JP2000351777A - Substituted condensed imidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having an excellent insulin resistance-improving activity, etc., less adverse reactions and a high lipid solubility, and useful as a preventing and treating agent of diabetes mellitus, etc. SOLUTION: This imidazole derivative is a compound of formula I R1 is H, a 1-6C alkyl or the like; R2 is H, a 1-6 C alkyl or the like; R3 to R5 are each H, a 1-6C alkyl or the like; X is a bond, CH2 or the like; Y is O or S; Z is CH or N; Q is O or S; A is a group of formula II [(m) is 0-8] or the like; (n) is 1-5; (q) is 0-5}, e.g. 5- 4-[6-(6-hydroxy-2,5,7,8-tetramethylchroman-2- ylmethoxy)-1-methyl-1H-benzoimidazol-2-ylmethoxy]benzyl)thiazolidine-2, 4-dione. The compound of the formula I can be obtained by reacting a compound of formula III (R1a is the same as R1, etc.), with a compound of formula IV [Aa is a group of formula V (Tr is triphenylmethyl) or the like] and removing a blocking group from the produced material, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an excellent insulin resistance improving action, a blood glucose lowering action, an anti-inflammatory action, an immunoregulatory action, an aldose reductase inhibitory action, a 5-lipoxygenase inhibitory action, an inhibitory action on lipid peroxide production, Substituted condensed imidazole derivatives having PPAR activating action, anti-osteoporotic action, leukotriene antagonizing action, adipocyte promoting action, cancer cell growth inhibitory action, calcium antagonizing action, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof About the kind.

Further, the present invention relates to a disease improved by the above-mentioned effects, such as diabetes, which contains the substituted condensed imidazole derivative, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient. Hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, gestational diabetes, Polycystic ovary syndrome, cardiovascular disease (eg, ischemic heart disease, etc.), cell damage caused by atherosclerosis or ischemic heart disease (eg, brain damage caused by stroke, etc.) Gout), gout, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory enteritis,
Acne, sunburn, psoriasis, eczema, allergic disease, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis and the like. ), Cancer, osteoporosis, cataract and the like.

Further, the present invention relates to a substituted condensed imidazole derivative, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof, a sulfonylurea agent, an α-glucosidase inhibitor, an aldose reductase inhibitor, and a biguanide agent. A pharmaceutical composition comprising a combination of at least one of a statin compound, a squalene synthesis inhibitor, a fibrate compound, an LDL catabolism promoter, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor and an antitumor agent (particularly preferably, Prophylactic and / or therapeutic agent for diabetes or diabetic complications).

[0004]

2. Description of the Related Art It has been reported that thiazolidine compounds and oxazolidine compounds are useful as preventive or therapeutic agents for various diseases such as diabetes and hyperlipidemia.

For example, a number of thiazolidine compounds having a hypoglycemic effect have been reported in Chem. Pharm. Bull., 30, 3580.
-3600 (1982), Prog. Clin. Biol. Res., 265, 177-192 (1
988), Diabetes, 37 (11), 1549-1558 (1988), Arzneim.-
Forsch., 40 (1), 37-42 (1990), EP 0441605A.

The action of thiazolidine compounds on hyperlipidemia is described in Diabetes, 40 (12), 1669-1674 (1991), Am. J. Ph.
ysiol., 267 (1 Pt 1), E95-E101 (1994), Diabetes, 43
(10), 1203-1210 (1994).

The effects of thiazolidine compounds on glucose intolerance and insulin resistance have been described by Arzneim.-Forsch., 40 (2)
Pt 1), 156-162 (1990), Metabolism, 40 (10), 1025-1
230 (1991), Diabetes, 43 (2), 204-211 (1994).

[0008] In recent years, a normal person having insulin resistance develops diabetes without impaired glucose tolerance, and a drug for improving insulin resistance has been used as a preventive agent for the onset of diabetes in normal persons as described above. N.En also be useful
gl. J. Med., 331 (18), 1226-1227 (1994).

The effects of thiazolidine compounds on hypertension are described in Metabolism, 42 (1), 75-80 (1993), and Am. J. Physi.
ol., 265 (4 Pt 2), R726-R732 (1993), Diabetes, 43
(2), 204-211 (1994).

The effect of thiazolidine compounds on coronary artery disease has been reported by Am. J. Physiol., 265 (4 Pt 2), R726-R732 (1
993), Hypertension, 24 (2), 170-175 (1994).

The effect of thiazolidine compounds on arteriosclerosis has been reported in Am. J. Physiol., 265 (4 Pt 2), R726-R732 (19).
93).

The action of thiazolidine compounds on cachexia is described in Endocrinology, 135 (5), 2279-2282 (1994), Endr.
ocrinology, 136 (4), 1474-1481 (1995).

Further, among the thiazolidine compounds having a blood glucose lowering effect, compounds having a heterocyclic group are described in WO 92/0.
No. 7839A, WO92 / 07850A, EP0745600A and EP0676398A
No. oxazolidine-2,4-having hypoglycemic effect
Dione compounds are disclosed in WO 92 / 02520A.

[0014]

SUMMARY OF THE INVENTION The present inventors have studied the synthesis of a series of substituted condensed heterocyclic compounds and their pharmacological activities over many years, and as a result, have found that substituted condensed heterocyclic compounds having a novel structure have been obtained. Excellent, insulin resistance improving action, blood glucose lowering action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, lipid peroxide production inhibitory action, PPAR activating action,
It has anti-osteoporosis, leukotriene antagonism, adipocyte-promoting action, cancer cell growth inhibitory action, calcium antagonism, fewer side effects, and furthermore, it has a characteristic of high lipophilicity, The present invention has been completed.

Another object of the present invention is to provide a disease improved by the above-mentioned effects, for example, diabetes, hyperlipidemia, obesity, which contains the above-mentioned substituted condensed heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient. Disease, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, heart Vascular disease (eg, ischemic heart disease, etc.), cell damage caused by atherosclerosis or ischemic heart disease (eg, brain damage caused by stroke, etc.), gout, Inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis,
Inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis and the like. ), Cancer, osteoporosis, cataract and the like.

Further, another object of the present invention is to provide the above-mentioned substituted condensed heterocyclic compound or a pharmaceutically acceptable salt thereof, a sulfonylurea agent, an α-glucosidase inhibitor, an aldose reductase inhibitor, a biguanide agent, a statin compound. , Squalene synthesis inhibitor, fibrate compound, L
At least one of a DL catabolism promoter, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor and an antitumor agent
It is an object of the present invention to provide a pharmaceutical composition comprising a combination of species (particularly preferably a prophylactic and / or therapeutic agent for diabetes or diabetic complications).

[0017]

Means for Solving the Problems The present invention provides: (1) The following general formula (I)

[0018]

Embedded image [In the above formula, R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group which may be substituted by 1 to 3 groups selected from a substituent group α, a substituent group a C ₇ -C ₁₆ aralkyl group, a hydroxyl group, an acyloxy group which may be substituted by 1 to 3 groups selected from α (the acyl group of the acyloxy group is a C ₁ -C ₇ aliphatic acyl group, C ₇ which may be substituted by 1 to 3 groups selected from the group α.
-C ₁₁ aromatic acyl group, C ₈ -C ₁₂ aromatic aliphatic acyl group which may be substituted by 1 to 3 groups selected from substituent group α, C ₄ -C ₁₁ cycloalkylcarbonyl group, or 5 to 7 having 1 to 3 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom which may be substituted by 1 to 5 groups selected from the substituent group α.
And a carbonyl group of a membered heteroaromatic ring. ), A C ₁ -C ₆ alkoxy group, or an amino group which may be substituted with one or two groups selected from the substituent group β (the amino group is combined with a nitrogen atom to form an oxygen atom, a nitrogen atom, R ² may be a hydrogen atom, a C ₁ -C ₆ alkyl group, or a saturated heterocyclic group having 1 to 3 hetero atoms selected from the group consisting of an atom and a sulfur atom. C ₇ -C ₁₆ which may be substituted by 1 to 3 groups selected from the substituent group α.
R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group, R ⁶ represents a hydrogen atom, C ₁ -C ₆ alkyl groups, 1 to 3 optionally substituted C ₆ -C ₁₀ aryl groups with a group selected from substituent group α, or 1 to 3 substituted with a group selected from substituent group α May be C ₇
A C ₁₆ aralkyl group, Q represents an oxygen atom or a sulfur atom, X represents a bond, CH ₂ , CO, CHOR ⁹ or C
ＮＯNOR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and are each a hydrogen atom, a C ₁ -C ₆ alkyl group (the alkyl group is
A C ₁ -C ₆ alkoxycarbonyl group which may be the same or different, and a C ₆ -C ₁₀ aryl group (the aryl group may be the same or different selected from a substituent group α) Or a C ₇ -C ₁₆ aralkyl group (the aralkyl group may be the same or different 1 to 3 substituents selected from the substituent group α). May be substituted) or an acyl group (the acyl group may be a C ₁ -C ₇ aliphatic acyl group or a C _7- which may be substituted by 1 to 3 groups selected from a substituent group α). C
₁₁ aromatic acyl groups, C ₈ -C ₁₂ araliphatic acyl groups, C ₄ -C ₁₁ cycloalkylcarbonyl groups, substituent groups which may be substituted by 1 to 3 groups selected from substituent group α a 5- to 7-membered heteroaromatic carbonyl group having 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may be substituted by 1 to 5 groups selected from α, Or a carbamoyl group which may be substituted with one or two groups selected from the substituent group β. )
A represents the following general formula (II-a), (II-b), (II-c) or
Represents a group represented by (II-d),

[0019]

Embedded image (In the above formula, m represents the same or different and represents an integer of 0 to 8, B represents an oxygen atom, a sulfur atom or a group represented by NR ⁸ , R ⁷ represents a hydrogen atom, C ₁ -C ₆ alkyl group, C _6-
A C ₁₀ aryl group (the aryl group may be substituted with 1 to 3 identical or different substituents selected from the substituent group α), a C ₇ -C ₁₆ aralkyl group (the aralkyl group is The same or different 1 selected from substituent group α
Or 3 substituents), or a halogeno C ₁ -C ₆ alkyl group, wherein R ⁸ is a hydrogen atom, C _1-
A C ₆ -alkyl group, a C ₆ -C ₁₀ aryl group which may be substituted by 1 to 3 groups selected from a substituent group α, C _3-
A C ₁₀ -cycloalkyl group, a C ₇ -C ₁₆ aralkyl group which may be substituted by 1 to 3 groups selected from a substituent group α, an acyl group (the acyl group is a C ₁ -C ₇ aliphatic acyl Group, a C ₇ -C ₁₁ aromatic acyl group which may be substituted by 1 to 3 groups selected from the substituent group α, and 1 to 3 groups substituted by a group selected from the substituent group α Good C ₈
—C _{12 represents an} araliphatic acyl group. ), A carbamoyl group which may be substituted with one or two groups selected from the substituent group β, a C ₁ -C ₆ alkylsulfonyl group, a halogeno C
_{A 1-} C ₆ alkylsulfonyl group, a C ₆ -C ₁₀ arylsulfonyl group which may be substituted by 1 to 3 groups selected from the substituent group α, or a 1 to 3 group selected from the substituent group α A C ₇ -C ₁₆ aralkylsulfonyl group which may be substituted three times, or when B is N (R ⁸ ), a nitrogen atom, R ⁷ and R ⁸ are taken together to form a saturated heterocyclic group May be formed. ), Y represents an oxygen atom or a sulfur atom, Z represents -CH = or a nitrogen atom, and n represents
Represents an integer of 1 to 5, q represents an integer of 0 to 5, and the substituent group α is a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C _{(6) an} alkoxy group or an amino group (the amino group may be substituted with one or two identical or different substituents selected from the substituent group β. To form a saturated heterocyclic group having 1 to 3 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.), A C ₆ -C ₁₀ aryl group, a cyano group And a nitro group, wherein the substituent group β is a C ₁ -C ₁₀ alkyl group, a C ₆ -C ₁₀ aryl group which may be substituted by 1 to 3 groups selected from a substituent group γ, Base group γ
1 to 3 optionally substituted C selected from
₇ -C ₁₆ aralkyl group and an acyl group (said acyl group, C ₁
-C ₇ aliphatic acyl group, optionally 1 to 3 substituted with a group selected from substituent group γ C ₇ -C ₁₁ aromatic acyl group, 1 to a radical selected from the substituent group gamma Optionally substituted C ₈ -C ₁₂ araliphatic acyl group, C ₄ -C
₁₁ having 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may be substituted with 1 to 5 cycloalkylcarbonyl groups and a group selected from the substituent group γ And a 5- to 7-membered heteroaromatic carbonyl group. ) Indicates, the γ substituent group, a halogen atom, a hydroxyl group, C ₁ -C ₆ alkyl group, halogeno C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, amino group And a nitro group. ], A pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof.

Among these, preferred compounds include the following. (2) The following general formula (I ')

[0021]

Embedded image [Wherein X ′ is CH ₂ , CO or C = NOR
¹⁰ (wherein, R ¹⁰ is a hydrogen atom, a C ₁ -C ₆ alkyl group (the alkyl group is the same or different from one to three C ₁ -C ₆
An optionally substituted alkoxycarbonyl group) or a C ₇ -C ₁₆ aralkyl group. A ′ represents a group represented by the following formula (II-b ′) or (II-d ′).

[0022]

Embedded image (In the above formula, B 'represents an oxygen atom or a sulfur atom, R ⁷
Is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group (the aryl group is substituted with 1 to 3 same or different substituents selected from a substituent group α. C ₇ -C ₁₆ aralkyl group (the aralkyl group may be substituted with 1 to 3 identical or different substituents selected from substituent group α), or halogeno C _1-.
It represents a C ₆ alkyl group. )], A pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. (Substituent group α) a halogen atom,
A hydroxyl group, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, an amino group (the amino group is the same or different one or two selected from the substituent group β). And the amino group is a saturated group having 1 to 3 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom together with a nitrogen atom. May form a heterocyclic group), C
₆ -C ₁₀ aryl group, a cyano group and a nitro group. (3) The substituted condensed imidazole derivative, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable ester thereof, wherein X ′ is CH ₂ in the above (2). (4) In the above (2) or (3), A ′ is a group represented by the formula (II-
a substituted condensed imidazole derivative, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof, which is a group represented by b ′). (5) In the above (2) or (3), A ′ is a group represented by the formula (II-
A substituted condensed imidazole derivative, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, wherein the group is represented by d ') and B' is an oxygen atom. (6) In the above (2) or (3), A ′ is a group represented by the formula (II-
A substituted condensed imidazole derivative, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, wherein the group is represented by d ') and B' is a sulfur atom. (7) In the above (2), (3), (5) or (6), R ⁷ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a phenyl group (the phenyl group is selected from the substituent group α). A benzyl group (the benzyl group may be substituted with the same or different 1 to 3 substituents selected from the substituent group α). Or a halogeno C ₁ -C ₆ alkyl group, a substituted condensed imidazole derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. (8) In the above (2), (3), (5) or (6), R ⁷ is a phenyl group (the 4-position of the phenyl group is substituted with one substituent selected from the substituent group α). Benzyl group (the 4-position of the benzyl group may be a substituent group α
May be substituted with one substituent selected from)
Or a substituted condensed imidazole derivative, which is a halogeno C ₁ -C ₆ alkyl group, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. (9) Any one selected from the above (1) to (8)
And substituted substituted imidazole derivatives. (10) A pharmacologically acceptable salt of the substituted condensed imidazole derivative in any one selected from the above (1) to (8). (11) The pharmacologically acceptable hydrochloride of the substituted condensed imidazole derivative in any one selected from the above (1) to (8). (12) A pharmacologically acceptable ester of the substituted condensed imidazole derivative in any one selected from the above (1) to (8). (13) The methyl ester of the substituted condensed imidazole derivative in any one selected from the above (1) to (8). (14) The ethyl ester of the substituted condensed imidazole derivative in any one selected from the above (1) to (8). (15) Any one compound selected from the following, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof.

5- {4- [6- (6-hydroxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl {thiazolidine-2,4-dione 3- {4- [6- (6-hydroxy- 2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} -2- (2,2,2-trifluoroethoxy)
2- (4-fluorobenzylthio) -3- {4- [6-propionic acid
(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} propionic acid 3- {4- [6- (6-hydroxy −2,5,7,8−
Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl {-2-phenylthiopropionic acid 2- (4-fluorobenzyloxy) -3- {4- [6
-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} propionic acid Include. (16) A pharmaceutical composition containing the compound according to any one of (1) to (15) as an active ingredient. (17) An insulin sensitizer, a hypoglycemic agent, an anti-inflammatory agent, an immunomodulator, an aldose reduction, comprising as an active ingredient the compound according to any one of the above (1) to (15). Enzyme inhibitors, 5-lipoxygenase inhibitors, lipid peroxide production inhibitors, PPAR activators, anti-osteoporosis agents, leukotriene antagonists, adipogenesis promoters, cancer cell growth inhibitors or calcium antagonists. (18) A pharmaceutical composition for improving insulin resistance, comprising as an active ingredient the compound according to any one of (1) to (15). (19) A pharmaceutical composition for lowering blood glucose, comprising the compound according to any one of (1) to (15) as an active ingredient. (20) Diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, comprising the compound according to any one of the above (1) to (15) as an active ingredient. Diabetic complications, arteriosclerosis, gestational diabetes, polycystic ovary syndrome, cardiovascular disease, cell damage caused by atherosclerosis, cell damage caused by ischemic heart disease, gout, osteoarthritis, rheumatism A preventive or therapeutic agent for osteoarthritis, allergic disease, asthma disease, GI ulcer, cachexia, autoimmune disease, pancreatitis, cancer, osteoporosis or cataract. (21) A pharmaceutical composition for preventing or treating diabetes, comprising the compound according to any one of (1) to (15) as an active ingredient. (22) Use of the compound according to any one of the above (1) to (15) for producing a pharmaceutical composition for improving insulin resistance. (23) Use of the compound according to any one of (1) to (15) for producing a pharmaceutical composition for lowering blood sugar. (24) Use of the compound according to any one of the above (1) to (15) for producing a pharmaceutical composition for preventing or treating diabetes.

In the present invention, "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably it is a fluorine atom or a chlorine atom, more preferably a fluorine atom.

In the present invention, "C ₁ -C ₆ alkyl group"
Represents a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, Examples include 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups.
Preferably a C ₁ -C ₄ alkyl group, more preferably a methyl or ethyl.

In the present invention, "C ₁ -C ₁₀ alkyl group"
Represents a linear or branched alkyl group having 1 to 10 carbon atoms, for example, the aforementioned C ₁ -C ₆ alkyl, heptyl, 1-
Methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-
Propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-
Ethylhexyl, 5,5-dimethylhexyl, nonyl,
3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl,
Examples include decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl and 7,7-dimethyloctyl groups. Preferably a C ₁ -C ₆ alkyl group, more preferably a C ₁ -C ₄ alkyl group, most preferably methyl or ethyl.

In the present invention, “C ₃ -C ₁₀ cycloalkyl” represents a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms which may be condensed, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Cycloheptyl, norbornyl and adamantyl. Preferably is C ₃ -C ₆ cycloalkyl.

In the present invention, the term "halogeno C ₁ -C ₆ alkyl group" refers to a group in which one to three halogen atoms are bonded to the C ₁ -C ₆ alkyl group, and includes, for example, trifluoromethyl and trichloromethyl. Methyl, tribromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,
2,2-trifluoroethyl, 2-bromoethyl, 2-
Chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 4,4
-Difluorobutyl, 6-iodohexyl, 2,2-difluoroethyl and 2,2-dibromoethyl groups. It is preferably a halogeno C ₁ -C ₄ alkyl group, and more preferably a halogeno C ₁ -C ₂ alkyl group.

In the present invention, the term "C ₁ -C ₆ alkoxy group" refers to a group in which the C ₁ -C ₆ alkyl group is bonded to an oxygen atom, such as methoxy, ethoxy, propoxy,
Isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-
Methyl butoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethyl Butoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy and 2-ethylbutoxy groups can be mentioned. Preferably C ₁ −
It is a C ₄ alkoxy group, more preferably a C ₁ -C ₂ alkoxy group.

In the present invention, “C ₁ -C ₇ aliphatic acyl group” refers to a group in which a hydrogen atom or a saturated or unsaturated C ₁ -C ₆ chain hydrocarbon group is bonded to a carbonyl group. Mention may be made of formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl and crotonoyl groups. Suitable a C ₁ -C ₇ aliphatic acyl group, more preferably C ₁ -C ₄ aliphatic acyl group, most preferably a C ₁ -C ₂ aliphatic acyl group.

In the present invention, "C_Four-C₁₁Cycloal
"Kilcarbonyl" is the same as the aforementioned C_Three-C _TenCycloalkyl
A group in which a carbonyl group is bonded to a group, for example, cyclopropyl
Ropylcarbonyl, cyclobutyrylcarbonyl, cyclo
Pentyl carbonyl, cyclohexyl carbonyl, cyclo
Roheptylcarbonyl, norbornylcarbonyl and
A damantylcarbonyl group can be mentioned. Suitably
Is C₆-C₁₁Cycloalkylcarbonyl, and more preferably
Suitably cyclohexylcarbonyl or adamantyl
It is a bonyl group.

In the present invention, the term "C ₁ -C ₆ alkylthio group" refers to a group in which the C ₁ -C ₆ alkyl group is bonded to a sulfur atom, and includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyl Thio, s-butylthio, t-butylthio, pentylthio,
Isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, 4-
Methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3-
Dimethylbutylthio, 2,2-dimethylbutylthio,
Examples include 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio, and 2-ethylbutylthio groups. Preferably a C ₁ -C ₄ alkylthio group, more preferably a C ₁ -C ₂ alkylthio group.

In the present invention, "C ₁ -C ₆ alkylsulfonyl group" refers to a group in which the above C ₁ -C ₆ alkyl group is bonded to sulfonyl, such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, Butanesulfonyl, isobutanesulfonyl, s-butanesulfonyl, t-butanesulfonyl, pentanesulfonyl, isopentanesulfonyl, 2-methylbutanesulfonyl, neopentanesulfonyl, 1-ethylpropanesulfonyl, hexanesulfonyl, 4-methylpentanesulfonyl, 3-methyl Pentanesulfonyl, 2-methylpentanesulfonyl, 3,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl, 1,1-
Dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3-dimethylbutanesulfonyl, 2,3
-Dimethylbutanesulfonyl and 2-ethylbutanesulfonyl. Preferably a C ₁ -C ₄ alkylsulfonyl group, more preferably a C ₁ -C ₃ alkylsulfonyl group.

In the present invention, "halogeno C ₁ -C ₆ alkylsulfonyl group" refers to a group in which the above-mentioned halogeno C ₁ -C ₆ alkyl group is bonded to sulfonyl, for example, trifluoromethanesulfonyl, trichloromethanesulfonyl,
Difluoromethanesulfonyl, dichloromethanesulfonyl, dibromomethanesulfonyl, fluoromethanesulfonyl, 2,2,2-trifluoroethanesulfonyl,
2,2,2-trichloroethanesulfonyl, 2-bromoethanesulfonyl, 2-chloroethanesulfonyl, 2-
Fluoroethanesulfonyl, 2-iodoethanesulfonyl, 3-chloropropanesulfonyl, 4-fluorobutanesulfonyl, 4,4-difluorobutanesulfonyl,
Examples include 6-iodohexanesulfonyl, 2,2-difluoroethanesulfonyl and 2,2-dibromoethanesulfonyl groups. It is preferably a halogeno C ₁ -C ₄ alkylsulfonyl group, more preferably a halogeno C _1.
—C ₂ alkylsulfonyl group.

In the present invention, the "C ₆ -C ₁₀ aryl group" refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include phenyl, indenyl and naphthyl groups. Preferably, it is a phenyl machine.

In the present invention, the "C ₇ -C ₁₆ aralkyl group" refers to a group in which the C ₆ -C ₁₀ aryl group is bonded to the C ₁ -C ₆ alkyl group, for example, benzyl, naphthylmethyl, indene Nilmethyl, diphenylmethyl, 1-
Phenethyl, 2-phenethyl, 1-naphthylethyl, 2
-Naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl,
1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl,
Examples include 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 5-phenylpentyl, 5-naphthylpentyl, 6-phenylhexyl and 6-naphthylhexyl groups. Preferably, it is a benzyl group.

In the present invention, the term "C ₇ -C ₁₁ aromatic acyl group" refers to a group in which the C ₆ -C ₁₀ aryl group is bonded to a carbonyl group, for example, benzoyl, 1-indanecarbonyl, 2-indane Carbonyl and 1- and 2
-A naphthoyl group. Preferably, it is a benzoyl group.

In the present invention, the term "C ₈ -C ₁₂ araliphatic acyl group" means that the C ₆ -C ₁₀ aryl group is a C ₂ -C ₆ aliphatic acyl group (linear or straight-chain having 1 to 5 carbon atoms). Represents a group in which a branched alkyl group is bonded to a carbonyl group), for example, phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl, Mention may be made of naphthylacetyl, 4-naphthylbutyryl and 6-naphthylhexanoyl groups.

In the present invention, “5- to 7-membered heteroaromatic carbonyl having 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur” includes, for example, furylcarbonyl, thienylcarbonyl, Pyrrolylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl,
5-membered heteroaromatic carbonyls such as triazolylcarbonyl and thiadiazolylcarbonyl, 6-membered heteroaromatic carbonyls such as pyranylcarbonyl, nicotinoyl, isonicotinoyl, pyridazinylcarbonyl, pyrimidinylcarbonyl and pyrazinylcarbonyl and Mention may be made of 7-membered heteroaromatic carbonyls such as azepinylcarbonyl.

In the present invention, the term "C ₆ -C ₁₀ arylsulfonyl group" refers to a group in which the C ₆ -C ₁₀ aryl group is bonded to sulfonyl, and includes, for example, phenylsulfonyl, naphthylsulfonyl and indenylsulfonyl groups. Can be.

In the present invention, "C ₇ -C ₁₆ aralkylsulfonyl group" refers to a group in which the aralkyl group is bonded to sulfonyl, such as benzylsulfonyl, naphthylmethylsulfonyl, indenylmethylsulfonyl, 1-
Phenethylsulfonyl, 2-phenethylsulfonyl, 1
-Naphthylethylsulfonyl, 2-naphthylethylsulfonyl, 1-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl, 1-naphthylpropylsulfonyl, 2-naphthylpropylsulfonyl, 3-naphthylpropylsulfonyl,
1-phenylbutylsulfonyl, 2-phenylbutylsulfonyl, 3-phenylbutylsulfonyl, 4-phenylbutylsulfonyl, 1-naphthylbutylsulfonyl,
Examples thereof include 2-naphthylbutylsulfonyl, 3-naphthylbutylsulfonyl, 4-naphthylbutylsulfonyl, 5-phenylpentylsulfonyl, 5-naphthylpentylsulfonyl, 6-phenylhexylsulfonyl, and 6-naphthylhexylsulfonyl.

In the present invention, the “C ₆ -C ₁₀ aryl group optionally substituted by 1 to 3 groups selected from the substituent group γ” in the definition of the substituent group β is the above-mentioned substituent And a group having a substituent, for example, methylphenyl, trifluoromethylphenyl, difluoromethylphenyl, hydroxyphenyl, 4-hydroxy-2,3,5-trimethylphenyl, 3,5-
Di-t-butyl-4-hydroxyphenyl, adamantylphenyl, 4-amino-3,5-dimethylphenyl,
Acetylphenyl, methoxyphenyl, benzoylphenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl, nitrophenyl, (dimethylamino) phenyl, biphenylyl, methylbiphenylyl, methylnaphthyl, trifluoronaphthyl, hydroxynaphthyl, Mention may be made of methoxynaphthyl, fluoronaphthyl and chloronaphthyl. It is preferably a phenyl group optionally having 1 to 3 substituents γ, more preferably a phenyl group optionally having 1 or 2 substituents γ, and most preferably a phenyl group optionally having 1 or 2 substituents γ. A phenyl group which may have one component γ.

In the present invention, the “C ₇ -C ₁₆ aralkyl group which may be substituted by 1 to 3 groups selected from the substituent group γ” in the definition of the substituent group β is the above-mentioned substituent In addition to the group having no, as a group having a substituent,
For example, methylbenzyl, trifluoromethylbenzyl,
Hydroxybenzyl, 4-hydroxy-2,3,5-trimethylbenzyl, 3,5-di-t-butyl-4-hydroxybenzyl, adamantylbenzyl, 4-amino-
3,5-dimethylbenzyl, acetylbenzyl, methoxybenzyl, benzoylbenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, dichlorobenzyl, bromobenzyl, dibromobenzyl, nitrobenzyl, aminobenzyl, (dimethylamino) benzyl, biphenylylmethyl, Methylbiphenylylmethyl, methylphenethyl, trifluoromethylphenethyl, hydroxyphenethyl, 4-hydroxy-2,3,5-trimethylphenethyl, 3,5-di-tert-butyl-4-hydroxyphenethyl, adamantylphenethyl, 4-amino-
3,5-dimethylphenethyl, acetylphenethyl, methoxyphenethyl, benzoylphenethyl, fluorophenethyl, difluorophenethyl, chlorophenethyl,
Nitrophenethyl, (dimethylamino) phenethyl, biphenylylethyl, methylbiphenylylethyl, methylphenylbutyl, trifluoromethylphenylbutyl,
Hydroxyphenylbutyl, 4-hydroxy-2,3,
5-trimethylphenylbutyl, 3,5-di-tert-butyl-4-hydroxyphenylbutyl, adamantylphenylbutyl, 4-amino-3,5-dimethylphenylbutyl, acetylphenylbutyl, methoxyphenylbutyl, fluorophenylbutyl, chlorophenyl Butyl,
Examples include nitrophenylbutyl, (dimethylamino) phenylbutyl, biphenylylbutyl, methylnaphthylmethyl, trifluoronaphthylmethyl, hydroxynaphthylmethyl, methoxynaphthylmethyl, fluoronaphthylmethyl and chloronaphthylmethyl. Preferable is phenyl optionally having 1 to 3 groups selected from substituent group γ and phenylalkyl group having C ₁ -C ₆ alkyl, more preferably selected from substituent group γ. And phenyl optionally having 1 to 3 groups
₁ -C ₄ a phenylalkyl group having an alkyl, group of 1 to 3 and still more preferably selected from γ substituent group
Phenyl and a phenylalkyl group having a C ₁ -C ₂ alkyl, most preferably a substituted γ
Is a benzyl or phenethyl group which may have one.

In the present invention, the “C ₇ -C ₁₁ aromatic acyl group which may be substituted by 1 to 3 groups selected from the substituent group γ” in the definition of the substituent group β is as described above. Examples of the group having a substituent in addition to the group having no substituent include methylbenzoyl, trifluoromethylbenzoyl, hydroxybenzoyl, 4-hydroxy-2,
3,5-trimethylbenzoyl, 3,5-di-tert-butyl-4-hydroxybenzoyl, adamantylbenzoyl, 4-amino-3,5-dimethylbenzoyl, acetylbenzoyl, methoxybenzoyl, fluorobenzoyl, difluorobenzoyl, chlorobenzoyl, Dichlorobenzoyl, nitrobenzoyl, aminobenzoyl,
(Dimethylamino) benzoyl, phenylbenzoyl,
Mention may be made of methylnaphthylcarbonyl, trifluoronaphthylcarbonyl, hydroxynaphthylcarbonyl, methoxynaphthylcarbonyl, fluoronaphthylcarbonyl and chloronaphthylcarbonyl. It is preferably benzoyl optionally having 1 to 3 substituents γ, more preferably benzoyl optionally having 1 or 2 substituents γ, most preferably γ. Is benzoyl optionally having one.

In the present invention, the “C ₈ -C ₁₂ araliphatic acyl group optionally substituted by 1 to 3 groups selected from the group of substituents γ” in the definition of the group of substituents β is the same as that described above. In addition to the group having no substituent, examples of the group having a substituent include methylphenylacetyl, trifluoromethylphenylacetyl, hydroxyphenylacetyl, 4-hydroxy-2,3,5-trimethylphenylacetyl, 3,5-di-t-butyl-4-hydroxyphenylacetyl, adamantylphenylacetyl, 4-
Amino-3,5-dimethylphenylacetyl, acetylphenylacetyl, methoxyphenylacetyl, benzoylphenylacetyl, fluorophenylacetyl, difluorophenylacetyl, chlorophenylacetyl,
Dichlorophenylacetyl, nitrophenylacetyl,
(Dimethylamino) phenylacetyl, biphenylylacetyl, 4- (methylphenyl) butyryl, 4- (trifluoromethylphenyl) butyryl, 4- (hydroxyphenyl) butyryl, 4- (4-hydroxy-2,3,
5-trimethylphenyl) butyryl, 4- (3,5-di-tert-butyl-4-hydroxyphenyl) butyryl, 4-
(Adamantylphenyl) butyryl, 4- (4-amino-3,5-dimethylphenyl) butyryl, 4- (methoxyphenyl) butyryl, 4- (fluorophenyl) butyryl, 4- (chlorophenyl) butyryl, 4-[(dimethyl Amino) phenyl] butyryl, methylnaphthylacetyl, trifluoronaphthylacetyl, hydroxynaphthylacetyl, methoxynaphthylacetyl and fluoronaphthylacetyl or chloronaphthylacetyl. Preferably, it is a phenylaliphatic acyl having phenyl which may have 1 to 3 groups selected from the substituent group γ, and more preferably has 1 group selected from the substituent group γ. And phenylacetyl having phenyl optionally having one group selected from the substituent group γ.

In the present invention, in the definition of the substituent group β, “a group selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may be substituted by 1 to 5 groups selected from the substituent group γ” Examples of the group having a substituent of "5- to 7-membered heteroaromatic carbonyl having 1 to 3 hetero atoms" include, in addition to the above-mentioned groups having no substituent, for example, fluorofurylcarbonyl, fluorothienylcarbonyl, fluoropyrrolyl and the like. Carbonyl, fluorooxazolylcarbonyl, fluorothiazolylcarbonyl, fluorotriazolylcarbonyl, fluoropyranylcarbonyl, fluoronicotinoyl, fluoropyridazinylcarbonyl, fluoropyrimidinylcarbonyl, methylfurylcarbonyl, methylthienylcarbonyl, methyl Pyrrolylcarbonyl, methylo Xazolylcarbonyl, methylthiazolylcarbonyl, methylnicotinoyl, methoxyfurylcarbonyl, methoxythienylcarbonyl, methoxypyrrolylcarbonyl, methoxyoxazolylcarbonyl, methoxythiazolylcarbonyl, methoxynicotinoyl, dimethylaminofurylcarbonyl, dimethyl Examples include aminothienylcarbonyl, dimethylaminopyrrolylcarbonyl, dimethylaminooxazolylcarbonyl, dimethylaminothiazolylcarbonyl, and dimethylaminonicotinoyl. Preferably, the substitution amount γ is 1
Or a 5- to 7-membered heteroaromatic carbonyl group having 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have 3 atoms,
More preferably, it is a 5- or 6-membered heteroaromatic carbonyl group having 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have one substituent γ. And most preferably a 5- or 6-membered heteroaromatic carbonyl group having one nitrogen atom which may have one substituent γ.

In the present invention, in the definition of R ¹ and the substituent group α, “an amino group which may be substituted by one or two groups selected from the substituent group β (the amino group is And may form a saturated heterocyclic group having 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.) And an amino group (the amino group is The amino group may be substituted with one or two same or different substituents selected from the substituent group β.
It may form a saturated heterocyclic group having 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom. )) Is, for example, amino, methylamino, N-methyl-N-hexylamino, N-methyl-N-phenylamino, ethylamino, N-methyl-N-ethylamino, N-ethyl-N-hexylamino, N-ethyl-N
-Phenylamino, propylamino, N-propyl-N
-Butylamino, N-propyl-N-pentylamino,
N-propyl-N-hexylamino, N-propyl-N
-Octylamino, N-propyl-N-nonylamino,
N-propyl-N-decylamino, isopropylamino, butylamino, N-butyl-N-hexylamino,
s-butylamino, t-butylamino, pentylamino, hexylamino, heptylamino, octylamino, nonylamino, decylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, diheptylamino, dioctylamino , Dinonylamino, didecylamino, phenylamino, fluorophenylamino, chlorophenylamino, bromophenylamino, difluorophenylamino, dichlorofluorophenylamino, dibromophenylamino, indenylamino, naphthylamino, diphenylamino, benzylamino, fluorobenzylamino, chloro Benzylamino, bromobenzylamino, difluorobenzylamino, difluorobenzylamino, dichlorobenzyl Amino, naphthylmethylamino, indenylmethylamino, phenethylamino, phenylpropylamino, phenylbutylamino, phenylbutylamino, phenylpentylamino, phenylhexylamino, dibenzylamino, formylamino, acetylamino, propionylamino, butyrylamino, iso Butyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotoylamino, benzoylamino, indanecarbonylamino, naphthoylamino, fluorobenzoylamino, chlorobenzoylamino, bromobenzoylamino, Difluorobenzoylamino, difluorobenzoylamino, dichlorobenzoylamino, diisopropylben Ylamino, trifluoromethylbenzoylamino, 4-hydroxy-3,5-dimethylbenzoylamino, 4-hydroxy-3,5-di-tert-butylbenzoylamino, indanecarbonylamino, naphthoylamino, phenylacetylamino, phenylpropionylamino, phenyl Butyrylamino, phenylpentanoylamino, phenylhexanoylamino, fluorophenylacetylamino, chlorophenylacetylamino, bromophenylacetylamino, difluorophenylacetylamino, difluorophenylacetylamino, dichlorophenylacetylamino, cyclopropionylamino, cyclobutyrylamino , Cyclopentanoylamino, cyclohexanoylamino, pyrrolylcarbonylamino, imidazolylcarboni Amino, pyrazolylcarbonylamino, triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinoylamino, isonicotinoylamino, pyrazinylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, thiazolylcarbonylamino, Oxazolylcarbonylamino,
Oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, N, N-diacetylamino, N-formyl-N-hexylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino, N-acetyl- N-propylamino, N-acetyl-N-butylamino, N-acetyl-N-pentylamino, N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino, N-benzoyl-N-propylamino, N-benzoyl-N-butylamino, N-benzoyl-N-pentylamino, N
-Benzoyl-N-hexylamino, N-benzoyl-
N-phenylamino, N-benzyl-N-benzoylamino, N-trifluoromethylbenzyl-N-difluorobenzoylamino, N-difluorobenzyl-N-nicotinoylamino, N-chlorobenzoyl-N-methylamino, N- Chlorobenzoyl-N-hexylamino,
N-chlorobenzyl-N-acetylamino, N-difluorobenzoyl-N-hexylamino, N-difluorobenzoyl-N-phenylamino, N-difluorobenzoyl-N-phenylamino, N-trifluoromethylbenzoyl-N-butyl Amino, N-di-tert-butyl-hydroxybenzoyl-N-hexylamino, N-hexyl-N-naphthoylamino, N-hexyl-N-phenylacetylamino, N-isobutyl-N-cycloheptanoylamino, N- Butyl-N-nicotinoylamino,
N-hexyl-N-nicotinoylamino, N-isonicotinoyl-N-hexylamino, N-methyl-N-trifluoromethylphenylamino, N-ethyl-N-methoxyphenylamino, N-methyl-N-benzylamino, N-methyl-N-fluorobenzylamino, N-ethyl-N-benzylamino, N-ethyl-N-methoxyphenylamino, N-propyl-N-fluorobenzylamino, N-phenyl-N-benzylamino, N- Phenyl-N-fluorobenzylamino, dimethoxybenzylamino, N-methyl-N-acetylamino, N-methyl-N-propionylamino, N-ethyl-N-formylamino, N-ethyl-N-acetylamino, N- Phenyl-N-formylamino, N-phenyl-N-acetylamino, N- Le -N- butyrylamino, N- hexanoyl -N- methoxyphenylamino, N- butyryl -N- fluorobenzylamino, N- hexanoyl -
N-bromobenzylamino, N-phenyl-N-acetylamino, nitrobenzoylamino, aminobenzoylamino, N-methyl-N-benzoylamino, 4-hydroxy-3,5-di-tert-butylbenzylamino, 4-hydroxy -3,5-di-tert-butylbenzoylamino, N
-Methyl-N-4-hydroxy-3,5-di-tert-butylbenzoylamino, N-ethyl-N-4-hydroxy-
3,5-di-tert-butylbenzoylamino, N-propyl-N-4-hydroxy-3,5-di-tert-butylbenzoylamino, N-butyl-N-4-hydroxy-3,5-
Di-t-butylbenzoylamino, N-hexyl-N-4
-Hydroxy-3,5-di-tert-butylbenzoylamino, N-phenyl-N-benzoylamino, N-fluorophenyl-N-4-hydroxy-3,5-di-tert-butylbenzoylamino, N-benzyl-N -Fluorobenzoylamino, N-fluorobenzyl-N-4-hydroxy-3,5-di-tert-butylbenzoylamino, N-trifluoromethylbenzoylamino, N-methyl-N-
Fluorobenzoylamino, N-methyl-N-trifluoromethylbenzoylamino, N-ethyl-N-benzoylamino, N-ethyl-N-fluorobenzoylamino, N-ethyl-N-trifluoromethylbenzoylamino, N-methyl -N-chlorobenzoylamino, N-
Butyl-N-benzylamino, N-yl-N-benzoylamino, N-methyl-N-dichlorobenzoylamino,
Examples include N-ethyl-N-benzoylamino, difluorobenzoylamino, dimethoxybenzoylamino, trimethoxybenzoylamino, N-hexyl-N-nitrobenzoylamino and 4-hydroxy-3,5-dimethylbenzoylamino groups. It is preferably an amino group optionally having 1 to 2 C ₁ -C ₁₀ alkyl or C ₁ -C ₇ aliphatic acyl as a substituent, more preferably C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl. _1- C ₂ aliphatic acyl is 1
Or an amino group which may have 2 or more.

An oxygen atom together with a nitrogen atom,
When forming a saturated heterocyclic group having 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom,
Examples include azetidino, pyrrolidino, piperidino, morpholino, thiomorpholino, oxazolidino, thiazolidino, imidazolidino, piperazino, homopiperazino, isoxazolidino, and isothiazolidino groups.

In the present invention, "C ₆ -C ₁₀ aryl optionally substituted by 1 to 3 groups selected from substituent group α" and R ⁷ in the definition of R ¹ and R ^{6 to} R ¹⁰ A “C ₆ -C ₁₀ aryl group in the definition, wherein the aryl group is
May be substituted with 1 to 3 same or different substituents selected from substituent group α)), in addition to the above-mentioned group having no substituent, as a group having a substituent,
For example, methylphenyl, dimethylphenyl, trifluoromethylphenyl, hydroxyphenyl, 4-hydroxy-2,3,5-trimethylphenyl, 3,5-di-t
-Butyl-4-hydroxyphenyl, adamantylphenyl, 4-amino-3,5-dimethylphenyl, acetylphenyl, methoxyphenyl, dimethoxyphenyl,
Benzoylphenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl, nitrophenyl, (dimethylamino) phenyl, biphenylyl, methylbiphenylyl, methylnaphthyl, trifluoromethylnaphthyl, hydroxynaphthyl, methoxynaphthyl, fluoronaphthyl , Chloronaphthyl and bromonaphthyl groups. It is preferably a phenyl group optionally having 1 to 3 substituents α, more preferably a phenyl group optionally having 1 or 2 substituents α, most preferably a substituted phenyl group. A phenyl group which may have one α.

In the present invention, R ¹ , R ² and R ^{6 to} R
¹⁰ "C ₇ -C ₁₆ aralkyl group in the definition of" optionally 1 to 3 substituted with a group selected from Substituent group α C ₇ -C ₁₆ aralkyl "and R ⁷ in the definition of (the aralkyl group May be substituted with the same or different 1 to 3 substituents selected from the substituent group α). ”Means, in addition to the above-mentioned group having no substituent, a group having a substituent Is, for example, methylbenzyl, trifluoromethylbenzyl, hydroxybenzyl, 3,4,5-trimethoxybenzyl, 4-hydroxy-3,5-dimethylbenzyl, 4-hydroxy-3,5-di-tert-butylbenzyl, adamantyl Benzyl, 4-amino-3,5-dimethylbenzyl, acetylbenzyl, methoxybenzyl, benzoylbenzyl, fluorobenzyl, difluorobenzyl, chloroben , Dichlorobenzyl, bromobenzyl, dibromobenzyl, nitrobenzyl, (dimethylamino) benzyl, biphenylylmethyl, methylbiphenylylmethyl, methylphenethyl, trifluoromethylphenethyl, hydroxyphenethyl, 4-hydroxy-2,3,5- Trimethylphenethyl, 3,5-di-tert-butyl-4-hydroxyphenethyl, adamantylphenethyl, 4-amino-3,5-dimethylphenethyl, acetylphenethyl, methoxyphenethyl, benzoylphenethyl, fluorophenethyl, difluorophenethyl, chlorophenethyl, nitro Phenethyl, (dimethylamino) phenethyl, biphenylylethyl, methylbiphenylylethyl, methylphenylbutyl, trifluoromethylphenylbutyl, hydroxyphenyl Rubuchiru, 4-hydroxy-2,3,5-trimethylphenyl-butyl, 3,5-di-t- butyl-4-hydroxyphenyl butyl, adamantyl phenylbutyl, 4-amino -
3,5-dimethylphenylbutyl, acetylphenylbutyl, methoxyphenylbutyl, fluorophenylbutyl, chlorophenylbutyl, nitrophenylbutyl,
(Dimethylamino) phenylbutyl, biphenylylbutyl, methylnaphthylmethyl, trifluoronaphthylmethyl, hydroxynaphthylmethyl, methoxynaphthylmethyl, fluoronaphthylmethyl and chloronaphthylmethyl. Preferable is phenyl optionally having 1 to 3 substituents α and phenylalkyl group having C ₁ -C ₆ alkyl, more preferably phenyl optionally having 1 substituent α. And a phenylalkyl group having a C ₁ -C ₆ alkyl, more preferably a phenyl optionally having one substituent α and a phenylalkyl group having a C ₁ -C ₄ alkyl, Is a phenyl optionally having one substituent α and C _1-
It is a phenylalkyl group having a C ₂ alkyl.

In the present invention, the acyloxy group for R ¹ and the C ₇ -C ₁₁ aromatic acyl which may be substituted by 1 to 3 groups selected from the substituent group α in the definition of R ^{8 to} R ¹⁰ are used. "Means a group having a substituent in addition to the group having no substituent described above, for example, methylbenzoyl, dimethylbenzoyl, isopropylbenzoyl, t
-Butylbenzoyl, trifluoromethylbenzoyl,
Hydroxybenzoyl, 4-hydroxy-3,5-di-t
-Butylbenzoyl, 4-hydroxy-3,5-dimethylbenzoyl, adamantylbenzoyl, 4-amino-
3,5-dimethylbenzoyl, acetylbenzoyl, methoxybenzoyl, 3,4,5-trimethoxybenzoyl, fluorobenzoyl, difluorobenzoyl, 2-
Fluoro-4-trifluoromethylbenzoyl, chlorobenzoyl, dichlorobenzoyl, bromobenzoyl,
Examples include dibromobenzoyl, nitrobenzoyl, aminobenzoyl, (dimethylamino) benzoyl, phenylbenzoyl, methylnaphthylcarbonyl, trifluoronaphthylcarbonyl, hydroxynaphthylcarbonyl, methoxynaphthylcarbonyl, fluoronaphthylcarbonyl and chloronaphthylcarbonyl. It is preferably benzoyl optionally having 1 to 3 substituents α, more preferably benzoyl optionally having 1 or 2 substituents α, and most preferably α.
Is benzoyl optionally having one.

In the present invention, the acyloxy group for R ¹ and “C ₈ -C ₁₂ araliphatic which may be substituted by 1 to 3 groups selected from the substituent group α in the definition of R ^{8 to} R ^10. “Acyl” refers to a group having a substituent in addition to the group having no substituent described above, for example, methylphenylacetyl, trifluoromethylphenylacetyl, hydroxyphenylacetyl, 4-hydroxy-3,5-
Dimethylphenylacetyl, 4-hydroxy-3,5-
Dimethoxyphenylacetyl, 4-hydroxy-3,5
-Di-t-butylphenylacetyl, adamantylphenylacetyl, 4-amino-3,5-dimethylphenylacetyl, acetylphenylacetyl, methoxyphenylacetyl, benzoylphenylacetyl, fluorophenylacetyl, difluorophenylacetyl, chlorophenylacetyl, dichlorophenylacetyl, Nitrophenylacetyl, (dimethylamino) phenylacetyl, biphenylylacetyl, 4- (methylphenyl) butyryl, 4- (trifluoromethylphenyl) butyryl, 4- (hydroxyphenyl) butyryl, 4- (4-
Hydroxy-2,3,5-trimethylphenyl) butyryl, 4- (3,5-di-tert-butyl-4-hydroxyphenyl) butyryl, 4- (adamantylphenyl) butyryl, 4- (4-amino-3,5 -Dimethylphenyl) butyryl, 4- (methoxyphenyl) butyryl, 4- (fluorophenyl) butyryl, 4- (chlorophenyl) butyryl, 4-[(dimethylamino) phenyl] butyryl, methylnaphthylacetyl, trifluoronaphthylacetyl, hydroxy Examples include naphthylacetyl, methoxynaphthylacetyl, fluoronaphthylacetyl and chloronaphthylacetyl. Preferably the substitution α
C ₈ having phenyl optionally having 1 to 3 a -
A C ₁₂ -C ₁₂ phenylacyl group, and more preferably a C ₈ -C ₁₂ phenylacyl group having phenyl which may have one substituent α.

In the present invention, the acyloxy group for R ¹ and the oxygen atom, nitrogen atom and sulfur atom which may be substituted by 1 to 5 groups selected from the substituent group α in the definition of R ^{9 to} R ¹⁰ The "5- to 7-membered heteroaromatic carbonyl having 1 to 3 heteroatoms selected from the group consisting of" refers to a group having a substituent in addition to the group having no substituent described above, for example, fluorofurylcarbonyl , Fluorothienylcarbonyl, fluoropyrrolylcarbonyl, fluorooxazolylcarbonyl, fluorothiazolylcarbonyl, fluorotriazolylcarbonyl, fluoropyranylcarbonyl, fluoronicotinoyl, fluoropyridazinylcarbonyl, fluoropyrimidinylcarbonyl, methylfuryl Carbonyl, methylthienylcarbonyl, methyl Pyrrolylcarbonyl, methyl benzoxazolyl carbonyl, methyl thiazolyl carbonyl, methyl nicotinoyl, methoxy furyl carbonyl,
Methoxythienylcarbonyl, methoxypyrrolylcarbonyl, methoxyoxazolylcarbonyl, methoxythiazolylcarbonyl, methoxynicotinoyl, dimethylaminofurylcarbonyl, dimethylaminothienylcarbonyl, dimethylaminopyrrolcarbonyl, dimethylaminooxazolylcarbonyl, dimethylamino Mention may be made of thiazolylcarbonyl and dimethylaminonicotinoyl. Preferably a 5- to 7-membered heteroaromatic carbonyl group having 1 to 3 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have 1 or 3 substituents γ And more preferably 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have one substituted moiety γ.
And most preferably a 5- or 6-membered heteroaromatic carbonyl group having one nitrogen atom which may have one substituent γ.

In the present invention, the “C ₆ -C ₁₀ arylsulfonyl group which may be substituted by 1 to 3 groups selected from the substituent group α” in R ⁸ does not have the substituent described above. In addition to the group, as a group having a substituent, for example, methylphenylsulfonyl, chlorophenylsulfonyl, fluorophenylsulfonyl, trifluoromethylphenylsulfonyl, nitrophenylsulfonyl, cyanophenylsulfonyl, acetylphenylsulfonyl, benzoylphenylsulfonyl, biphenylylsulfonyl, Mention may be made of methylbiphenylylsulfonyl, methylnaphthylsulfonyl, acetylnaphthylsulfonyl and benzoylnaphthylsulfonyl. It is preferably a phenylsulfonyl group optionally having 1 to 3 substituents α, and more preferably a phenylsulfonyl group optionally having 1 substituent α.

In the present invention, the “C ₇ -C ₁₆ aralkylsulfonyl group which may be substituted by 1 to 3 groups selected from the substituent group α” for R ⁸ does not have the substituent described above. In addition to the group, as a group having a substituent,
For example, methylbenzylsulfonyl, chlorobenzylsulfonyl, fluorobenzylsulfonyl, trifluoromethylbenzylsulfonyl, nitrophenylsulfonyl,
Cyanophenylsulfonyl, acetylbenzylsulfonyl, benzoylbenzylsulfonyl, biphenylylmethylsulfonyl, methylbiphenylylmethylsulfonyl,
Methylnaphthylmethylsulfonyl, acetylnaphthylmethylsulfonyl, benzoylnaphthylmethylsulfonyl, methylphenethylsulfonyl, chlorophenethylsulfonyl, fluorophenethylsulfonyl, trifluoromethylphenethylsulfonyl, nitrophenethylsulfonyl, cyanophenethylsulfonyl, acetylphenethylsulfonyl, methylnaphthylethylsulfonyl, methylnaphthylethylsulfonyl Acetylnaphthylethylsulfonyl, methylphenylbutylsulfonyl, acetylphenylbutylsulfonyl, methylnaphthylbutylsulfonyl and acetylnaphthylbutylsulfonyl can be mentioned. Preferably, phenyl optionally having 1 to 3 substituents α and C ₁ -C ₆
A phenylalkylsulfonyl group having an alkyl, more preferably a phenyl optionally having one substituent α and a phenylalkylsulfonyl group having a C ₁ -C ₄ alkyl, most preferably a substituent α A benzylsulfonyl group or a phenethylsulfonyl group which may have one.

R⁸Or R^TenIs selected from the substituent group β
Carbamoyl optionally substituted with one or two groups
A `` group '', the group includes, for example, carbamoy
, Methylcarbamoyl, ethylcarbamoyl, propyl
Rucarbamoyl, isopropylcarbamoyl, butyl carb
Rubamoyl, s-butylcarbamoyl, t-butylcarb
Bamoyl, pentylcarbamoyl, hexylcarbamoy
Dimethylcarbamoyl, diethylcarbamoyl, N
-Ethyl-N-methylcarbamoyl, dipropylcarba
Moyl, dibutylcarbamoyl, dipentylcarbamoy
, Dihexylcarbamoyl, N-methyl-N-phenyl
Rucarbamoyl, N-methyl-N-isopropylcarba
Moyl, N-methyl-N-propylcarbamoyl, N-
Methyl-N-ethylcarbamoyl, N-ethyl-N-y
Sopropylcarbamoyl, N-ethyl-N-propylca
Rubamoyl, trifluoromethylphenylcarbamoy
, N-hydroxy-N-phenylcarbamoyl, 4-
Hydroxy-2,3,5-trimethylphenylcarbamo
Yl, 4-hydroxy-3,5-di-tert-butylphenyl
Carbamoyl, N-fluorophenyl-N-ethylcar
Bamoyl, adamantylphenylcarbamoyl, 4-A
Mino-3,5-dimethylphenylcarbamoyl, acetyl
Luphenylcarbamoyl, methoxyphenylcarbamoy
Benzoylphenylcarbamoyl, fluorophenyl
Rucarbamoyl, N-fluorophenyl-N-ethylca
Rubamoyl, N-chlorophenyl-N-ethylcarbamo
Yl, N-fluorophenyl-N-methylcarbamoy
, N-chlorophenyl-N-methylcarbamoyl,
Lorophenylcarbamoyl, difluorophenylcarba
Moyl, dichlorophenylcarbamoyl, dichlorofe
Nilcarbamoyl, nitrophenylcarbamoyl, (di
Methylamino) phenylcarbamoyl, biphenylilca
Rubamoyl, methyl biphenylylcarbamoyl, methyl
Naphthylcarbamoyl, trifluoronaphthylcarbamo
Yl, hydroxynaphthylcarbamoyl, methoxynaph
Tylcarbamoyl, fluoronaphthylcarbamoyl,
Loronaphthylcarbamoyl, phenylcarbamoyl,
Fluorophenylcarbamoyl, 1- or 2-indene
Nilcarbamoyl, 1- or 2-naphthylcarbamo
Yl, diphenylcarbamoyl, formylcarbamoy
, Acetylcarbamoyl, propionylcarbamoy
, Butyrylcarbamoyl, isobutyrylcarbamoy
, Valerylcarbamoyl, isovalerylcarbamoy
, Pivaloylcarbamoyl, hexanoylcarbamoy
, Acryloylcarbamoyl, methacryloylcarba
Moyl, crotoylcarbamoyl, benzoylcarbamo
Yl, 1-indancarbonylcarbamoyl, 1-young
2-naphthoylcarbamoyl, 2,6-diisopro
Pyrbenzoylcarbamoyl, 1-indanecarbonyl
Carbamoyl, 1- or 2-naphthoylcarbamoy
, Diphenylcarbamoyl, phenylacetylcarba
Moyl, 3-phenylpropionylcarbamoyl, 4-
Phenylbutyrylcarbamoyl, 5-phenylpentano
Ilcarbamoyl, 6-phenylhexanoylcarbamo
Yl, cyclopropionylcarbamoyl, cyclobutylyl
Rucarbamoyl, cyclopentanoylcarbamoyl,
Clohexanoylcarbamoyl, pyrrolylcarbonylka
Rubamoyl, imidazolylcarbonylcarbamoyl,
Lazolylcarbonylcarbamoyl, triazolylcarbo
Nilcarbamoyl, tetrazolylcarbonylcarbamoy
Le, nicotinoylcarbamoyl, isonicotinoylcal
Bamoyl, pyrazinylcarbonylcarbamoyl, pirimi
Dinylcarbonylcarbamoyl, pyridazinylcarboni
Rucarbamoyl, thiazolylcarbonylcarbamoyl,
Oxazolylcarbonylcarbamoyl, oxadiazoli
Carbonylcarbamoyl, thiadiazolylcarbonyl
Carbamoyl, 4-trifluoromethylphenylcarba
Moylcarbamoyl, N, N-diacetylcarbamoy
, N-formyl-N-hexylcarbamoyl, NA
Cetyl-N-methylcarbamoyl, N-acetyl-N-
Ethylcarbamoyl, N-acetyl-N-propylcal
Bamoyl, N-acetyl-N-butylcarbamoyl, N
-Acetyl-N-pentylcarbamoyl, N-acetyl
-N-hexylcarbamoyl, benzoylcarbamoy
, N-benzoyl-N-methylcarbamoyl, N-
Nzoyl-N-ethylcarbamoyl, N-benzoyl-
N-propylcarbamoyl, N-benzoyl-N-buty
Rucarbamoyl, N-benzoyl-N-pentylcarba
Moyl, N-benzoyl-N-hexylcarbamoyl,
N-benzoyl-N-phenylcarbamoyl, N-ben
Jil-N-benzoylcarbamoyl, benzylcarbamo
Yl, fluorobenzylcarbamoyl, chlorobenzyl
Carbamoyl, trifluoromethylbenzylcarbamoy
, N-benzyl-N-methylcarbamoyl, N-ben
Jil-N-ethylcarbamoyl, N-benzyl-N-propyl
Ropylcarbamoyl, N-benzyl-N-isopropyl
Carbamoyl, N-benzyl-N-phenylcarbamoy
4-hydroxy-3,5-di-tert-butylbenzylca
Rubamoyl, N-hexyl-N-1-naphthoylcarba
Moyl, N-hexyl-N-2-naphthoylcarbamoy
, N-hexyl-N-phenylacetylcarbamoy
, N-isobutyl-N-cycloheptanoylcarbamo
Yl, N-butyl-N-nicotinoylcarbamoyl, N
-Hexyl-N-nicotinoylcarbamoyl and N-a
Sonicotinoyl-N-hexylcarbamoyl
Can be. Preferably C is substituted as ₁-C₆Alkyl,
C optionally having 1 to 3 substituents β₆-C_TenAnts
Which may have 1 to 3 substituents β₆-C
_TenAryl and C₁-C₆Aralkyl having alkyl,
C optionally having 1 to 3 substituents β₇-C₁₁Aroma
Carbamoyl optionally having one or two aromatic acyl groups
And more preferably C₁-C₆Alkyl, substitution β
Optionally having one phenyl, having one substituent β
Optionally phenyl and C₁-C_FourFe with alkyl
Phenyl, phenyl which may have one substituent β
Carbamoy optionally having one or two carbonyls
And most preferably a C₁-C₆Archi
Or phenyl optionally having one substituent β
A carbamoyl group which may have one
Suitably, there may be one substituent β having one substituent β.
Carbamoyl group which may have one phenyl.

In the present invention, a “C ₁ -C ₆ alkyl group (the alkyl group may be substituted with _{1 to} 3 identical or different C ₁ -C ₆ alkoxycarbonyl groups) in the definition of R ⁹ and R ^10. ") May be the unsubstituted C _1-
1 to 3 C ₁ -C ₆ alkoxycarbonyl groups which are the same as or different from the C ₆ alkyl group or the C ₁ -C ₆ alkyl group (showing a group in which the C ₁ -C ₆ alkoxy group is bonded to a carbonyl group) Represents a group bonded to, for example, the aforementioned C ₁ -C ₆
Alkyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, isopropoxycarbonylmethyl group, t-butoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group, methoxycarbonylpropyl group,
An ethoxycarbonylpropyl group can be mentioned.
Preferably, they are a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylmethyl group, and an ethoxycarbonylethyl group.

The compound (I) of the present invention can be converted into a salt according to a conventional method. Those salts are also included in the present invention. Examples of such salts include sodium salts, potassium salts, alkali metal salts such as lithium salts, calcium salts, alkaline earth metal salts such as magnesium salts,
Metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts; inorganic salts such as ammonium salts;
t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N ' -Amine salts such as organic salts such as dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-N-phenethylamine salt, piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt. ; Hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate; methane sulfone Acid salt, trifluoromethanesulfonic acid salt, ethanesulfonic acid salt Lower alkane sulfonates such as benzene sulfonate, aryl sulfonates such as p-toluene sulfonate, acetic acid, malic acid, fumarate, succinate, citrate, tartrate Organic acid salts such as oxalate, maleate and the like; and amino acid salts such as ornithate, glutamate and aspartate, and are preferably hydrohalides or organic acid salts. is there.

The substituted condensed imidazole derivative having the general formula (I) of the present invention can be converted into a pharmacologically acceptable ester according to a conventional method. Those esters are also included in the present invention. A pharmaceutically acceptable ester of the substituted fused imidazole derivative having the general formula (I) is
There is no particular limitation as long as it is more medically used and pharmacologically acceptable than the substituted condensed imidazole derivative having the general formula (I).

Examples of the ester of the substituted condensed imidazole derivative of the general formula (I) of the present invention include linear or branched alkyl having 1 to 6 carbons, and 7 to 19 carbons. Aralkyl, 1-6 carbon atoms
Linear or branched alkyl having 1 to 5 carbon atoms, substituted by linear or branched alkanoyloxy having 1 to 5 carbon atoms, linear or branched alkyl having 1 to 6 carbon atoms Linear or branched alkyl having 1 to 5 carbon atoms substituted by a chain alkyloxycarbonyloxy, 1 to 5 carbon atoms substituted by a cycloalkylcarbonyloxy having 5 to 7 carbon atoms A linear or branched alkyl having 5 to 7 carbon atoms, a linear or branched alkyl having 1 to 5 carbon atoms and substituted by cycloalkyloxycarbonyloxy having 5 to 7 carbon atoms, Straight-chain or branched alkyl having 1 to 5 carbon atoms substituted with 6 to 10 arylcarbonyloxy, 6 to 10 carbon atoms
Substituted or substituted linear or branched alkyl group having 1 to 5 carbon atoms and linear or branched substituted or unsubstituted aryloxycarbonyloxy group having 1 to 6 carbon atoms at the 5-position Examples thereof include a 2-oxo-1,3-dioxolen-4-ylmethyl group having a chain alkyl.

Here, a linear or branched alkyl group having 1 to 4 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms are, for example, methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, methylbutyl, dimethylpropyl, ethylpropyl, hexyl, methylpentyl, dimethylbutyl, ethylbutyl,
Or trimethylpropyl, preferably a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl; Preferably it is methyl or ethyl.

The aralkyl group having 7 to 19 carbon atoms includes, for example, benzyl, phenethyl, phenylpropyl,
It can be phenylbutyl, naphthylmethyl or dibenzyl, preferably benzyl.

The cycloalkyl group having 5 to 7 carbon atoms is, for example, cyclopentyl, cyclohexyl, cycloheptyl, preferably cyclohexyl.

The aryl group having 6 to 10 carbon atoms can be, for example, phenyl or naphthyl, preferably phenyl.

Specific examples of R of the suitable ester residue (—COOR) are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetoxymethyl, 1- (acetoxy) ethyl, propionyloxy Methyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, isobutyryloxyethyl, valeryloxymethyl, valeryloxyethyl, isovaleryloxymethyl, isovaleryloxyethyl, pivaloyloxymethyl, Pivaloyloxyethyl, methoxycarbonyloxymethyl, methoxycarbonyloxyethyl, ethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl, propoxycarbonyloxymethyl, propoxycarbonyloxyethyl, isopropoxy Carbonyloxymethyl, isopropoxycarbonyloxyethyl, butoxycarbonyloxymethyl, butoxycarbonyloxyethyl, isobutoxycarbonyloxymethyl, isobutoxycarbonyloxyethyl, t-butoxycarbonyloxymethyl, t-butoxycarbonyloxyethyl, cyclopentanecarbonyloxy Methyl, cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxymethyl, cyclohexanecarbonyloxyethyl, cyclopentyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxyethyl, benzoyloxymethyl, benzoyloxyethyl, Phenoxycarboni Oxymethyl,
Phenoxycarbonyloxyethyl or 5-methyl-2
-Oxo-1,3-dioxolen-4-ylmethyl, more preferably methyl, ethyl.

The compound (I) of the present invention may be left in the air or recrystallized to absorb water, adsorb water or form hydrates. When forming such a solvate, all of these are included in the present invention.

Furthermore, the compound (I) of the present invention may absorb some other solvent to form a solvate, and such a solvate is also included in the present invention.

Further, the present invention also includes all compounds which are metabolized in vivo and converted into the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, so-called prodrugs.

The compound (I) of the present invention has various isomers.

That is, A is a 2,4-dioxothiazolidine-5-yl group or a 2,4-dioxooxazolidine-
When it contains a 5-yl group, the thiazolidine ring or the oxazolidine ring has an asymmetric carbon atom at the 5-position, and there are stereoisomers that are R-coordinated or S-coordinated. Each of them, or any proportion thereof, is encompassed by the present invention. Such a stereoisomer can be obtained by synthesizing compound (I) using the optically resolved starting compound or compound (I)
Can be optically split using a normal optical splitting method or a separation method, if desired. In the compound (I) of the present invention, A represents a 2,4-dioxothiazolidine-5-yl group or 2,4-dioxooxazolidine-5.
In the case of a group having an -yl group, the existence of various tautomers is considered, and each of them or a compound in any ratio thereof is included in the present invention.

Further, as a drug for forming a pharmaceutical composition in combination with the compound (I) of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof, a sulfonylurea agent, an α-glucosidase inhibitor, Examples include aldose reductase inhibitors, biguanides, statins, squalene synthesis inhibitors, fibrate compounds, LDL catabolism promoters, angiotensin II antagonists, angiotensin converting enzyme inhibitors, and antitumor agents.

In the present invention, a sulfonylurea agent is a drug that promotes insulin secretion, and examples thereof include tolbutamide, acetohexamide, tolazamide, and chlorpropamide.

In the present invention, an α-glucosidase inhibitor is a drug which has an action of inhibiting digestion enzymes such as amylase, maltase, α-dextrinase and sucrase to delay the digestion of starch and sucrose. For example,
Acarbose, N- (1,3-dihydroxy-2-propyl) valiolamine (generic name: voglibose), miglitol and the like can be mentioned.

In the present invention, an aldose reductase inhibitor is a drug that inhibits diabetic complications by inhibiting the rate-limiting enzyme in the first step of the polyol pathway, such as tolrestat, epalrestat, 2,
7-difluoro-spiro (9H-fluorene-9,4'-
Imidazolidine) -2 ', 5'-dione (generic name: imirestat), 3-[(4-bromo-2-fluorophenyl) methyl] -7-chloro-3,4-dihydro-2,4-
Dioxo-1 (2H) -quinazolineacetic acid (general name: zenarestat), 6-fluoro-2,3-dihydro-2 ′,
5'-dioxo-spiro [4H-1-benzopyran-4,
4'-Imidazolidine] -2-carboxamide (SN
K-860), zopolrestat, sorbinyl, 1-
[(3-Bromo-2-benzofuranyl) sulfonyl]
-2,4-Imidazolidinedione (M-16209) and the like.

In the present invention, the biguanide agent is a drug having an anaerobic glycolysis-promoting action, an insulin action enhancement at the peripheral, suppression of glucose absorption from the intestinal tract, suppression of hepatic gluconeogenesis, inhibition of fatty acid oxidation and the like. For example, phenformin, metformin, buformin and the like can be mentioned. In the present invention, a statin compound is a drug that lowers blood cholesterol by inhibiting hydroxymethylglutaryl-CoA (HMG-CoA) reductase. For example, pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin And fluvastatin.

In the present invention, a squalene synthesis inhibitor is a drug that lowers blood cholesterol by inhibiting squalene synthesis. For example, (S) -α
-[Bis (2,2-dimethyl-1-oxopropoxy)
Methoxy] phosphinyl-3-phenoxybenzenebutanesulfonic acid monopotassium salt (BMS-188494)
And the like.

In the present invention, the fibrate compound is a drug which suppresses triglyceride synthesis and secretion in the liver and activates lipoprotein lipase to lower triglyceride in blood. For example, bezafibrate, beclobrate, Binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pyrifibrate, ronifibrate, simfibrate,
Theofibrate and the like can be mentioned.

In the present invention, the LDL catabolic promoter is
It is a drug that lowers blood cholesterol by increasing LDL (low density lipoprotein) receptor. 4-bis (4-fluorophenyl) methyl-1-piperazinyl] ethyl]-
7,7-diphenyl-2,4,6-heptatrienoic acid amide and the like can be mentioned.

The above-mentioned statins, squalene synthesis inhibitors, fibrate compounds and LDL catabolism promoters may be replaced with other drugs having an effect of lowering blood cholesterol and triglyceride. Examples of such agents include nicotinic acid derivative preparations such as nicomol and niceritrol; antioxidants such as probucol;
An ion exchange resin preparation such as cholestyramine can be used.

In the above, an angiotensin II antagonist is a drug which strongly suppresses an increase in blood pressure caused by angiotensin II and lowers blood pressure. Examples of such a drug include losartan potassium, candesartan cilexetil, irbesartan, valsartan, telmisartan, olmesartan, and the like.

In the present invention, an angiotensin converting enzyme inhibitor is a drug which lowers blood pressure and at the same time partially lowers blood glucose in diabetic patients by inhibiting angiotensin converting enzyme, and includes, for example, captopril, enalapril Alacepril, delapril,
Ramipril, lisinopril, imidapril, benazepril, selonapril, cilazapril, enalaprilate,
Fosinopril, mobertopril, perindopril, quinapril, spirapril, temocapril, trandolapril and the like. In the compound represented by the general formula (I), R ¹ is preferably a hydroxyl group or an acyloxy group, and most preferably a hydroxyl group. R ² is preferably a C ₁ -C ₆ alkyl group, most preferably a methyl group. R ³ , R ⁴ and R ⁵ are preferably a C ₁ -C ₆ alkyl group, most preferably a methyl group. R ⁶ is preferably a C ₁ -C ₆ alkyl group, most preferably a methyl group. Y is preferably an oxygen atom. Z is preferably CH. n is preferably 1. q is preferably 1. Q is preferably an oxygen atom. X is
Preferably it is CH ₂ , CO or a group represented by C ＝ NOR ¹⁰ , most preferably CH ₂ . R ¹⁰ is preferably
A hydrogen atom, a C ₁ -C ₆ alkyl group (the alkyl group may be substituted by _{1 to} 3 identical or different C ₁ -C ₆ alkoxycarbonyl groups) or a C ₇ -C ₁₆ aralkyl group; And most preferably a hydrogen atom or a methyl group. A is preferably a group represented by the general formula (II-b) or (II-d). m is preferably 0 in the general formulas (II-a), (II-b) and (II-c), and in the general formula (II-d),
Preferably it is 1. B is preferably an oxygen atom or a sulfur atom. R ⁷ is preferably a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group (the aryl group is the same or different 1 to 3 substituents selected from substituent group α) ), A C ₇ -C ₁₆ aralkyl group (the aralkyl group may be substituted with 1 to 3 identical or different substituents selected from the substituent group α), Or a halogeno C ₁ -C ₆ alkyl group, more preferably a hydrogen atom, a C ₁ -C ₆ alkyl group, or a phenyl group (the phenyl group is the same or different from 1 to 3 selected from the substituent group α). Or a benzyl group (the benzyl group may be substituted with 1 to 3 identical or different substituent (s) selected from the substituent group α), or halogeno. C ₁ -C ₆ alkyl group, still more preferably a phenyl group (said The 4-position of the phenyl group may be substituted with one substituent selected from the substituent group α), a benzyl group (the 4-position of the benzyl group is one of the substituents selected from the substituent group α). Or a halogeno C ₁ -C ₆ alkyl group. Substituent group α is preferably a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a cyano group and a nitro group, more preferably is a halogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, a cyano group and a nitro group.

The compounds of the present invention include, for example, the compounds described in the following table. However, the present invention is not limited to these compounds. In addition,
The meanings of the abbreviations in the table are as follows. Ac: acetyl group Ada (1): 1-adamantyl group Boz: benzoyl group Bu: butyl group cBu: cyclobutyl group iBu: isobutyl group tBu: tertiary butyl group Byr: butyryl group Bz: benzyl group Dc: decyl group Et: ethyl Group Hp: Heptyl group Hx: Hexyl group cHx: Cyclohexyl group Hxn: Hexanoyl group Me: Methyl group Oc: Octyl group Ph: Phenyl group Pn: Pentyl group cPn: Cyclopentyl group iPn: Isopentyl group Pnto: Pentanoyl group Pr: Propyl group cPr : Cyclopropyl group iPr: isopropyl group Prn: propionyl group Nn: nonyl group

[0083]

Embedded image

[0084]

[Table 1]

[0085]

[Table 2]

[0086]

[Table 3]

[0087]

[Table 4]

[0088]

[Table 5]

[0089]

[Table 6]

[0090]

[Table 7]

[0091]

[Table 8]

[0092]

[Table 9]

[0093]

[Table 10]

[0094]

Embedded image

[0095]

[Table 11]

[0096]

[Table 12]

[0097]

[Table 13]

[0098]

[Table 14]

[0099]

[Table 15]

[0100]

[Table 16]

[0101]

[Table 17]

[0102]

[Table 18]

[0103]

[Table 19]

[0104]

[Table 20]

[0105]

Embedded image

[0106]

[Table 21]

[0107]

[Table 22]

[0108]

[Table 23]

[0109]

[Table 24]

[0110]

[Table 25]

[0111]

[Table 26]

[0112]

[Table 27]

[0113]

[Table 28]

[0114]

[Table 29]

[0115]

[Table 30]

[0116]

Embedded image

[0117]

[Table 31]

[0118]

[Table 32]

[0119]

[Table 33]

[0120]

[Table 34]

[0121]

[Table 35]

[0122]

[Table 36]

[0123]

[Table 37]

[0124]

[Table 38]

[0125]

[Table 39]

[0126]

[Table 40]

[0127]

[Table 41]

[0128]

[Table 42]

[0129]

Embedded image

[0130]

[Table 43]

[0131]

[Table 44]

[0132]

[Table 45]

[0133]

[Table 46]

[0134]

[Table 47]

[0135]

[Table 48]

[0136]

[Table 49]

[0137]

[Table 50]

[0138]

[Table 51]

[0139]

[Table 52]

[0140]

[Table 53]

[0141]

[Table 54]

[0142]

[Table 55]

[0143]

Embedded image

[0144]

[Table 56]

[0145]

Embedded image

[0146]

[Table 57]

[0147]

[Table 58]

[0148]

[Table 59]

[0149]

[Table 60]

[0150]

[Table 61]

[0151]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) of the present invention can be easily produced according to the following method. (Method A) Method A is a method for producing compound (I).

[0152]

Embedded image In the above formula, R ^{1 to} R ⁶ , X, Y, Z, A, Q, n and q
Other have the same meanings as described above, R ^1a is an amino group and / or hydroxyl group included in the definition of group R ¹ is an amino group which may be protected and / or a hydroxyl group, R ¹
Indicates the same groups in the definition of groups, X ^a is hydroxyimino group and / or hydroxyl group included in the definition of X the group is optionally protected hydroxyimino group and /
Or a hydroxyl group, and represents the same group as the group in the definition of the group X, and A ^a is ^a group represented by the formula

[0153]

Embedded image (In the above formula, Tr represents a triphenylmethyl group;
Represents the same meaning as described above, B and R ^7a are B and R ⁷ mentioned above is, "hydroxyl which may be protected" described later, have been and "optionally protected thiol group,""Protection represents the same meaning as groups in the definition of other B and R ⁷ groups is also an amino group "refers to a" protective group of a carboxyl group "R ^{1 1} will be described later. ).

In the above, R ^1a and B and R ^7a
"Protecting group" as defined in the "protected unprotected amino group" is not particularly limited as long as it is a protecting group for amino groups used in the field of organic synthetic chemistry, for example, the C ₁ -C ₇ aliphatic acyl group, chloroacetyl, dichloroacetyl, trichloroacetyl, C ₂ -C substituted with halogeno C ₂ -C ₇ alkylcarbonyl group or a C ₁ -C ₆ alkoxy such as methoxy acetyl like trifluoroacetyl ₇ "aliphatic acyl such" such as an alkylcarbonyl group; the C ₇ -C ₁₁ aromatic acyl group, 2-bromobenzoyl, 4-halogeno such as chloro benzoyl C ₇ -
C ₁₁ aromatic acyl group, 2,4,6-trimethylbenzoyl, C ₇ -C ₁₁ aromatic acyl group, such substituted by C ₁ -C ₆ alkyl as 4-toluoyl, 4-C _1, such as anisoyl -C ₆ alkoxy-substituted C ₇ -C ₁₁ aromatic acyl group, 4-nitrobenzoyl, 2-nitrobenzoyl C ₇ -C ₁₁ aromatic acyl group such substituted with nitro as yl, 2- (methoxycarbonyl C) like benzoyl
A C ₇ -C ₁₁ aromatic acyl group substituted by a _2- C ₇ alkoxycarbonyl or a C ₇ -C such as 4-phenylbenzoyl
₆ -C ₁₀ Ari - "aromatic acyl such" such as C ₇ -C ₁₁ aromatic acyl group substituted with Le; the C ₂ -C ₇ alkoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl, 2 - "alkoxycarbonyl such" such as C ₂ -C ₇ alkoxycarbonyl group substituted with a halogen or tri C ₁ -C ₆ alkylsilyl as trimethylsilyl ethoxycarbonyl; "alkenyloxy such as vinyl or allyloxycarbonyl Carbonyls "; such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl;
"Aralkyloxycarbonyls" in which the aryl ring may be substituted with _{1 to} 2 C ₁ -C ₆ alkoxy or nitro; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, Tri-C ₁ -C ₆ alkylsilyl groups such as methyldi-t-butylsilyl and triisopropylsilyl, aryls such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl or phenyldiisopropylsilyl and C _1-
"Silyls" such as a silyl group substituted by three groups selected from C ₆ alkyl; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α C ₁ -C ₆ alkyl substituted with 1 to 3 aryl, such as -naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3, 4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2
-Nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4
_1-3 aryl groups substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, nitro, halogen, cyano, such as cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl or piperonyl; "aralkyl such" such as C ₁ -C ₆ alkyl group substituted with Le group - number of ants;
Or N, N-dimethylaminomethylene, benzylidene,
4-methoxybenzylidene, 4-nitrobenzylidene,
Salicylidene, 5-chlorosalicylidene, diphenylmethylene or (5-chloro-2-hydroxyphenyl)
"Substituted methylene group forming a Schiff base" such as phenylmethylene; a and, preferably, C ₁ -C ₇ aliphatic acyl group, C ₇ -C ₁₁ aromatic acyl group or a C ₂ -C ₇ It is an alkoxycarbonyl group, more preferably a C ₂ -C ₇ alkoxycarbonyl group, and particularly preferably a t-butoxycarbonyl group.

In the above, R^1a, X^aAnd B and
And R^7a"Hydroxyimis which may be protected"
The "protecting group" of the "amino group and / or hydroxyl group"
Limited as long as it is a hydroxyl-protecting group used in the field of science
Although not performed, for example, the C₁-C₇Aliphatic acyl group,
Cal like succinoyl, glutaroyl, adipoyl
C substituted with boxy_Two-C₇Alkylcarbonyl group,
Loroacetyl, dichloroacetyl, trichloroacetyl
, Halogeno C such as trifluoroacetyl_Two-C₇A
C such as alkylcarbonyl or methoxyacetyl
₁-C₆C substituted with alkoxy_Two-C₇Alkyl carb
"Aliphatic acyls" such as a nyl group; ₇-C₁₁Aromatic
Acyl group, 2-bromobenzoyl, 4-chlorobenzoy
Halogeno C like Le₇-C₁₁Aromatic acyl group, 2,
Like 4,6-trimethylbenzoyl, 4-toluoyl
Na C₁-C₆C substituted with alkyl₇-C₁₁Aromatic reed
Group, such as 4-anisoyl₁-C₆Place with alkoxy
Transformed C₇-C₁₁Aromatic acyl group, 2-carboxybe
Nzoyl, 3-carboxybenzoyl, 4-carboxy
C substituted with a carboxy such as benzoyl₇-C₁₁
Aromatic acyl group, 4-nitrobenzoyl, 2-nitrobe
C substituted with nitro such as nzoyl₇-C_{1 1}Aromatic
Acyl group, 2- (methoxycarbonyl) benzoyl
Una C_Two-C₇C substituted with alkoxycarbonyl₇−
C₁₁Aromatic acyl group or 4-phenylbenzoyl
Una C₆-C_TenC substituted with aryl₇-C₁₁Aromatic
"Aromatic acyls" such as a sil group; tetrahydropyran-
2-yl, 3-bromotetrahydropyran-2-yl,
4-methoxytetrahydropyran-4-yl, tetrahi
Dorothiopyran-2-yl, 4-methoxytetrahydro
"Tetrahydropyranyl" such as thiopyran-4-yl
Or tetrahydrothiopyranyls "; tetrahydrofura
2--2-yl and tetrahydrothiofuran-2-yl
"Tetrahydrofuranyl or tetrahydrothiofura
Nyls ”; trimethylsilyl, triethylsilyl, iso
Propyldimethylsilyl, t-butyldimethylsilyl,
Methyldiisopropylsilyl, methyldi-t-butylsilyl
Ril, tri-C such as triisopropylsilyl₁-C₆A
Rusilsilyl group or diphenylmethylsilyl, dife
N-butylsilyl, diphenylisopropylsilyl,
Aryls such as phenyldiisopropylsilyl and C₁
-C₆Silyl substituted by three groups selected from alkyl
"Silyls" such as methoxymethyl, 1,1-dimes
Tyl-1-methoxymethyl, ethoxymethyl, propoxy
Cimethyl, isopropoxymethyl, butoxymethyl, t
-Such as butoxymethyl (C₁-C₆Alkoxy) meth
Group, C such as 2-methoxyethoxymethyl₁-C₆A
Substituted with alkoxy (C₁-C₆Alkoxy) methyl group
Or 2,2,2-trichloroethoxymethyl, bis
A halogeno such as (2-chloroethoxy) methyl (C₁
-C₆"Alkoxymethyl" such as alkoxy) methyl
1-ethoxyethyl, 1- (isopropoxy) d
Like chill (C₁-C₆Alkoxy) ethyl group or
Halogenated ethyls such as 2,2,2-trichloroethyl
"Substituted ethyls" such as benzyl, α-naphthyl
Tyl, β-naphthylmethyl, diphenylmethyl, trif
Phenylmethyl, α-naphthyldiphenylmethyl, 9-a
Substituted with one to three aryl groups such as thrill methyl
Done C₁-C₆An alkyl group or 4-methylbenzyl,
2,4,6-trimethylbenzyl, 3,4,5-trime
Tylbenzyl, 4-methoxybenzyl, 4-methoxyphenyl
Enyldiphenylmethyl, 2-nitrobenzyl, 4-ni
Trobenzyl, 4-chlorobenzyl, 4-bromobenzyl
Such as 4-cyanobenzyl, methyl, piperonyl
C₁-C₆Alkyl, C₁-C₆Alkoxy, halogen, silicon
1 to 3 aryl groups in which an aryl ring is substituted by ano
C substituted with₁-C₆"Aralkyl" such as alkyl group
"; C_Two-C₇An alkoxycarbonyl group, 2,2
2-trichloroethoxycarbonyl, 2-trimethylsi
Halogen such as lylethoxycarbonyl or tri-C₁
-C₆C substituted with an alkylsilyl group_Two-C₇Alkoki
"Alkoxycarbonyls" such as a cicarbonyl group; vinyl
Such as ruoxycarbonyl, allyloxycarbonyl
“Alkenyloxycarbonyls”; benzyloxyca
Rubonyl, 4-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 2-d
Trobenzyloxycarbonyl, 4-nitrobenzylo
1-2 C atoms, such as xycarbonyl₁-C₆Arco
The aryl ring may be substituted with xy or nitro
"Aralkyloxycarbonyls", preferably,
C₁-C₇Aliphatic acyl group, C₇-C₁₁Aromatic acyl group,
C_Two-C₇An alkoxycarbonyl group or (C₁-C₆Arco
Xy) methyl, more preferably C ₇-C₁₁Aroma
Group acyl group or (C₁-C₆An alkoxy) methyl group
And particularly preferably a benzoyl group or a methoxymethyl group.
is there.

In the above, the “protecting group” of the “optionally protected thiol group” in B and R ^7a is not particularly limited as long as it is a protecting group for a thiol group that can be used in the field of synthetic organic chemistry. Is, for example, the aforementioned C ₁ -C ₇ aliphatic acyl group, a carboxy-substituted C ₂ -C ₇ alkylcarbonyl group such as succinoyl, glutaroyl, adipoyl or a C ₁ -C ₆ alkoxy such as methoxyacetyl. "Aliphatic acyls" such as C ₂ -C ₇ alkylcarbonyl groups; halogeno C ₇ -C ₁₁ aromatics such as the aforementioned C ₇ -C ₁₁ aromatic acyl groups, 2-bromobenzoyl and 4-chlorobenzoyl Acyl group, 2,4,6-
C _1- such as trimethylbenzoyl, 4-toluoyl
A C ₇ -C ₁₁ aromatic acyl group substituted with a C ₆ alkyl, 4
- C ₇ -C ₁₁ aromatic acyl group such substituted by C ₁ -C ₆ alkoxy as anisoyl, 2-carboxybenzoyl, 3-carboxybenzoyl, 4-carboxyphenyl C ₇ substituted by carboxy, such as benzoyl - C ₁₁ -C ₁₁ aromatic acyl groups, C ₇ -C ₁₁ aromatic acyl groups substituted by nitro, such as 4-nitrobenzoyl, 2-nitrobenzoyl, 2- (methoxycarbonyl) benzoyl, etc.
A C ₇ -C ₁₁ aromatic acyl group substituted by a _2- C ₇ alkoxycarbonyl or a C ₇ -C such as 4-phenylbenzoyl
₆ -C ₁₀ Ari - "aromatic acyls" of C ₇ -C ₁₁ aromatic acyl groups substituted with Le; tetrahydropyran-2-yl, 3-bromo-tetrahydropyran-2-yl, 4-methoxytetrahydropyran "Tetrahydropyranyl or tetrahydrothiopyranyls" such as pyran-4-yl, tetrahydrothiopyran-2-yl or 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl or tetrahydrothiofuran-2 - "tetrahydrofuranyl or tetrahydrothiofuranyl acids" such as yl; trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, t- butyl-dimethyl-silyl, tri C ₁ such as methyl diisopropylsilyl, methyldi -t- butylsilyl, triisopropylsilyl −
A C ₆ alkylsilyl group or diphenylmethylsilyl,
Diphenyl butylsilyl, diphenyl isopropylsilyl, ants such as phenyl diisopropylsilyl - "silyl ethers", such as three-substituted silyl group in the selected group from Le and C ₁ -C ₆ alkyl; methoxymethyl, 1, 1 −
(C ₁ -C ₆ alkoxy) methyl groups such as dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, C such as 2-methoxyethoxymethyl
Substituted with ₁ -C ₆ alkoxy (C ₁ -C ₆ alkoxy)
Methyl groups or “alkoxymethyls” such as halogeno (C ₁ -C ₆ alkoxy) methyl such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; benzyl, α-naphthylmethyl, β -Naphthylmethyl, diphenylmethyl, triphenylmethyl, α-
A C ₁ -C ₆ alkyl group substituted with 1 to 3 aryl groups such as naphthyldiphenylmethyl, 9-anthrylmethyl or 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4 , 5-trimethylbenzyl, 4-
Methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-
Chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, methyl, C ₁ -C ₆ alkyl such as piperonyl,
C ₁ -C ₆ alkoxy, halogen, cyano Ali - Le ring of 1 to 3 substituted ants - C ₁ substituted with Le group -
C "aralkyl such" such as ₆ alkyl group; the C ₂ -C ₇ alkoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl, halogen or tri C ₁ -C ₆ alkylsilyl group such as 2-trimethylsilyl-ethoxycarbonyl in "alkoxycarbonyl such" such substituted C ₂ -C ₇ alkoxycarbonyl group; "alkenyloxy carbonyls" such as vinyloxycarbonyl or allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, The aryl ring may be substituted with one or two C ₁ -C ₆ alkoxy or nitro, such as 4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl. Aralkyloxycarbonyls And preferably ₁ to 3 such as a C ₁ -C ₇ aliphatic acyl group, a C ₇ -C ₁₁ aromatic acyl group, a C ₂ -C ₇ alkoxycarbonyl group, diphenylmethyl, triphenylmethyl, and the like. number of ants - C ₁ substituted with Le group
A C ₆ alkyl group or a (C ₁ -C ₆ alkoxy) methyl group, more preferably a C ₇ -C ₁₁ aromatic acyl group,
A C ₁ -C ₆ alkyl group or a (C ₁ -C ₆ alkoxy) methyl group substituted with 1 to 3 aryl groups, particularly preferably a benzoyl group, a diphenylmethyl group, a triphenylmethyl group or It is a methoxymethyl group.

In the above, the term “protecting group for carboxyl group” in the definition of R ¹¹ is not particularly limited as long as it is a protecting group for carboxyl group used in the field of synthetic organic chemistry. n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-
Butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 2
An "alkyl group" such as ethylbutyl; ethenyl, 1
-Propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1
-Propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl,
-Methyl-2-butenyl, 1-methyl-1-butenyl,
3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-
Pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl,
1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl,
“Alkenyl groups” such as 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl; ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2 -Methyl-2
-Propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1
-Methyl-3-butynyl, 2-methyl-3-butynyl,
1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3
-Pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4
Alkynyl groups such as -pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl; trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2
"Halogenoalkyl groups" such as -iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, 2,2-dibromoethyl; 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, "Hydroxyalkyl group" such as 3,4-dihydroxybutyl, 4-hydroxybutyl; "aliphatic acylalkyl group" such as acetylmethyl; benzyl;
One to three ants such as phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl -Alkyl group substituted with a benzyl group ", 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,
4,5-trimethylbenzyl, 4-methoxybenzyl,
4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl,
-Bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl)
Alkyl such as methyl, piperonyl, 4-methoxycarbonylbenzyl, alkoxy, nitro, halogen, cyano, alkyl group substituted with one to three aryl groups having an aryl ring substituted with an alkoxycarbonyl group, etc. “Aralkyl group” of trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl Such a "silyl group" can be mentioned, preferably, C ₁ -C ₆
An alkyl group or a C ₇ -C ₁₀ aralkyl group, more preferably a C ₁ -C ₆ alkyl group, and particularly preferably a C ₁ -C ₆ alkyl group.
It is ₁ -C ₄ alkyl group.

The substituent groups α and / or
Alternatively, in the case of a compound having a group substituted with a group selected from the substituent group γ, the compound is protected with the above-described protecting group or the like as required, and the protecting group is removed by a method described later.

Step A1 is a step for producing a compound having the general formula (V), and comprises a phosphine (preferably tributylphosphine or triphenylphosphine) and an azodicarboxylic acid compound in an inert solvent. (Preferably diethyl azodicarboxylate or 1,1-azodicarbonyldipiperidine) by reacting a compound having the general formula (III) with a compound having the general formula (IV) Done.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene , Toluene, xylene; aromatic hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; halogenated hydrocarbons such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether And amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; or a mixed solvent of the above solvents; preferably, aliphatic hydrocarbons, aromatic hydrocarbons, and halogens. Hydrocarbons, Athe A mixed solvent of s or the solvent (more preferably, an aromatic hydrocarbon or an ether, particularly preferably toluene or tetrahydrofuran) is.

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually from -20 ° C to 150 ° C (preferably 0 ° C
To 60 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 30 minutes to 5 days (preferably 5 hours to 72 hours).

After completion of the reaction, the target compound (V) of this reaction is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate are added, the organic layer containing the target compound is separated, washed with water or the like, and dried over anhydrous magnesium sulfate, It is obtained by drying over anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and then distilling off the solvent.
If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

Step A2 is a step of producing a compound having the general formula (I), in which compound (V) is reacted with an acid in the presence or absence (preferably in the presence) of an inert solvent. And removing the triphenylmethyl group in A ^a
It is carried out by removing R ^1a , X ^a and R ¹¹ which is a protecting group for amino group, hydroxyimino group, hydroxyl group and / or thiol group and / or a carboxyl group in B and R ^{7 if} desired.

The acid used in the above-mentioned first-stage reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction. Examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid. Inorganic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, Bronsted acids such as organic acids such as trifluoromethanesulfonic acid; zinc chloride,
Lewis acids such as tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins; preferably inorganic or organic acids (particularly preferably hydrochloric acid, acetic acid or trifluoro Acetic acid).

The inert solvent used in the above-mentioned reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether. Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and carbonic acid Esters such as diethyl; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, and n-butanol. , Isobutanol, t-butanol, Soamiruaruko - le, diethylene glycol, glycerin, octanol, cyclohexanol, alcohol such as methyl cellosolve - Le acids;
Amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; water; or water or a mixed solvent of the above solvents; preferably ethers, alcohols or water (particularly preferable). Is dioxane, tetrahydrofuran, ethanol or water.

The reaction temperature depends on the starting compound, the acid used,
Although it depends on the solvent and the like, it is usually from -20 ° C to the boiling point (preferably 0 ° C to 100 ° C).

The reaction time depends on the starting compound, the acid used,
The time is usually from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours), although it depends on the solvent, the reaction temperature and the like.

[0169] Also, this step, in an inert solvent, (preferably under pressure) atmospheric pressure or under pressure performed catalytic reduction reaction to the compound (V), after removal of the triphenylmethyl group in A ^a Optionally removing R ^1a , X ^a and R ¹¹ which is a protecting group for amino, hydroxyimino, hydroxyl and / or thiol groups and / or a protecting group for carboxyl group in B and R ⁷ . (I)
Can also be manufactured.

The catalyst used in the above-mentioned catalytic reduction reaction is not particularly limited as long as it is used in a usual catalytic reduction reaction.
Nickel, rhodium-aluminum oxide, triphenylphosphine-rhodium oxide, palladium-barium sulfate, palladium black, platinum oxide, platinum black, and preferably palladium-carbon.

The inert solvent used in the above catalytic reduction reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether are used. Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin , Octanol, cyclohex Alcohols such as phenol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; organic acids such as acetic acid and trifluoroacetic acid; or a mixed solvent of the above solvents. Preferred are ethers, alcohols or organic acids (particularly preferred are alcohols).

The reaction temperature depends on the starting compound, the catalyst used, the solvent and the like, but is usually from 0 ° C. to 100 ° C.
(Preferably 10 ° C. to 50 ° C.).

The reaction time varies depending on the starting compound, the catalyst used, the solvent, the reaction temperature and the like, but is usually from 30 minutes to 48 hours (preferably from 1 hour to 24 hours).

The removal of the protecting groups for the amino group, hydroxyl group and thiol group varies depending on the kind thereof, but it is generally known in the art of synthetic organic chemistry, for example, TWGreen, (Pr
otective Groups in Organic Synthesis), John Wiley
& Sons: JFWMcOmis, (Protective Groups in Organic
Chemistry), Plenum Press.

When the protecting group for the amino group is a silyl, a compound which generates a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride is usually used. And is removed by treating with

The solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. Examples of the solvent include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Is preferred.

The reaction temperature and reaction time are not particularly limited, but the reaction is usually carried out at 0 ° C. to 50 ° C. for 10 hours to 18 hours.

When the protecting group for the amino group is an aliphatic acyl, an aromatic acyl, an alkoxycarbonyl or a substituted methylene group forming a Schiff base, an acid or a base is added in the presence of an aqueous solvent. Can be removed.

The acid used in the above reaction is not particularly limited as long as it is a commonly used acid and does not inhibit the reaction. Examples thereof include hydrobromic acid, hydrochloric acid, sulfuric acid, and the like.
Inorganic acids such as perchloric acid, phosphoric acid and nitric acid, preferably hydrochloric acid.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, but is preferably an alkali metal such as lithium carbonate, sodium carbonate or potassium carbonate. Carbonates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; ammonia water ,
Ammonia, such as concentrated ammonia-methanol.

The solvent used in the above reaction is not particularly limited as long as it is one used in a usual hydrolysis reaction. For example, methanol, ethanol, n-propanol, isopropanol, etc. Alcohols such as toluene, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve;
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether;
Water; a mixed solvent of water and the above organic solvent; and preferably ethers (particularly preferably dioxane).

The reaction temperature and the reaction time vary depending on the starting compound, the solvent and the acid or base to be used and are not particularly limited. Let react for ~ 10 hours.

When the amino-protecting group is an aralkyl or aralkyloxycarbonyl, it is usually brought into contact with a reducing agent in an inert solvent (preferably by catalytic reduction at room temperature under a catalyst at room temperature). ) A method of removing or using an oxidizing agent is preferred.

The solvent used for the removal by catalytic reduction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as toluene, benzene, xylene; methyl acetate,
Esters such as ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n- Alcohols such as propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; Such organic acids; water; a mixed solvent of the above solvent and water; preferably alcohols, ethers,
Organic acids or water (particularly preferably, alcohols or organic acids).

The catalyst used for the removal by catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction.
Carbon, Raney-nickel, platinum oxide, platinum black, rhodium-
Aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate are used.

Although the pressure is not particularly limited, it is usually 1 to 1
It is performed at 0 atm.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually 0 ° C. to 100 ° C.
For 5 minutes to 24 hours.

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the present reaction, but is preferably a water-containing organic solvent.

Examples of such organic solvents include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, and the like. Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and sulfoxides such as dimethyl sulfoxide; And preferably halogenated hydrocarbons, ethers or sulfoxides (particularly preferably halogenated hydrocarbons or sulfoxides).

The oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation. Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3- Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 150 ° C.
For 10 minutes to 24 hours.

When the amino-protecting group is an alkenyloxycarbonyl, the amino-protecting group is usually substituted with an aliphatic acyl, an aromatic acyl, an alkoxycarbonyl or a Schiff base. It is carried out by treating with a base in the same manner as the conditions for the removal reaction in the case of a methylene group.

In the case of an allyloxycarbonyl group,
In particular, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be performed with few side reactions.

When a silyl is used as a protecting group for a hydroxyimino group, a hydroxyl group and a thiol group, usually, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride are used. Treated with a compound that produces a stable fluoride anion, or an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, It can be removed by treating with an organic acid such as camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid.

When removing with a fluorine anion,
The reaction may be accelerated by adding organic acids such as formic acid, acetic acid, propionic acid.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Preferably, diethyl ether or diisopropyl ether is used.
Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water;

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 100 ° C.
(Preferably 10 ° C. to 50 ° C.) for 1 hour to 24 hours.

When the hydroxyimino group, hydroxyl protecting group and thiol group are aralkyls or aralkyloxycarbonyls, they are usually brought into contact with a reducing agent in an inert solvent (preferably under a catalyst). In the case of a protecting group for a hydroxyl group, a method of removing with an oxidizing agent is preferable.

The solvent used for the removal by catalytic reduction is not particularly limited as long as it does not take part in the present reaction. Aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; toluene, benzene , Xylene and the like; aromatic hydrocarbons such as xylene; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, Ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoric triamide; fatty acids such as formic acid and acetic acid; water; a mixed solvent of the above solvents; Preferred are alcohols (particularly preferred is methanol).

As the catalyst used for the removal by catalytic reduction, if it is usually used for the catalytic reduction reaction,
Although not particularly limited, for example, palladium-carbon, palladium-black, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, preferably palladium- Carbon.

The pressure is not particularly limited, but is usually 1 to 1
It is performed at 0 atm.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 100 ° C.
(Preferably 20 ° C. to 70 ° C.) for 5 minutes to 48 hours (preferably 1 hour to 24 hours).

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.

As such organic solvents, ketones such as acetone, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, nitriles such as acetonitrile, diethyl ether, tetrahydrofuran, and the like are preferable. Ethers such as dioxane, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and sulfoxides such as dimethylsulfoxide can be mentioned.

The oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation. Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3- Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 150 ° C.
For 10 minutes to 24 hours.

Further, in liquid ammonia or methano-
, Ethanol, n-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
In alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve at -78 ° C.
At ~ 0 ° C, it can also be removed by the action of alkali metals such as metallic lithium and metallic sodium.

Further, it can be removed using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide in a solvent.

The solvent used is not particularly limited as long as it does not participate in the present reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform and carbon tetrachloride; and a solvent such as acetonitrile. Nitriles;
A mixed solvent of the above solvents.

The reaction temperature and the reaction time vary depending on the starting compound, solvent and the like, but are usually carried out at 0 ° C. to 50 ° C. for 5 minutes to 72 hours.

In the case where the reaction substrate has a sulfur atom,
Preferably, aluminum chloride-sodium iodide is used.

When the protecting groups for hydroxyimino group, hydroxyl group and thiol group are aliphatic acyls, aromatic acyls or alkoxycarbonyl groups, they are removed by treating with a base in a solvent.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, and examples thereof include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide; Metal alkoxides such as sodium ethoxide and potassium t-butoxide; ammonia such as aqueous ammonia and concentrated ammonia-methanol; preferably alkali metal hydroxides, metal alkoxides or ammonia (Especially preferably alkali metal hydroxides or metal alkoxides) It is the earth).

The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and examples thereof include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. Ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; water; mixed solvents of the above solvents are preferred.

The reaction temperature and reaction time vary depending on the starting compound, base used, solvent and the like, and are not particularly limited.
In order to suppress side reactions, usually -20 ° C to 150 ° C
For 1 to 10 hours.

A protecting group for a hydroxyimino group or a hydroxyl group is
In the case of alkoxymethyls, tetrahydropyranyls, tetrahydrothiopyranyls, tetrahydrofuranyls, tetrahydrothiofuranyls or substituted ethyls, they are usually removed by treating with an acid in a solvent. .

The acid used is not particularly limited as long as it is generally used as a Bronsted acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or Bronsted acids such as organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid: Lewis acids such as boron trifluoride, but strongly acidic cations such as Dowex 50W Exchange resins can also be used.

The solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether Such ethers; methanol, ethanol
Alcohols such as toluene, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water; a mixed solvent of the above solvents; preferably ethers (particularly preferably tetrahydrofuran) or alcohols ( Particularly preferred is methanol).

The reaction temperature and the reaction time vary depending on the starting compound, the acid used, the solvent and the like, but are usually -10 ° C to 200 ° C (preferably 0 to 150 ° C) for 5 minutes to 48 hours ( Preferably, it is 30 minutes to 10 hours.

A protecting group for a hydroxyimino group or a hydroxyl group is
When it is an alkenyloxycarbonyl, it is usually treated with a base in the same manner as the removal reaction when the protecting group for the hydroxyl group is the above-mentioned aliphatic acyl, aromatic acyl or alkoxycarbonyl. Achieved.

In the case of an allyloxycarbonyl group,
In particular, the removal method using palladium and triphenylphosphine, or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphate is simple and is carried out with few side reactions. Can be.

By carrying out the above-mentioned reaction of bringing compound (V) into contact with an acid or carrying out a catalytic reduction reaction of compound (V), the protecting group for the amino group, hydroxyimino group, hydroxyl group and / or thiol group is obtained. It may be removed at the same time.

The removal of the protecting group for the amino group, hydroxyimino group, hydroxyl group and / or thiol group can be carried out in any order in the desired order.

The carboxyl-protecting group can be removed by treating with an acid or a base in the presence of an aqueous solvent. The acid used in the above reaction is not particularly limited as long as it is a substance usually used as an acid and does not inhibit the reaction, and examples thereof include hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, and nitric acid. And preferably hydrochloric acid.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, but is preferably an alkali metal such as lithium carbonate, sodium carbonate or potassium carbonate. Carbonates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; ammonia water ,
Ammonia, such as concentrated ammonia-methanol.

The solvent used in the above reaction is not particularly limited as long as it is a solvent used in a usual hydrolysis reaction. Examples thereof include methanol, ethanol, n-propanol and isopropanol. Alcohols such as toluene, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve;
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether;
Water; a mixed solvent of water and the above organic solvent; and preferably ethers (particularly preferably dioxane).

The reaction temperature and reaction time vary depending on the starting compound, solvent and acid or base used, and are not particularly limited. However, in order to suppress a side reaction, the reaction is usually performed at 0 ° C. to 150 ° C. for 1 hour. Let react for ~ 10 hours. After completion of the reaction, the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After washing with water etc.
It is obtained by drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and then distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method,
For example, recrystallization, reprecipitation, etc., usually appropriately combined with methods commonly used for separation and purification of organic compounds, and separation by eluting with a suitable eluent by applying chromatography,
It can be purified. (Method B) In the method B, in the compound (I), A is a compound represented by the formula (I)
Compound (XIII), (XIV) or (XII) which is a group having Ia), (II-b) or (II-c)
This is the step of manufacturing.

[0228]

Embedded image Wherein R ^{1 to} R ⁶ , R ^1a , X, X ^a , Y, Z, Q, n,
q and m have the same meanings as described above, D represents a halogen atom, and E represents an oxygen atom or a sulfur atom.

Step B1 is a step for producing a compound having the general formula (VIII), in which compound (VI) is reacted with a base in the presence or absence (preferably in the presence) of an inert solvent. Then, the reaction is carried out by reacting with a compound having the general formula (VII).

The base used in the above reaction includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-
Diazabicyclo [5.4.0] -7-undecene (DB
Organic amines such as U); preferably alkali metal hydrides (particularly preferably sodium hydride).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethylformamide;
Amides such as dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent of the above solvents;
Preferably, they are amides (particularly preferably, dimethylformamide).

The reaction temperature for reacting compound (VI) with a base varies depending on the starting compound, the base used, the solvent and the like, but is usually -50 ° C to 200 ° C (preferably 0 ° C to 200 ° C).
° C to 120 ° C).

The reaction time for reacting compound (VI) with a base varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 1 hour To 10 hours).

The reaction temperature when reacting compound (VI) with compound (VII) is usually from -20 ° C to 200 ° C.
(Preferably 0 ° C. to 150 ° C.).

The reaction time for reacting the compound (VI) with the compound (VII) is usually 30 minutes to 48 hours (preferably 1 hour to 24 hours).

After the completion of the reaction, the desired compound (VII)
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

Step B2 is a step for producing a compound having the general formula (X), in an inert solvent in the presence or absence of a catalyst such as sodium acetate, piperidinium acetate, piperidinium benzoate. The reaction is carried out below (preferably in the presence) by reacting compound (VIII) with a compound having the general formula (IX).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol; Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethyl Amides such as phosphoric acid triamide;
Or a mixed solvent of the above-mentioned solvents; and preferably an amide (particularly preferably, dimethylformamide or dimethylacetamide).

The reaction temperature varies depending on the starting compound, the catalyst used, the solvent and the like, but is usually from 0 ° C. to 200 ° C.
(Preferably 10 ° C. to 150 ° C.).

The reaction time varies depending on the starting compound, the catalyst used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 2 hours to 24 hours).

After completion of the reaction, the target compound (X) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

Step B3 is a step for producing a compound having the general formula (XI), and is carried out by subjecting compound (X) to a catalytic reduction reaction in an inert solvent. The catalytic reduction reaction is carried out in the same manner as in Method A, Step A2.

This step is also performed by reacting compound (X) with a metal hydride. The method of reacting a compound (X) with a metal hydride is described in WO93 /
It can be performed according to the method disclosed in 1309A.

Step B4 is a step for producing a compound having the general formula (XII), which is carried out by performing a reaction for removing an amino group, a hydroxyimino group and / or a hydroxyl-protecting group in an inert solvent. Will be The reaction for removing the protecting group for the amino group, hydroxyimino group and / or hydroxyl group is carried out in the same manner as in the above-mentioned Method A, Step A2.

[0245] The B5 step is a step for preparing a compound having the general formula (XIII), in the compound (X), an amino group in R ^1a and X ^a of the compound E is a sulfur atom (X), hydroxy This step is carried out by removing the protecting group for the imino group and / or the hydroxyl group. This step is carried out by the amino group, hydroxyimino group and / or
Alternatively, it is carried out in the same manner as in the method of removing the hydroxyl-protecting group.

Step B6 is a step for producing a compound having the general formula (XIV), which is carried out by subjecting compound (XIII) to a catalytic reduction reaction in an inert solvent. The catalytic reduction reaction is carried out in the same manner as in Method A, Step A2.

This step can also be carried out by reacting compound (XIII) with a metal hydride. The method of reacting compound (XIII) with a metal hydride is described in W
It can be carried out according to the method disclosed in O93 / 1309A. (Method C) Method C is another method for synthesizing compound (I).

[0248]

Embedded image In the above formula, R ^{1 to} R ⁶ , R ^1a , X, X ^a , Y, Z, A,
Aa, Q, n and q are as defined above,
Boc represents a t-butoxycarbonyl group, and G means “optionally protected formyl group” or “optionally protected carboxyl group”.

In the above G, the “protecting group” of the “optionally protected formyl group” is not particularly limited as long as it is a protecting group for a formyl group used in the field of synthetic organic chemistry. Methyl, diethoxymethyl,
The above C such as dipropoxymethyl, dibutoxymethyl
₁ -C ₆ alkoxy substituted methyl group, 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl,
1,3-dithian-2-yl, 1,3-dithiolan-2
-Yl, preferably dimethoxymethyl, diethoxymethyl, 1,3-dioxolan-2-yl or 1,3
-Dithian-2-yl.

In the above G, the phrase “may be protected
The "protecting group" of "carboxyl group" is used in the field of synthetic organic chemistry.
Limited as long as it is a carboxyl protecting group used in
But not for example, methyl, ethyl, propyl,
Such as isopropyl, butyl, s-butyl, t-butyl
C₁-C₆Alkyl group, benzyl, phenethyl, 3-fe
Nylpropyl, 1-naphthylmethyl, diphenylmethyl
, Triphenylmethyl, 4-methylbenzyl,
Toxibenzyl, 4-nitrobenzyl, 4-fluorobe
C, such as benzyl, 4-cyanobenzyl₁-C₆Archi
Le, C₁-C₆Alkoxy, nitro, halogen or sulfur
1 to 3 C which may be substituted by ano ₆-C_TenA
C replaced by reel₁-C₆An alkyl group, preferably
Is C₁-C₆It is an alkyl group or a benzyl group.

Step C1 is a step for producing a compound having the general formula (V), and is carried out by reacting a compound having the general formula (XV) with a compound having the general formula (XVI).

When G is a formyl group in compound (XV), compound (XV) and compound (X
After the reaction of VI), the t-butoxycarbonyl group, which is a protecting group for the amino group, is removed with an acid to effect ring closure, and further reacted with an oxidizing agent.

In this step, after reacting compound (XV) with compound (XVI), t is a protecting group for an amino group.
Alternatively, the intermediate obtained by removing the butoxycarbonyl group with an acid to effect ring closure may be isolated and purified, and then contacted with an oxidizing agent.

The inert solvent used in reacting compound (XV) with compound (XVI) is not particularly limited as long as it is inert to the present reaction. For example, hexane, heptane, ligroin, petroleum Aliphatic hydrocarbons such as ethers; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol Alcohols such as n-propanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve. Le; formamide, di Amides such as tylformamide, dimethylacetamide and hexamethylphosphoric acid triamide; acids such as acetic acid and propionic acid; sulfoxides such as dimethylsulfoxide; sulfolane; or a mixed solvent of the above solvents; Ethers (particularly preferably tetrahydrofuran).

The reaction temperature for reacting the compound (XV) with the compound (XVI) depends on the starting compound, the base used,
Although it differs depending on the solvent and the like, it is usually 0 ° C to 200 ° C (preferably 10 ° C to 120 ° C).

The reaction time for reacting the compound (XV) with the compound (XVI) is based on the starting compound, the base used,
It usually varies from 1 hour to 5
0 hours (preferably 5 hours to 24 hours).

The method for removing the t-butoxycarbonyl group which is a protecting group for an amino group using an acid is described in the above-mentioned Method A-2.
The step is carried out in the same manner as in the step of removing with an acid when the amino-protecting group is an alkoxycarboxy group in the step.

The oxidizing agent used in the above reaction is not particularly limited as long as it is usually used in the oxidizing reaction. Examples thereof include manganese oxides such as potassium permanganate and manganese dioxide; Ruthenium oxides such as ruthenium; selenium compounds such as selenium dioxide; iron compounds such as iron chloride; osmium such as osmium tetroxide, potassium osmate dihydrate (K ₂ OsO ₄ .2H ₂ O) Compounds: Silver compounds such as silver oxide; Mercury compounds such as mercury acetate; Lead oxide compounds such as lead oxide and lead tetraacetate; Chromium such as potassium chromate, chromate-sulfuric acid complex, and chromate-pyridine complex Acid compounds, inorganic metal oxidizing agents such as cerium compounds such as ammonium cerium nitrate (CAN); halogen molecules such as chlorine molecules, bromine molecules and iodine molecules; Periodic acids such as sodium iodate; ozone; aqueous hydrogen peroxide; nitrous acid compounds such as nitrous acid; chlorite compounds such as potassium chlorite and sodium chlorite; potassium persulfate, sodium persulfate Inorganic oxidizing agents such as persulfuric acid compounds, etc .; reagents used for DMSO oxidation (complex of dimethyl sulfoxide and dicyclohexylcarbodiimide, oxalyl chloride, acetic anhydride or phosphorus pentoxide, or pyridine-sulfuric anhydride complex) -Combinations of peroxides such as butyl hydroperoxide with vanadium or molybdenum complexes; stable cations such as triphenylmethyl cation;
Combinations of succinimides such as N-bromosuccinimide and alkali; oxiranes such as dimethyldioxirane; hypochlorous compounds such as t-butyl hypochlorite; azo compounds such as azodicarboxylic acid ester Dicarboxylic acid compounds; peracids such as m-chloroperbenzoic acid and perphthalic acid; disulfides such as dimethyl disulfide, diphenyl disulfide and dipyridyl disulfide and triphenylphosphine; nitrites such as methyl nitrite; Organic oxidizing agents such as tetrahalogenated carbons such as methane bromide, and quinone compounds such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ); Particularly preferred is iodine molecule).

The solvent used for contacting with the oxidizing agent is not particularly limited as long as it is inert to the present reaction. Preferably, the solvent is used when reacting compound (XV) with compound (XVI). The solvent used.

The reaction temperature and reaction time when contacting with the oxidizing agent are the same as the reaction temperature and reaction time when reacting compound (XV) with compound (XVI).

When G is a carboxyl group in the compound (XV), the compound having the general formula (XV) or a reactive derivative thereof (acid halides, active esters or mixed acid anhydrides) is used in an inert solvent. After reacting a compound having the general formula (XVI) or an acid addition salt thereof (for example, a mineral salt such as hydrochloride, nitrate or sulfate), a t-butoxycarbonyl group which is a protecting group for an amino group is converted to an acid And ring closure.

In the present step, after the amide compound as an intermediate is isolated and purified, it is removed by using a t-butoxycarbonyl group which is a protecting group for an amino group and an acid in the same manner as in the above reaction, and then the ring is closed. It is also done by doing.

In the acid halide method, compound (XV) is converted into a halogenating agent (eg, thionyl chloride, thionyl bromide, oxalic chloride, oxalic dichloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride) in an inert solvent. To produce an acid halide, and the acid halide and compound (XVI) or an acid addition salt thereof in an inert solvent in the presence or absence (preferably in the presence) of a base, It is performed by reacting.

The base used in the above reaction includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-
Diazabicyclo [5.4.0] -7-undecene (DB
Organic amines such as U), preferably organic amines (particularly preferably triethylamine).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride Hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Kind;
Sulfoxides such as dimethyl sulfoxide; sulfolane; and preferably halogenated hydrocarbons, ethers or amides (particularly preferably, dichloromethane, chloroform, tetrahydrofuran or dimethylformamide).

The reaction temperature depends on the starting compounds, reagents and the like, but the reaction between the halogenating agent and the compound (XV) and the reaction between the acid halides and the compound (XVI) or an acid addition salt thereof are usually -20 ° C. To 150 ° C, and preferably, the reaction between the halogenating agent and the compound (XV) is at -10 ° C.
To 100 ° C, acid halides and compound (XVI)
Alternatively, the reaction with the acid addition salt is at -20 ° C to 100 ° C.

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like, but the reaction between the halogenating agent and the compound (XV) and the reaction between the acid halides and the compound (XVI) or the acid addition salt thereof are usually It is 30 minutes to 80 hours (preferably 1 hour to 48 hours).

In the active ester method, the compound (XV) is reacted with an active esterifying agent in an inert solvent to produce active esters, and then, in an inert solvent, in the presence or absence of a base (preferably). In the presence of), compound (XVI) or an acid addition salt thereof.

The active esterifying agent used in the above reaction is, for example, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide or the like. Compounds; disulfide compounds such as dipyridyl disulfide; carbodiimides such as dicyclohexylcarbodiimide; carbonyldiimidazole; triphenylphosphine;

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether. Aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane,
Halogenated hydrocarbons such as 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; formamide, dimethylformamide Amides such as dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; sulfolane;
And preferably ethers or amides (particularly preferred are dioxane, tetrahydrofuran or dimethylformamide).

As the base used in the above reaction, for example, the same bases as those used in the above-mentioned acid halide method can be mentioned.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is generally -70 ° C to 150 ° C (preferably -10 ° C to 100 ° C) in the active esterification reaction.
In the reaction of the active ester with the compound (XV) or an acid addition salt thereof, the temperature is −20 ° C. to 100 ° C. (preferably 0 ° C. to 50 ° C.).

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like, but is usually 30 minutes to 80 hours for both the active esterification reaction and the reaction of the active ester with the compound (XVI) or the acid addition salt thereof. (1 hour to 48 hours).

In the mixed acid anhydride method, the compound (X) is prepared in an inert solvent in the presence or absence (preferably in the presence) of a base.
V) is reacted with a mixed acid anhydride agent to produce mixed acid anhydrides, and then reacted with the mixed acid anhydrides and compound (XVI) or an acid addition salt thereof in an inert solvent.

The base used in the above reaction includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-
Diazabicyclo [5.4.0] -7-undecene (DB
Organic amines such as U), preferably organic amines (particularly preferably triethylamine).

Examples of the mixed anhydride agent used in the above reaction include C ₁ -C ₄ alkyl halides such as ethyl chlorocarbonate and isobutyl chlorocarbonate; C ₁ -C ₅ alkanoyl such as pivaloyl chloride. Halide; di-C ₁ -C ₄ alkyl or di-C ₆ -C ₁₄ arylcyanophosphoric acid such as diethyl cyanophosphonate and diphenyl cyanophosphonate, preferably di-C ₁ -C ₄ alkyl or di-C ₆ —C ₁₄ arylcyanophosphate (particularly preferably diethyl cyanophosphonate).

The inert solvent used for producing the mixed acid anhydrides is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, hexane, heptane, ligroin Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether Ethers such as, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and dimethyl sulfoxide Sulfoxy S; sulfolane; are, preferably, ethers or amides (particularly preferably include tetrahydrofuran or dimethylformamide) it is.

The reaction temperature in the reaction for producing the mixed acid anhydrides varies depending on the starting compounds, reagents and the like.
It is -50 ° C to 100 ° C (preferably 0 ° C to 60 ° C).

The reaction time in the reaction for producing mixed acid anhydrides varies depending on the starting compounds, reagents, reaction temperature and the like, but is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours). is there.

The reaction between the mixed acid anhydrides and the compound (XVI) or an acid addition salt thereof is carried out in an inert solvent in the presence or absence (preferably in the presence) of a base. The base and the inert solvent are the same as those used in the reaction for producing the mixed acid anhydrides described above.

The reaction temperature in the reaction of the mixed acid anhydrides with the compound (XVI) or an acid addition salt thereof is as follows:
Usually varies from -30 ° C to 100 ° C
(Preferably 0 ° C. to 80 ° C.).

The reaction time in the reaction of the mixed acid anhydrides with the compound (XVI) or an acid addition salt thereof is as follows:
Usually varies from 5 minutes to 2 minutes, depending on the reagent, reaction temperature, etc.
4 hours (preferably 30 minutes to 16 hours).

When diC ₁ -C ₄ alkyl cyanophosphoric acid or di C ₆ -C ₁₄ arylcyanophosphoric acid is used in this reaction, compound (XV) may be used in the presence of a base.
And compound (XVI) can also be reacted directly. The method for removing the t-butoxycarbonyl group which is an amino-protecting group using an acid includes a method for removing the amino-protecting group using an acid in the case where the amino-protecting group is an alkoxycarbonyl in step A2 of Method A. The same is done.

The method of removing the t-butoxycarbonyl group, which is a protecting group for the amino group, with an acid to effect ring closure is described in the above A.
It is carried out in the same manner as the method of removing with an acid when the amino-protecting group is an alkoxycarboxy in step A2 of the method.

When G in the compound (XV) is a C ₂ -C ₇ alkoxycarbonyl group, in the presence or absence (preferably absence) of an inert solvent, in the presence or absence of a base, After reacting the compound (XV) with the compound (XVI), the reaction is carried out by removing the t-butoxycarbonyl group, which is a protecting group for the amino group, with an acid and closing the ring.

In this step, after the amide compound as an intermediate is isolated and purified, the t-butoxycarbonyl group, which is a protecting group for the amino group, is removed using an acid and the ring is closed in the same manner as in the above reaction. It is also done by doing.

The base used in the reaction for reacting compound (XV) with compound (XVI) includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate, sodium hydrogen carbonate, carbonate Alkali metal bicarbonates such as potassium hydrogen; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; lithium hydroxide;
Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine;
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5. 4.0] -7-undecene (DB
Organic amines such as U), preferably organic amines (particularly preferably triethylamine).

The inert solvent used in the reaction for reacting the compound (XV) with the compound (XVI) is not particularly limited as long as it is inert to this reaction. For example, hexane, heptane, ligroin, petroleum Aliphatic hydrocarbons such as ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol Alcohols such as n-propanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve. Le; formamide, Methylformamide, dimethylacetamide, amides such as hexamethylphosphoric triamide; or a mixed solvent of the above solvents; is, preferably,
Ethers or amides (particularly preferred are tetrahydrofuran, dioxane or dimethylformamide).

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually from 0 ° C. to 200 ° C.
(Preferably 50 ° C. to 150 ° C.).

The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 24 hours).

The method for removing the t-butoxycarbonyl group which is a protecting group for the amino group with an acid to effect ring closure is described in the above A.
It is carried out in the same manner as the method of removing with an acid when the amino-protecting group is an alkoxycarboxy in step A2 of the method.

After completion of the reaction, the target compound (V) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

Step C2 is a step for producing a compound having the general formula (I), wherein the amino, hydroxyimino and / or hydroxyl protecting groups for R ^1a and X ^a, the amino group for A ^a , The method for removing the protecting group for the thiol group and / or the hydroxyl group is the same as the method for removing the protecting group for the amino group, the hydroxyimino group, the thiol group and / or the hydroxyl group in Step A2 of Method A described above.

After completion of the reaction, the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. (Method D) In method D, compound (I) is modified such that A is (II-
a compound (XXIII) having d) and m is 1 and a compound (XI) wherein A has (II-b) and m is 0
V).

[0295]

Embedded image In the above formula, R ^{1 to} R ⁷ , R ¹¹ , R ^1a , R ^7a , Xa, X,
Y, Z, B, D, Q, n and q have the same meanings as described above.

Step D1 is a step for producing a compound having the general formula (XVIII). The compound having the general formula (VI) is converted to a compound having the general formula (VI) in an inert solvent in the presence of a base.
This step is carried out in the same manner as in the above-mentioned Method B, Step B1.

Step D2 is a step of producing a compound having the general formula (XIX), and is carried out by reducing the compound (XVIII). This reaction is performed by using a catalytic reduction reaction or a zinc-acetic acid method, a tin-alcohol method, or a tin-hydrochloric acid method, which is a general method for reducing a nitro group.

Step D3 is a step of producing a compound having the general formula (XX), and adding Compound (XIX) to Meerwe
This is achieved by performing an in Arylation reaction. Meer
The weinArylation reaction is performed by the method described in JP-A-55-22657 (US Pat. No. 4,258,193) and the method of S. Oae et al. [Bull.
Chem. Soc. Jpn., 53, 1065 (1980) and the like. The method is performed according to the method described in [1].

Step D4 is a step of producing compound (XXII), which is carried out by reacting compound (XX) with a compound having the general formula (XXI). This step is carried out by reacting a compound having the general formula (XX) with a compound having the general formula (XXI) in an inert solvent in the presence of a base. Done in

Step D5 is a step of producing compound (XXIII), which is carried out by removing a protecting group for an amino group, a hydroxyimino group, a hydroxyl group and / or a thiol group, and a protecting group for a carboxyl group.

Step D6 is a step for producing a compound (XIV). The compound (XX) is reacted with thiourea, then hydrolyzed, and if necessary, the protecting groups for Xa and R ^1a are removed. Done.

The reaction of reacting compound (XX) with thiourea is carried out according to the method described in JP-A-55-22636.

After completion of the reaction, the desired compound (XXI
II) and (XIV) are collected from the reaction mixture in a conventional manner. For example, the reaction mixture is appropriately neutralized,
If insolubles are present, they are removed by filtration, and an immiscible organic solvent such as water and ethyl acetate is added.The organic layer containing the target compound is separated, washed with water and the like, and then dried over anhydrous magnesium sulfate and sulfuric anhydride. It is obtained by drying with sodium or anhydrous sodium hydrogen carbonate and then distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

Compounds (I), (XII) and (XII) obtained by Method A, Method B, Method C and Method D
When I), (XIV), and (XXIII) have an amino group, the amino group can be further alkylated, arylated, aralkylated or acylated, if desired. These reactions are carried out by a known method or a method similar thereto [The Chemistry of the Amino Group, chap.
ter6, 1968, John Wiley & Sons, The Chemistry of the
Amino Group, chapter2, 1970, John Wiley & Sons
etc. ). That is, alkylation or aralkylation of an amino group is a synthesis method in which a basic salt of an amine is reacted with an alkyl halide or an aralkyl halide, and arylation is a reaction between an amine and an aryl halide in the presence of a base. It can be performed by a synthesis method or the like.

Starting compounds (IV), (VII) and (I
X), (XVII) and (XXI) are known or are easily produced according to known methods or methods analogous thereto.

Starting compounds (III), (VI) and (X
V), (XXXI), (XXXIII), (XVI) and (XXXV) can also be produced, for example, by the following method. (Method E) Method E is a step of producing compound (III) when compound (VI) or Q is an oxygen atom.

[0307]

Embedded image In the above formula, R ^1a , R ^{2 to} R ⁶ , X ^a , Y, Z, G, Q,
n, q and Boc have the same meaning as described above.

In the step E1, the compound (VI) [(II
I); when Q = O], the general formula (X
The reaction is carried out by reacting the compound having the formula (XIV) with the compound (XVI), removing the t-butoxycarbonyl group which is a protecting group for the amino group using an acid, and closing the ring.
In this step, the compound (X)
V) is reacted with compound (XVI), and the t-butoxycarbonyl group, which is a protecting group for the amino group, is removed using an acid;
It is performed in the same manner as in the method of ring closure.

In particular, when Z in compound (XVI) is a nitrogen atom, the ring-closing method is preferably carried out in a large excess of compound (XXIV) in the absence of a solvent.

After completion of the reaction, the desired compound (VI) of this reaction
[(III); when Q = O] is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized,
If any insoluble matter is removed by filtration,
Add an immiscible organic solvent such as water and ethyl acetate, separate the organic layer containing the target compound, wash with water, etc., dry with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and evaporate the solvent. Obtained by leaving. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. (Method F) Method F is a method for producing compound (XV).

[0311]

Embedded image In the above formula, Q, Aa, G, D and q have the same meanings as described above, and Ga is ^a protected formyl group or a protected carboxyl group (the "protecting group" is a group represented by G in the above-mentioned Method C). Has the same significance as described above).

Step F1 is a step for producing a compound (XV), which is carried out in an inert solvent in the presence of a base in the presence of a compound of the formula (IV).
After reacting the compound having V) with the compound having the general formula (XXV), if the formyl group or carboxyl group in G is a protected formyl group or protected carboxyl group, the protecting group is optionally removed. It is done by doing.

The base used when reacting the compound having the general formula (IV) with the compound having the general formula (XXV) is the same as that used in the above-mentioned Method B, Step B1, and is preferably used. An alkali metal hydride (particularly preferably sodium hydride).

The solvent used for reacting the compound having the general formula (IV) with the compound having the general formula (XXV) is the same as that used in the above-mentioned Method B, Step B1, and is preferably used. Amides or amides and other mixed solvents (particularly preferably dimethylformamide).

The reaction temperature for reacting the compound having the general formula (IV) with the compound having the general formula (XXV) varies depending on the starting compound, the base, the solvent and the like, but is usually from -50 ° C to 200 ° C. ° C (preferably 0 ° C to 120 ° C).

The reaction time for reacting the compound having the general formula (IV) with the compound having the general formula (XXV) varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 30 minutes. To 24 hours (preferably 1 hour to 10 hours).

The removal of the protecting group for the formyl group or the carboxy group as desired depends on the kind thereof, and is generally a method well known in the art of synthetic organic chemistry, for example, TWGree.
n, (Protective Groups in Organic Synthesis), John
Wiley &Sons; JFWMcomie, (Protective Groups in
Organic Synthesis), which can be performed according to Plenum Press.

Further, G of compound (XV) or compound (X
The compound of XV) wherein G ^a is a carboxyl group or a protected carboxyl group can be easily produced from a compound wherein G or G ^a is a formyl group or ^a protected formyl group according to a conventional method.

After completion of the reaction, the desired compound (XV) of this reaction
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. And dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and then the solvent is distilled off. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. (Method G) In the method G, the compound (XV) is modified such that Aa is (II)
-(B)) wherein m is 0 (XXXIII)
Alternatively, this is a method for producing a compound (XXXI) in which Aa has (II-d ′) and m is 1.

[0320]

Embedded image In the above formula, R ⁷ , R ¹¹ , R ^7a , G ^a , G, D, B, Q and q have the same meanings as described above. Step G1 is a step of producing a compound having the general formula (XXVII), and is carried out in an inert solvent in the presence of a base in the presence of a general formula (XVII).
Is carried out by reacting a compound having the formula (XXVI) with a compound having the general formula (XXVI).
It is performed in the same manner as the process.

Step G2 is a step for producing a compound having the general formula (XXIII),
It is carried out by reducing I). This reaction is performed by using a catalytic reduction reaction or a zinc-acetic acid method, a tin-alcohol method, or a tin-hydrochloric acid method, which is a general method for reducing a nitro group.

Step G3 is a step for producing a compound having the general formula (XXIX),
This is achieved by performing a Meerwein Arylation reaction. The Meerwein Arylation reaction is described in JP-A-55-2265.
No. 7 (US Pat. No. 4,258,193) and the method of S. Oae et al. [Bull. Chem. Soc. Jpn., 53, 1065 (1980) and the like. The method is performed according to the method described in [1].

Step G4 is a step of producing compound (XXX), which comprises compound (XXIX) and compound of general formula (XXI)
By reacting with a compound having the following formula: This step is carried out in an inert solvent in the presence of a base by the general formula (XXI)
X) is carried out by reacting a compound having the general formula (XXI) with a compound having the general formula (XXI).
It is performed in the same manner as in the four steps.

Step G5 is a step of producing compound (XXXI), which is carried out by removing the protected formyl group or the protected group of the protected carboxyl group. Method for removing the protecting group of the formyl group or carboxyl group in the definition of group G ^a is performed in the same manner as the method for removing the protecting group of the formyl group or carboxyl group in the F method.

Step G6 is a step of producing compound (XXXII), which comprises reacting compound (XXIX) with thiourea, followed by hydrolysis.

The reaction of reacting compound (XXIX) with thiourea and then hydrolyzing it is described in JP-A-55-2265.
No. 7 (US Pat. No. 4,258,193).

[0327] in the G7 process, a method for removing the protective group of the formyl group or carboxyl group in the definition of group G ^a is performed in the same manner as the method for removing the protecting group of the formyl group or carboxyl group in Method F .

After the completion of the reaction, the target compound of the present reaction (XXX
I) and (XXXIII) are collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized,
If any insoluble matter is removed by filtration,
Add an immiscible organic solvent such as water and ethyl acetate, separate the organic layer containing the target compound, wash with water, etc., dry with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and evaporate the solvent. Obtained by leaving. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. (Method H) Method H is a method for producing compound (XVI).

[0329]

Embedded image In the above formula, R ^1a , R ^{2 to} R ⁶ , X ^a , Y, Z, D, Bo
c and n have the same meaning as described above.

Step H1 is a step of preparing a compound of the formula (XXXVI) in an inert solvent in the presence of a base in a compound of the formula (XXXV) in the presence of a base.
This step is performed in the same manner as in the above-mentioned Method D, Step D1.

Step H2 is a step of producing compound (XVI), and is carried out by reducing compound (XXXVI). This step is carried out in the same manner as in Method D, step D2.

After the completion of the reaction, the desired compound (XV
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. (Method I) Method I is a method for producing compound (XXXV).

[0333]

Embedded image In the above formula, R ⁶ , Z, D and Boc have the same meanings as described above.

The step I1 is represented by the general formula (XXXVIII)
In which a compound having the general formula (XXX)
VII) by protecting the amino group of the compound with a t-butoxycarbonyl group, which is generally a method well known in the art of synthetic organic chemistry, for example, T.I.
W. Green, (Protective Groups in Organic Synthesi
s), John Wiley &Sons; JFWMcomie, (Protective
Groups in Organic Synthesis), which can be performed according to Plenum Press.

Step I2 is a step of producing compound (XXXV), which is carried out by reacting compound (XXXVIII) with a compound having general formula (XXXIX) in an inert solvent in the presence of a base.

The base used in the above reaction is the same as that used in the above-mentioned Method B, Step B1, and is preferably an alkali metal hydride (particularly preferably sodium hydride).

The inert solvent used in the above reaction is the same as that used in the above-mentioned Method B, Step B1, and is preferably an ether or an amide (particularly preferably tetrahydrofuran, dioxane Or dimethylformamide).

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually from -50 ° C to 200 ° C.
° C (preferably 0 ° C to 120 ° C).

The reaction time varies depending on the starting compound, base used, solvent, reaction temperature and the like, but is usually 30 minutes to 24 hours (preferably 1 hour to 10 hours).

After the completion of the reaction, the desired compound (XXX)
V) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. (Method J) Compound J (Method X) can be used for compound (XLVI; compound (XXXV).
(I) wherein Xa is a carbonyl group).

[0341]

Embedded image In the above formula, R ^1a , R ^{2 to} R ⁶ , Y, Z, D, n and B
oc has the same meaning as described above, and Halo represents a halogen atom such as a chlorine atom, a bromine atom and an iodine atom.

Step J1 is a step for producing a compound of the formula (XL), in which a compound of the formula (XL) is reacted with a compound of the formula (XXXV) in an inert solvent in the presence of a base. This step is performed in the above D
This is performed in the same manner as in the method D1 step.

Step J2 is a step of producing compound (XLII), which is carried out by subjecting compound (XLI) to debenzylation. When Y is an oxygen atom, it is carried out oxidatively. When is a sulfur atom, the reaction is carried out by an acid catalyst.

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the present reaction. Suitable examples of such organic solvents include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, diethyl ether, tetrahydrofuran, and dioxane. And ethers, amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide, and sulfoxides such as dimethylsulfoxide.

The oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation. Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3- Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 150 ° C.
For 10 minutes to 24 hours.

The solvent used in the removal with the acid catalyst is not particularly limited as long as it does not participate in the reaction. Suitable examples of such organic solvents include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, diethyl ether, tetrahydrofuran, and dioxane. And ethers, amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; and aromatic hydrocarbons such as benzene and toluene.

The acid used is not particularly limited, but is preferably sulfuric acid, hydrochloric acid, bromic acid, trifluoroacetic acid,
Trifluoromethanesulfonic acid is used.

The reaction temperature and reaction time vary depending on the starting compound, acid catalyst, solvent and the like, but are usually from 0 ° C. to 150 ° C.
For 10 minutes to 24 hours.

Step J3 is a step for producing a compound of the formula (XLIV), in which a compound of the formula (XLII) is reacted with a compound of the formula (XLIII) in an inert solvent in the presence of a base. This step is performed according to Method D, Step D1.

Step J4 is a step of preparing a compound of the general formula (XLIV), in which a compound of the general formula (XLIV) is reacted with a compound of the general formula (XLV) in an inert solvent in the presence of a base. This step is carried out in the same manner as in the synthesis of chromanone derivatives described in JP-A-60-51189.

After completion of the reaction, the desired compound (XLV
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. (Method K) The method K can be performed by treating the compound (XLVIII; compound (I)
Excluding those in which X is a bond and carbonyl (> CO)).

[0353]

Embedded image In the above formula, R ^1a , R ^{2 to} R ⁶ , A, Q, Y, Z and n have the same meanings as described above, and Xb is a bond and carbonyl (> CO) in the definition of X described above. Shows the group excluding some.

Step K1 is a step for producing a compound of the general formula (XLVIII) in an inert solvent.
A ketone oximation reaction or ketone reduction reaction usually performed on the compound having I), and the resulting oxime or alcohol compound is subjected to a conventional etherification reaction, carbamoylation reaction or acylation reaction, if desired. . Further, the alcohol form obtained by reduction can be converted to a chromene form by an acid-catalyzed dehydration reaction,
Then, a chroman compound can be obtained by a usual catalytic hydrogenation reaction.

After completion of the reaction, the desired compound (XLV
III) is collected from the reaction mixture in a conventional manner.
For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

When the compound having the above general formula (I), its pharmaceutically acceptable salt and its pharmaceutically acceptable ester of the present invention are used as the above-mentioned therapeutic or prophylactic agent, Is mixed with an appropriate pharmacologically acceptable excipient, diluent, etc., for example, tablets, capsules,
It can be administered orally with granules, powders or syrups or parenterally with injections or suppositories.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as white sugar, glucose, mannitol, sorbitol; corn starch, potato starch,
Starch derivatives such as α-starch and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and metasilicate aluminate Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax; boric acid; adipic acid; Sodium sulfate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; Derivatives can be mentioned.) Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (for example, , Low-substituted hydroxypropyl Cellulose derivatives such as loin, carboxymethylcellulose, carboxymethylcellulose calcium, and internally cross-linked sodium carboxymethylcellulose; and chemically modified starch and celluloses such as carboxymethyl starch, sodium carboxymethyl starch, and cross-linked polyvinyl pyrrolidone.) Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;
Dehydroacetic acid; and sorbic acid. ), Flavoring agents (e.g., commonly used sweeteners, sour agents, flavors, etc.) and diluents can be used in a well-known method.

The dosage varies depending on the condition, age, administration method and the like. For example, in the case of oral administration,
The lower limit is 0.001 mg / kg body weight (preferably 0.0
1 mg / kg body weight), up to 500 mg / kg body weight (preferably 50 mg / kg body weight).
In each dose, the lower limit is 0.005 mg / kg body weight (preferably 0.05 mg / kg body weight) and the upper limit is 50 mg / kg body weight (preferably 5 mg / kg body weight), depending on the symptoms, once or several times a day. Administration. Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples, but the scope of the present invention is not limited thereto.

[0359]

The reaction formulas of Examples and Reference Examples are shown below. In the reaction formula, `` Ex. '' Indicates an example, `` Ref.Ex. '' indicates a reference example, `` t-Bu '' indicates a t-butyl group, `` Ph '' indicates a phenyl group, “HCl” or “HCl salt” next to a compound indicates that it is the hydrochloride salt of the compound. In addition, “CH ₃ ” may be omitted from a methyl group.

[0360]

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[0361]

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[0362]

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[0363]

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[0364]

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[0365]

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[0366]

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[0367]

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[0368]

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[0369]

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[0370]

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[0371]

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[0372]

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[0373]

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[0374]

Example 1 5- {4- [6- (6-hydroxy-2,
5,7,8-tetramethylchroman-2-ylmethoki
B) -1-Methyl-1H-benzimidazol-2-i
[Lemethoxy] benzyl} thiazolidine-2,4-dione
-Hydrochloride (Exemplified Compound No. 2-1) N- {2- [4- (2,4-dioxothiazolidine-5)]
-Ylmethyl) phenoxyacetylamino] -5- (6
-Methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamic acid t-butyl ester (compound of Reference Example 3)
15 ml of 4N hydrochloric acid-dioxane was added to 0.70 g,
Stirred at room temperature for 5 hours. After completion of the reaction, dioxane was distilled off from the reaction mixture, and ethyl acetate was added to the obtained residue.
Crystallization yielded 0.32 g of the desired compound having a melting point of 160 ° C to 162 ° C.

[0375]

Example 2 3- {4- [6- (6-hydroxy-2,
5,7,8-tetramethylchroman-2-ylmethoki
B) -1-Methyl-1H-benzimidazol-2-i
Rumethoxy] phenyl} -2- (2,2,2-trifur
Oroethoxy) propionic acid methyl ester (exemplified compound
Object No. 7-34) N- {2- [4- [2- (2,2,2-trifluoroethoxy) -2-methoxycarbonylethyl] phenoxyacetylamino] -5- (6-methoxymethoxy-2,
1.0 g of 5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamic acid t-butyl ester (compound of Reference Example 6), 4N hydrochloric acid
Using 10 ml of 1,4-dioxane and 10 ml of 1,4-dioxane, the reaction was carried out at room temperature for 7 hours according to Example 1. The solvent was distilled off, water was added to the residue, and the mixture was neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1).
0.72 g of the title compound having an Rf value = 0.28 (silica gel thin layer chromatography; n-hexane: ethyl acetate 1: 1) was obtained.

[0376]

Example 3 3- {4- [6- (6-hydroxy-2,
5,7,8-tetramethylchroman-2-ylmethoki
B) -1-Methyl-1H-benzimidazol-2-i
Rumethoxy] phenyl} -2- (2,2,2-trifur
Oroethoxy) propionic acid (Exemplary Compound No. 4-
7) 3- {4- [6- (6-hydroxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} -2- (2,2,2-trifluoroethoxy)
-Methyl propionate (compound of Example 2)
To a mixture of 0.70 g and 7 ml of anhydrous tetrahydrofuran was added 7 ml of an aqueous solution of 0.13 g of lithium hydroxide monohydrate at room temperature, and the mixture was stirred for 2 hours. After completion of the reaction, water was added to the reaction mixture, acidified with 2N hydrochloric acid, neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate.
The extract was washed with a saturated aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the obtained residue was purified by liquid chromatography [DIOL (filler trade name; manufactured by Merck); ethyl acetate].
0.34 g of the desired compound having 0.51 ("HPTLC: DIOL F254S"(MERCK); ethyl acetate) was obtained.

[0377]

Example 4 2- (4-fluorobenzylthio) -3-
{4- [6- (6-hydroxy-2,5,7,8-tet)
Lamethylchroman-2-ylmethoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy] phenyi
Methyl rupropionate (Exemplified Compound No. 7-54) N- {2- [4- [2- (4-fluorobenzylthio)]
-2-methoxycarbonylethyl] phenoxymethylcarbonylamino] -5- (6-methoxymethoxy-2,
0.67 g of 5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamic acid t-butyl ester (compound of Reference Example 11), 5 ml of 1,4-dioxane and 1,4-dioxane 1,4-dioxane Dioxane 2m
Using l, the reaction was carried out according to Example 1. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1).
1,2: 1,3: 1) to give 0.18 g of the target compound as a yellow oil having Rf = 0.32 (ethyl acetate: n-hexane = 1: 1).

[0378]

Example 5 2- (4-fluorobenzylthio) -3-
{4- [6- (6-hydroxy-2,5,7,8-tet)
Lamethylchroman-2-ylmethoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy] phenyl
Rupropionic acid (Exemplified compound No. 4-27) 2- (4-Fluorobenzylthio) -3- {4- [6-
0.16 g of methyl (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} propionate (compound of Example 4) , 1,4-
The reaction was carried out according to Example 3 using 2 ml of dioxane and 2.6 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was distilled off from the reaction mixture under reduced pressure, and water was added to the residue.
Extracted with ethyl acetate. The extract was washed with 2N hydrochloric acid and saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to reverse phase preparative high performance liquid chromatography (acetonitrile: water = 1: 1,
3: 2, 11: 7). The solvent was concentrated under reduced pressure from the eluent, and the precipitated powder was collected by filtration.
45 mg of the target compound as a yellow powder having a temperature of 0 ° C. are obtained.

[0379]

Example 6 2- [bis (4-fluorophenyl) metho
Xy] -3- {4- [6- (6-hydroxy-2,5,
7,8-tetramethylchroman-2-ylmethoxy)-
1-methyl-1H-benzimidazol-2-ylmeth
[Xy] phenyl} propionate methyl (Exemplified Compound N
o. 7-57) N- {2- [4- [2- [bis (4-fluorophenyl) methoxy] -2-methoxycarbonylethyl] phenoxyacetylamino] -5- (6-methoxymethoxy-2,5,7 0.98 g of t-butyl (8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 33), 15 ml of 1,4-dioxane, and a solution of 4N hydrochloric acid in 1,4-dioxane 5
The reaction and post-treatment were carried out according to Example 1 using
This gave 0.23 g of the target compound as a tan oil having an Rf value of 0.15 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 1).

[0380]

Example 7 2- [bis (4-fluorophenyl) metho
Xy] -3- {4- [6- (6-hydroxy-2,5,
7,8-tetramethylchroman-2-ylmethoxy)-
1-methyl-1H-benzimidazol-2-ylmeth
Xy] phenyl} propionic acid (Exemplary Compound No. 7-
2) 2- [bis (4-fluorophenyl) methoxy] -3-
{4- [6- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-
Methyl 1H-benzimidazol-2-ylmethoxy] phenyl} propionate (compound of Example 6) 0.21
g, lithium hydroxide monohydrate 0.034 g, distilled water 2
After performing a reaction and a post-treatment according to Example 3 using 2 ml of tetrahydrofuran and 2 ml of tetrahydrofuran, the mixture was subjected to liquid chromatography (“LiChroprepDIOL” (registered trademark, MERCK), ethyl acetate: n-hexane = 2: 1). Then, the residue was recrystallized from ethyl acetate, n-hexane and diisopropyl ether to obtain 0.104 g of a brown powdery target compound having a melting point of 116 ° C to 126 ° C.

[0381]

Example 8 3- {4- [6- (6-hydroxy-2,
5,7,8-tetramethylchroman-2-ylmethoki
B) -1-Methyl-1H-benzimidazol-2-i
Rumethoxy] phenyl} -2-phenylthiopropion
Ethyl acid (Exemplified compound No. 7-106) N- {2- [4- (2-ethoxycarbonyl-2-phenylthioethyl) phenoxyacetylamino] -5-
T-butyl (6-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 16)
The reaction and after-treatment were carried out according to Example 1 using 73 g, ethanol 1 ml and 4 N hydrochloric acid 1,4-dioxane solution 5 ml, and the Rf value was 0.36 (silica gel thin-layer chromatography, ethyl acetate: n-hexane). = 1: 1) in the form of a white glass having 0.48 g.

[0382]

Example 9 3- {4- [6- (6-hydroxy-2,
5,7,8-tetramethylchroman-2-ylmethoki
B) -1-Methyl-1H-benzimidazol-2-i
Rumethoxy] phenyl} -2-phenylthiopropion
Acid / hydrochloride (hydrochloride of Exemplified Compound No. 4-24) 3- {4- [6- (6-hydroxy-2,5,7,8-
0.46 g of ethyl tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} -2-phenylthiopropionate (compound of Example 8), lithium hydroxide monohydrate 0.12g, distilled water 4ml, tetrahydrofuran 5ml
After performing the reaction and post-treatment according to Example 3 using 3 ml of N, N-dimethylformamide, and liquid chromatography ("LiChroprepDIOL" (MERCK, registered trademark), ethyl acetate: n-hexane = 2: In 1), 0.25 g of the obtained glassy product was dissolved in 10 ml of diethyl ether, and 4N hydrochloric acid in 1,4-dioxane was added.
The resulting precipitate was collected by filtration to obtain 0.17 g of a milky white powdery target compound having a melting point of 116 ° C to 124 ° C (softening point).

[0383]

Example 10 2-hydroxy-3- {4- [6- (6
-Hydroxy-2,5,7,8-tetramethylchroman
-2-ylmethoxy) -1-methyl-1H-benzoimid
Dazol-2-ylmethoxy] phenyl} propionic acid
Ethyl (Exemplified Compound No. 7-83) N- {2- [4- (2-hydroxy-2-ethoxycarbonylethyl) phenoxyacetylamino] -5- (6
T-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (compound of Reference Example 15) 0.7
g, 2 ml of ethanol and 5 ml of 4N hydrochloric acid in 1,4-dioxane, and the reaction and post-treatment were carried out according to Example 1, and the Rf value was 0.04 (silica gel thin-layer chromatography, ethyl acetate: n-hexane). = 1: 1) in the form of a white glass having 0.43 g.

[0384]

Example 11 2-hydroxy-3- {4- [6- (6
-Hydroxy-2,5,7,8-tetramethylchroman
-2-ylmethoxy) -1-methyl-1H-benzoimid
Dazol-2-ylmethoxy] phenyl} propionic acid
-Hydrochloride (hydrochloride of Exemplified Compound No. 4-1) 2-hydroxy-3- {4- [6- (6-hydroxy-
2,5,7,8-Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazole-2-
According to Example 3, using 0.4 g of ethyl [ylmethoxy] phenyl} propionate (the compound of Example 10), 0.12 g of lithium hydroxide monohydrate, 4 ml of distilled water and 10 ml of N, N-dimethylformamide. 0.14 g of the powdery crude product obtained by the reaction and the post-treatment was added to 1,4
-Suspended in 5 ml of dioxane, 5 ml of 4N hydrochloric acid 1,4-dioxane solution was added at room temperature, and the mixture was stirred for 30 minutes. The residue obtained by distilling off the solvent was crystallized from acetonitrile to obtain 0.13 g of a light yellow powdery target compound having a melting point of 200 ° C. or higher (decomposition point).

[0385]

Example 12 2-ethoxy-3- {4- [6- (6-
Hydroxy-2,5,7,8-tetramethylchroman-
2-ylmethoxy) -1-methyl-1H-benzimidida
Zol-2-ylmethoxy] phenyl} propionic acid
Tyl (exemplified compound No. 7-85) N- {2- [4- (2-ethoxy-2-ethoxycarbonylethyl) phenoxyacetylamino] -5- (6-
T-butyl methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 23) 0.65
g, 2 ml of ethanol and 5 ml of a 4N hydrochloric acid solution in 1,4-dioxane, and the reaction and post-treatment were carried out according to Example 1, and the Rf value was 0.28 (silica gel thin layer chromatography, ethyl acetate: n-hexane). = 1: 1) in the form of a pale yellow oil having 0.37 g.

[0386]

Example 13 2-ethoxy-3- {4- [6- (6-
Hydroxy-2,5,7,8-tetramethylchroman-
2-ylmethoxy) -1-methyl-1H-benzimidida
Zol-2-ylmethoxy] phenyl} propionic acid
Hydrochloride (hydrochloride of Exemplified Compound No. 4-3) 2-ethoxy-3- {4- [6- (6-hydroxy-
2,5,7,8-Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazole-2-
Ilmethoxy] phenyl} ethyl propionate 0.35
g, lithium hydroxide monohydrate 0.076 g, distilled water 5
After performing a reaction and a post-treatment according to Example 3 using 10 ml of N, N-dimethylformamide and liquid chromatography (“LiChroprepDIOL” (MERCK), ethyl acetate: n-hexane = 3: 1). Then, 0.14 g of the obtained glassy product was dissolved in 5 ml of a 4N hydrochloric acid 1,4-dioxane solution, and the mixture was allowed to stand at room temperature for 10 minutes. The residue obtained by distilling off the solvent was crystallized from diethyl ether to obtain 0.15 g of the target compound as a light red powder having a melting point of 122 ° C to 132 ° C (softening point).

[0387]

Example 14 2- (4-fluorobenzyloxy)-
3- {4- [6- (6-hydroxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -1-methyl
1H-benzimidazol-2-ylmethoxy] f
Ethyl dipropionate (Exemplary Compound No. 7-4)
0) N- {2- [4- [2- (4-fluorobenzyloxy) -2-ethoxycarbonylethyl] phenoxyacetylamino] -5- (6-methoxymethoxy-2,5
Performed using 0.6 g of t-butyl 7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (compound of Reference Example 24), 2 ml of ethanol and 5 ml of 4N hydrochloric acid in 1,4-dioxane. The reaction and work-up were carried out according to Example 1 to obtain 0.35 g of a pale yellow glassy target compound having an Rf value of 0.31 (silica gel thin-layer chromatography, ethyl acetate: n-hexane = 1: 1). Was done.

[0388]

Example 15 2- (4-fluorobenzyloxy)-
3- {4- [6- (6-hydroxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -1-methyl
1H-benzimidazol-2-ylmethoxy] f
Enyl dipropionic acid hydrochloride (Exemplified Compound No. 4-
Hydrochloride of 13) 2- (4-fluorobenzyloxy) -3- {4- [6
Ethyl-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} propionate (compound of Example 14) After performing the reaction and post-treatment according to Example 3 using 33 g, lithium hydroxide monohydrate 0.063 g, distilled water 5 ml and N, N-dimethylformamide 10 ml, liquid chromatography ("LiChroprepDIOL") (MERCK, registered trademark), ethyl acetate: n-hexane = 3: 1), and 0.2 g of the obtained glassy product was treated with 4N hydrochloric acid 1,4-.
It was dissolved in 5 ml of a dioxane solution and left at room temperature for 10 minutes. The residue obtained by distilling off the solvent was crystallized from diethyl ether to obtain 0.16 g of an off-white powdery target compound having a melting point of 110 ° C to 120 ° C (softening point).

[0389]

Example 16 2-ethylthio-3- {4- [6- (6
-Hydroxy-2,5,7,8-tetramethylchroman
-2-ylmethoxy) -1-methyl-1H-benzoimid
Dazol-2-ylmethoxy] phenyl} propionic acid
Methyl (Exemplified Compound No. 7-44) N- [2-amino-5- (6-methoxymethoxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl] 1.45 g of t-butyl-N-methylcarbamate (compound of Reference Example 2), 3- (4-carboxymethoxyphenyl) -2-ethylthiopropion 0.86 g of methyl acrylate (compound of Reference Example 35), 0.35 g of anhydrous triethylamine, 0.57 g of diethyl cyanophosphate
And Reference Example 3 using 50 ml of anhydrous tetrahydrofuran
The crude product obtained by carrying out the reaction and post-treatment according to the above was dissolved in 30 ml of methanol, 30 ml of a 4N hydrochloric acid 1,4-dioxane solution was added at room temperature, and the mixture was allowed to stand for 18 hours. The solvent was distilled off, diluted with water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After distilling off the solvent,
The residue was subjected to column chromatography (silica gel, ethyl acetate: n-hexane = 2: 1), and the Rf value was 0.4.
7 (silica gel thin layer chromatography, ethyl acetate:
0.53 g of a colorless glassy target compound having n-hexane = 2: 1) was obtained.

[0390]

Example 17 2-ethylthio-3- {4- [6- (6
-Hydroxy-2,5,7,8-tetramethylchroman
-2-ylmethoxy) -1-methyl-1H-benzoimid
Dazol-2-ylmethoxy] phenyl} propionic acid
Hydrochloride (hydrochloride of Exemplified Compound No. 4-17) 2-ethylthio-3- {4- [6- (6-hydroxy-
2,5,7,8-Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazole-2-
According to Example 3, using 0.52 g of methyl [ylmethoxy] phenyl} propionate (the compound of Example 17), 0.106 g of lithium hydroxide monohydrate, 2 ml of distilled water and 10 ml of N, N-dimethylformamide. After the reaction and post-treatment, the product is subjected to reverse phase preparative high performance liquid chromatography (ODS, acetonitrile: water = 2: 1), and the obtained glassy product is dissolved in a 4N ethyl acetate hydrochloride solution. After that, the solvent was distilled off, n-hexane was added to the residue, and the insoluble matter was collected by filtration to obtain 0.14 g of a white powdery target compound having a melting point of 173 ° C to 177 ° C.

[0391]

Example 18 3- {4- [6- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) -1-methyl-1H-benzimidazole-2-
Ylmethoxy] phenyl} -2- (4-nitrophenoxy
B) Ethyl propionate (Exemplified Compound No. 7-11)
9) N- {2- [4- (2- [4-nitrophenoxy] -2]
-Ethoxycarbonylethyl) phenoxyacetylamino] -5- (6-methoxymethoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) phenyl
2.64 g of t-butyl-N-methylcarbamate (compound of Reference Example 30), 25 ml of 1,4-dioxane and 4
The reaction and post-treatment were carried out according to Example 1 using 25 ml of a normal hydrochloric acid 1,4-dioxane solution, and the Rf value was 0.19.
(Silica gel thin layer chromatography, ethyl acetate: n
1.58 g of a yellow glassy target compound having -hexane = 1: 1) was obtained.

[0392]

Example 19 3- {4- [6- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) -1-methyl-1H-benzimidazole-2-
Ylmethoxy] phenyl} -2- (4-nitrophenoxy
B) Propionic acid (exemplified compound No. 7-9) 3- {4- [6- (6-hydroxy-2,5,7,8-
1.55 g of ethyl tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl {-2- (4-nitrophenoxy) propionate (compound of Example 18), lithium hydroxide -After performing the reaction and post-treatment according to Example 3 using 0.27 g of monohydrate, 25 ml of distilled water and 25 ml of tetrahydrofuran, column chromatography ("Li
ChroprepDIOL ”(MERCK, registered trademark), ethyl acetate:
(n-hexane = 4: 1) to give 0.25 g of a yellow glassy target compound having a melting point of 135 ° C. or higher (softening point).

[0393]

Example 20 3- {4- [6- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) -1-methyl-1H-benzimidazole-2-
Ylmethoxy] phenyl} -2- (4-nitrophenyl
Thio) ethyl propionate (Exemplified Compound No. 7-12)
1) N- {5- (6-methoxymethoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -2- [4
T-butyl- [2- (4-nitrophenylthio) -2-ethoxycarbonylethyl] phenoxyacetylamino] phenyl} -N-methylcarbamate (Reference Example 17
1 g), ethanol 5 ml and 4N hydrochloric acid 1,
The reaction and post-treatment were carried out according to Example 1 using 10 ml of a 4-dioxane solution, and the Rf value was 0.20 (silica gel thin layer chromatography, ethyl acetate: n-hexane =
0.6 g of the yellow glassy target compound having the formula 2: 3) was obtained.

[0394]

Example 21 3- {4- [6- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) -1-methyl-1H-benzimidazole-2-
Ylmethoxy] phenyl} -2- (4-nitrophenyl
Thio) propionic acid hydrochloride (Exemplary Compound No. 7-1)
Hydrochloride of 1) 3- {4- [6- (6-hydroxy-2,5,7,8-
0.58 g of ethyl tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} -2- (4-nitrophenylthio) propionate (compound of Example 20), hydroxylated 0.11 g of lithium monohydrate, 8 ml of distilled water and N, N
After performing the reaction and the post-treatment according to Example 3 using 15 ml of dimethylformamide, the mixture was subjected to liquid chromatography ("LiChroprepDIOL" (MERCK, registered trademark), ethyl acetate: n-hexane = 10: 1). And 0.38 g of the obtained glassy product was added to 5 ml of tetrahydrofuran.
And 5 ml of a 4N hydrochloric acid 1,4-dioxane solution was added thereto, and the mixture was allowed to stand at room temperature for 10 minutes. The residue obtained by distilling off the solvent was crystallized from diethyl ether to give a melting point of 130 ° C.
0.35 g of the target compound in the form of a yellow powder having a temperature of １138 ° C. (softening point) was obtained.

[0395]

Example 22 3- {4- [6- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) -1-methyl-1H-benzimidazole-2-
Ilmethoxy] phenyl} -2-phenoxypropion
Ethyl acid (Exemplified Compound No. 7-92) N- {2- [4- (2-ethoxycarbonyl-2-phenoxyethyl) phenoxyacetylamino] -5- (6
T-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 29) 0.58
g, 5 ml of ethanol and 10 ml of a 4N hydrochloric acid solution in 1,4-dioxane, and the reaction and post-treatment were carried out according to Example 1. = 1: 2), 0.39 g of the target compound in the form of a white glass was obtained.

[0396]

Example 23 3- {4- [6- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) -1-methyl-1H-benzimidazole-2-
Ilmethoxy] phenyl} -2-phenoxypropion
Acid / hydrochloride (hydrochloride of Exemplified Compound No. 4-10) 3- {4- [6- (6-hydroxy-2,5,7,8-
0.37 g of ethyl tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} -2-phenoxypropionate (compound of Example 22), lithium hydroxide monohydrate After performing reaction and post-treatment according to Example 3 using 0.076 g, 5 ml of distilled water and 10 ml of N, N-dimethylformamide, liquid chromatography ("LiChropr")
epDIOL "(MERCK, registered trademark), ethyl acetate: n-hexane = 3: 1), and the obtained glassy product was dissolved in 5 ml of a 4N hydrochloric acid solution in 1,4-dioxane (5 ml). The solvent was distilled off, and the residue was dissolved in 5 ml of tetrahydrofuran.
It was added dropwise to 50 ml with stirring. The mixture was further stirred for 20 minutes, and the resulting precipitate was collected by filtration to give a melting point of 128 ° C to 135 ° C.
(Softening point) 0.22 as an off-white powdery target compound
g was obtained.

[0397]

Example 24 2- (4-cyanophenoxy) -3-
{4- [6- (6-hydroxy-2,5,7,8-tet)
Lamethylchroman-2-ylmethoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy] phenyl
Ethyl rupropionate (Exemplified Compound No. 7-12
2) N- {2- [4- [2- (4-cyanophenoxy) -2]
-Ethoxycarbonylethyl] phenoxyacetylamino] -5- (6-methoxymethoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) phenyl
Example 1 was prepared using 0.57 g of t-butyl-N-methylcarbamate (compound of Reference Example 18), 3 ml of 1,4-dioxane and 3 ml of 4N hydrochloric acid in 1,4-dioxane.
The reaction and after-treatment were carried out according to Rf value = 0.38 ("H
0.27 white glassy target compound having PTLC NH ₂ F _254S “(MERCK), ethyl acetate: n-hexane = 3: 2)
g was obtained.

[0398]

Example 25 2- (4-cyanophenoxy) -3-
{4- [6- (6-hydroxy-2,5,7,8-tet)
Lamethylchroman-2-ylmethoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy] phenyl
Rupropionic acid / hydrochloride (Exemplified Compound No. 7-12
Hydrochloride) 2- (4-cyanophenoxy) -3- {4- [6- (6
-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} propionate (compound of Example 24) 0.48 g, water 0.09 g of lithium oxide monohydrate, 5 ml of distilled water and N, N-
After performing the reaction and post-treatment according to Example 3 using 10 ml of dimethylformamide, the mixture was subjected to liquid chromatography ("LiChroprepDIOL" (MERCK, registered trademark), ethyl acetate: n-hexane = 5: 1). The obtained glassy product was dissolved in 1,4-dioxane (5 ml), 4N hydrochloric acid 1,4-dioxane solution (2 ml) was added at room temperature, and 1
Left for 0 minutes. This solution was dissolved in diethyl ether (100 m).
The mixture was added dropwise with stirring. The mixture was further stirred for 15 minutes, and the resulting precipitate was collected by filtration to obtain 0.33 g of a pinkish powdery target compound having a melting point of 142 ° C to 146 ° C (softening point).

[0399]

Example 26 3- {4- [6- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) -1-methyl-1H-benzimidazole-2-
Ylmethoxy] phenyl} -2- (4-methylphenyl
Thio) ethyl propionate (Exemplified Compound No. 7-12)
7) N- {2- [4- [2-ethoxycarbonyl-2- (4
-Methylphenylthio) ethyl] phenoxyacetylamino] -5- (6-methoxymethoxy-2,5,7,8
T-butyl-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Reference Example 19
Using 0.92 g of ethanol, 4 ml of ethanol and 10 ml of 4N hydrochloric acid in 1,4-dioxane, the reaction and post-treatment were carried out according to Example 1, and the Rf value was 0.31 ("HPT").
_{LC NH 2 F 254S "(MERCK} ), ethyl acetate: n-hexane =
0.57 g of a white glassy target compound having 1: 1)
was gotten.

[0400]

Example 27 2- (4-methylphenylthio) -3-
{4- [6- (6-hydroxy-2,5,7,8-tet)
Lamethylchroman-2-ylmethoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy] phenyl
Rupropionic acid / hydrochloride (Exemplary Compound No. 7-1)
7) 3- {4- [6- (6-hydroxy-2,5,7,8-
0.55 g of ethyl tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} -2- (4-methylphenylthio) propionate (compound of Example 26), hydroxylated 0.1 g of lithium monohydrate, 5 ml of distilled water and N, N-
After performing the reaction and post-treatment according to Example 3 using 10 ml of dimethylformamide, the mixture was subjected to liquid chromatography ("LiChroprepDIOL" (registered trademark), ethyl acetate: n-hexane = 2: 1). The obtained glassy product (0.3 g) was dissolved in 1,4-dioxane (5 ml), 4N hydrochloric acid (1,4-dioxane) (2 ml) was added at room temperature, and the mixture was allowed to stand for 30 minutes. The residue obtained by distilling off the solvent was dissolved in 1,4-dioxane (5 ml) and added dropwise to diethyl ether (200 ml) with stirring. The mixture was further stirred for 30 minutes, and the resulting precipitate was collected by filtration.
0.2 g of an off-white powdery target compound having a softening point of 0.2 ° C.
6 g were obtained.

[0401]

Example 28 2- (4-chlorophenylthio) -3-
{4- [6- (6-hydroxy-2,5,7,8-tet)
Lamethylchroman-2-ylmethoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy] phenyl
Ethyl rupropionate (Exemplified Compound No. 7-13)
0) N- {2- [4- [2- (4-chlorophenylthio)-]
2-ethoxycarbonylethyl] phenoxyacetylamino] -5- (6-methoxymethoxy-2,5,7,8
T-butyl-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Reference Example 20)
Using 0.75 g of ethanol, 4 ml of ethanol and 10 ml of 4N hydrochloric acid in 1,4-dioxane, the reaction and post-treatment were carried out according to Example 1, and the Rf value was 0.33 ("HPT").
_{LC NH 2 F 254S "(MERCK} ), ethyl acetate: n-hexane =
0.51 g of a white glassy target compound having 1: 1)
was gotten.

[0402]

Working Example 29 2- (4-Chlorophenylthio) -3-
{4- [6- (6-hydroxy-2,5,7,8-tet)
Lamethylchroman-2-ylmethoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy] phenyl
Rupropionic acid hydrochloride (Exemplified Compound No. 7-20
Hydrochloride) 2- (4-chlorophenylthio) -3- {4- [6-
0.49 g of ethyl (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} propionate (compound of Example 28) , 0.09 g of lithium hydroxide monohydrate, 5 ml of distilled water and N,
After performing a reaction and a post-treatment according to Example 3 using 10 ml of N-dimethylformamide, the mixture was subjected to liquid chromatography ("LiChroprepDIOL" (trademark of MERCK, registered trademark), ethyl acetate: n-hexane = 2: 1). And 0.23 g of the obtained glassy product was added to 5 ml of 1,4-dioxane.
And 2 ml of a 4N hydrochloric acid 1,4-dioxane solution was added at room temperature, and the mixture was allowed to stand for 30 minutes. The residue obtained by distilling off the solvent was dissolved in 1,4-dioxane (5 ml) and added dropwise to diethyl ether (200 ml) with stirring. 30 more
The resulting precipitate was collected by filtration and the melting point was 120 ° C.
0.2 g of the target compound in the form of a pale yellow powder having 124 ° C. (softening point) was obtained.

[0403]

Working Example 30 2- (4-t-butylphenylthio)-
3- {4- [6- (6-hydroxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -1-methyl
1H-benzimidazol-2-ylmethoxy] f
Ethyl dipropionate (Exemplary Compound No. 7-1)
33) N- {2- [4- [2- (4-t-butylphenylthio) -2-ethoxycarbonylethyl] phenoxyacetylamino] -5- (6-methoxymethoxy-2,5,
0.75 g of t-butyl 7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (compound of Reference Example 21), 8 ml of ethanol and 8 ml of 4N hydrochloric acid 1,4-dioxane solution were used. Example 1
The reaction and after-treatment were carried out according to Rf value = 0.42 ("H
0.55 white glassy target compound having PTLC NH ₂ F _254S "(MERCK), ethyl acetate: n-hexane = 1: 1)
g was obtained.

[0404]

Example 31 2- (4-t-butylphenylthio)-
3- {4- [6- (6-hydroxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -1-methyl
1H-benzimidazol-2-ylmethoxy] f
Enyl dipropionic acid hydrochloride (Exemplified Compound No. 7-
23 hydrochloride) 2- (4-t-butylphenylthio) -3- {4- [6
0.53 g of ethyl-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} propionate, lithium hydroxide / 1 After performing the reaction and post-treatment according to Example 3 using 0.1 g of hydrate, 5 ml of distilled water and 15 ml of N, N-dimethylformamide, liquid chromatography ("LiChroprepDI")
OL "(MERCK, registered trademark), ethyl acetate: n-hexane = 2: 1), and the resulting glassy product was
After dissolving in 5 ml of 4-dioxane, 2 ml of 4N hydrochloric acid in 1,4 dioxane was added at room temperature, and the mixture was allowed to stand for 15 minutes. The residue obtained by distilling off the solvent was dissolved in 1,4-dioxane (5 ml) and added dropwise to diethyl ether (200 ml) with stirring. After stirring for further 15 minutes, the resulting precipitate was collected by filtration to obtain 0.24 g of a pale yellow powdery target compound having a melting point of 134 ° C to 138 ° C (softening point).

[0405]

Example 32 3- {4- [6- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) -1-methyl-1H-benzimidazole-2-
Ylmethoxy] phenyl} -2- (4-methoxyphenyi
Ethyl ruthio) propionate (Exemplified Compound No. 7-1)
36) N- {5- (6-methoxymethoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -2- [4
T-butyl- [2- (4-methoxyphenylthio) -2-ethoxycarbonylethyl] phenoxyacetylamino] phenyl} -N-methylcarbamate (Reference Example 22
Using 0.7 g of ethanol, 8 ml of ethanol and 8 ml of 4N hydrochloric acid in 1,4-dioxane, the reaction and post-treatment were carried out according to Example 1, and the Rf value was 0.26 ("HPTLC N
_{H 2 F 254S "(MERCK)} , ethyl acetate: n-hexane = 1:
0.5 g of a white glassy target compound having 1) was obtained.

[0406]

Example 33 3- {4- [6- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) -1-methyl-1H-benzimidazole-2-
Ylmethoxy] phenyl} -2- (4-methoxyphenyi
Ruthio) propionic acid hydrochloride (Exemplified Compound No. 7-
26 hydrochloride) 3- {4- [6- (6-hydroxy-2,5,7,8-
0.48 g of ethyl tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} -2- (4-methoxyphenylthio) propionate (compound of Example 32), hydroxylated 0.1 g of lithium monohydrate, 5 ml of distilled water and N, N
After carrying out the reaction and aftertreatment according to Example 3 using 15 ml of dimethylformamide, the mixture was subjected to liquid chromatography ("LiChroprepDIOL" (MERCK, registered trademark), ethyl acetate: n-hexane = 2: 1). The obtained glassy product was dissolved in 5 ml of 1,4-dioxane,
2 ml of normal hydrochloric acid 1,4-dioxane solution was added at room temperature,
Left for 15 minutes. The residue obtained by distilling off the solvent was concentrated in 1,4
-Dissolved in 5 ml of dioxane and 200 ml of diethyl ether
The solution was added dropwise to the solution while stirring. Stir for another 15 minutes,
The resulting precipitate was collected by filtration to obtain 0.22 g of a light pink powdery target compound having a melting point of 122 ° C to 125 ° C (softening point).

[0407]

Embodiment 345- {4- [6- (6-hydroxy-4
-Oxo-2,5,7,8-tetramethylchroman-2
-Ylmethoxy) -1-methyl-1H-benzimidazo
2-ylmethoxy] benzyl {thiazolidine-
2,4-dione (exemplified compound No. 2-20) N- {5- (6-acetoxy-4-oxo-2,5,
7,8-tetramethylchroman-2-ylmethoxy)-
2- [4- (2,4-dioxothiazolidin-5-yl
Methyl) phenoxyacetylamino] phenyl} -N-
T-butyl methylcarbamate (compound of Reference Example 41)
0.25 g, distilled water 5 ml and 4N hydrochloric acid 1,4-dioxide
The mixture of 30 ml of the hexane solution was left at room temperature for 5 days,
The mixture was heated under reflux for 1 hour. Solvent is distilled off from the reaction mixture
Water was added to the residue and neutralized with sodium hydrogen carbonate.
Then, the mixture was extracted with ethyl acetate. Wash the extract with saturated saline
Thereafter, it was dried over anhydrous magnesium sulfate. Distill off the solvent,
The obtained residue is subjected to reversed-phase preparative high-performance liquid chromatography.
(ODS, acetonitrile: (0.2% acetic acid + 0.2%
Triethylamine) aqueous solution = 1: 1), and the Rf value =
0.32 (“HPTLC DIOL F _254S"(MERK), ethyl acetate
: Pale yellow glassy eye having n-hexane = 3: 1)
0.18 g of the target compound was obtained.

[0408]

Example 35 5- {4- [6- (6-hydroxy-4)
-Oxo-2,5,7,8-tetramethylchroman-2
-Ylmethoxy) -1-methyl-1H-benzimidazo
2-ylmethoxy] benzyl {thiazolidine-
2,4-dione hydrochloride (exemplified compound No. 2-20
Hydrochloride) 5- {4- [6- (6-hydroxy-4-oxo-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl {thiazolidine-2,4-dione (the compound of Example 34) 0.17 g, ethyl acetate 3 ml
And a mixture of 2 ml of 4N ethyl acetate hydrochloride solution was stirred at room temperature for 10 minutes. 50 ml of n-hexane was added to the reaction mixture, and the mixture was stirred for 30 minutes. The resulting precipitate was collected by filtration to obtain 0.14 g of a pale yellow powdery target compound having a melting point of 150 ° C to 154 ° C.

[0409]

Working Example 36 5- ｛4- [6- (6-hydroxy-4)
-Methoxyimino-2,5,7,8-tetramethylclo
Man-2-ylmethoxy) -1-methyl-1H-benzo
Imidazol-2-ylmethoxy] benzyl @ thiazoli
Gin-2,4-dione (Exemplified Compound No. 2-24) 5- {4- [6- (6-hydroxy-4-oxo-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl {thiazolidine-2,4-dione (compound of Example 34) 0.3 g, O- A mixture of 0.13 g of methylhydroxylamine hydrochloride, 0.12 g of pyridine and 15 ml of anhydrous methanol was stirred at room temperature for 1 hour, and then left for 2 days. The mixture was further refluxed for 4 hours, and left overnight. The solvent was distilled off, and the residue was subjected to reversed-phase preparative high-performance liquid chromatography (ODS, acetonitrile: (0.2% acetic acid + 0.2% triethylamine) aqueous solution = 6: 4), and Rf value = 0. 56 (“HPTLC DIOL F _254S ” (MER
K), 0.22 g of the target compound in the form of a pink glass having ethyl acetate: n-hexane = 3: 1) was obtained.

[0410]

Working Example 37 5- ｛4- [6- (6-hydroxy-4)
-Methoxyimino-2,5,7,8-tetramethylclo
Man-2-ylmethoxy) -1-methyl-1H-benzo
Imidazol-2-ylmethoxy] benzyl @ thiazoli
Gin-2,4-dione hydrochloride (Exemplary Compound No. 2-
24 hydrochloride) 5- {4- [6- (6-hydroxy-4-methoxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1-H-benzimidazole -2-ylmethoxy] benzyl} thiazolidine-2,4
A mixture of 0.21 g of -dione (the compound of Example 36), 5 ml of ethyl acetate and 10 ml of a 4N hydrochloric acid ethyl acetate solution was irradiated with ultrasonic waves for 10 minutes. The solvent was distilled off, and the obtained residue was crystallized from diethyl ether.
There was obtained 0.2 g of the target compound as a pale yellow powder having a temperature of 146 ° C. (softening point).

[0411]

Working Example 38 5- {4- [6- (4-benzyloxy)
Imino-6-hydroxy-2,5,7,8-tetramethi
Lucroman-2-ylmethoxy) -1-methyl-1H-
Benzimidazol-2-ylmethoxy] benzyldithio
Azolidine-2,4-dione (Exemplary Compound No. 2-2
5) 5- {4- [6- (6-hydroxy-4-oxo-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl {thiazolidine-2,4-dione (compound of Example 34) 0.3 g, O- Benzyl hydroxylamine hydrochloride 0.24 g, pyridine 0.12 g
The reaction and after-treatment were carried out in the same manner as in Example 36 using 15 ml of anhydrous methanol and anhydrous methanol, and the Rf value was 0.58 (“HPTLC
DIOL F _254S "( _MERK ), ethyl acetate: n-hexane = 3:
0.24 g of a light yellow glassy target compound having 1) was obtained.

[0412]

Working Example 39 5- {4- [6- (4-benzyloxy)
Imino-6-hydroxy-2,5,7,8-tetramethi
Lucroman-2-ylmethoxy) -1-methyl-1H-
Benzimidazol-2-ylmethoxy] benzyldithio
Azolidine-2,4-dione hydrochloride (Exemplary Compound N
o. Hydrochloride of 2-25) 5- {4- [6- (4-benzyloxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2
-Ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl {thiazolidine-
0.24 g of 2,4-dione (the compound of Example 38), 5 ml of ethyl acetate and 10 ml of 4N hydrochloric acid in ethyl acetate
The reaction and post-treatment were carried out in the same manner as in Example 37 to obtain 0.2 g of the target compound as a pale yellow powder having a melting point of 135 ° C to 142 ° C (softening point).

[0413]

Working Example 40 5- ｛4- [6- (6-hydroxy-4)
-Hydroxyimino-2,5,7,8-tetramethylc
Roman-2-ylmethoxy) -1-methyl-1H-ben
Zoimidazol-2-ylmethoxy] benzyldithiazo
Lysine-2,4-dione (Exemplified Compound No. 2-23) 5- {4- [6- (6-hydroxy-4-oxo-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl {thiazolidine-2,4-dione (the compound of Example 34) 0.6 g, hydroxylamine A mixture of 0.21 g of hydrochloride, 0.24 g of pyridine and 30 ml of anhydrous methanol was stirred at room temperature for 1 hour, and then stirred for 1.5 hours.
Left for days. After further heating and refluxing for one day, 0.21 g of hydroxylamine hydrochloride and 0.24 g of pyridine were added, and the mixture was stirred at room temperature for 2 hours and left for 2 days. The solvent is distilled off, and the residue is subjected to reverse phase preparative high performance liquid chromatography (ODS, acetonitrile: (0.2% acetic acid + 0.2%
Triethylamine) aqueous solution = 1: 1), and the Rf value =
0.33 g of the target compound was obtained as a pale yellow glass having 0.36 ("HPTLC DIOL F _254S " ( _MERK ), ethyl acetate: n-hexane = 3: 1).

[0414]

Example 41 5- {4- [6- (6-hydroxy-4)
-Hydroxyimino-2,5,7,8-tetramethylc
Roman-2-ylmethoxy) -1-methyl-1H-ben
Zoimidazol-2-ylmethoxy] benzyldithiazo
Lysine-2,4-dione hydrochloride (Exemplary Compound No. 2
Hydrochloride of -23) 5- {4- [6- (6-hydroxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazole- 2-ylmethoxy] benzyl} thiazolidine-2,4
The reaction and post-treatment were carried out according to Example 37 using 0.32 g of dione (the compound of Example 40), 10 ml of ethyl acetate and 15 ml of a 4N hydrochloric acid ethyl acetate solution to give a melting point of 1
0.32 g of the target compound in the form of a yellow powder having a temperature of 58 ° C. to 162 ° C. (softening point) was obtained.

[0415]

Example 42 5- {4- [6- (4-ethoxycarbo)
Nylmethoxyimino-6-hydroxy-2,5,7,8
-Tetramethylchroman-2-ylmethoxy) -1-me
Tyl-1H-benzimidazol-2-ylmethoxy]
Benzyl dithiazolidine-2,4-dione (exemplary compound
No. 6-2) 5- {4- [6- (6-hydroxy-4-oxo-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl {thiazolidine-2,4-dione (compound of Example 34) 0.3 g, aminooxy Acetic acid t
A mixture of 0.48 g of -butyl p-toluenesulfonate, 0.12 g of pyridine, and 15 ml of anhydrous methanol was stirred at room temperature for 1 hour, and then left for 1.5 days. Further 3.5
After heating under reflux for an hour, the mixture was left overnight. The solvent was distilled off, and the residue was dissolved in 5 ml of ethanol and 10 ml of a 4N hydrochloric acid solution in 1,4-dioxane, and allowed to stand for 2 days. The solvent is distilled off, and the residue is subjected to reverse phase preparative high performance liquid chromatography (O
DS, acetonitrile: (0.2% acetic acid + 0.2% triethylamine) aqueous solution = 3: 2), Rf value = 0.
_{32 ( "HPTLC DIOL F 25 4S} " (MERK), ethyl acetate: n-
0.25 g of a pale yellow glassy target compound having hexane = 3: 1) was obtained.

[0416]

Example 43 5- {4- [6- (4-ethoxycarbo)
Nylmethoxyimino-6-hydroxy-2,5,7,8
-Tetramethylchroman-2-ylmethoxy) -1-me
Tyl-1H-benzimidazol-2-ylmethoxy]
Benzyldithiazolidine-2,4-dione hydrochloride (eg
Compound No. Hydrochloride of 6-2) 5- {4- [6- (4-ethoxycarbonylmethoxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H- Benzimidazol-2-ylmethoxy] benzyl {thiazolidine-2,4-dione (compound of Example 42)
The reaction and post-treatment were carried out according to Example 37 using 24 g, 5 ml of ethyl acetate and 10 ml of a 4N hydrochloric acid ethyl acetate solution, and the target compound was obtained as a pale yellow powder having a melting point of 127 ° C to 133 ° C (softening point). 19 g were obtained.

[0417]

[Reference example]

[0418]

Reference Example 1 N- [5- (6-methoxymethoxy-2,
5,7,8-tetramethylchroman-2-ylmethoki
B) -2-Nitrophenyl] -N-methylcarbamic acid
t-butyl ester (raw material of Reference Example 2) 6-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethanol 5.00 g, N- (5-
0.78 g of sodium hydride (55% by weight) was added to a mixture of 5.11 g of chloro-2-nitrophenyl) -N-methylcarbamic acid t-butyl ester and 100 ml of dimethylformamide under ice cooling, and the mixture was stirred at room temperature for 3 hours. Stirred. After allowing the reaction mixture to stand overnight, dimethylformamide was distilled off from the reaction mixture, water was added to the obtained residue, the mixture was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain an Rf value = 0.30 (silica gel thin-layer chromatography; hexane: ethyl acetate = 3.18 g of the desired compound having 3) were obtained.

[0419]

Reference Example 2 N- [2-amino-5- (6-methoxymeth
Toxi-2,5,7,8-tetramethylchroman-2-
Ylmethoxy) phenyl] -N-methylcarbamic acid t
-Butyl ester (raw material of Reference Example 3) N- [5- (6-methoxymethoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -2-nitrophenyl] -N-methylcarbamic acid t-butyl ester (compound of Reference Example 1) 4.00 g, 10% palladium-carbon 0.40 g, and a mixture of methanol 80 ml in a hydrogen atmosphere. The mixture was stirred at room temperature for 3 hours. After the reaction,
The catalyst was filtered off from the reaction mixture, and the filtrate was concentrated.
2. The desired compound having a value = 0.12 (silica gel thin layer chromatography; hexane: ethyl acetate = 3: 1).
77 g were obtained.

[0420]

Reference Example 3 N- {2- [4- (2,4-dioxothia)
Zolidin-5-ylmethyl) phenoxyacetylamido
No] -5- (6-methoxymethoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) phenyl
-N-methylcarbamic acid t-butyl ester (Example
1) N- [2-amino-5- (6-methoxymethoxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -N-methylcarbamic acid t-butyl ester (compound of Reference Example 2) 0.60 g, 4- (2,4
-Dioxothiazolidine-5-ylmethyl) phenoxyacetic acid 0.34 g and anhydrous tetrahydrofuran 10 ml
In a mixture of the above, under ice cooling, triethylamine 0.20 ml
Then, 0.22 ml of diethyl cyanophosphonate was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After leaving the reaction mixture overnight, tetrahydrofuran was distilled off from the reaction mixture,
Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain an Rf value = 0.30 (silica gel thin-layer chromatography; hexane: ethyl acetate = 1: 0.84 g of the desired compound having 1) was obtained.

[0421]

Reference Example 4 3- [4- (t-butoxycarbonylmethoate)
Xy) phenyl] -2- (2,2,2-trifluoroe
Toxic acid) propionic acid methyl ester (Reference Example 5
Material) 3- (4-hydroxyphenyl) -2- (2,2,2-
In a mixture of 3.40 g of trifluoroethoxy) propionic acid methyl ester and 60 ml of acetone at room temperature,
5.97 g of cesium carbonate was added, and 3.58 g of bromoacetic acid t-butyl ester was added dropwise, followed by stirring at room temperature for 1 hour and 30 minutes. After completion of the reaction, acetone was distilled off from the reaction mixture,
Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1).
0: 1) to give 4.12 g of the desired compound having an Rf value of 0.50 (silica gel thin layer chromatography; n-hexane / ethyl acetate = 3: 1).

[0422]

Reference Example 5 3- (4-carboxymethoxyphenyl)
-2- (2,2,2-trifluoroethoxy) propio
Acid methyl ester (raw material of Reference Example 6) 3- [4- (t-butoxycarbonylmethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propionic acid methyl ester (Compound of Reference Example 4) 4.05
g, 40 ml of 4N hydrochloric acid dioxane was added to a mixture of 40 ml of 1,4-dioxane at room temperature, and the mixture was stirred at room temperature for 5 days. After completion of the reaction, 4N hydrochloric acid was added from the reaction mixture.
When 1,4-dioxane is distilled off and crystallized, the melting point is 75.
3.63 g of the title compound having a temperature between 81 ° C. and 81 ° C. are obtained.

[0423]

Reference Example 6 N- {2- [4- [2-methoxycarboni ]
2- (2,2,2-trifluoroethoxy) ethyl
Ru] phenoxyacetylamino] -5- (6-methoxy
Methoxy-2,5,7,8-tetramethylchroman-2
-Ylmethoxy) phenyl} -N-methylcarbamic acid
t-butyl ester (raw material of Example 2) N- [2-amino-5- (6-methoxymethoxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -N-methylcarbamic acid t-butyl ester (compound of Reference Example 2) 0.80 g, 3- (4-carboxymethoxyphenyl) -2- (2 , 2,2-trifluoroethoxy) propionic acid methyl ester (compound of Reference Example 5) 0.59 g, triethylamine 0.18
g, diethyl cyanophosphonate 0.29 g and anhydrous tetrahydrofuran 20 ml, the reaction and post-treatment were carried out according to Reference Example 3 to obtain Rf = 0.56.
(Silica gel thin layer chromatography; n-hexane:
1.09 g of the desired compound having ethyl acetate = 1: 1) were obtained.

[0424]

Reference Example 7 3- (4-hydroxyphenyl) -2-me
Methyl rucaptopropionate ( raw material of Reference Example 8) To a solution of 879 g of 5- (4-acetoxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione in 1.5 l of toluene, 368 g of a 28% sodium methoxide methanol solution was added. Was added dropwise under ice cooling. After stirring at room temperature for 2 hours, 1 l of tetrahydrofuran and ice water were added to the reaction solution. 0.8
1 and 10% hydrochloric acid were added to adjust the pH to 2. Unnecessary substances in the organic layer of the reaction solution were removed by filtration, and the mother liquor was washed with a 5% aqueous citric acid solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the filtrate, isopropyl ether was added to the residue, and the precipitated insoluble material was removed by filtration. The solvent was distilled off from the filtrate, and the residue was subjected to silica gel column chromatography (first time; ethyl acetate: n-hexane = 1: 6,
1: 5, 1: 4, second time; ethyl acetate: n-hexane =
1: 6, 1: 5) to give 0.33 g of the desired compound as an orange oil with Rf = 0.35 (ethyl acetate: n-hexane = 1: 4).

[0425]

Reference Example 8 2- (4-fluorobenzylthio) -3-
Methyl (4-hydroxyphenyl) propionate (reference
( Raw material of Example 9) Triethylamine was added to a solution of 200 mg of methyl 3- (4-hydroxyphenyl) -2-mercaptopropionate (compound of Reference Example 7) in 4 ml of anhydrous tetrahydrofuran.
14 ml and 4-fluorobenzyl bromide 0.12 m
was added and stirred at room temperature for 1 hour. After standing at room temperature for 4 days, the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 2, 1: 2).
According to 1), the target compound 0.2 as a colorless oil having Rf = 0.44 (ethyl acetate: n-hexane = 1: 2) was obtained.
6 g were obtained.

[0426]

Reference Example 9 3- (4-t-butoxycarbonyl methoxy)
(Ciphenyl) -2- (4-fluorobenzylthio) pro
Methyl pionate (raw material of Reference Example 10 ) 0.20 g of methyl 2- (4-fluorobenzylthio) -3- (4-hydroxyphenyl) propionate (compound of Reference Example 8), 0.13 ml of t-butyl bromoacetate ,
The reaction was carried out according to Reference Example 4 using 4 ml of anhydrous N, N-dimethylformamide and 31 mg of sodium hydride (55% or more, oily). The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 9, 1: 4) to give Rf = 0.21 (ethyl acetate: n-hexane = 0.25 g of a colorless oil having the formula (1: 9) was obtained.

[0427]

Reference Example 10 3- (4-carboxymethoxyphenyl )
L) -2- (4-Fluorobenzylthio) propionic acid
Methyl (raw material of Reference Example 11) 3- (4-t-butoxycarbonylmethoxyphenyl)
4.00 g of methyl-2- (4-fluorobenzylthio) propionate (compound of Reference Example 9), 10 ml of 1,4-dioxane and 40 ml of 4N hydrochloric acid 1,4-dioxane
And the reaction was carried out according to Reference Example 5. The solvent was distilled off from the reaction mixture under reduced pressure to obtain 4.53 g (1,4-dioxane mixture) of a light orange oily target compound having Rf = 0.12 (ethyl acetate: n-hexane = 1: 2). Was done.

[0428]

Reference Example 11 N- {2- [4- [2- (4-fluoro
Benzylthio) -2-methoxycarbonylethyl] fe
Nonoxymethylcarbonylamino] -5- (6-methoxy
Methoxy-2,5,7,8-tetramethylchroman-2
-Ylmethoxy) phenyl} -N-methylcarbamic acid
t-butyl ester (raw material of Example 4) 3- (4-carboxymethoxyphenyl) -2- (4-
Methyl fluorobenzylthio) propionate (Reference Example 1)
0) 586 mg, N- [2-amino-5- (6
-Methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -N-methylcarbamic acid t-butyl ester (compound of Reference Example 2) 5
00 mg, triethylamine 0.42 ml, anhydrous tetrahydrofuran 10 ml and diethyl cyanophosphate 0.2
The reaction was carried out according to Reference Example 6 using 3 ml. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 3, 1: 2, 1: 1).
According to 1), 0.69 of the target compound was obtained as a yellow oil having Rf = 0.63 (ethyl acetate: n-hexane = 1: 1).
g was obtained.

[0429]

[Reference Example 12] Ethyl 4-hydroxyphenyl lactate (See
Raw material of Example 13) 30 g of 4-hydroxyphenyl lactic acid, anhydrous ethanol 5
0 ml and 100 m of 4 N hydrochloric acid in 1,4-dioxane
The mixture was left overnight at room temperature. After the solvent was distilled off, the residue was diluted with water and neutralized with sodium hydrogen carbonate. After extraction with ethyl acetate, the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the Rf value was 0.78.
35.7 g of the target compound as pale yellow oil having (silica gel thin layer chromatography, ethyl acetate) was obtained.

[0430]

Reference Example 13 3- (4-t-butoxycarbonylmethoate)
Ethyl (xyphenyl) -2-hydroxypropionate
(Raw materials of Reference Examples 14 and 25) Ethyl 4-hydroxyphenyl lactate (compound of Reference Example 12) 35.6 g, bromoacetic acid t-butyl ester 58.
Using 2 g, 83 g of cesium carbonate and 700 ml of acetone, the reaction and post-treatment were carried out according to Reference Example 4, and the Rf value was
28 g of the desired compound as a pale yellow oil having 0.3 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 4) were obtained.

[0431]

Reference Example 14 3- (4-carboxymethoxyphenyl )
E) ethyl 2-hydroxypropionate (Reference Example 15)
Raw material) 3- (4-t-butoxycarbonylmethoxyphenyl)
18 g of ethyl 2-hydroxypropionate (compound of Reference Example 13) and 4N hydrochloric acid in 1,4-dioxane 1
The reaction and post-treatment were carried out according to Reference Example 5 using 50 ml, and the Rf value was 0.35 (“HPTLC DIOL F _254S ” (MER
K), 17.5 g of a brown oily target compound having ethyl acetate: n-hexane = 1: 2) was obtained.

[0432]

Reference Example 15 N- {2- [4- (2-ethoxycarbo)
Nyl-2-hydroxyethyl) phenoxyacetylamino
No] -5- (6-methoxymethoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) phenyl
T-butyl N-methylcarbamate (see Example 10, see
Raw materials for Examples 16 to 24) N- [2-amino-5- (6-methoxymethoxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -t-butyl N-methylcarbamate (compound of Reference Example 2) 16 g, ethyl 3- (4-carboxymethoxyphenyl) -2-hydroxypropionate ( Compound of Reference Example 14) Using 17.4 g, 4.86 g of anhydrous triethylamine, 7.82 g of diethyl cyanophosphate, and 250 ml of anhydrous tetrahydrofuran, the reaction and post-treatment according to Reference Example 3 yielded an Rf value of 0.1 ( Silica gel thin layer chromatography, yellow glassy target compound 2 having ethyl acetate: n-hexane = 2: 1)
0.6 g was obtained.

[0433]

Reference Example 16 N- {2- [4- (2-ethoxycarbo)
Nyl-2-phenylthioethyl) phenoxyacetyla
Mino] -5- (6-methoxymethoxy-2,5,7,8
-Tetramethylchroman-2-ylmethoxy) phenyi
T-butyl ru-N-methylcarbamate (of Example 8)
Raw material) N- {2- [4- (2-ethoxycarbonyl-2-hydroxyethyl) phenoxyacetylamino] -5- (6
1-g of t-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (0.22 g of thiophenol, 1,1′-) A mixture of 0.53 g of (azodicarbonyl) dipiperidine, 0.42 g of tri-n-butylphosphine and 20 ml of anhydrous toluene was stirred at room temperature for 3 hours and then left overnight. After filtering off the insoluble matter, the solvent was distilled off, and the obtained residue was subjected to liquid chromatography (silica gel, ethyl acetate: n-hexane = 1: 1).
By subjecting to 2), 0.75 g of the target compound as a white glass having an Rf value of 0.75 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 1) was obtained.

[0434]

Reference Example 17 N- {2- [4- [2-ethoxycarbo ]
Nyl-2- (4-nitrophenylthio) ethyl] pheno
[Xyacetylamino] -5- (6-methoxymethoxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) t-butyl phenyl} -N-methylcarbamate
(Raw materials of Example 20) N- {2- [4- (2-ethoxycarbonyl-2-hydroxyethyl) phenoxyacetylamino] -5- (6
T-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 15) 1.5
g, 4-nitrothiophenol 0.78 g, 1,1'-
(Azodicarbonyl) dipiperidine 1.5 g, tri-n
-1.4 g of butylphosphine and 30 ml of anhydrous toluene
The reaction and post-treatment were carried out according to Reference Example 16 using
f value = 0.47 (silica gel thin layer chromatography,
0.44 g of the target compound as a pale yellow oil having ethyl acetate: n-hexane = 1: 2) was obtained.

[0435]

Reference Example 18 N- {2- [4- [2- (4-cyanofu)
Enoxy) -2-ethoxycarbonylethyl] phenoxy
[Sciacetylamino] -5- (6-methoxymethoxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) t-butyl phenyl} -N-methylcarbamate
(Raw materials of Example 24) N- {2- [4- (2-ethoxycarbonyl-2-hydroxyethyl) phenoxyacetylamino] -5- (6
T-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (compound of Reference Example 15) 1 g, 4 g
Using 0.36 g of cyanophenol, 0.76 g of 1,1 ′-(azodicarbonyl) dipiperidine, 0.61 g of tri-n-butylphosphine and 20 ml of anhydrous toluene, the reaction and post-treatment were carried out according to Reference Example 16. , Rf value =
0.57 g of a white glassy target compound having 0.29 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 2) was obtained.

[0436]

Reference Example 19 N- {2- [4- [2-ethoxycarbo ]
Nyl-2- (4-methylphenylthio) -ethyl] fe
Nonoxyacetylamino] -5- (6-methoxymethoxy
-2,5,7,8-tetramethylchroman-2-ylme
Toxi) phenyl tert-butyl N-methylcarbamate
(Raw material of Example 26) N- {2- [4- (2-ethoxycarbonyl-2-hydroxyethyl) phenoxyacetylamino] -5- (6
T-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 15) 1.2
g, 4-methylthiophenol 0.37 g, 1,1'-
(Azodicarbonyl) dipiperidine 0.81 g, tri-
0.65 g of n-butylphosphine and 25 of anhydrous toluene
The reaction and post-treatment were carried out in the same manner as in Reference Example 16 using 0.1 ml of the desired compound 0 in the form of a white glass having a Rf value of 0.61 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 2). .94 g were obtained.

[0437]

Reference Example 20 N- {2- [4- [2- (4-chlorophenyl)
Enylthio) -2-ethoxycarbonylethyl] pheno
[Xyacetylamino] -5- (6-methoxymethoxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) t-butyl phenyl} -N-methylcarbamate
(Raw materials of Example 28) N- {2- [4- (2-ethoxycarbonyl-2-hydroxyethyl) phenoxyacetylamino] -5- (6
T-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 15) 1.2
g, 4-chlorothiophenol 0.43 g, 1,1′-
(Azodicarbonyl) dipiperidine 0.81 g, tri-
0.65 g of n-butylphosphine and 25 of anhydrous toluene
The mixture was subjected to a reaction and a post-treatment according to Reference Example 16 using the same ml, and the target compound 0 as a white glass having an Rf value of 0.54 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 2). .77 g were obtained.

[0438]

Reference Example 21 N- {2- [4- [2- (4-t-butyl)
Ruphenylthio) -2-ethoxycarbonylethyl] f
Enoxyacetylamino] -5- (6-methoxymethoxy)
C-2,5,7,8-tetramethylchroman-2-yl
Methoxy) phenyl} -N-methylcarbamic acid t-butyl
Cyl (raw material of Example 30) N- {2- [4- (2-ethoxycarbonyl-2-hydroxyethyl) phenoxyacetylamino] -5- (6
T-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 15) 1.2
g, 4-t-butylthiophenol 0.5 g, 1,1 ′
-(Azodicarbonyl) dipiperidine 0.81 g, tri-n-butylphosphine 0.65 g and anhydrous toluene 2
The reaction and after-treatment were carried out in the same manner as in Reference Example 16 using 5 ml of a white glassy target compound having an Rf value of 0.61 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 2). .78 g were obtained.

[0439]

Reference Example 22 N- {2- [4- [2-ethoxycarbo ]
Nyl-2- (4-methoxyphenylthio) ethyl] fe
Nonoxyacetylamino] -5- (6-methoxymethoxy
-2,5,7,8-tetramethylchroman-2-ylme
Toxi) phenyl tert-butyl N-methylcarbamate
(Raw material of Example 32) N- {2- [4- (2-ethoxycarbonyl-2-hydroxyethyl) phenoxyacetylamino] -5- (6
T-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 15) 1.2
g, 4-methoxythiophenol 0.42 g, 1,1 ′
-(Azodicarbonyl) dipiperidine 0.81 g, tri-n-butylphosphine 0.65 g and anhydrous toluene 2
The reaction and after-treatment were carried out in the same manner as in Reference Example 16 using 5 ml of the desired compound 0 in the form of a white glass having an Rf value of 0.42 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 2). .72 g were obtained.

[0440]

Reference Example 23 N- {2- [4- (2-ethoxy-2-)
Ethoxycarbonylethyl) phenoxyacetylamino
No] -5- (6-methoxymethoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) phenyl
T-butyl-N-methylcarbamate (the raw material of Example 12)
Fee) N- {2- [4- (2- ethoxycarbonyl-2-hydroxyethyl) phenoxy acetyl amino] -5- (6
1-g of t-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (1.2 g of ethyl iodide), silver (I) oxide A mixture of 1.1 g and 15 ml of anhydrous toluene was heated under reflux for 2 hours. After being left overnight at room temperature, the mixture was further heated under reflux for 7 hours. The insolubles were removed, the solvent was distilled off, and the residue was subjected to liquid chromatography (silica gel, ethyl acetate: n-hexane = 2: 5) to give Rf
0.46 g of the target compound was obtained as a pale yellow oil having a value of 0.51 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 2).

[0441]

Reference Example 24 N- {2- [4- [2-ethoxycarbo ]
Nyl-2- (4-fluorobenzyloxy) ethyl] f
Enoxyacetylamino] -5- (6-methoxymethoxy)
C-2,5,7,8-tetramethylchroman-2-yl
Methoxy) phenyl} -N-methylcarbamic acid t-butyl
Cyl (raw material of Example 14) N- {2- [4- (2-ethoxycarbonyl-2-hydroxyethyl) phenoxyacetylamino] -5- (6
T-butyl-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamate (Compound of Reference Example 15) 1.5
g, 2.26 g of 4-fluorobenzyl bromide, 1.63 g of silver (I) oxide and 20 ml of anhydrous toluene, and the reaction and post-treatment were carried out according to Reference Example 23, and the Rf value was 0.8.
0 (silica gel thin layer chromatography, ethyl acetate:
0.62 g of the target compound as pale yellow oil having (n-hexane = 1: 2) was obtained.

[0442]

Reference Example 25 3- (4-t-butoxycarbonylmethoate)
Ethyl (xyphenyl) -2-phenoxypropionate
(Raw material of Reference Example 27) 3- (4-t-butoxycarbonylmethoxyphenyl)
To a mixture of 2 g of ethyl 2-hydroxypropionate (the compound of Reference Example 13), 0.69 g of anhydrous triethylamine and 20 ml of anhydrous tetrahydrofuran, 1 g of chloromethanesulfonic acid chloride was added under ice-cooling, followed by stirring for 1 hour. After the solvent was distilled off, the residue was diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the obtained residue was dissolved in 10 ml of anhydrous tetrahydrofuran. To this anhydrous tetrahydrofuran solution, a mixture of 0.58 g of phenol, 0.28 g of sodium hydride (55%, oil) and 10 ml of anhydrous N, N-dimethylformamide stirred at room temperature for 30 minutes was added dropwise at room temperature, and further added for 7 hours. Stirred. After standing overnight, the solvent was distilled off, diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to liquid chromatography (LiChroprepNH ₂ "(MERCK), ethyl acetate:
n-hexane = 1: 6) and Rf value = 0.84 (゛
_{0.46 g} of a colorless oily target compound having HPTLC NH ₂ F _254S “(MERCK), ethyl acetate: n-hexane = 1: 5)
was gotten.

[0443]

Reference Example 26 3- (4-t-butoxycarbonylmethoate)
(Xyphenyl) -2- (4-nitrophenoxy) propi
Ethyl onoate (raw material of Reference Example 28) 3- (4-t-butoxycarbonylmethoxyphenyl)
1.8 g of ethyl 2-hydroxypropionate, 0.91 g of chloromethanesulfonic acid chloride, 0.62 g of anhydrous triethylamine, 40 ml of anhydrous tetrahydrofuran,
Using 0.77 g of 4-nitrophenol, 0.24 g of sodium hydride (55%, oil) and 55 ml of anhydrous N, N-dimethylformamide, the reaction and post-treatment were carried out according to Reference Example 25 to obtain a crude product. The product is subjected to column chromatography (silica gel, ethyl acetate: n-hexane =
1: 4), Rf value = 0.50 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 1)
2.15 g of the target compound having 3) as a pale yellow oil were obtained.

[0444]

Reference Example 27 3- (4-carboxymethoxyphenyl )
E) -2-Phenoxypropionate (Reference Example 29)
Raw material) 3- (4-t-butoxycarbonylmethoxyphenyl)
Using 0.43 g of ethyl-2-phenoxypropionate (the compound of Reference Example 25) and 10 mL of 4N hydrochloric acid in 1,4-dioxane, the reaction and post-treatment were carried out according to Reference Example 5, and the Rf value was 0.43. (“HPTLC DIOL F _254S ” (MER
K), 0.38 g of a light yellow oily target compound having ethyl acetate: n-hexane = 1: 3) was obtained.

[0445]

Reference Example 28 3- (4-carboxymethoxyphenyl )
) -2- (4-nitrophenoxy) propionic acid
(Raw material of Reference Example 30) 3- (4-t-butoxycarbonylmethoxyphenyl)
1.86 g of ethyl 2- (4-nitrophenoxy) propionate (compound of Reference Example 26), 20 ml of 1,4-dioxane, and a 4N hydrochloric acid 1,4-dioxane solution 60
The reaction and post-treatment were carried out according to Reference Example 5 using
1.44 g of the target compound was obtained as a reddish brown oil.

[0446]

Reference Example 29 N- {2- [4- (2-ethoxycarbo)
Nyl-2-phenoxyethyl) phenoxyacetylamino
No] -5- (6-methoxymethoxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) phenyl
T-butyl-N-methylcarbamate (the raw material of Example 22)
Fee) N-[2-Amino-5- (6-methoxy-methoxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl] 0.45 g of t-butyl-N-methylcarbamate (compound of Reference Example 2), 3- (4-carboxymethoxyphenyl) -2-phenoxypropionic acid Ethyl (compound of Reference Example 27) 0.37 g, anhydrous triethylamine 0.15 g, diethyl cyanophosphate 0.24 g
And Example 10 using anhydrous tetrahydrofuran 10 ml
When the reaction and the post-treatment are performed according to the formula, Rf value = 0.53
(Silica gel thin layer chromatography, ethyl acetate: n
0.6 g of a white glassy target compound having -hexane = 1: 2) was obtained.

[0447]

Reference Example 30 N- {2- [4- (2- [4-nitroph)
[Enoxy] -2-ethoxycarbonylethyl) phenoxy
[Sciacetylamino] -5- (6-methoxymethoxy-
2,5,7,8-tetramethylchroman-2-ylmeth
Xy) t-butyl phenyl} -N-methylcarbamate
(Raw material of Example 18) N- [2-amino-5- (6-methoxymethoxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -t-butyl N-methylcarbamate (compound of Reference Example 2) 1.72 g, 3- (4-carboxymethoxyphenyl) -2- (4- Nitrophenoxy)
1.34 ethyl propionate (compound of Reference Example 28)
g, anhydrous triethylamine 0.38 g, diethyl cyanophosphate 0.62 g, and anhydrous tetrahydrofuran 50 ml
When the reaction and post-treatment are carried out according to Reference Example 3 using
f value = 0.61 (silica gel thin layer chromatography,
2.74 g of the target compound in the form of a yellow glass having ethyl acetate: n-hexane = 1: 1) were obtained.

[0448]

Reference Example 31 2- [bis (4-fluorophenyl) meth
Toxy] -3- (4-t-butoxycarbonylmethoxy
Methyl phenyl) propionate (raw material of Reference Example 32) 3- (4-t-butoxycarbonylmethoxyphenyl)
3 g of methyl 2-hydroxypropionate, 4,4'-
Using 4.61 g of difluorobenzhydryl chloride, 8.96 g of silver (I) oxide and 60 ml of anhydrous toluene, the crude product obtained by the reaction and post-treatment according to Reference Example 23 was subjected to column chromatography (silica gel, ethyl acetate). : N-hexane = 1: 9) and then reversed phase preparative high performance liquid chromatography (ODS, acetonitrile: water =
3: 1) and an Rf value = 0.39 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 1).
2.41 g of the colorless oily target compound having 5) were obtained.

[0449]

Reference Example 32 2- [bis (4-fluorophenyl) meth
Toxi] -3- (4-carboxymethoxyphenyl) p
Methyl lopionate (raw material of Reference Example 33) 2- [bis (4-fluorophenyl) methoxy] -3-
1.46 g of methyl (4-t-butoxycarbonylmethoxyphenyl) propionate (the compound of Reference Example 31),
Using 20 ml of 1,4-dioxane and 20 ml of 4N hydrochloric acid 1,4-dioxane solution, the reaction and post-treatment were carried out according to Reference Example 5, to obtain 1.69 g of the target compound as a colorless oil.

[0450]

Reference Example 33 N- {2- [4- [2- [bis (4-f
Fluorophenyl) methoxy] -2-methoxycarbonyl
Ethyl] phenoxyacetylamino] -5- (6-meth
Xymethoxy-2,5,7,8-tetramethylchroman
-2-ylmethoxy) phenyl} -N-methylcarbami
T-butyl acid salt (raw material of Example 6) N- [2-amino-5- (6-methoxymethoxy-2,
1.3 g of t-butyl 5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -N-methylcarbamate (compound of Reference Example 2), 2- [bis (4-fluorophenyl) methoxy] -3- 1.3 g of methyl (4-carboxymethoxyphenyl) propionate, 0.29 g of anhydrous triethylamine, 0.4 of diethyl cyanophosphate
When 6 g and 20 ml of anhydrous tetrahydrofuran were used for the reaction and post-treatment according to Reference Example 3, the Rf value was 0.3.
1 (silica gel thin layer chromatography, ethyl acetate:
1.04 g of a yellow oily target compound having (n-hexane = 1: 2) was obtained.

[0451]

Reference Example 34 3- (4-t-butoxycarbonylmethoate)
Methyl (xyphenyl) -2-ethylthiopropionate
(Raw materials of Reference Example 35) 1.29 g of methyl 3- (4-hydroxyphenyl) -2-mercaptopropionate, 1.9 g of ethyl iodide, 1.23 g of triethylamine and anhydrous tetrahydrofuran 3
0 ml of the mixture was stirred at room temperature for 20 hours. The solvent was distilled off, diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in 20 ml of anhydrous acetone, 2.97 g of cesium carbonate and 1.78 g of t-butyl bromoacetate were added at room temperature, and the reaction and post-treatment were carried out according to Reference Example 4. Rf value = 0.21 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 5)
1.53 g of the target compound as a colorless oil having the formula:

[0452]

Reference Example 35 3- (4-carboxymethoxyphenyl )
Methyl) -2-ethylthiopropionate (Example 16)
Raw material) 3- (4-t-butoxycarbonylmethoxyphenyl)
1.49 g of methyl-2-ethylthiopropionate (compound of Reference Example 35), 2 ml of concentrated aqueous hydrochloric acid and 10 m of acetic acid
The mixture was stirred at 80 ° C. for 3.5 hours. The solvent was distilled off, and the residue was washed with n-hexane to obtain the desired compound (0.86).
g was obtained as a crude product. This crude product was used immediately in Example 16.

[0453]

Reference Example 36 N- [5- (3,4-dimethoxybenzyl)
Loxy) -2-nitrophenyl] -N-methylcarba
To a suspension of 2.6 g of sodium hydride (55%, oily) in 100 ml of anhydrous toluene, 10 g of 3,4-dimethoxybenzyl alcohol in anhydrous N, N-dimethylformamide 1
A 00 ml solution was added dropwise at room temperature and stirred for 40 minutes. Then, 11.5 g of t-butyl N- (5-chloro-2-nitrophenyl) -N-methylcarbamate in anhydrous N, N-
A 100 ml solution of dimethylformamide was added dropwise under ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off, diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 250 ml of diisopropyl ether and 500 ml of n-hexane were added to the obtained residue, and the mixture was irradiated with ultrasonic waves for 1 hour. The precipitate was collected by filtration to obtain 11.6 g of the target compound as a yellow powder having a melting point of 94 ° C to 97 ° C.

[0454]

Reference Example 37 N- (5-hydroxy-2-nitrophene)
Tert-butyl) -N-methylcarbamate (Reference Example 3
8) N- [5- (3,4-dimethoxybenzyloxy) -2
-Nitrophenyl] -t-butyl N-methylcarbamate (compound of Reference Example 36) 11 g, 2,3-dicyano-
A mixture of 9.1 g of 5,6-dichloro-1,4-benzoquinone, 5 ml of distilled water and 150 ml of 1,2-dichloroethane was stirred at room temperature for 7 hours. Further, 2,3-dicyano-
5 g of 5,6-dichloro-1,4-benzoquinone was added,
Stirred at room temperature for 2.5 hours. After standing overnight, 300 ml of ethyl acetate and 500 ml of a 5% aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred for 10 minutes. The insoluble material was removed by filtration, and the organic layer was separated. After the aqueous layer was further extracted with ethyl acetate, the extracts were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was subjected to liquid chromatography (silica gel, ethyl acetate: n-hexane = 1: 2).
3.85 g of the target compound in the form of a yellow powder having a temperature of 54 ° C. are obtained.

[0455]

Reference Example 38 N-methyl-N- [2-nitro-5-
(2-oxopropoxy) phenyl] carbamic acid t-
Butyl (raw material of Reference Example 39) t-butyl N- (5-hydroxy-2-nitrophenyl) -N-methylcarbamate (Compound of Reference Example 37)
3.8 g, bromoacetone 3.2 g, cesium carbonate 7 g
And 100 ml of acetone were stirred at room temperature for 1.5 hours. After the solvent was distilled off, the residue was diluted with water and extracted with ethyl acetate. The extract was washed with a 5% aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the Rf value was 0.17 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 1).
4.65 g of the desired compound as a brown oil having 3) were obtained.

[0456]

Reference Example 39 N- [5- (6-acetoxy-4-oxo)
So-2,5,7,8-tetramethylchroman-2-yl
Methoxy) -2-nitrophenyl] -N-methylcarba
T-Butyl mitinate (raw material of Reference Example 40) t-butyl N-methyl-N- [2-nitro-5- (2-oxopropoxy) phenyl] carbamate (Reference Example 3)
4.1 g of acetic acid (3-acetyl-4-hydroxy-2,5,6-trimethyl) phenyl ester 3
g, a mixture of 0.9 g of pyrrolidine and 50 ml of anhydrous methanol was stirred for 7 hours under ice cooling. After standing overnight, the solvent was distilled off, and 200 ml of ethyl acetate and 100 ml of a 2N aqueous hydrochloric acid solution were added to the residue, followed by stirring for 30 minutes. The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The extracts were combined, washed twice with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was subjected to liquid chromatography (゛ LiChroprepNH ₂ "(MERCK), ethyl acetate: n-hexane = 2: 5) and then reversed-phase preparative high performance liquid chromatography (ODS, acetonitrile:
(0.2% acetic acid + 0.2% triethylamine) aqueous solution =
13: 7), Rf value = 0.71 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 2:
1.62 g of a brown glassy target compound having 5) were obtained.

[0457]

[Reference Example 40] N- [5- (6-acetoxy-4-oxo)
So-2,5,7,8-tetramethylchroman-2-yl
Methoxy) -2-aminophenyl] -N-methylcarba
T-butyl mitinate ( raw material of Reference Example 41) N- [5- (6-acetoxy-4-oxo-2,5,
7,8-tetramethylchroman-2-ylmethoxy)-
The reaction and post-treatment were carried out according to Reference Example 2 using 1.6 g of t-butyl 2-nitrophenyl] -N-methylcarbamate (compound of Reference Example 39), 0.2 g of 10% palladium carbon catalyst and 150 mL of methanol. , Rf value = 0.
1.55 g of a brown glassy target compound having 21 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 2: 3) was obtained.

[0458]

Reference Example 41 N- {5- (6-acetoxy-4-oxo)
So-2,5,7,8-tetramethylchroman-2-yl
Methoxy) -2- [4- (2,4-dioxothiazolidi
-5-ylmethyl) phenoxyacetylamino] fe
T-butyl nyl} -N-methylcarbamate (Example 3
4) N- [5- (6-acetoxy-4-oxo-2,5,
7,8-tetramethylchroman-2-ylmethoxy)-
2-aminophenyl] -tert-butyl N-methylcarbamate (Compound of Reference Example 40) 1.53 g, 4- (2,4
1.3 g of -dioxothiazolidine-5-ylmethyl) phenoxyacetic acid, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (WSC-HC
l) 0.9 g, 1-hydroxybenzotriazole / 1
A mixture of 0.7 g of hydrate, 50 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 1.5 hours. After standing overnight, the solvent was distilled off, diluted with water, and extracted with ethyl acetate. The extract was diluted with a 1N aqueous hydrochloric acid solution and a 5% aqueous sodium hydrogen carbonate solution (2%).
Times) and then washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was subjected to liquid chromatography ("LiChroprepDIOL" (registered trademark, MERCK), ethyl acetate: n-hexane = 1: 1), and Rf value = 0.35 (silica gel thin film). 1.94 g of a white glassy target compound having layer chromatography, ethyl acetate: n-hexane = 3: 2) were obtained.

[0459]

[Test Example] Hypoglycemic action Blood was collected from the tail vein of a KK mouse (4-5 months old) who developed diabetes, and the blood glucose level was measured. Next, the mice were divided into groups (4 mice per group) so that the average of the blood glucose levels of the mice in each group was the same, and then a powdered feed for mice (F- (1, Funabashi Farm) for 3 days. The group of mice receiving the test compound was designated as the drug-administered group. In addition, the group which received the powder feed which does not contain a test compound was set as the control group. Three days later, blood was collected from the tail vein of the mouse, and the glucose concentration in the plasma obtained by centrifugation was measured using a glucose analyzer (Gluco Lauder, A & T). The blood glucose lowering rate was determined from the following equation. Hypoglycemia reduction rate (%) = (average blood glucose level of control group−average blood glucose level of drug administration group) × 100 / blood glucose level of control group 対 照── Test compound Hypoglycemic rate (%) Compound of Example No. 1 66.7 Compound of Example No. 3 35.7 Compound of Example No. 5 34.9 Compound of Example No. 9 36.7 Example No. 15 Compound 54.1} From the above results, it was revealed that the compound of the present invention exhibits an excellent blood glucose lowering effect. .

[0460]

The compound of the present invention having the above general formula (I), its pharmacologically acceptable salt and its pharmacologically acceptable ester are excellent in improving insulin resistance, lowering blood glucose, and improving insulin resistance. Inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, lipid peroxide production inhibitory action, PPAR activating action, anti-osteoporosis action, leukotriene antagonistic action, adipocyte promoting action,
Has cancer cell growth inhibitory action, calcium antagonism, diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, Coronary artery disease, etc.), arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular disease (for example, ischemic heart disease, etc.), non-atherosclerotic disease or ischemic heart disease. Cell damage (eg, brain injury caused by stroke, etc.), gout, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema) , Allergic disease, asthma, GI ulcer, cachexia, autoimmune disease,
Pancreatitis. ), Cancer, osteoporosis, cataract and the like.

The compounds of the present invention having the above general formula (I), their pharmaceutically acceptable salts and their pharmaceutically acceptable esters, α-glucosidase inhibitors, aldose reductase inhibitors, and biguanide agents , Statin compounds, squalene synthesis inhibitors, fibrate compounds, L
Pharmaceutical compositions comprising at least one of a DL catabolism promoter and an angiotensin converting enzyme inhibitor (particularly preferably a prophylactic and / or therapeutic agent for diabetes or diabetic complications) are also useful.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/04 A61P 3/04 3/06 3/06 3/08 3/08 3/10 3/10 3 / 14 3/14 5/50 5/50 9/10 9/10 101 101 9/12 9/12 11/06 11/06 15/00 15/00 19/02 19/02 19/06 19/06 19 / 10 19/10 27/12 27/12 29/00 29/00 101 101 35/00 35/00 37/00 37/00 37/02 37/02 37/08 37/08 39/06 39/06 43 / 00 111 43/00 111 C07D 417/14 C07D 417/14 (72) Inventor Minoru Oguchi 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Within Sankyo Co., Ltd. 1-258 Hiromachi, Sankyo Co., Ltd. (72) Inventor Toshihiko Fujiwara 1-258, Hiromachi, Shinagawa-ku, Tokyo F-term in Sankyo Co., Ltd. 4C063 AA01 AA03 BB08 CC79 DD26 EE01 4C086 AA01 AA02 AA03 BC39 BC82 GA02 GA 07 GA10 MA01 MA04 NA14 ZA33 ZA39 ZA40 ZA42 ZA45 ZA70 ZA81 ZA89 ZA97 ZB07 ZB11 ZB13 ZB15 ZB26 ZC20 ZC33 ZC35 ZC50

Claims (24)

[Claims] 1. A compound represented by the following general formula (I): [In the above formula, R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C _6- which may be substituted by 1 to 3 groups selected from a substituent group α.
A C ₁₀ aryl group, a C ₇ -C ₁₆ aralkyl group which may be substituted by 1 to 3 groups selected from the substituent group α, a hydroxyl group, an acyloxy group (an acyl group of the acyloxy group is a C ₁ -C ₇ aliphatic acyl groups, 1 to 3 C ₇ -C ₁₁ aromatic acyl groups optionally substituted with 1 to 3 groups selected from substituent group α, 1 to 3 groups selected from substituent group α An optionally substituted C ₈ -C ₁₂ araliphatic acyl group,
A C ₄ -C ₁₁ cycloalkylcarbonyl group or a heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may be substituted by 1 to 5 groups selected from the substituent group α. And represents a 5- to 7-membered heteroaromatic carbonyl group having 1 to 3 carbon atoms. ), A C ₁ -C ₆ alkoxy group, or an amino group which may be substituted with one or two groups selected from the substituent group β (the amino group is combined with a nitrogen atom to form an oxygen atom, a nitrogen atom, R ² may represent a hydrogen atom, a C ₁ -C ₆ alkyl group, or a saturated heterocyclic group having 1 to 3 hetero atoms selected from the group consisting of an atom and a sulfur atom. Substituent group α
1 to 3 optionally substituted C selected from
₇ -C ₁₆ aralkyl group, R ^3, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, C ₁ -C
₆ alkyl group, or a C ₁ -C ₆ or an alkoxy group, R ⁶ is a hydrogen atom, C ₁ -C ₆ alkyl group, which may be 1 to 3 substituted with a group selected from Substituent group alpha C ₆ −
A C ₁₀ aryl group or a group selected from substituent group α
Represents an optionally substituted C ₇ -C ₁₆ aralkyl group, Q represents an oxygen atom or a sulfur atom, X represents a bond, CH ₂ , CO, CHOR ⁹ or C ＝ NOR ¹⁰
(In the formula, R ⁹ and R ¹⁰ represent a hydrogen atom, a C ₁ -C ₆ alkyl group (the alkyl group may be the same or different 1 to 3 C
_A C ₁ -C ₆ alkoxycarbonyl group, which may be substituted with a C ₆ -C ₁₀ aryl group (the aryl group is substituted with 1 to 3 identical or different substituents selected from a substituent group α) A C ₇ -C ₁₆ aralkyl group (the aralkyl group may be substituted with 1 to 3 identical or different substituents selected from the substituent group α), or an acyl group. Group (the acyl group is a C ₁ -C ₇ aliphatic acyl group, a C ₇ -C ₁₁ aromatic acyl group which may be substituted with 1 to 3 groups selected from a substituent group α, a substituent group 1 to 3 C ₈ -C ₁₂ araliphatic acyl groups, C ₄ -C ₁₁ cycloalkylcarbonyl groups which may be substituted with 1 to 3 groups selected from α, 1 to 3 groups selected from the substituent group α Selected from the group consisting of five optionally substituted oxygen, nitrogen and sulfur atoms A 5- to 7-membered heteroaromatic carbonyl group having 1 to 3 selected heteroatoms or a carbamoyl group which may be substituted by 1 or 2 groups selected from the substituent group β). A represents the following general formula (II-
a) represents a group represented by (II-b), (II-c) or (II-d); (In the above formula, m represents the same or different and represents an integer of 0 to 8, B represents an oxygen atom, a sulfur atom or a group represented by NR ⁸ , R ⁷ represents a hydrogen atom, C ₁ -C ₆ alkyl groups, C ₆ -C ₁₀ aryl groups (the aryl groups may be substituted with 1 to 3 identical or different substituents selected from the substituent group α), C ₇ -C ₁₆ An aralkyl group (the aralkyl group is
May be substituted with 1 to 3 identical or different substituents selected from substituent group α), or halogeno C ₁
-C ₆ represents an alkyl group, R ⁸ is a hydrogen atom, C ₁ -C ₆ alkyl, optionally 1 to 3 substituted with a group selected from Substituent group alpha C ₆ -
A C ₁₀ aryl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₇ -C ₁₆ aralkyl group which may be substituted by 1 to 3 groups selected from a substituent group α, an acyl group (the acyl group is
A C ₁ -C ₇ aliphatic acyl group, a C ₇ -C ₁₁ aromatic acyl group which may be substituted by 1 to 3 groups selected from a substituent group α, a group selected from a substituent group α even 1 to be three substituents represent an C ₈ -C ₁₂ aromatic aliphatic acyl group. ), A carbamoyl group which may be substituted by one or two groups selected from the substituent group β, a C ₁ -C ₆ alkylsulfonyl group, a halogeno C ₁ -C ₆ alkylsulfonyl group,
1 to 3 C ₆ -C ₁₀ arylsulfonyl groups which may be substituted with 1 to 3 groups selected from substituent group α, or 1 to 3 groups which may be substituted with a group selected from substituent group α A C ₇ -C ₁₆ aralkylsulfonyl group, or when B represents N (R ⁸ ), a nitrogen atom, R ⁷
And R ⁸ may together form a saturated heterocyclic group. ), Y represents an oxygen atom or a sulfur atom; Z represents -CH = or a nitrogen atom; n represents an integer of 1 to 5; q represents an integer of 0 to 5; Halogen atom, hydroxyl group, C ₁ -C ₆ alkyl group, halogeno C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, amino group (the amino group may be the same or different The amino group may be substituted with 1 to 2 substituents, and the amino group may be substituted with 1 to 3 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom together with a nitrogen atom. May form a saturated heterocyclic group having one or more), a C ₆ -C ₁₀ aryl group, a cyano group and a nitro group, and the substituent group β is a C ₁ -C ₁₀ alkyl group and a substituent group C _6- which may be substituted by 1 to 3 groups selected from γ
A C ₁₀ aryl group, a C ₇ -C ₁₆ aralkyl group and an acyl group which may be substituted by 1 to 3 groups selected from a substituent group γ (the acyl group is a C ₁ -C ₇ aliphatic acyl group) A C ₇ -C ₁₁ aromatic acyl group which may be substituted with 1 to 3 groups selected from the substituent group γ, and 1 to 3 groups which may be substituted with a group selected from the substituent group γ Good C ₈ -C ₁₂
Selected from the group consisting of an araliphatic acyl group, a C ₄ -C ₁₁ cycloalkylcarbonyl group, and an oxygen atom, a nitrogen atom and a sulfur atom which may be substituted by 1 to 5 groups selected from the substituent group γ And a 5- to 7-membered heteroaromatic carbonyl group having 1 to 3 heteroatoms. And the substituent group γ is a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group. And a nitro group. ], A pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. 2. A compound represented by the following general formula (I ′): Wherein X ′ is CH ₂ , CO or C ＝ NOR ¹⁰ (wherein R
¹⁰ is a hydrogen atom, a C ₁ -C ₆ alkyl group (the alkyl group may be substituted with the same or different 1 to 3 C ₁ -C ₆ alkoxycarbonyl groups) or C ₇ -C ₁₆
Represents an aralkyl group. A ′ represents a group represented by the following formula (II-b ′) or (II-d ′). Embedded image (In the above formula, B ′ represents an oxygen atom or a sulfur atom, R ⁷ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group (the aryl group is selected from the substituent group α) Which may be substituted with 1 to 3 identical or different substituents), a C ₇ -C ₁₆ aralkyl group (the aralkyl group is
May be substituted with 1 to 3 identical or different substituents selected from substituent group α), or halogeno C ₁
—C _{6 represents} an alkyl group. )], A pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. (Substituent group α) halogen atom, hydroxyl group, C ₁ -C ₆ alkyl group, halogeno C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, amino group (the amino group is selected from substituent group β. And the amino group is selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom together with a nitrogen atom. And may form a saturated heterocyclic group having 1 to 3 hetero atoms).
C ₆ -C ₁₀ aryl group, a cyano group and a nitro group. 3. The method according to claim 2, wherein X ′ is CH ₂ .
A substituted condensed imidazole derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. 4. The method according to claim 2, wherein A ′ is a group represented by the formula (II-b ′):
A substituted condensed imidazole derivative, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. 5. The method according to claim 2, wherein A ′ is a compound of the formula (II-d ′)
A substituted condensed imidazole derivative, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof, wherein B ′ is an oxygen atom. 6. The method according to claim 2, wherein A ′ is a group represented by the formula (II-d ′):
A substituted condensed imidazole derivative, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof, wherein B ′ is a sulfur atom. 7. The method according to claim 2, wherein R ⁷ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a phenyl group (the phenyl group may be the same or different from the substituent group α). 1
Or 3 substituents), a benzyl group (the benzyl group may be substituted with 1 to 3 identical or different substituents selected from the substituent group α) Or a substituted condensed imidazole derivative, which is a halogeno C ₁ -C ₆ alkyl group, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. 8. The method according to claim 2, wherein R ⁷ is a phenyl group (the 4-position of the phenyl group may be substituted with one substituent selected from substituent group α). A) benzyl group (the 4-position of the benzyl group may be substituted with one substituent selected from substituent group α) or a halogeno C ₁ -C ₆ alkyl group, And pharmacologically acceptable salts thereof and pharmacologically acceptable esters thereof. 9. Any one selected from claims 1 to 8
3. A substituted condensed imidazole derivative according to item 1. 10. A pharmacologically acceptable salt of the substituted condensed imidazole derivative according to any one of claims 1 to 8. 11. A pharmacologically acceptable hydrochloride of the substituted condensed imidazole derivative according to any one of claims 1 to 8. 12. A pharmacologically acceptable ester of the substituted condensed imidazole derivative according to any one of claims 1 to 8. 13. A methyl ester of a substituted condensed imidazole derivative according to any one of claims 1 to 8. 14. The ethyl ester of a substituted condensed imidazole derivative according to any one of claims 1 to 8. 15. The compound according to claim 1, wherein the compound is selected from the following, a pharmacologically acceptable salt thereof, and a pharmacologically acceptable ester thereof. 5- {4- [6- (6-hydroxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl {thiazolidine-2,4-dione 3- {4- [6- (6-hydroxy-2,5,7, 8-
Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} -2- (2,2,2-trifluoroethoxy)
2- (4-fluorobenzylthio) -3- {4- [6-propionic acid
(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} propionic acid 3- {4- [6- (6-hydroxy −2,5,7,8−
Tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl {-2-phenylthiopropionic acid 2- (4-fluorobenzyloxy) -3- {4- [6
-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] phenyl} propionic acid 16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 as an active ingredient. 17. An insulin sensitizer, a hypoglycemic agent, an anti-inflammatory agent, an immunomodulator, an aldose reductase, comprising the compound according to any one of claims 1 to 15 as an active ingredient. Inhibitor, 5-lipoxygenase inhibitor, lipid peroxide production inhibitor, PPAR activator, anti-osteoporosis agent, leukotriene antagonist, adipocyte promoter, cancer cell growth inhibitor or calcium antagonist. 18. A pharmaceutical composition for improving insulin resistance, comprising a compound according to any one of claims 1 to 15 as an active ingredient. 19. A pharmaceutical composition for lowering blood sugar, comprising the compound according to any one of claims 1 to 15 as an active ingredient. 20. Diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetes, comprising the compound according to any one of claims 1 to 15 as an active ingredient. Complications, arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular disease, cell damage caused by atherosclerosis, cell damage caused by ischemic heart disease, gout, osteoarthritis, rheumatic A preventive or therapeutic agent for arthritis, allergic disease, asthma disease, GI ulcer, cachexia, autoimmune disease, pancreatitis, cancer, osteoporosis or cataract. 21. A pharmaceutical composition for preventing or treating diabetes, comprising the compound according to any one of claims 1 to 15 as an active ingredient. 22. Use of a compound according to any one of claims 1 to 15 for producing a pharmaceutical composition for improving insulin resistance. 23. Use of a compound according to any one of claims 1 to 15 for producing a pharmaceutical composition for lowering blood sugar. 24. Use of a compound according to any one of claims 1 to 15 for producing a pharmaceutical composition for preventing or treating diabetes.