38 g of aminoguanidine hydrochloride was added at room temperature. After heating for 14 hours under reflux and cooling, the ethanol and excess pyridine are distilled off using an evaporator, the concentrate is mixed with water and extracted with ethyl acetate, the organic layer is washed with saturated brine, anhydrous magnesium sulfate Dry over phase and then concentrate. The concentrate was purified by silica gel column chromatography (eluent: chloroform containing 5% methanol) to give 9.31 g of 1- {4-[(5-acetoxy-4,6-di-tert-butyl-2- Methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzylideneamino} guanidine (rotary isomer mixture) was obtained as a pale yellow oil (yield 97%).

    3) of 1- {4-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzylideneamino} guanidine synthesis
    Under a nitrogen stream, 2.0 g of 1- {4-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzyl Lidenamino} guanidine was dissolved in 100 ml of tetrahydrofuran, 10 ml of n-butyl lithium (1.6 M in n-hexane) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform containing 10% methanol) to give 0.46 g of 1- {4-[(4,6-di-tert-butyl-5-hydroxy-2- Methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzylideneamino} guanidine was obtained as a pale yellow oil (yield 25%).

    Example 86
    1- {4-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzylamino} guanidine
    1.0 g of 1- {4-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran dissolved in 15 ml of tetrahydrofuran under a stream of nitrogen A solution of -2-yl) methoxy] benzylideneamino} guanidine was added dropwise to a suspension of 0.3 g lithium aluminum hydride dissolved in 15 ml of tetrahydrofuran at room temperature. After heating at reflux for 4 hours, the solution was cooled to room temperature and 0.15 g of lithium aluminum hydride was carefully added and the mixture was heated at reflux for 4 hours. After the reaction, saturated aqueous ammonium chloride solution was added under ice-cooling, the insoluble material was filtered off over celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform with 10% methanol) to give 0.59 g of 1- {4-[(4,6-di-tert-butyl-5-hydroxy-2- Methyl-2,3-dihydrobenzofuran-2-yl) methoxy] benzylamino} guanidine was obtained as a pale yellow oil (yield 65%).

    Example 87
    1-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methylamino] guanidine
    1) Synthesis of 5-acetoxy-4,6-di-tert-butyl-2-formyl-2-methyl-2,3-dihydrobenzofuran
    Under a nitrogen stream, 2.64 ml of oxalyl chloride was added to 40 ml of dichloromethane and the mixture was cooled to -78 ° C. Thereafter, a solution of 3.62 ml of dimethyl sulfoxide dissolved in 10 ml of dichloromethane was added dropwise at −78 ° C., and the mixture was stirred for 30 minutes. 5.4 g of 5-acetoxy-4,6-di-tert-butyl-2-hydroxymethyl-2,3-dihydrobenzofuran synthesized in Example 47 dissolved in 15 ml of dichloromethane were added dropwise. The mixture was further stirred at -78 ° C for 1 hour. This mixture is mixed with 15.3 ml of triethylamine and left for 1 hour to warm to room temperature. After the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: n-hexane containing 20% ethyl acetate) to give 3.95 g of 5-acetoxy-4,6-di-tert-butyl-2-formyl-2 -Methyl-2,3-dihydrobenzofuran (rotary isomer mixture) was obtained as white crystals (yield 71%).

    2) Synthesis of 1-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl) methylideneamino] guanidine
    Dissolve 3.9 g of 5-acetoxy-4,6-di-tert-butyl-2-formyl-2-methyl-2,3-dihydrobenzofuran in a mixed solvent of 20 ml ethanol and 8 ml pyridine. 1.42 g of aminoguanidine hydrochloride were added at room temperature. After heating for 14 hours at reflux and cooling, ethanol and excess pyridine were distilled off using an evaporator, the concentrate was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform containing 10% methanol) to give 4.48 g of 1-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2 , 3-dihydrobenzofuran-2-yl) methylideneamino] guanidine (rotary isomer mixture) was obtained as pale yellow oil (yield 99%).

    3) Synthesis of 1-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl) methylamino] guanidine
    Under nitrogen stream, 1.0 g of 1-[(5-acetoxy-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran-2- dissolved in 10 ml of tetrahydrofuran A solution of I) methylideneamino] guanidine was added dropwise to a suspension of 0.98 g of lithium aluminum hydride dissolved in 20 ml of tetrahydrofuran at room temperature. After heating at reflux for 14 h, saturated aqueous ammonium chloride solution was added under ice cooling, the insoluble material was filtered off over celite and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform containing 10% methanol) to give 0.68 g of 1-[(4,6-di-tert-butyl-5-hydroxy-2-methyl-2 , 3-dihydrobenzofuran-2-yl) methylamino] guanidine was obtained as a pale yellow oil (yield 76%).

    The structural formulas of the compounds are shown in Tables 1-8 below.


    Test Example 1
    Protective Effects of Porcine Kidney Induction-LLC-PK1 Cells Against Cellular Injury (1)
    To assess the in vitro cytoprotective effect of the compounds according to the invention, cell protection using porcine kidney induced-LLC-PKI cells (ATCC-CRL-13921) injured by oxidized low density fat protein (oxidized LDL) Sex studies were performed.
    Oxidized LDL was prepared by 1 mg / ml rabbit LDL in PBS (−) in the presence of 10 μM CuSO 4 for 24 hours at 37 ° C. Cell culture was performed by plating at 1.25 × 10 4 cells / 250 μl / well on a 48-well plate containing M119 medium containing 3% FBS. Test compounds were dissolved or suspended in ethanol and added to the wells in amounts of 1.25 μl / well to bring concentrations of 0.1, 1 or 10 μM in each well. After 16 hours, or immediately after compound addition, oxidized LDL was added to each well. Trobulox, a water-soluble analog of probucol, α-tocopherol and α-tocopherol, was used as reference control compound. The oxidized LDL was diluted twice with saline and added to a concentration of 100 µg / ml in an amount of 62.5 μl / well per well, and after the addition of oxidized LDL, the cells were incubated for 6 hours. 162.5 μl / well of culture medium was then collected and measured for lactate dehydrogenase (LDH) levels (LD-L: SIGMA DIAGNOSTICS) flowing into the medium.
    The magnitude of the cytoprotective effect was expressed as a cell protection rate by calculating data assuming a size of 0% in a well containing oxidized LDL and a 100% effect in a well containing saline.
    The results are shown in Table 9.
    Each value represents the mean ± standard deviation.
    As shown in Table 9, the compounds of the present invention inhibit cellular injury by oxidized LDL.
    Test Example 2
    Protective Effects of Porcine Kidney-induced LLC-PK1 Cells Against Cellular Injury (2)
    To assess the in vitro cytoprotective effect of the compounds according to the invention, porcine kidney induction-LLC-PKI, injured by oxidized low-density fat protein (oxidized LDL) in the same manner as in Example 1, with a few exceptions Cell protection studies with cells (ATCC-CRL-13921) were performed.
    Preparation of oxidized LDL and cell culture conditions and addition of test compound were carried out as in Example 1. However, oxidized LDL was added to a concentration of 91 μg / ml in an amount of 25 μl / well per well without diluting with saline, and after addition of oxidized LDL, cells were incubated for 6 hours. 150 μl / well of culture medium was then collected and measured for lactate dehydrogenase (LDH) levels (LD-L: SIGMA DIAGNOSTICS) flowed into the medium. The results are shown in Table 10.
    Each value represents the mean ± standard deviation.
    As shown in Table 10, the compounds of the present invention inhibit cellular injury by oxidized LDL.
    Test Example 3
    Protective Effects of Rat Vascular Membrane Cells Against Cytotoxicity [In Vitro]
    Cell Protection Using Rat Vascular Induced MES Cells (ATCC-CRL-1927) Injured by Oxidative LDL to Assess the In Vitro Cytoprotective Effect of Compounds of the Present Invention on Mesialial Cells Sex studies were performed.
    Oxidized LDL was prepared as in Test Example 1. Cell culture was performed by plating at 2.5 × 10 4 cells / 250 μl / well on 48-well plates using FBS free medium (3: 1 mixture of DME medium and F 12 medium). Test compounds were dissolved or suspended in ethanol and added to the wells at concentrations of 1 or 10 μM in each well in an amount of 1.25 μl / well. After addition of the compound, oxidized LDL was added to the concentration of 91 μg / ml after 16 hours or immediately in an amount of 25 μl / well, and cells were incubated for 10 hours after addition of the oxidized LDL. 150 μl / well of culture medium was then collected and measured for lactate dehydrogenase level (LDL: SIGMA DIAGNOSTICS) flowing into the medium.
    The magnitude of the cytoprotective effect was expressed as the cell protection rate by calculating data assuming a size of 0% in a well containing oxidized LDL and a size of 100% in a well containing saline.
    The results are shown in Table 11.
    Each value represents the mean ± standard deviation.
    As shown in Table 11, the compounds of the present invention inhibit cellular injury by oxidized LDL.
    Test Example 4
    Effects of Puromycin-Induced Nephropathy (1) (In vivo)
    The effect of the compounds of the present invention on renal disease in vivo was studied using the puromycin-induced nephropathy model.
    Puromycin-induced renal insufficiency model was prepared from rats in each of 5-8 groups each fed a high fat diet (6 week male SD rats). The high fat diet specification began with a free access to high fat diet (cholesterol level 1.25%) from 7 days prior to puromycin treatment. Puromycin (puromycin aminonucleoside, SIGMA Chemical Co.) treatment was performed by intraperitoneal administration at a dose of 100 mg / kg. Test compounds were administered as a solution in soybean oil through the oral cavity (4 ml / kg). The control group was orally administered only soybean oil. Administration of the compound started 3 days prior to puromycin treatment once a day. After puromycin treatment, oral administration of the compound was continued.
    Kidney function was determined using urine and blood samples collected 8 days after puromycin treatment. The volume of urine and creatinine levels in serum and urine were evaluated to calculate creatinine clearance as an indicator of renal function.
    The results are shown in Table 12.
    Each value represents the mean ± standard deviation.
    a P <0.05
    * P <0.01
    ** P <0.001
    As shown in Table 12, the compounds of the present invention showed an inhibitory effect on an increase in serum creatinine and a decrease in creatinine clearance in the rat puromycin-induced renal insufficiency model when the compound was administered prior to puromycin treatment. .
    Test Example 5
    Effect of Puromycin-Induced Nephropathy (2) (In vivo)
    The effect of the compounds of the present invention on renal disease in vivo was studied using the puromycin-induced nephropathy model.
    Puromycin-induced renal insufficiency model was prepared from rats in each of 5-8 groups each fed a high fat diet (6 week male SD rats). The high fat diet specification began with a free access to high fat diet (cholesterol level 1.25%) from 7 days prior to puromycin treatment. Puromycin (puromycin aminonucleoside, SIGMA Chemical Co.) treatment was performed by intraperitoneal administration at a dose of 100 mg / kg. Test compounds were administered as a solution in soybean oil through the oral cavity (4 ml / kg). The control group was orally administered only soybean oil. Fubucolol and the water soluble α-tocopherol analogue, trolox were used as reference control compounds. Compounds were administered orally once a day from the day after puromycin treatment.
    Kidney function was determined using urine and blood samples collected 8 days after puromycin treatment. The volume of urine and creatinine levels in serum and urine were evaluated to calculate creatinine clearance as an indicator of renal function.
    The results are shown in Table 13.
    Each value represents the mean ± standard deviation.
    a P <0.05
    * P <0.01
    ** P <0.001
    As shown in Table 13, the compounds of the present invention show an inhibitory effect on an increase in serum creatinine level and a decrease in creatinine clearance by administration after puromycin treatment in a rat puromycin-induced renal insufficiency model.
    Test Example 6
    Effects on Acute Renal Insufficiency Model of Ischemia (in vivo)
    The effect of the compounds of the present invention on renal disease in vivo was studied using ischemia acute renal insufficiency model.
    Ischemia acute renal insufficiency models were prepared from a group of 8 rats each of which were fed a high fat diet (male SD rats, body weight: 224-285 g). High fat diet specification was initiated by independent nephrectomy and free access to high fat diet (cholesterol level 1.25%) from 7 or 8 days before arterial clamping of the left kidney. Test compounds were administered as a solution in soybean oil via the oral route (4ml / kg). The control group was orally administered only soybean oil. Administration of the compound started at 4 or 5 days before ischemia treatment once daily at a dose of 200 mg / kg. After treatment of ischemia, oral administration of the compound was continued once daily. Ischemia treatment was performed by removing the right kidney and clipping the renal artery of the left kidney for 30 or 60 minutes.
    After treatment of ischemia, renal function was measured daily using urine and blood samples. The volume of urine and creatinine levels in serum and urine were evaluated to calculate creatinine clearance as an indicator of renal function. Serum cholesterol levels were measured to monitor the impact of high fat diet specifications.
    The results are shown in Table 14 and Table 15.
    Each value represents the mean ± standard deviation.
    a P <0.05
    Each value represents the mean ± standard deviation.
    a P <0.05
    * P <0.01
    As shown in Table 14 and Table 15, the compounds of the present invention show an inhibitory effect on an increase in serum creatinine levels and a decrease in creatinine clearance in a rat model of acute renal insufficiency of ischemia.
    Therapeutic agent for renal disease and long-term preservation containing 2,6-di-t-butylphenol derivative according to the present invention as an active ingredient against cellular injury induced by oxidized LDL in renal-induced cells in culture In addition to the potential cellular protective effects, they have potential enhancements in renal function in the models of puromycin-induced nephropathy and ischemic acute renal insufficiency. It is useful as a therapeutic or prophylactic agent for renal disease such as acute renal failure, nephropathy caused by a platinum complex-based anticancer agent such as cisplatin, nephropathy caused by agrochemicals such as paracoat, and uremia. They are also useful as long term preservatives.
    权利要求:
    Claims (35)
    [1" claim-type="Currently amended] A therapeutic agent for kidney disease containing the compound represented by the following formula (1) or an optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient:

    [Wherein X represents an oxygen atom or a group represented by the following general formula (2):

    (Wherein n represents an integer of 0 to 2),
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 3 represents a lower alkyl group,
    R 4 , R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted aryl group, and R 6 is also a formyl group , Carboxyl group, lower alkoxycarbonyl group or optionally substituted carbamoyl group,
    R 3 and R 4 together may form a 5-membered ring, or
    R 5 and R 6 may form a saturated heterocyclic group or a cycloalkyl group containing one or more oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms,
    Provided that the 5-membered ring formed by R 3 and R 4 and the benzene ring together are benzofuran, benzo [b] thiophene, benzo [b] thiophene-1-oxide or benzo [b] thiophene-1,1-diox When forming a seed, there is no R 6 ].
    [2" claim-type="Currently amended] The agent for treating kidney disease according to claim 1, wherein the compound represented by the formula (1) is selected from the compound represented by the formula (3):

    [Wherein X represents an oxygen atom or a group represented by the formula (2):

    (Wherein n represents an integer of 0 to 2),
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 5 and R 6 may be the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted aryl group, R 6 is also a formyl group, A carboxyl group, a lower alkoxycarbonyl group or an optionally substituted carbamoyl group, or
    R 5 and R 6 may together form a saturated heterocyclic group or cycloalkyl group containing one or more oxygen atoms, sulfur atoms or alkyl substituted nitrogen atoms,
    Provided that the bicyclic ring containing X represents benzofuran, benzo [b] thiophene, benzo [b] thiophen-1-oxide or benzo [b] thiophene-1,1-dioxide, 6 is missing.
    [3" claim-type="Currently amended] A compound according to claim 1, wherein R 4 , R 5 and R 6 of formula (1) are the same or different and each is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted A kidney disease therapeutic agent showing an aryl group.
    [4" claim-type="Currently amended] 3. A compound according to claim 2, wherein R 4 , R 5 and R 6 in formula (3) are the same or different and each is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted A kidney disease therapeutic agent showing an aryl group.
    [5" claim-type="Currently amended] The agent for treating kidney disease according to claim 1, wherein the compound represented by the formula (1) is selected from the group consisting of the compound represented by the following formula (4):

    [Wherein X represents an oxygen atom or a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 5 and R 6 are the same or different and each is a hydrogen atom, a C 1-20 optionally substituted alkyl group, a C 2-20 optionally substituted alkenyl group, a C 2-20 optionally substituted alkynyl group or an optionally substituted aryl group R 6 also represents a formyl group, a carboxyl group, a lower alkoxycarbonyl group or an optionally substituted carbamoyl group, or
    R 5 and R 6 may together form a saturated heterocyclic group or cycloalkyl group containing one or more oxygen atoms, sulfur atoms or alkyl substituted nitrogen atoms.
    [6" claim-type="Currently amended] A therapeutic agent for kidney disease according to claim 5, wherein in formula (4):
    [X represents an oxygen atom or a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 5 represents a hydrogen atom, a C 1-20 optionally substituted alkyl group, a C 2-20 optionally substituted alkenyl group, a C 2-20 optionally substituted alkynyl group or an optionally substituted aryl group,
    R 6 is (i) formyl, carboxyl, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl substituted carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbo Nyl or morpholinocarbonyl group; (ii) cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl substituted carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl and mor A C 1-20 alkyl group substituted with one or more substituents selected from the group consisting of polynocarbonyl groups; Or (iii) cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl substituted carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl and C 2-20 alkenyl group substituted with one or more substituents selected from the group consisting of morpholinocarbonyl groups.
    [7" claim-type="Currently amended] The agent for treating kidney disease according to claim 6, wherein in formula (4):
    [X represents an oxygen atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom or a lower alkyl group.
    [8" claim-type="Currently amended] The agent for treating kidney disease according to claim 6, wherein in formula (4):
    [X represents a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom or a lower alkyl group.
    [9" claim-type="Currently amended] A therapeutic agent for kidney disease according to claim 5, wherein in formula (4):
    [X represents an oxygen atom or a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 5 and R 6 are the same or different and each is a hydrogen atom, a C 1-20 optionally substituted alkyl group, a C 2-20 optionally substituted alkenyl group, a C 2-20 optionally substituted alkynyl group or an optionally substituted aryl group Indicates,
    R 5 and R 6 may together form a saturated heterocyclic group or cycloalkyl group containing one or more oxygen atoms, sulfur atoms or alkyl substituted nitrogen atoms.
    [10" claim-type="Currently amended] The therapeutic agent for kidney disease according to claim 9, wherein in formula (4):
    [X represents an oxygen atom,
    R 1 represents a hydrogen atom,
    R 2 represents a hydrogen atom or a lower alkyl group.
    [11" claim-type="Currently amended] The therapeutic agent for kidney disease according to claim 9, wherein in formula (4):
    [X represents a sulfur atom,
    R 1 represents a hydrogen atom,
    R 2 represents a hydrogen atom or a lower alkyl group.
    [12" claim-type="Currently amended] The therapeutic agent for kidney disease according to claim 9, wherein in formula (4):
    [X represents an oxygen atom or a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 5 represents a hydrogen atom, a C 1-20 optionally substituted alkyl group, a C 2-20 optionally substituted alkenyl group, a C 2-20 optionally substituted alkynyl group or an optionally substituted aryl group,
    R 6 represents (i) thioureido, 3-aminoguanidino, N-guanidinoamino, 4-guanidinophenoxy and 4- (N-guanidinoaminomethyl) phenoxy group C 1-20 alkyl group substituted with one or more substituents selected from; Or (ii) thioureido, 3-aminoguanidino, N-guanidinoamino, 4-guanidinophenoxy and 4- (N-guanidinoaminomethyl) phenoxy group C 2-20 alkenyl group substituted with one or more substituents.
    [13" claim-type="Currently amended] 13. The agent for treating kidney disease according to claim 12, wherein in formula (4):
    [X represents an oxygen atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom or a lower alkyl group.
    [14" claim-type="Currently amended] 13. The agent for treating kidney disease according to claim 12, wherein in formula (4):
    [X represents a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom or a lower alkyl group.
    [15" claim-type="Currently amended] The nephropathy of claim 1, wherein the kidney disease is caused by chronic renal failure, diabetic nephropathy, glomerulonephritis, immunocomplex nephritis, acute renal failure, platinum complexes such as cisplatin or other drugs such as gentamicin, para A therapeutic agent for kidney disease selected from nephropathy, uremia and the like caused by pesticides such as coats.
    [16" claim-type="Currently amended] 3. Nephropathy according to claim 2, wherein the kidney disease is caused by chronic renal failure, diabetic nephropathy, glomerulonephritis, immunocomplex nephritis, acute renal failure, a platinum complex such as cisplatin or other drugs such as gentamicin, para A therapeutic agent for kidney disease selected from nephropathy, uremia and the like caused by pesticides such as coats.
    [17" claim-type="Currently amended] The nephropathy of claim 5, wherein the kidney disease is caused by chronic renal failure, diabetic nephropathy, glomerulonephritis, immunocomplex nephritis, acute renal failure, platinum complexes such as cisplatin or other drugs such as gentamicin, para A therapeutic agent for kidney disease selected from nephropathy, uremia and the like caused by pesticides such as coats.
    [18" claim-type="Currently amended] The nephropathy of claim 6, wherein the kidney disease is caused by chronic renal failure, diabetic nephropathy, glomerulonephritis, immunocomplex nephritis, acute renal failure, a platinum complex such as cisplatin or other drugs such as gentamicin, para A therapeutic agent for kidney disease selected from nephropathy, uremia and the like caused by pesticides such as coats.
    [19" claim-type="Currently amended] 11. The nephropathy of claim 10, wherein the kidney disease is caused by chronic renal failure, diabetic nephropathy, glomerulonephritis, immunocomplex nephritis, acute renal failure, platinum complexes such as cisplatin or other drugs such as gentamicin, para A therapeutic agent for kidney disease selected from nephropathy, uremia and the like caused by pesticides such as coats.
    [20" claim-type="Currently amended] A long-term preservative containing the compound of claim 1 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [21" claim-type="Currently amended] A long-term preservative comprising the compound of claim 2 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [22" claim-type="Currently amended] A long-term preservative containing the compound of claim 5 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [23" claim-type="Currently amended] A long-term preservative comprising the compound of claim 6 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [24" claim-type="Currently amended] A long-term preservative containing the compound of claim 10 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [25" claim-type="Currently amended] A long-term preservative for kidney transplant containing the compound of claim 1 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [26" claim-type="Currently amended] A long-term preservative for kidney transplant containing the compound of claim 2 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [27" claim-type="Currently amended] A long-term preservative for kidney transplant containing the compound of claim 5 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [28" claim-type="Currently amended] A long-term preservative for renal transplantation containing the compound of claim 6 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [29" claim-type="Currently amended] A long-term preservative for kidney transplant containing the compound of claim 10 or the optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
    [30" claim-type="Currently amended] Compound represented by formula (4) or optically active isomer or pharmaceutically acceptable salt thereof:

    [Wherein X represents an oxygen atom or a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 5 represents a hydrogen atom, a C 1-20 optionally substituted alkyl group, a C 2-20 optionally substituted alkenyl group, a C 2-20 optionally substituted alkynyl group or an optionally substituted aryl group,
    R 6 is (i) formyl, carboxyl, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl substituted carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbo Nyl or morpholinocarbonyl group; (ii) cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl substituted carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl and mor A C 1-20 alkyl group substituted with one or more substituents selected from the group consisting of polynocarbonyl groups; Or (iii) cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl substituted carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl and C 2-20 alkenyl group substituted with one or more substituents selected from the group consisting of morpholinocarbonyl groups.
    [31" claim-type="Currently amended] The compound according to claim 30, wherein the compound or optically active isomer or pharmaceutically acceptable salt thereof:
    [Wherein X represents an oxygen atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom or a lower alkyl group.
    [32" claim-type="Currently amended] The compound according to claim 30, wherein the compound or optically active isomer or pharmaceutically acceptable salt thereof:
    [Wherein X represents a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom or a lower alkyl group.
    [33" claim-type="Currently amended] Compound represented by formula (4) or optically active isomer or pharmaceutically acceptable salt thereof:

    [Wherein X represents an oxygen atom or a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group,
    R 5 represents a hydrogen atom, a C 1-20 optionally substituted alkyl group, a C 2-20 optionally substituted alkenyl group, a C 2-20 optionally substituted alkynyl group or an optionally substituted aryl group,
    R 6 represents (i) thioureido, 3-aminoguanidino, N-guanidinoamino, 4-guanidinophenoxy and 4- (N-guanidinoaminomethyl) phenoxy group C 1-20 alkyl group substituted with one or more substituents selected from; Or (ii) thioureido, 3-aminoguanidino, N-guanidinoamino, 4-guanidinophenoxy and 4- (N-guanidinoaminomethyl) phenoxy group C 2-20 alkenyl group substituted with one or more substituents.
    [34" claim-type="Currently amended] The compound according to claim 33, wherein the compound or optically active isomer thereof or a pharmaceutically acceptable salt thereof:
    [Wherein X represents an oxygen atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom or a lower alkyl group.
    [35" claim-type="Currently amended] The compound according to claim 33, wherein the compound or optically active isomer thereof or a pharmaceutically acceptable salt thereof:
    [Wherein X represents a sulfur atom,
    R 1 represents a hydrogen atom or an acyl group,
    R 2 represents a hydrogen atom or a lower alkyl group.
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    同族专利:
    公开号 | 公开日
    KR100383835B1|2003-08-27|
    WO1997049388A1|1997-12-31|
    EP0950405A1|1999-10-20|
    US6133279A|2000-10-17|
    AU2791897A|1998-01-14|
    EP0950405A4|2004-03-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-06-26|Priority to JP20091796
    1996-06-26|Priority to JP96-200917
    1997-05-23|Application filed by 나가야마 오사무, 쥬가이 세이야쿠 가부시키가이샤
    2000-04-25|Publication of KR20000022211A
    2003-08-27|Application granted
    2003-08-27|Publication of KR100383835B1
    优先权:
    申请号 | 申请日 | 专利标题
    JP20091796|1996-06-26|
    JP96-200917|1996-06-26|
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