WO2000061582A1 - Substituted fused imidazole derivatives - Google Patents

Abstract

Compounds represented by general formula (I), and salts and esters of the same: wherein R?1, R2, R3, R4, R5 and R6¿ are each hydrogen, C¿1?-C6 alkyl, or the like; Q and Y are each oxygen or sulfur; X is CH2, CO, or the like; Z is -CH= or nitrogen; n and q are each 1 to 5; and A is a group represented by general formula (II-a), (II-b), (II-c) or (II-d), (wherein m is 0 to 8; B is oxygen, sulfur, or the like; and R?7¿ is hydrogen, C¿1?-C6 alkyl, or the like).

Description

 Description Substituted condensed imidazole derivatives (Technical field)

 The present invention provides excellent insulin resistance improving action, hypoglycemic action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, peroxidized lipid production inhibitory action, PPAR activation Substituted condensed imidazolyl derivative having pharmacological action, anti-osteoporosis action, leukotriyun antagonistic action, adipocyte promoting action, cancer cell growth inhibitory action, calcium antagonistic action, its pharmacologically acceptable salt or its pharmacologically acceptable action Related to polyester.

 Furthermore, the present invention relates to a disease improved by the above-mentioned effects, comprising the substituted condensed condensed imidazole derivative, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient, such as diabetes, Lipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, gestational diabetes, many Cystic 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, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcers) , Cachexia, autoimmune disease, a knee inflammation and the like.), Cancer, osteoporosis, relates to a preventive agent and Z or therapeutic agent such as a cataract.

Further, the present invention provides the above-mentioned substituted condensed imidazole derivative, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof, a sulfonyliderea agent, an _α -darcosidase inhibitor, an aldose reductase A combination of at least one of an inhibitor, a biguanide, a statin compound, a squalene synthesis inhibitor, a fibrate compound, an LDL catabolic promoter, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor, and an antitumor agent The present invention relates to a pharmaceutical composition (particularly preferably, a prophylactic and / or therapeutic agent for diabetes or diabetic complications). (Background technology)

 At present, it has been reported that thiazolidine compounds, oxazolidine compounds and the like are useful as preventive or therapeutic agents for various diseases such as diabetes and hyperlipidemia. For example, a large number of thiazolidine-based compounds having a hypoglycemic effect are described in Chem. Pharm. Bull., 30, 3580-3600 (1982), Prog. Clin. Biol. Res., 265, 177-192 (1988), Diabetes, 37 (11), 1549-1558 (1988), Arzneim. -Forsch., 40 (1), 37-42 (1990), EP 0441605A.

 The effects of thiazolidine compounds on hyperlipidemia are described in Diabetes, 40 (12), 1669-1674 (1991), Am. J. Physiol., 267 (1Ρΐ1), Ε95-Ε101 (1994), Diabetes, 43 (10), 1203-1210 (1994).

 The effects of thiazolidine compounds on glucose intolerance and insulin resistance have been reported by Arzneim.—Forsch., 40 (2 Pt 1), 156—162 (1990), Metabolism, 40 (10), 1025-1230 (1991), Diabetes , 43 (2), 204-211 (1994).

 Also, in recent years, medicines that improve diabetes in normal individuals with insulin resistance and improve insulin resistance without impaired glucose tolerance have also been used as preventive agents for the onset of diabetes in normal persons as described above. Usefulness is reported in N. Engl. J. Med., 331 (18), 1226-1227 (1994).

 The effects of thiazolidine compounds on hypertension have been reported in Metabolism, 42 (1), 75-80 (1993), Am. J. Physiol., 265 (4 Pt 2), R726-R732 (1993), Diabetes, 43 (2 ), 204-211 (1994).

 The effects of thiazolidine compounds on coronary artery disease have been reported in Am. J. Physiol., 265 (4 Pt 2), R726-R732 (1993), Hypertension, 24 (2), 170-175 (1994). The effects of thiazolidine compounds on arteriosclerosis have been reported in Am. J. Physiol., 265 (4 Pt 2), R726-R732 (1993).

The effects of thiazolidine compounds on cachexia are reported in Endocrinology, 135 (5), 2279-2282 (1994), and Endrocrinology, 136 (4), 1474-1481 (1995). Further, among the thiazolidine compounds having a hypoglycemic effect, they have a heterocyclic group. Compounds are disclosed in W092 / 07839A, W092 / 07850A, EP07 / 600A and EP0676398A, and oxazolidin-1,2,4-dione compounds having a hypoglycemic effect are disclosed in W092 / 02520A. (Disclosure of the Invention)

 Over the years, the present inventors have studied the synthesis of a series of substituted condensed heterocyclic compounds and their pharmacological activities.As a result, the substituted condensed heterocyclic compounds having a novel structure can be used to improve insulin resistance. Action, hypoglycemic action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, lipid peroxide production inhibitory action, PPAR activation action, antiosteoporosis action, leukotriene antagonism, The present invention has been found to have an effect of promoting adipogenesis, an inhibitory effect on cancer cell growth, and a calcium antagonism, with few side effects, and a high fat-solubility, thereby completing the present invention. .

 Another object of the present invention is to provide a disease improved by the above-mentioned effects, which contains the above-mentioned substituted condensed heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient, such as diabetes, hyperlipidemia, obesity, and glucose tolerance. Dysfunction, 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, inflammatory disease (Eg osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, tanning, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune disease, knee inflammation By it.), It is to provide cancer, osteoporosis, a prophylactic and Z or therapeutic agent such as a cataract.

Further, another object of the present invention is to provide the above-mentioned substituted condensed heterocyclic compound or a pharmaceutically acceptable salt thereof, a sulfonyldiarea complex, an α-glucosidase inhibitor, an aldose reductase inhibitor, a biguanie A pharmaceutical composition comprising a combination of at least one of a drug, a statin compound, a squalene synthesis inhibitor, a fibrate compound, an LDL catabolic promoter, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor and an antitumor agent object (Especially preferred are preventive and therapeutic agents for diabetes or diabetic complications.) The present invention

 (1) The following general formula (I)

[In the above formula,

R ¹ may be substituted by 1 to 3 hydrogen atoms, a C ₆ alkyl group, or a group selected from substituent group α. Ariru group, optionally substituted 3 1乃optimum with a group selected from substituent group _α C ₇ - C ₁₆ Ararukiru group, a hydroxyl group, Ashiru group Ashiruokishi group (said Ashiruokishi group, over aliphatic Ashiru group 1 to 3 substituents which may be substituted with a group selected from the substituent group α, C ₇ -C „aromatic sacyl group, and 1 to 3 substituents which may be substituted with a group selected from the substituent group good C ₈ - C ₁₂ araliphatic Ashiru group, C ₄ -C _u cycloalkylcarbonyl group, or a 1 to 5 substituted by a group selected from substituent group monument also have Yo Le, oxygen atom, nitrogen atom And a 5- to 7-membered heteroaromatic carboxy group having 1 to 3 heteroatoms selected from the group consisting of: and a sulfur atom.), A C ₆ alkoxy group, or a group selected from substituent group iS An amino group which may be substituted with 1 or 2 amino groups (the amino group is Connexion oxygen atom such together with the atom, the hetero atom may form a 1 to 3 having a saturated heterocyclic group to be selected from the group consisting of nitrogen atom and sulfur atom.) Indicates,

R ² represents a hydrogen atom, a Ci—Ce alkyl group, or a C ₇ —C ₁₆ aralkyl group which may be substituted by 1 to 3 groups selected from a substituent group _α ;

R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a C ₆ alkyl group, or a C, C ₆ alkoxy group,

R ⁶ is a hydrogen atom, C "C ₆ alkyl group, 1 to 3 groups selected from Substituent Group monument Optionally substituted C ₆ — C ₁ . Aryl group, or a C ₇ —C ₁₆ aralkyl group which may be substituted by 1 to 3 groups selected from a substituent group α,

 Q represents an oxygen atom or a sulfur atom,

X is a bond, CH ₂ , C〇, CHOR ⁹ or C-NOR ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, a 0-06 alkyl group (the alkyl group is the same or May be substituted with 1 to 3 different C, 1 C ₆ alkoxycarbonyl groups, and C ₆ — aryl group (the aryl group may be the same or different selected from substituent group α) And C ₇ —C _{1 S} aralkyl group (the aralkyl group may be the same or different 1 to 3 substituents selected from substituent group _α ). may be substituted), or Ashiru group (said Ashiru group, C: one C ₇ aliphatic Ashiru group, which may be 1 to 3 substituted with a group selected from substituent group alpha C ₇ - C "aromatic Ashiru group, 1 to 3 optionally substituted C ₈ one C ₁₂ araliphatic groups selected from substituent group α Ashiru , C ₄ - C _i black alkylcarbonyl group, Yo Le be one to five substituted with a group selected from Substituent group alpha, oxygen atom, terrorism to be selected from the group consisting of nitrogen atom and a sulfur atom A 5- to 7-membered heteroaromatic carbonyl group having 1 to 3 atoms or a rubamoyl group which may be substituted by 1 or 2 groups selected from the substituent group / 3).

 Α represents a group represented by the following general formula (II-a), (II-b), (II-c) or (II-d),

 (II-a) (Il-b) (II-c) (Π-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 N—R ⁸ ;

R ⁷ is a hydrogen atom, C, —C _e alkyl group, C ₆ —C ,. Aryl group (the aryl group may be substituted with 1 to 3 identical or different substituents selected from a substituent group), C _: 1 C ₁₆ aralkyl group (the aralkyl group is substituted Selected from the base group α Or the same or different 1 to 3 substituents), or a halogeno C _t -C ₆ alkyl group,

R ⁸ is a hydrogen atom, a C, —C ₆ alkyl group, or a group selected from the substituent group α, Ce—C, which may be substituted by 1 to 3 groups. Ariel group,. A cycloalkyl group, a C ₇ —C ₁₆ aralkyl group which may be substituted by 1 to 3 groups selected from the substituent group α, an acyl group (the acryl group is a Ci 1 ₇ aliphatic aliphatic group) , which may be 1 to 3 substituted with a group selected from substituent group _{alpha C:} one Cu aromatic Ashiru group may be 1 to 3 substituted with a group selected from substituent group monument C ₈ -. C ₁₂ indicates araliphatic Ashiru group to) one to two substituents which may be the force Rubamoi Le group with a group selected from substituent group, 〇 ₆ § Honoré kills Suzo Reho Nino les group, Halogeno c! —C ₆ anolequinoles renoyl group, one or three C ₆ —C ₁₀ arylsulfonyl groups or substituents which may be substituted with a group selected from substituent group α Represents a C ₇ —C ₁₆ aralkylsulfol group which may be substituted by 1 to 3 groups selected from the group _α ,

Alternatively, when B represents N (R ⁸ ), the nitrogen atom, R ⁷ and R ⁸ may be taken together to 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,

Substituent group α represents a halogen atom, a hydroxyl group, C _t one C ₆ alkyl group, halogeno one C ₆ alkyl group, one C ₆ alkoxy group, an amino group (said Amino groups are selected from substituent group] 3 The amino group may be substituted with the same or different 1 or 2 substituents, and the amino group is a hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom together with a nitrogen atom. A saturated heterocyclic group having 1 to 3 atoms may be formed.), A C ₆ _C ₁₀ aryl group, a cyano group, and a nitro group;

Substituent group] 3 is a group represented by C—, an alkyl group, Ce—Ci which may be substituted by 1 to 3 groups selected from substituent group γ, a aryl group, a group selected from substituent group γ. 1 to 3 _optionally substituted C ₇ — C lfiaralkyl groups and acryl groups (the acryl groups are 1 to 3 substituents which may be substituted with an aliphatic acyl group or a group selected from substituent group γ 1 to 3 C ₇ — C „aromatic acyl group, a group selected from substituent group γ Optionally substituted C ₈ —C ₁₂ araliphatic acyl group, C ₄ -C 1 cycloalkylcarbonyl group, and 1 to 5 groups selected from substituent group 基A 5- to 7-membered heteroaromatic carboxy group having 1 to 3 heteroatoms selected from the group consisting of sulfur atoms, oxygen atoms, nitrogen atoms and sulfur atoms.)

The substituent group γ represents a halogen atom, a hydroxyl group, a C ₆ alkyl group, a halogen Ci—C ₆ alkyl group, a dimer group; a —C ₆ alkoxy group, a C—C ₆ alkylthio group, an amino group, and a nitro group. ]

Or a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.

 Among them, preferred compounds include the following.

 (2) The following general formula (I ')

 [In the above formula,

X 'is CH ₂ ,. 0 or Ji = ^ 01¾ ¹⁰

(Wherein, R ¹ is a hydrogen atom, a C ₆ alkyl group (the alkyl group may be substituted with the same or different 1 to 3 C! -Cs alkoxycarbonyl groups) or C ₇ - shows the C ₁₆ Ararukiru group).

Indicates that

A ′ represents a group represented by the following formula (II-b ′) or (Il-d ′).

(In the above formula,

 B 'represents an oxygen atom or a sulfur atom,

R ⁷ is a hydrogen atom, a Ci—C ₆ alkyl group, or C ₆ —. Ariru group (said Ariru group, it may also be substituted by the same or different ivy 1 to 3 substituents selected from Substituent Group monument les, c ₇ - c ₁₆ Ararukiru group (said Ararukiru group, a substituted may be substituted with 1 to 3 substituents the same or different Ru is selected from group "), or an halogeno d-C ₆ alkyl group.)]

Or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof.

(Substituent group a halogen atom, a hydroxyl group, one C ₆ alkyl group, halogeno CI- C ₆ 7 alkyl group, C! -Cs alkoxy group, an amino group (said Amino groups were the same or different are selected from substituent group The amino group may be substituted with one or two substituents, and the amino group together with the nitrogen atom may form a heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. but it may also form a 1 to 3 having a saturated heterocyclic group.), c ₆ -c ₁₀ Ariru group, Shiano group and nitro group.

(3) The substituted condensed imidazole derivative, pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof, wherein X and CH in the above (2) are CH ₂ .

 (4) In the above (2) or (3), A is a group represented by the formula (II-b,), and is a substituted condensed imidazole derivative; a pharmaceutically acceptable salt thereof; or a pharmacology thereof. Above acceptable esters.

 (5) In the above (2) or (3), A 'is a group represented by the formula (Π-d,), B, a substituted oxygen imidazole derivative having a power oxygen atom, and a pharmaceutically acceptable derivative thereof. Salts or pharmacologically acceptable esters thereof.

In (6) above (2) or (3) a group represented by A, the ^force? Formula (II-d,), B, Is a substituted condensed imidazole derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof.

(7) In any one selected from the above (2), (3), (5) or (6), R ⁷ is a hydrogen atom, a C! -Ce alkyl group, a phenyl group (the phenyl group May be substituted with the same or different 1 to 3 substituents selected from substituent group α), benzyl group (the benzyl group may be the same or different A substituted condensed imidazole derivative, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof, which may be substituted with 1 to 3 substituents) or a halogeno C, —C ₆ alkyl group.

(8) In any one selected from the above (2), (3), (5) or (6), R ^{7 is a} phenyl group (the 4-position of the phenyl group is selected from a substituent group α). A benzyl group (the 4-position of the benzyl group may be substituted with one substituent 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.

 (9) The substituted condensed imidazole derivative according to any one of the above (1) to (8).

 (10) The 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) The 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 according to any one of the above (1) to (8).

(15) Any one compound selected from the following, a pharmacologically acceptable salt or Its pharmacologically acceptable esters ₌

 5— {4— [6— (6-hydroxy2,5,7,8-tetramethylchroman-12-ylmethoxy) -1-1-methyl-1H-benzoimidazole-1-2-ylmethoxy] benzyl ) Thiazolidine mono 2, 4-dione

 3— {4 1 [6— (6—hydroxy 2,5,7,8—tetramethylchromane

2-ylmethoxy) 1-methyl-1H-benzoimidazole-2-ylmethoxy] phenyl} —2- (2,2,2-trifluoroethoxy) propionic acid

 2— (4-Fluorobenzylthio) 1 3— {4— [6- (6—Hydroxy-1 2,

5,7,8-Tetramethylchroman-1-ylmethoxy) 1-Methyl-1H-Benzoimidazo-l-2-ylmethoxy] phenyl] Bropionic acid

 3— {4--1 [6 -— (6-hydroxy-2,5,7,8-tetramethylchroman-1-ylmethoxy)) 1-methyl-1-H-benzylazomidazole-1-2-ylmethoxy] Hue -Le} 1-2-phenylthiopropionic acid

 2-((4-fluorobenzyloxy)) 1- (4-hydroxy [2,5,7,8-tetramethylchroman-2-ylmethoxy) 1-methyl-1H —Benzoimidazo-l-2-ylmethoxy] phenyl} propionic acid The present invention also includes the following.

 (16) A pharmaceutical composition comprising 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, comprising as an active ingredient the compound according to any one of the above (1) to (15). Agent, aldose reductase inhibitor, 5-riboxygenase inhibitor, lipid peroxide production inhibitor, PPAR activator, anti-osteoporosis agent, leukotriyun antagonist, adipogenesis promoter, cancer cell growth inhibitor or Calcium antagonist.

 (18) A pharmaceutical composition for improving insulin resistance, comprising as an active ingredient the compound according to any one of the above (1) to (15).

(19) The compound according to any one of (1) to (15) above is contained. A pharmaceutical composition for lowering blood sugar, which is contained as an active ingredient.

 (20) Diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fat containing the compound according to any one of the above (1) to (15) as an active ingredient Liver, diabetic complications, arteriosclerosis, gestational diabetes, polycystic ovary syndrome, cardiovascular disease, cell damage caused by atherosclerosis, cell damage caused by ischemic heart disease, gout, osteoarthritis Prophylactic or therapeutic agent for rheumatoid arthritis, allergic disease, asthma disease, GI ulcer, cachexia, autoimmune disease, inflammation, cancer, osteoporosis or cataract

 (21) A pharmaceutical composition for preventing or treating diabetes, comprising as an active ingredient the compound according to any one of (1) to (15).

 (22) Use of the compound according to any one of (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, “Ci-C ₆ alkyl group” represents a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentynole, isopentyl, 2-methinolebutynole, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methinolepentyl, 3,3-dimethinolebutyl, 2,2- Examples include the dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups. It is preferably a C ₄ -C ₄ alkyl group, more preferably methyl or Chill. -In the present invention, "C i. Alkyl group" refers to a linear or branched alkyl group having 1 to 10 carbon atoms, for example, the above-mentioned C i-C ₆ alkyl, heptyl, 1-methylhexyl. , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylbentyl, octinole, 1-methylheptyl, 2-methylheptyl , 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methylinoleoctyl , 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethizoleheptyl, desinole, 1-methinolenoninole, 3-me Examples include chinorenoninore, 8-methinolenoninole, ₃ -ethinoleoctyl, 3,7-dimethinoleoctinole, and 7,7-dimethyloctyl group. Preferably a C! -C e al Kill group, more preferably a C ₄ alkyl group, most preferably methyl or Echiru.

In the present invention, “C ₃ —.cycloalkyl” represents a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms which may be condensed, and includes, for example, cyclopropyl, cyclobutynole, cyclopentynole, cyclopentine, and cycloalkyl. Lohexinole, cycloheptire, nonolebonore, and adamantyl can be mentioned. Preferably c ₃ - a Ji ₆ cycloalkyl.

In the present invention, the “halogeno C ₆ alkyl group” refers to the C “C ₆ alkyl group”

Represents a group in which 1 to 3 of the above halogen atoms are bonded, and includes, for example, trifluoromethyl, trichloromethinole, tribromomethyl, diphnoleolomethinole, dichloromethyl, dibutomole, fenolelomethinole, 2 , 2,2-Trichloroethynole, 2,2,2-Triphenylolenoethyl, 2-Bromoethynole, 2-Chloroethyl, 2-Fenoleolochinole, 2-Ethylethyl, 3-Chloropropyl, 4-Fluorobutylinole , 4,4-difluorobutyl, 6-hexylhexyl, 2,2-difluoroethyl and 2,2-dibromoethyl groups. It is preferably a halogeno C, —C ₄ alkyl group, and more preferably a halogeno C, — C alkyl group. In the present invention, the “C 1 -C ₆ alkoxy group” represents a group in which the above-mentioned c ₆ alkyl group is bonded to an oxygen atom, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, bentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethyl Butoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy and 2-ethylbutoxy groups. Preferably a C _t one C ₄ alkoxy group, even more preferably is C, _ C ₂ alkoxy group - in the present invention, "c, one c ₇ aliphatic Ashiru group" is a hydrogen atom or a saturated or It represents a group in which one c ₆ chain unsaturated hydrocarbon group is bonded to a carbonyl group, e.g., formyl, Kisanoiru Asechiru, propionyl, butyryl, isobutyryl, carbonochloridate Reriru, Isopareri Le, Pibaroiru to, Akuriroiru, methacryloyl and Kuno tonyl group. Preferably, it is a C 1, ₇ aliphatic aliphatic group, more preferably, a Ci-CJ aliphatic aliphatic group, and most preferably, a Ci-C ₂ aliphatic acyl group. In the present invention, “C—C cycloalkylcarbonyl” refers to the aforementioned C—C

 4 11 3

. Indicates a group in which a carbonyl group is bonded to an alkyl group in the mouth, such as pirkanoleponinole, cyclobutyrylcarbonisole, cyclopentinolecanolebonyl, cyclohexylcanolebonyl, and cycloheptylcarbonyl And norbornylcarbonyl and adamantylcarbonyl groups. Preferably it is C ₆ -C i cycloalkylcarbonyl, more preferably a cyclohexylcarbonyl or adamantylcarbonyl group.

In the present invention, “one c ₆ alkylthio group” refers to a group in which the c, —c ₆ alkyl group is bonded to a sulfur atom, and includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentinolethio, 2-methylbutinorethio, neopentylthio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1- Methylpentylthio, 3,3-dimethyl List the butylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio groups. Can be. Preferably a C i one C ₄ alkyl Chio group, more preferably a C i-C ₂ alkylthio groups.

In the present invention, “C—C ₆ alkylsulfonyl group” refers to a group in which the aforementioned C i _C ₆ alkyl group is bonded to sulfonyl, such as methanesulfonyl, ethanesulfoel, propanesulfonyl, isopronosulfonyl, butanth / Lefonyl, Isobutans Nolehoninole, s-Butans / Lehoninole, t-Butansolenoninole, Pentanszolehonyl, Isopentansnoreoninole, 2-Methylbutans Zolehoninole, Neopentansnolehoninole, 1-Ethylprononol sulfonyl, Hexanesulfonyl, 4-methylpentanesulfonyl, 3-methylpentanesulfonyl, 2-methylpentanesulfonyl, 3,3-dimethinolebutans / norhonizole, 2,2-dimethyl / lebutans / levoninole, 1,1-dimethine Lobutane sulfoninole, 1, 2-di Examples thereof include methylbutanesulfonyl, 1,3-dimethylbutanesulfonyl, 2,3-dimethylbutanesulfonyl and 2-ethylbutanesulfonyl. Suitable a C i one C ₄ alkylsulfonyl group, and more favorable apply a C, _ C ₃ alkylsulfonyl group.

In the present invention, the “halogeno C—C ₆ alkylsulfonyl group” refers to the halogeno

C i—C e represents a group in which an alkyl group is bonded to a sulfonyl, such as trifluoromethanesulfonyl, trichloromethanesulfonyl, difluoromethanesulfonyl, dichloromethanes / lefonyl, dibromomethanesnolephonyl, fluoromethanes / lefonyl, 2,2 , 2—trifonore, rotansulfonore, 2,2,2—trichon ethaneshonole, 2-bromoethaneshonolenore, 2-cloth ethaneshonolenore, 2-hues ethanesnorhonole, 2—yo De-Etans Norehoninore, 3-black mouth prono. Snolephonyl, 4-funoroleolobutanesulfonyl, 4,4-difuzoleolobutanesulfonyl, 6-nodehexanesulfonyl, 2,2-difluoroethanesulfonyl and 2,2-dibromoethane suitable _c which may be mentioned sulfonyl group is halogeno ^ ten ₄ § alkylsulfonyl group, more preferably a halogeno C - is a C ₂ alkylsulfonyl group. In the present invention, “C ₆ -aryl group” refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, and includes, for example, phenyl, indul and naphthyl groups. Preferably, it is a phenyl machine.

In the present invention, the “di: -di ₁₆ aralkyl group” is the aforementioned C ₆ —. Aryl group represents a group bonded to the C—C ₆ alkyl group, for example, benzyl, naphthylmethyl, indenylmethyl, diphenylmethyl, 1-phenyl, 2-phenyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenyl Propyl, 2-phenylpropynole, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthinolev pill, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutynole, 4-funylbutyl, Examples thereof include 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 5-phenylpentyl, 5-naphthylpentyl, 6-phenylhexyl and 6-naphthylhexyl. Preferably, it is a benzyl group.

In the present invention, the “C _: one C„ aromatic acyl group ”is the aforementioned C ₆ —. The aryl group represents a group bonded to a carbonyl group, and examples thereof include benzoyl, 1-indanecarbonyl, 2-indanecarbonyl, and 1- and 2-naphthoyl groups. Preferably, it is a benzyl group.

In the present invention, "C _S - C ₁₂ araliphatic Ashiru group", said C ₆ -. Aryl group represents a group bonded to a C ₂ -C ₆ aliphatic acyl group (showing a group in which a linear or branched alkyl group having 1 to 5 carbon atoms is bonded to a carbonyl group), for example, phenylacetinole, Examples thereof include 3-phenylpropioninole, 4-phenylenobutylinole, 5-phenylenopentanole, 6-phenylhexanoyl, naphthylacetyl, 4-naphthylbutyryl, and 6-naphthylhexanoyl.

In the present invention, “a 5- to 7-membered heteroaromatic carbonyl having 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom” is, for example, a furylcarbonyl, a chenylcarbonyl, a pyrrolyl, 1,2,3-oxaziryl, pyrazolylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl ^6- membered heteroaromatic carbonyls such as azolylcarbonyl, triazolylcarbonyl and thiadiazolylcarbonyl, bilanylcarbonyl, nicotinoyl, isonicotynyl, pyridazinylcarbonyl, pyrimidinylcarbonyl and pyrazinylcarbonyl 6 Mention may be made of 7-membered heteroaromatic carbonyls such as 6-membered heteroaromatic carbonyls and azepinylcarbonyl.

In the present invention, r C g—C i. The arylsulfonyl group is the same as defined above for C ₆ —. And a phenylsulfonyl, naphthylsulfonyl, and indenylsulfonyl group.

In the present invention, "Ji ₇ - Ji _{1 6} § Lal Kill sulfonyl group" refers to groups of the Ararukiru group is bonded to a sulfonyl, e.g. downy Njirusuruhoniru, Nafuchirumechirusu Norehoniru indenyl methylsulfonyl, 1 off Enethylsulfonyl, 2-phenylethynolesulfonole, 1-naphthinoleethynolesnorefole, 2-naphthinolethynolesolefinole, 1-phenylphenylsulfonyl, 2-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3 —Phenylphenolsulfonyl, 1 —Naphthinolepropylsulfonyl, 2-Naphthylpropylsulfonyl, 3-Naphthylpropylsulfonyl, 1 —Phenylbutylsnorethonyl

2-pheninolebutynoles / lehoninole, 3-phenylenolebutynoles zolehoninole, 4-phenylphenylsulfonyl, 1-naphthylbutynolesulfonyl, 2-naphthinolebutinolesulfonyl,

3 _ naphthylbutynolesulfonyl, 4-naphthylbutylsulfonyl, 5-phenylphenylsulfonyl, 5-naphthynolepentinolesulfonyl, 6-phenylhexynolesulfonyl and 6-naphthylhexylsulfonyl groups .

In the present invention, "C e-C, aryl group which may be substituted by 1 to 3 groups selected from substituent group γ" in the definition of substituent group Examples of a group having a substituent in addition to a group having no, for example, methylphenyl, trifluoromethyl 7 lepheninole, difusoleolomethinolephenyl, hydroxyphenyl, 4-hydroxy2,3,5-trimethylphenyl, 3 , 5-di-t-butyl-1-hydroxy phenyl, adamanti / rephenyl, 4-amino-1,3,5-dimethynolephenyl, acetylphenyl, methoxyphenyl, benzoylphenyl, fluorophenyl, diphenylolenophenyl Nore, black mouth feninole, dichloropheninole, bromophenigre, dibromo Examples thereof include phenyl, nitrophenyl, (dimethylamino) phenyl, biphenyl, methyl biphenyl, methylnaphthyl, trifluoronaphthyl, hydroxynaphthyl, methoxynaphthyl, fluoronaphthyl and clonaphthyl. It is preferably a phenyl group optionally having 1 to 3 substituents γ, more preferably a phenyl group optionally having 1 or 2 substitutions γ, most preferably Is a phenyl group optionally having one substituent y.

In the present invention, in the definition of the substituent group jS, the “C ₇ -C ₁₆ aralkyl group which may be substituted by 1 to 3 groups selected from the substituent group γ” has the substituent described above. Examples of a group having a substituent in addition to a non-substituted group include methylbenzyl, trifluoromethylbenzyl, hydroxybenzyl, 4-hydroxy-1,2,3,5-trimethylbenzyl, 3,5-di-t-butyl-4 —Hydroxybenzyl, adamantyl benzyl, 4-amino-3,5-dimethylbenzyl, acetylbenzyl, methoxybenzyl, benzoylbenzyl, fluorobenzyl, difluorobenzyl, cyclobenzyl, dichlorobenzyl, bromo Benzyl, dibromobenzyl, nitrobenzyl, aminobenzyl, (dimethylamino) benzyl, biphenylylmethyl Methylbiphenylinolemethinole, methizolephenetinole, trifrenoleolomethinolephenethyl, hydroxyphenethyl, 4-hydroxy-1,2,3,5-trimethylphenethyl, 3,5-di-t Butyl-1-hydroxyphenethyl, adamantylphenethyl, 4-amino-3,5-dimethylphenethylenol, acetylphenethyl, methoxyphenethylen, benzinole fenethylenole, fenoleolophenetinole, diphnolet Olofenetinole, black mouth phenetine, ditrophenethyl, (dimethylamino) phenethyl, biphenylylethyl, methylbiphenylylethyl, methylphenylbutyl, trifluoromethylphenylbutyl, hydroxyphenylenolebutyl, 4-hydroxy One, two, three, five—trimethylphenylbutyl, three, five—di-t — Cyl 4-hydroxyphenyl butyl, adamantyl phenyl butyl, 4-amino-3,5-dimethylphenyl butyl, acetyl phenyl butyl, methoxy phenyl butynole, fenoleolopheninolebutinole, black phenyl butinole, Nitrophenylbutyl, (dimethylamino) phenylbutyl, biphenyl-butyl, methylnaphthylmethyl, trifluoronaphthylmethyl, hydroxynaphthylmethyl, Methoxynaphthylmethyl, fluoronaphthylmethyl and kuguchiguchi naphthylmethyl can be mentioned. Preferably, it is a phenyl optionally having 1 to 3 groups selected from the substituent group γ and a phenylalkyl group having C-alkyl, more preferably a group selected from the substituent group γ A phenylalkyl group having 1 to 3 carbon atoms and a phenylalkyl group having 1 C ₄ alkyl, and more preferably 1 to 3 groups selected from the substituent group γ. also a phenylalanine alkyl radical having good phenyl and C i-C s T alkyl, most preferably base may have one of the substituents γ may Njiru or phenethyl _c

In the present invention, the "optionally 1 to 3 substituted with a group selected from Substituent Group 7 C _T one C" aromatic Ashiru group "in the definition of Substituent group i3, the substituents mentioned above Examples of groups having substituents in addition to the groups not having, for example, methylbenzoyl, triphenylolemethyzolebenzoinole, hydroxybenzoinole, 4-hydroxy2,3,5

—Trimethylbenzoyl, 3,5-di-t-butyl-1-4-hydroxybenzoyl, adamantizolebenzisle, 4-amino-3,5-dimethylbenzoyl, acetinolbenzoyl, methoxybenzoyl , Fluorobenzoyl, Difluo benzoyl, Black lip benzoinole, Dichloro benzoinole, Nitro benzoinole, Amino benzoinole, (Dimethylamino) benzoyl, Fuel benzoyl, Methyl naphthyl carbonyl, Triflufur Olonaphthylcarbonyl, hydroxynaphthylcarbonyl, methoxynaphthynolecarbonyl, fluoronaphthylcarbonyl and chloronaphthylcarbonyl can be mentioned. It is preferably benzoyl optionally having 1 to 3 substituents γ, more preferably benzoyl optionally having 1 or 2 substituents γ, and most preferably substituted benzoyl. It is a benzoyl optionally having one γ.

In the present invention, a "one to three substituents which do may be C ₈ _ C _{1 2} araliphatic Ashiru group with a group selected from substituent group Τ" in the definition of Substituent group] 3, previously described In addition to the group having no substituent, examples of the group having a substituent include, for example, methylphenylacetyl, trifluoromethylphenylacetyl, hydroxyphenylacetyl, 4-hydroxy2,3,5-trimethylphenyl. Nilacetyl, 3,5-di-t-butyl-14-hydroxy phenyl acetyl, adamantyl phenylenoleacetyl, 4-amino No 3,5-dimethylphenylacetyl, acetylphenylacetyl, methoxyphenylacetyl, benzoylphenylacetyl, fluorophenylacetinole, diphenololenophenylacetyl, diphenylphenolacetylene, diphenylphenylacetylene, dichlorophenylenolacetinole, nitro Rucetyl, (dimethylamino) phenylacetyl, biphenylylacetyl, 4- (methylphenyl) butyrinole, 4- (trifluoromethylphenyl) butyryl, 4- (hydroxyphenyl) butyryl, 4_ (4-hydroxy1-2) , 3,5-trimethylphenyl) butyryl, 4_ (3,5-di-tert-butyl- 1-hydroxy-phenyl) butyryl, 4- (adamantylphenyl) butyryl, 4_ (4-amino-3 , 5-dimethylphenyl) butyryl, 4-(methoxyphenyl ) Butyryl, 4-(fluorophenyl) butyryl, 4-(Cloh-phenyl) butyryl, 4-[(dimethylamino) phenyl] butyryl, methylnaphthylacetyl, trifrenole-naphthylacetyl, hydroxynaphthylacetyl, methoxy Mention may be made of naphthylacetyl and phenolylonaphthylacetyl or chloronaphthylacetyl. Preferably, it is a phenyl-containing fuunyl aliphatic acyl 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. A phenylaliphatic acyl having a phenyl which may be substituted, and most preferably a phenylacetyl having a fuenyl which may have one group selected from the substituent group γ.

In the present invention, in the definition of the "substituent group" 3, "one to five substituents selected from the substituent group γ, selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom Examples of the group having a substituent of 5 to 7-membered heteroaromatic ring carbonyl having 1 to 3 heteroatoms '' include, in addition to the above-mentioned groups having no substituent, for example, fluorofurylcarbonyl, fluorochenylcarbonyl , Fluoropyrrolylcarbonyl, Fluoroxazolylcarbonyl, Fluorothiazolylcarbonyl, Fluorotriazolylcarbonyl, Fluorobilanylcarbonyl, Fluoronicotinoinole, Fluoropyridazinylcarbonyl, Phonore Mouth pyrimidinylcarbonyl, methylfurylcarbonyl, methylphenylcarbonyl, methylpyrrolylcarbonyl Methylol Norre benzoxazolyl carbonyl, methyl thiazolyl carbonyl, methyl nicotinate Noi Le, main Tokishifuri Carbonyl, methoxyphenylcarbonyl, methoxypyrrolylcarbonyl, methoxyoxazolylcarbonyl, methoxythiazolylcarbonyl, methoxynicotinol, dimethylaminofurylcarbonyl, dimethylaminophenylcarbonyl, Mention may be made of methylaminopyrrolylcarbonyl, dimethylaminoxazolylcarboel, dimethylaminothiazolylcarbonyl and dimethylaminonicotinol. Preferably a 5- to 7-membered heteroaromatic carbonyl having 1 to 3 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom optionally having 1 or 3 substituents γ And more preferably a 5- or 6-membered complex 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 one substituent γ. It is an aromatic ring carbonyl group, most preferably a 5- or 6-membered heteroaromatic carbonyl group having one substituent γ and one nitrogen atom.

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 / 3” (the amino group is taken together with a nitrogen atom 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 substituted The amino group may be substituted with one or two same or different substituents 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 1 to 3 heteroatoms selected from the group consisting of:), for example, amino, methylamino, Ν-methyl-1-hexylamino, Ν-methyl 100—phenylamino, ethylamino, Ν—Metinole ノ —Echinolemino, Ν—Echinolene Ν—Hexinoleamino, Ν—Echinolene Ν—Phenylamino, propylamino, Ν—Propyl-1-butylamine, Ν—Propyl—Ν—Pentylamino, Ν—Propylamine —Hexinoleamino, Ν-propyl-1-octylamino, Ν-propyl-1-nonylamino, Ν-propynoleΝ-decylamino, isopropylamino, butyramino, Ν-butyl-1-hexylamino, s-butylamino, t— Butylamino, pentylamino, hexylamino, heptylamino, octylamino, nonylamino, decylamino, dimethylamino, jet Lumino, Jib mouth pyramino, dibutylamino, dibenthylamino, dihexylamino, diheptylamino, dioctylamino, dinonylamino, didecylamino, phenylenoamino, phenolinophenylamino, clonorphenylino, bromophenylamino, bromophenolinoamino Lophenylamino, jib mouth mofenilamino, indenylamino, naphthylamino, diphenylamino, benzilamino, fluorobenzylamino, black mouth benzylamino, bromobenzylamino, difluorobenzylamino, difluorobenzylamino, Dichlorobenzylamino, naphthylmethylamino, indenylmethylamino, phenylethylamino, phenylpropylamino, phenylbutylamino No, phenylbutylamino, phenylpentylamino, phenylhexylamino, dibenzylamino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, noklerylamino, isovalerylamino, vivaloylamino, hexanolamino Chryloylamino, methacryloylamino, crotoylamino, benzoylamino, indanecarboni / reamino, naphthoylamino, fluorobenzoylamino, black benzoizoleamino, bromobenzoylamino, difuzoleo benzobenzoleamino, difluorobenzobe N-zilamino, diclo-open-l-benzoylamino, di-so-propyl-benzylamino, tris-zoleolomethylbenzoylamino, 4-hydroxy-1,3,5-dimethylthiolamine N-zylamino, 4-hydroxy-1,3,5-di-t-butylbenzoylamino, indancarbonylamino, naphthoylamino, phenylacetylamino, phenylpropionylamino, phenylbutyrylamino, phenylpentanoyl Mino, phenylhexanoylamino, fluorophenylacetylamino, black phenylacetylamino, bromophenylacetylamino, diphenoleolophenylacetylamino, difluorophenylacetylamino, dichlorophenylinoleacetylamino, cyclopropionylamino , Cyclobutyrylamino, cyclopentanoylamino, cyclohexanoylamino, pyrrolylcarbonylamino, imidazolylcarbonylamino, pyrazolylcarbonylamino, triazolylcarbo Nilamino, tetrazolylcarbonylamino, nicotinylamino, isonicotinoylamino, virazinylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcar To bonylamino, thiazolylcaronylamino, oxazolylcarbonylamino, oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, N, N-diacet / reamino, N-honoremil-N- Xinoleamino, N-Acetyl-N-Methynoleamino, N-Acetyl-N-Ethylamino, N-Acetyl-N-Propylamino, N-Acetyl-N-Butylamino, N-Acetyl-N-Pentylamino, N-Acetinol-N Hexylamino, N-benzoinole N-methylamino, N-benzoinole N-ethynoleamino, N-benzoylone N-propynoleamino, N-benzoinole N-butylamino, N-benzoyl-1-N-pentylamino, N-benzoinole N-hexinoleamino , N-benzoinole N-pheninoleamino, N-benzino N-benzoinoleamino, N-trifthreon methyl benzoinole / N-diphnoleo benzoyl / reamino, N-diphnoleo benzyl-1-N-nicotinoinoleamino, N-methyl benzoinole N-methylamino, N— N-Hexylamino, N-Hexylamino, N-Acetinoleamino, N-Difluorobenzoyl-N-Hexyleneoleamino, N-Di-Fenoleno Benzoinole-N-Feninoleamino, N-Diphnoleo Benzoinole N-phenylamino, N-trifluoromethylbenzoyl-1-N-butylamino, N-di-t-butynole-hydroxybenzoyl-N-hexynoleamino, N-hexynole-N-naphtho N-hexyl-N-phenylacetylamino, N-isobutyl-N-cycloheptanoinoleamino, N-butyl 1-N-nicotinylamino, N-hexyl-N-nicotinylamino, N-isonicotinyl-N-hexynoleamino, N-methinol- 1-N-Triphnorelomethinolefeninoleamino, N-ethyl N-Methoxy-N-aminoamino, N-Methyl-N-Penzinoleamino, N-Methyl-1-N-Fenolenobenzino-amino, N-Ethyl-1-N-benzylamino, N-Ethyl-N-Methoxypheninoleamino, N —Propyl-N-fluorobenzylamino, N-phenyl-1-N-benzylamino, N-phenyl-1-N-fluorobenzylamino, dimethoxybenzylamino, N-methyl-1-N-acetylamino, N— N-methyl-N-propionylamino, N-ethyl-N-formylamino, N-ethyl-N-acetylamino, N-phenyl N-honoleminoleamine, N-phenyl Les one N- Asechinoreami Bruno, N- phenylene Honoré one N- butyl Riruamino, N Kisanoiru one N- main Toki Schiff enyl § amino, N- butyryl one N —Penzinoleamino, N-xanolyl N-bromopenzinoleamino, N—Fenilou N—acetylamino, ditrobenzoylamino, aminobenzoylamino, N-methyl-1-N-benzoylamino, 4-hydroxy-13 , 5-Di-tert-butylbenzylamino, 4-hydroxy-3,5-di-tert-butylbenzoylamino, N-methyl-1-N-4-hydroxy-3,5-di-tert-butylbenzoylamino, N —Ethanol N— 4-Hydroxy-3,5-di-t-butylbenzoylamino, N—propyl-N—4-Hydroxy-1,3,5-di-t-butylbenzoylamino, N— Butyl-N—4-hydroxy-1,3,5-di-tert-butylbenzoylamino, N-xyl-1-N—4-hydroxy-1,3,5-di-t-butynolebenzoinamino, N-phenyl Nzylua N, N-fluorophenyl-1-N-4-hydroxy-1,3,5-di-tert-butylbenzoylamino, N-benzyl-1-N-fluorobenzoinoleamino, N-fluorobenzyl-1-N-4 Hydroxy 3,5-di-tert-butylbenzoinoleamino, N-trifluoromethylbenzoylamino, N-methyl-1-N-fluorobenzoylamino, N-methyl-1-N-trifluoromethyl Benzoylamino, N-Ethyl-1-N-Benzoizoleamino, N-Ethyru-N-Fenoleno benzoinoleamino, N-Ethynole-1-N-Trifrenole methyl-benzylamino, N-Methyl-1-N-C N-Zylamino, N-Butyl-N-benzylamino, N-L-N-Benzoylamino, N-Methyl-N-Dichlorobenzoylamino, N-Ethyl N-Benzoinoleamino, Difnoleopen And dimethyl benzo I le amino group - Iruamino, dimethyl butoxy-benzo I Rua Mino, trimethyl-butoxy-benzo I Rua Mino, hexyl N- one N- two Torobe Nzoiruamino and 4-arsenide Dorokishi one 3, 5. C Suitable for substituents is - C 3 ₀ alkyl or mono C ₇ aliphatic Ashiru 1 to 2 have optionally may be Amino groups, more preferably C - C ₆ alkyl, or one C ₂ fatty It is an amino group which may have one or two aromatic groups.

In addition, when forming 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 together with a nitrogen atom, for example, an azetidino group, a pyrrolidino group, Piperidino group, morpholino group, thiomorpholino group, oxazolidino group, thiazolidino group, imidazolidino group, piperazino group, homopyridino group Radino, isoxazolidino and isotizazolidino groups can be mentioned. In the present invention, in the definitions of R ¹ and R ^{6 to} R ^{1 G} , “C ₆ —.aryl” which may be substituted by 1 to 3 groups selected from the substituent group α ”and R ⁷ “C ₆ — aryl group (the aryl group may be substituted with the same or different 1 to 3 substituent (s) selected from substituent group α)” Examples of the group having a substituent in addition to the group having no group include methylphenyl, dimethylphenyl, trifluoromethylphenyl, hydroxyphenyl, 4-hydroxy2,3,5-trimethylphenyl, and 3,5-diphenyl. _ t-Butyl 4-hydroxyphenyl, adamantinolepheninole, 4-amino-1,3,5-dimethinolephenyl, acetinolephenyl, methoxyphenyl, dimethoxyphenyl, benzoylphen Nil, Fluoro phenol, Diphnoleolopheninole, Fluoro phenol, Dichlorophenyl, Bromophenyl, Dibromophenyl, Nitrophenyl, (Dimethylamino) phenyl, Biphenyl, Methylbiphenyl, Methinolenaftinole, Mention may be made of trif / reolomethylnaphthinole, hydroxynaphthyl, methoxynaphthyl, fluoronaphthyl, chloronaphthyl and bromonaphthyl groups. Preferably, it is a phenyl group which may have 1 to 3 substituents α, more preferably a phenyl group which may have 1 or 2 substituents, most preferably A phenyl group which may have one moiety _α .

In the present invention, “C ₇ —C ₁₆ aralkyl which may be substituted by 1 to 3 groups selected from the substituent group α” in the definition of R ¹ R ² and R ^{6 to} R ^{1 Q} and R "C ₇ -〇 ₁₆ Ararukiru group (said Ararukiru group may be substituted with the same Ru is selected from substituent group α or different 1 to 3 substituents)" is ⁷ in the definition of, Examples of the group having a substituent in addition to the group having no substituent described above include methylbenzyl, trifluoromethylbenzyl, hydroxybenzyl, 3,4,5-trimethoxybenzyl, and 4-hydroxy. 1,3,5-dimethylbenzyl, 4-hydroxy-1,3,5-di-t-butylbenzyl, adamantylbenzyl, 4-amino-1,3,5-dimethylbenzinole, acetylbenzyl, methoxybenzyl, benzoy Lebenzyl, Fluo Base Njinore, difluoromethyl O b benzyl, black hole base Njizore, dichloro base Njinore, bromo base Nji Dibromobenzyl, nitrobenzyl, (dimethylamino) benzyl, biphenylylmethizole, methinolebiphenylinolemethyl, methinolephenethyl, trifluoromethylphenethyl, hydroxyphenethyl, 4-hydroxy-1,2,3,5-trimethylphenyl Enethyl, 3,5-di-tert-butyl-14-hydroxyphenylene, adamanthiphenethyl, 41-amino-3,5-dimethylphenethyl, acetylphenethyl, methoxyphenethylene, benzoinolepheneno F, fenoleolophenethylen, diphnooleolophenethyl, chlorophenethyl, nitropheneethyl, (dimethylamino) phenethyl, bibuenylylethyl, methylbiphenylylethyl, methylphenylbutyl, trifluoromethylphenylbutinole, hydroxy Enylbutyl, 4-hydroxy-1,2,3,5-trimethylphenylbutyl, 3,5-di-tert-butyl-1-hydroxyphenylbutyl, adamanthizolefeninolebuti /, 4-amino-3,5 —Dimethylphenyl acetyl, acetylphenylbutyl, methoxyphenylenobutyl, phenolylphenylphenyl, phenylenobutylbutanol, nitrophenylbutyl, (dimethylinoamino) phenylbutyl, biphenylylbutyl, methylnaphthylmethyl And trifluoronaphthylmethyl, hydroxynaphthylmethyl, methoxynaphthylmethyl, fluoronaphthylmethyl, and naphthylmethyl laurate. Preferable is phenyl optionally having 1 to 3 substituents α and phenylalkyl group having C—C ₆ alkyl, more preferably phenyl optionally having 1 substituent α. And C i is a phenylalkyl group having ₆ alkyls, even more preferably a phenyl optionally having one substituent _α and a phenylalkyl group having a C—C alkyl. Is a phenyl optionally having one substituent α and a phenylalkyl group having Ci-Cs alkyl.

In the present invention, Ashiruokishi group and R ⁸ to R ^{1 Q} 1 to ₃ optionally substituted C ₇ even if one C _u aromatic § Shi Le with a group selected from the "Substituent group _α in the definition of R ¹ "In addition to the above-mentioned groups having no substituent, examples of the group having a substituent include, for example, methyl benzoyl, dimethyl benzoyl, isopropynole benzoyl, t-butynole benzoyl, tribenzoyl methyl benzoyl, Hydroxybenzoyl, 4-hydroxy-1,3,5-di-tert-butylbenzoyl, 4-hydroxy_3,5-dimethylbenz Zyl, adamantyl benzoyl, 4-amino-1,3,5-dimethylbenzoyl, acetyl benzoyl, methoxy benzoyl, 3,4,5-trimethoxy benzoyl, fluorobenzoyl, difluorobenzoyl, 2 —Fluoro-4—Trifluorometinolbenzoyl, Black Benzo / Re, Dichlorobenzoinole, B, Lomobenzoinole, Nbromobenzoinole, Nitrobenzoyl, Aminobenzoyl, (Dimethinoleamino) benzoyl, Phenylbenzoyl, Methyl Examples thereof include naphthylcarbonyl, trifluoronaphthylcarbonyl, hydroxynaphthylcarbonyl, methoxynaphthylcarbonyl, fluoronaphthylcarbonyl and cloonaphthylcarbonyl. 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 a benzoyl optionally having one.

In the present invention, in the definition of Ashiruokishi group and R ⁸ to R ^{1 Q} of R ¹ 'may be substituted 1 to 3 groups selected from Substituent group α C ₈ - C ₁₂ araliphatic Ashiru " Is a group having a substituent, in addition to the group having no substituent described above, for example, methylphenylacetyl, trifluoromethylphenylacetyl, hydroxyphenylenoleacetyl, 4-hydroxy-1,3,5 —Dimethylpheninoleacetyl, 4-hydroxy-1,3,5-dimethoxyphenylacetyl, 4-hydroxy-1,3,5-di-tert-butylphenylacetyl, adamantylphenylacetyl, 4-amino-1,3,5-dimethylphenyl Lucacetyl, acetyl phenyl acetyl, methoxyphenyl acetyl, benzoyl phenyl acetyl, fluorophenyl acetyl, difluo Phenylenocetinole, black pheninoreacetinoles, dichlorophenylinocetinoles, nitrophenylacetyl, (dimethylamino) phenylacetyl, biphenylylacetinole, 4- (methylphenyl) butyryl, 4- (trifluoromethylphenyl) ) Butyryl, 4- (hydroxyphenyl) butyryl, 4- (4-hydroxy-1,2,3,5-trimethylphenyl) butyryl, 4_ (3,5-di-tert-butyl-14-hydroxyphenyl) butyryl , 4- (adamantylphenyl) butyryl, 4- (4-amino-1,3,5-dimethylphenyl) butyryl, 4- (methoxyphenyl) butyryl, 4- (fluorophenyl) butyryl, 4 _ (chloro Mouth phenyl) butyryl, 4— [(dimethyl Amino) phenyl] butyryl, methylnaphthylacetyl, trifluoronaphthylacetyl, hydroxynaphthizoleacetyl, methoxynaphthylacetyl, phenolic naphthylacetyl and chloronaphthylacetyl. It is preferably a C ₈ —C ₂ phenylacyl group having a phenyl optionally having 1 to 3 substituents α, and more preferably a C ₈ -C ₂ phenylacyl group having a phenyl optionally having 1 substituent α. ₈ is a _ C 2 Fueniruashiru group.

In the present invention, in the definition of R ^1, an alkoxy group and R ^{9 to} R ^{1 Q} , 1 to 5 substituents selected from a substituent group α may be substituted, an oxygen atom, a nitrogen atom and a sulfur atom. The `` 5- to 7-membered heteroaromatic carbonyl having 1 to 3 heteroatoms selected from the group consisting of atoms '' means, in addition to the unsubstituted group described above, a group having a substituent, For example, fluorofuryl carbonyl, fluoronenocarbonyl, fluoropyrrolylcarbonyl, fluoroxazolylcarbonyl, fluorothiazolylcarbonyl, fluorotriazolylcarbonyl, fluoroviranylcarbonyl, fluoronicotinol, and fluoro Olopyridazinyl carbonyl, fluoropyrimidinyl carbonyl, methylfurylcarbonyl, methylthenylcarbonyl, Tylpyrrolylcarbonyl, methyloxazolylcarbonyl, methylthiazolylcarbonyl, methylnicotinol, methoxyfurylcarbonyl, methoxyphenylcarbonyl, methoxypyrrolylcarbonyl, methoxyxazolylcarbonyl, methoxythiazolylcarbonyl, Mention may be made of methoxynicotinol, dimethylaminofurylcarbonyl, dimethylaminoaminocarbonyl, dimethylaminopyrrolylcarbonyl, dimethylaminoxazolylcarbonyl, dimethylaminothiazolylcarbonyl and dimethylaminonicotinol. Preferably, it may have i or 3 substitutions γ! /, A 5- to 7-membered heteroaromatic carbonyl group having 1 to 3 hetero atoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom, more preferably one substitution γ A 5- or 6-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 It is a 5- or 6-membered heteroaromatic carbonyl group having one nitrogen atom which may have one. In the present invention, the term “C ₆ —. Arylsulfonyl group which may be substituted by 1 to 3 groups selected from the group of substituents” for R ⁸ does not have the substituent described above. In addition to the group, the group having a substituent includes, for example, methylphenylsulfonyl, chlorophenylenolesnorhonole, phenylosolenophthalene, trif7-chloromethylphenylsulfonole, nitrophenylsulfonyl, cyanophenylsulfonyl, cyanophenylosolenoyl Honisole, acetynorrefenylsulfonyl, benzoylphenylsnolephonyl, biphenyls / levoninole, methylbiphenylsulfonyl, methylnaphthylsulfonyl, acetylnaphthylsulfur and benzoylnaphthylsulfonyl may be mentioned. it can. Preferably, it is a phenylsulfonyl group optionally having 1 to 3 substituents α, and more preferably a phenylsulfonyl group optionally having 1 substitution 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 a” for R ⁸ does not have the substituent described above. In addition to the group, the group having a substituent includes, for example, methylbenzylsulfonyl, chlorobenziles / lefonyl, benzolenosolefoninole with phenolic oleo, methinolebenzyls / lefonyl with phenolic trifleole, nitrophenylsulfonyl, cyanophenyl Sulfonyl, acetylbenzizolesulfonolene, benzoylbenzylsulfonyl, biphenylylmethylsnorefonyl, methylbiphenylylsulfonyl, methylnaphthylmethylsulfoni, methylphenetinolesnorhonolene, chlorophenetinolesnorhonolene , Funoleolofenetinole sulfonyl, Trifluorome Ruphenethylsulfonyl, Nitrophenethylsulfonyl, Cyanophenethinolesulfonyl, Acetylphenethylsulfonyl, Methylnaphthylethylsulfonyl, Acetylnaphthylethylsulfonyl, Methylphenylbutenolesulfonyl, Acetinolesulfonyl And methylnaphthylbutylsulfonyl and acetylnaphthylbutylsulfonyl. It is preferably a phenyl optionally having 1 to 3 substituents α and a phenylalkylsulfonyl group having 1C ₆ alkyl, more preferably a phenyl optionally having 1 substituent _α. A phenylenolequinoleth / lefonyl group having a bino group and a C i—C ₄ anolequinolene group, most preferably a benzylsulfonyl group optionally having one substituent α, or a phenylene group; A tylsulfonyl group.

R ⁸ or _{R l.} Represents `` a radical group that may be substituted with i or two substituents selected from the group of substituent groups '', for example, the group may be, for example, a radical group of methyl carbamoyl, methyl carbamoyl, ethyl carbamoyl, propyl carbamoyl, Isopropizole canolebamoyl, butyl carbamoyl, s-butyl carbamoyl, t-butyl carbamoyl, pentinorecanolebamoinole, hexylcanolebamoinole, dimethinorecanolebamoyl, jetinole canoleno moynole, N-ethyl N-methizolecanolebamoinole, dipropyl rubamoine, dibutizole rubamoyl, dipentylcarbamoyl, dihexizolecanolebamoinole, N-methyl-1-N-phenylcarbamoyl, N-methyl-1-N-isopropyl carbamoyl , N-Methinole N-propinolecanolebamo Nole, N-Methylenol N-Echinole, N-Ethyl-1-N-Isopropyl N-isopropylpropyl, N-Ethyl-N-propylcarbamoyl, Trifluoromethylphenylcarbamoyole, N-Hydroxy-N-phenyl N-phenyl Carbamoyl , 4-Hydroxy 2,3,5-trimethylphenylcarbamoyl, 4-Hydroxy-1,3,5-di-t-butynolephenynorecanolebamoinole, N-funolelofenyl-1-N-ethylethylcarbamoyl, adamantylfenylcarbamoyl , 4-amino-3,5-dimethylphenylcarbamoyl, acetylphenylcarbamoyl, methoxyphenylcarbamoyl, benzoylphenyl carbamoyl, fusoleole Echinorekanoreno Kumoinore, N-Black mouth D-N-ethylcarbamoyl, N-fluorophenyl-N-methylcarbamoyl, N-methyl-N-methyl-N-methyl-N-methyl-N-methyl Carbamoyl, dichlorophenolecanolevamoinole, dichlorophenolenocarbamoyl, nitrophenylcarbamoyl, (dimethylamino) phenylcarbamoyl, biphenylsilylcarbamoyl, methylbiphenylylrubamoyl, methylnaphthylcarbamoyl, trifluorocarbamoyl, trifluorocarbamoyl Droxynaphthyl carbamoyl, methoxynaphthylcarbamoyl, fluoronaphthylcarbamoyl, chloronaphthylcarbamoyl, phenylcarbamoyl, fluorophenylcarbamoyl, 1- or 2-indenylcal Moil, 1- or 2-Nafuchirukaru Bamoiru, Jifue carbamoylmethyl, Hol groove Les Kano lever moil, § cetyl carbamoylthiopheno Nore, propionylcarbamoyl, butyryl rubamoyl,

Nore, Norileryl Canolebamoyl, Isonorelylcarbamoyl, Pivalo

Hexanoyl carbamoyl, acryloyl carbamoyl, methacryloyl carbamo black toinorecanoleno moine, benzoinolecarnomomoyl, 1-indancarbyl, 1- or 2-naphthoylcarbamoyl, 2,6-diisopropylpyrbenzo 1- or 2-naphthylcarbamoyl, 1- or 2-naphthylcarbamoyl, diphenylcarbamoyl, phenylacetylcarbamoyl, 3-phenylpropionylcarbamoyl, 4-phenylbutyrylcarbamoyl, 5 —Phenylpentanoinolecarbamoinole, 6_phenylphenyloxanoylcarnoxyl, cyclopropioninolecanolenole, cyclobutyrinolecanolenoyl, cyclopentanoinolecarbamoinole, cyclohexano Norecanoreno carbamoyl, p-orylcarbonylcarbamoyl, imidazolylcarbonylcarbamoyl, pyrazoly norecanolebonylcarbamoyl, triazolinolecarbonylcarbamoyl, tetrazolinolecarbonylcarbamoyl, nicotinolcarbanoyl, nicotinol Yl, pyrazinyl carbamoyl carbamoyl, pyrimigel carbyl carbamoyl, pyridazinyl carbamoyl, thiazolyl carbamoyl, oxosazolyl carbamoyl carboxayl, oxaziazolyl carbamoyl, thiadiazolyl carbamoyl, 4 Trifluoromethylphenylcarbamoinolecanolenormoyl, N, N-diacetizolecarnomoyl, N-formisole-N-hexylcal Moyl, N-Acetyl-1-N-methylcarbamoyl, N-Acetyl-1-N-ethylcarbamoyl, N-Acetyl-N-propyl carbamoyl, N-Acetinole N-butylcarbamoyl, N-Acetyl-N-pentylcarbamoyl, N— Acetinole —N—hexizolecanolebamoinole, benzoinolecanolebamoinole, N—benzoizoleone N—methinolecarbamoyl, N—benzoylone N—ethylcanolebamoinole, N—benzoylone N—prohine . N-Benzoinole N-Benzoinole N-Pentinolecanenole, N-Benzoinole N-Hexinolecanolebone, N-Benzoinole N- N-benzinolone N-benzinolene phenolic moyl, benzylcarbamoyl. Fluorobenzylcarbamoyl. Zolecanolevamoyl, Trinoleoleometinorebenzinorecanolevamoinole, N-Penzinole N-Mechinorecanolevamoinole, N-Penzinole N-Echinorecanolebamoinole, N-Benzinole N — Propyl rubamoyl, N-benzyl-N-isopropyl rubamoyl, N-benzyl-1-N-phenylcarbamoyl, 4-hydroxy-1,3,5-di-t-butylbenzyl / recanolevamoinole, N-hexinole N-1-1-naphthoinolecanolebamoinole, N-hexyl-1-N-2-2-naphthoylcarbamoyl, N-hexyl-N-phenylacetylcarnoxmoyl, N-isobutyl-1-N-cyclohepta Nylcarbamoyl, N-butyl-N-nicotinylcarbamoyl, N-hexyl-N-nicotinoy-norecanolevamoisole and N-isonicotinoyl-N-hexylka Bamoiru can be mentioned. Preferably, the substituent is —C ₆ alkyl, and C _e —C optionally has 1 to 3 substituents j3. Cs-Ci which may have 1 to 3 Aryl and aralkyl having a C ₆ alkyl, a substituted or unsubstituted C ₇ —C „C 1 -C„ alkyl group optionally having 1 to 2 aromatic acyl groups And more preferably a C i -C e alkyl, a phenyl optionally having one substitution / 3, a phenyl optionally having one substitution jS and a C 1 -C ₄ alkyl Phenylalkyl, substituted moiety] is a carbamoyl group optionally having one or two phenylcarbonyls which may have one, and most preferably a C—C ₆ alkyl, Or a rubamoyl group optionally having one substituent i3 which may have one substituent i3, and more preferably one substituent having substituents i3 It is a molybmoyl group which may have one phenyl.

In the present invention, an rC i-Ce alkyl group in the definition of R ⁹ and R ¹⁰ (the alkyl group may be substituted with the same or different 1 to 3 mono-C ₆ alkoxycarbonyl groups ) "refers to unsubstituted said one C ₆ alkyl group or the C i one C ₆ identical alkyl group or different 1 to 3 one C ₆ alkoxycarbonyl group (wherein C, and one C ₆ alkoxy group represents a group represents a group linked to a carbonyl group) is bonded, if example embodiment, the C, - c ₆ alkyl group, main butoxycarbonyl methyl group, ethoxycarbonyl two Rumechiru group, propoxycarbonyl methyl group, isopropoxycarbonyl methyl , T-butoxycarbonylmethyl group, methoxycarbonylethyl group. Ethoxycarbo Examples include a nilethyl group, a methoxycarbonylpropyl group, and an ethoxycarbonylpropyl group. Preferably, they are a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycanolebonylmethyl 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. Such salts include, for example, alkali metal salts such as sodium salts, potassium salts, lithium salts, alkaline earth metal salts such as calcium salts, magnesium salts, aluminum salts, iron salts, zinc salts, copper salts. Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methyldalcamine salts , Guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylene diamine salt, clomouth pro-force salt, pro-force salt, jetanoylamine, N-benzyl-N Phenethylamine, piperazine, tetramethylammonium salts Amine salts such as organic salts such as tris (hydroxymethyl) amino methane salt; hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; nitrates; Inorganic acid salts such as perchlorates, sulfates and phosphates; lower alkane sulfonates such as methanesulfonate, trifluorosulfonic methanesulfonate and ethanesulfonate, benzenesulfonate, p-toluenesulfone Organic acid salts such as arylsulfonate, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc .; and orditic acid Salts, amino acids such as glutamate and aspartate can be mentioned, and preferred are hydrohalides or organic acid salts.

 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. The pharmacologically acceptable ester of the substituted condensed imidazole derivative having the general formula (I) is more medically used and pharmacologically acceptable than the substituted condensed imidazole derivative having the general formula (I). There is no particular limitation if it exists.

As the ester of the substituted condensed imidazole derivative of the general formula (I) of the present invention, For example, linear or branched alkyl having 1 to 6 carbons, aralkyl having 7 to 19 carbons, linear or branched alkano having 1 to 6 carbons Straight- or branched-chain alkyl having 1 to 5 carbons substituted by yloxy, straight- or branched-chain alkyloxy having 1 to 6 carbons substituted A linear or branched alkyl having 1 to 5 carbons, a linear or branched alkyl having 1 to 5 carbons substituted by a cycloalkylcarbonyloxy having 5 to 7 carbons Branched alkyl, cycloalkyloxycarbonyloxy having 5 to 7 carbon atoms, substituted or substituted linear or branched alkyl having 1 to 5 carbon atoms, 6 to 10 carbon atoms Carbonyl X-substituted linear or branched alkyl having 1 to 5 carbon atoms, aryloxycarbonyl having 6 to 10 carbon atoms having 1 to 5 carbon atoms substituted 2-oxo-1,3-dioxolen 1-4 having a straight-chain or branched-chain alkyl group and a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms as a substituent at the 5-position. _Ylmethyl group.

 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 having 1 to 4 carbon atoms. And more preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl, and most preferably methyl or ethyl.

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

The cycloalkyl group having 5 to 7 carbon atoms is, for example, cyclopentyl, cyclohexyl, cycloheptyl, and preferably cyclohexyl. The aryl group having 6 to 10 carbon atoms can be, for example, phenyl or naphthyl, and is preferably fuunyl.

 Specific examples of R of a suitable ester residue (—COOR) are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetomethyl, 1_ (acetooxy) ethyl, propionylo Xymethyl, propionyloxyxetil, butyryloxymethyl, butyryloxethyl, isobutyryloxyethyl, valeryloxymethyl, valeryloxetil, isovaleryloxymethyl, isovaleryloxyxetil, p Valyloxymethyl, Vivaloyloxixetino, Methoxycarboni / leoxymethinole, Methoxycarboni / reoxymethinole, Ethoxycanolebonoxymethinole, Ethoxycarboninoleoxyety /, Propoxycanolevoninoleoxy Methyl, propoxycarbo Loxoshetyl, isopropoxycarboxyloxymethyl, isopropoxycarbonyloxyshetyl, butoxycarboninoleoxymethyl, butoxycarbonyloxyshetyl, isobutoxycarbo- / reoxymethyl, isobutoxycarbonyloxyshetyl, t-butoxycarbo Nyloxymethine, t_butoxycanoleboninoleoxyethynole, cyclopentane force Leponinoleoxymethyl, cyclopentanecarbonyloxyshetyl, cyclohexanecarbonyloxymethyl, cyclohexanecarbonyloxyshetyl, cyclopentyl Oxycarbonyloxymethyl, Cyclopentyloxycarbonyloxyshetyl, Cyclohexyloxycanoleboninole, Ximetinole, Cyclohexinoleoxy force / Leponinole, Benzoinoleoxymethyl, benzoinoleoxyethyl, phenoxycarboninoleoxymethyl, phenoxycarbonyloxetyl or 5-methyl-12-oxo-1,3-dioxolen-14-frumethyl And more preferably methyl or ethyl. In addition, the compound (I) of the present invention may absorb moisture, become adsorbed water, or form a hydrate when left in the air or recrystallized. All of these are included in the present invention when forming a suitable solvate.

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

Further, the compound (I) of the present invention is metabolized in a living body or a pharmacologically acceptable compound thereof. Also included are all compounds that are converted to salts, so-called prodrugs.

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

 That is, when A contains a 2,4-dioxothiazolidine-5-yl group or a 2,4-dioxooxazolidine-15-yl group, position 5 of the thiazolidine ring or oxazolidine ring is an asymmetric carbon atom. And there are stereoisomers that are R-coordinated and S-coordinated. Each of them, or any proportion thereof, is encompassed by the present invention. Such a stereoisomer may be obtained by synthesizing compound (I) using the optically resolved raw material compound, or subjecting the synthesized compound (I) to optical resolution using an ordinary optical resolution method or separation method as required. Can be. In the compound (I) of the present invention, A is a group having a 2,4-dioxothiazolidine-15-yl group or a 2,4-dioxoxazolidine-15-yl group. In some cases, the existence of various tautomers is conceivable, and each of the tautomers or any ratio thereof is included in the present invention.

 In addition, as a drug forming a pharmaceutical composition in combination with the compound (1) of the present invention, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, a sulfonylurea agent, an a-dalcosidase inhibitor, an aldose Monosulfonase inhibitors, biguanides, statin compounds, squalene synthesis inhibitors, fibrate compounds, LDL catabolic promoters, angiotensin II antagonists, angiotensin converting enzyme inhibitors and antitumor agents I can do it.

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

 In the present invention, an α-darcosidase inhibitor is a drug having an action of inhibiting digestion enzymes such as amylase, maltase, α-dextrinase, and sucrose to delay the digestion of starch and sucrose. Examples thereof include acarbose, Ν- (1,3-dihydroxy-2-propyl) valiolamine (general name: poglibose), and miglitol.

In the present invention, an aldose reductase inhibitor is an agent that inhibits diabetic complications by inhibiting the rate-limiting enzyme in the first step of the polyol pathway, for example, For example, tolrestat, epalrestat, 2,7-difluorospiro (9H-fluorene-1,9,4, -imidazolidin) _2,5,1-dione (generic name: imirestat), 3-[(4 1-Bromo_2-fluoropheninole) Methynole] 1-7-Chloro-3,4-dihydro2,4-dioxo1-1 (2H) -quinazolineacetic acid (generic name: Zenarestat), 6-Fluoro1-2,3— Dihydro-1,2,5,1-dioxo-spiro [4H-1-benzopyran-1,4, __ imidazolidine] -12-carboxamide (SNK-860), zopolrestat, sorbininole, 1- [ (3-bromo-12-benzofuranyl) sulfonyl] —2,4-imidazolidinedione (M—16209).

 In the present invention, the biguanide agent is a drug having an action of promoting anaerobic glycolysis, enhancing insulin action in the periphery, suppressing intestinal glucose absorption, suppressing hepatic gluconeogenesis, and inhibiting fatty acid oxidation. 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 hydroxymethyldaltharyl CoA (HMG-CoA) reductase, for example, pravastatin and its drug. Sodium salt, simpastatin, lovastatin, atorvastatin, flupastatin and the like.

 In the present invention, a squalene synthesis inhibitor is a drug that lowers blood cholesterol by inhibiting squalene synthesis, and includes, for example, (S) -a- [bis (2,2-dimethyl_1-one). Oxopropoxy) methoxy] phosphinyl-1-phenoxybenzenebutanesulfonate monolithium salt (BMS—188494).

In the present invention, a fibrate compound is a drug that suppresses triglyceride synthesis and secretion in the liver and activates lipoprotein lipase, thereby lowering blood triglyceride.For example, bezafibrate, Vecrobrato, Vini fibrate, Ciprofibrate, Clinofibrate, Crofibrate, Crofibulinic acid, Etofibrate, Fuenofibrate, Gemfib mouth gill, Nicofibrate, Pirifibrate, Ronifibrate, Simfibrate, Theo ₂ which may be mentioned the fibrates, etc.

 In the present invention, the LDL catabolism promoter is a drug that lowers blood cholesterol by increasing LDL (low-density lipoprotein) receptor, and is described in, for example, JP-A-7-316164. Or a salt thereof, specifically N- [2- [4-bis (4-fluorophenyl) methyl-1-piperazyl-ethyl] -17,7-diphenyl-2,4,6-heptatrienoic acid Amides and the like can be mentioned.

 The above-mentioned statin compound, squalene synthesis inhibitor, fibrate compound and LDL catabolism promoter may be replaced with another drug having an action of lowering cholesterol triglyceride in blood. Examples of such agents include nicotinic acid derivative preparations such as nicomol and niceritrol; antioxidants such as probucol; and ion-exchange resin preparations such as cholestyramine.

 In the above, an angiotensin II antagonist is a drug that strongly suppresses an increase in blood pressure caused by angiotensin II and lowers blood pressure. Such agents include, for example, rosanoretan potassium, candesanoretan cilexetinole, inolebesanoretan, nokuresa / letan, telmisartan, olmesartan and the like.

 In the present invention, an angiotensin converting enzyme inhibitor is a drug that inhibits angiotensin converting enzyme and thereby lowers blood pressure and at the same time partially lowers blood glucose in diabetic patients, for example, captopril, enalapril , Arasepril, delapril, ramipril, lisinopril, imidapril, benazepril, celonapril, cilazapril, enalabrilate, fosinopril, mobertopril, perindopril, quinapril, spirapril, temocapril, trandolapril, etc. 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, 1 C ₆ alkyl group, most preferably a methyl group.

R ³ and R \ R ⁵ are preferably a C i -C ₆ alkyl group, and most preferably a methyl group. R ⁶ is preferably —C ₆ alkyl, most preferably methyl.

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 CH ₂ , CO or a group represented by C = N〇R ^{1 C)} , most preferably CH ₂ .

R ^{1 C)} is preferably a hydrogen atom, a C 1, C ₆ alkyl group (the alkyl group may be substituted with 1 to 3 identical or different C i -C ^ alkoxycarbonyl groups. Or a C ₇ -C ₁₆ aralkyl group, most preferably a hydrogen atom or a methyl group. A is preferably a group represented by the general formula (Π-b) or (II_d).

m is preferably 0 in the general formulas (Π-a), (Π-b) and (II-c), and is preferably 1 in the general formula (Π-d).

B is preferably an oxygen atom or a sulfur atom.

R ⁷ is preferably a hydrogen atom, a C “C ₆ alkyl group, a C ₆ — aryl group (the aryl group is the same or different from one to three substituents selected from substituent group α). A C ₇ -C ₁₆ aralkyl group (the aralkyl 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, more preferably a hydrogen atom, a C i —C ₆ alkyl group, a phenyl group (the phenyl group being the same or different from a substituent group). Or a benzyl group (the benzyl group may be substituted with the same or different 1 to 3 substituents selected from a substituent group). Or a halogeno d-C ₆ alkyl group, and more preferably a phenyl group (the phenyl group). The 4-position of the benzyl group may be substituted with one substituent selected from the substituent group α), a benzyl group (the 4-position of the benzyl group is Or a halogeno-C ₆ alkyl group.

Substituent group α is preferably a halogen atom, a hydroxyl group, a C—C ₆ alkyl group, a halogeno C — A C ₆ alkyl group, a c ₆ alkoxy group, a cyano group and a nitro group, more preferably a halogen atom, a Ci—Ce alkyl group, a C 1, —C ₆ alkoxy group, a cyano group and a nitro group is there. Examples of the compound of the present invention include the compounds described in the following table. However, the present invention is not limited to these compounds. The meanings of the abbreviations in the table are as follows.

 Ac: acetyl group

 Ada (l): 1—adamantyl group

 Boz: Benzoinole group

 Bu: butyl group

cBu: cyclobutyl group

iBu: isobutyl group

tBu: Tertiary butyl group

 Byr: Butyryl group

 Bz: Benzy / Le group

 Dc: Decyl group

 Et: ethyl group

 Hp: heptyl group

Hx: Hexyl group

cHx: Hexanol group

 Hxn: Hexanoyl group

 Me: methyl group

 0c: Octyl group

Ph: phenyl group

 Pn: Pentinole group

cPn: pentyl group

iPn: isopentyl group Pnto: Pentanoiru group Pr: propyl group cPr: Shikuropurohi ⁼ Honoré group iPr: isopropyl group Prn: propionyl group Nn: nonyl

 9W HO ΐ-ΐ

 HO 9ΐ-ΐ

HO S T-ΐ

HO η-ι

91 HO ει-ι

 HO ζ \-\

9W ^a w HO π-ΐ

HO Οΐ-ΐ

 HO 8-ΐ

HO L-1

HO 9-ΐ

HO. 9-ΐ

HO

3W HO ε-ΐ

 HO ζ- \

HO ΐ-Τ m SH en IM

/.IZiO/OOdf/lDd Z8S19 / 00 OAS. sss / oo〇AV

Φ S S S

 ω ω Q) Q)

 S S S

 s s s n ^ =: C IX

 o o o o o o o o o o o o o o o o 〇 〇 o 〇 o o o 〇 〇

- T i

-T i

0)

s s s s s s s s s s

1-7δ 0 (3-Cl-Boz) Me Me Me Me Me 丄 / b U ό ~ Γ ~ Ώ0Ζ) Me Me ΜΘ ΜΘ ΜΘ 丄 一 / (J 4HJH-J o— di-t DU-DOZ) Me Me ΜΘ Me 丄 丄 一 / ^ (J then U then Me Me ΜΘ Θ Θ 丄 one / y D then (JLhl ₂ (, 4-ϋπ-, o— di— t tiu— Me Me Me Me me rn)

ULU 'υH ₂ ((, 4-r- Drn Me Me Me ΜΘ Μθ _

丄 δ 丄 U then U ftp Μθυ li)

 1-82 OCOCH, (4-Me-Ph) Me Me Me Me Me _QQ

 U then U then J Γ rfl ノ ivie Me IV J Θ I UVlpc

1-84 0C0CH ₂ (2-MeO-Ph) Me Me Me Me Me 丄 8 ΰ U U U Ho Ho Me rn ΜΘ Μ 1 Θ ΜΘ ΜΘ ΜΘ ΜΘ

1-ob UL (J and H ₂ (4—OH— 3, 5—di—Met) — Me Me Me Me Me

8 丄 ー 8 U ϋ Η Η ₂ (4-UH-, 5— di— Me— Me Me Me Me Me

 D rn;

 _QQ

U then U then H ₂ J o di r rn; Me Me Me ΜΘ ΜΘ u

丄 n ΜΘ ΜΘ ΜΘ ΜΘ Μθ 丄 Θ ΜΘ Μθ ΜΘ ΜΘ Θ Θ 丄 1 Μθ Me ΜΘ ΜΘ Θ 丄 y rr Me Me Me Me Me

1 U

丄 — QQ r Dn Me Me Me Me Me One CH D

 4-r-rfl Me Me Me Me Me

1-95 3-CFfBz Me Me Me Me Me

1-96 NH ₂ Me Me Me Me Me

1-97 NH (Me) Me Me Me Me Me

1-98 NH (Et) Me Me Me Me Me

1-99 NH (Pr) Me Me Me Me Me -100 NH (iPr) Me Me Me Me Me-101 NH (Oc) Me Me Me Me Me-102 Ne ₂ Me Me Me Me Me-103 NMe (Et) Me Me Me Me Me-104 NEt (Hx) Me Me Me Me Me-105 NPr, Me Me Me Me Me Me-106 NPr (Bu) Me Me Me Me Me-107 NPr (Pn) Me Me Me Me Me

,

-108 NPr (Hx) Me Me Me Me Me-109 NPr (Oc) Me Me Me Me Me-110 NPr (Dc) Me Me Me Me Me-111 • NBu ₂ Me Me Me Me Me-112 NBu (Hx) Me Me Me Me Me-113 N (Pn) ₂ Me Me Me Me Me-114 N (Nn) ₂ Me Me Me Me Me-115 NH (Ph) Me Me Me Me Me-116 NH (3-Cl-Ph) Me Me Me Me Me-11 ヮ 7 NMe (3-CF ₃ -Ph) Me Me Me Me Me-118 NEt (Ph) Me Me Me Me Me-119 NEt (4-MeO-Ph) Me Me Me Me Me one 120 NPh ₂ Me Me Me Me Me-121 NMe (Bz) Me Me Me Me Me-122 NMe (4-F-Bz) Me Me Me Me Me-123 NEt (Bz) Me Me Me Me Me-124 NPr (4- F-Bz) Me Me Me Me Me-125 NPh (Bz) Me Me Me Me Me-126 NPh (4-F-Bz) Me Me Me Me Me-127 N (3-Me0-Bz) ₂ Me Me Me Me Me Me ³ Vi ³ W one ng ¾ -τρ-g 'ε-ΗΟ-ΐ') XHN OSl- -I

 (zog

aW ^a W one ng 1 -τρ-g ε-ΗΟ-ΐ ⁷ ) ⁿ 9N 6f l- -I

 (zog

³ W ⁹ W ^a w ^a W -ng -τρ-Q ε-ΗΟ-ΐ ')-^ dN 8 ^ 1- -I

 (zog

^Θ Μ ³ W ⁹ W — ng -τρ-g 'ε-ΗΟ-ΐ ⁷ ) 1HN m- -T

 (zog

⁹ W ^a w ⁹ W one rig α -ϊΡ-9 'ε- HO- ) a WN 9 Les - ΐ

 (zog

 — Ng ^ -τρ-Q 'ε-HO-f HN -ΐ

^Θ 1Λ [(zog) 3 Marauder -ΐ

9R (zog— ¾—) HN -ΐ

 (zoe-¾N-i ') HN Z l--ΐ

(zog-j- ^) H I l--ΐ

( ^zo e) HN Ofl--ΐ

⁹ W (zg- ^ ac) ( ^ux H) 6C1--ΐ ew (zg-d-(-i ^ g) N 8C1--ΐ

⁹ W (4d-0 ³ We) ( ^UX H) N Cl- -Τ

⁹ W 9ετ- -I aw (° V) -ΐ

 (OHO) 4dN -ΐ

( ^D V) ^ 3N εει.- ΐ

⁹ 1Λ1 (OH) ζζι- -I

 (υ · ¾) 3 刚 -I

(:. V) s 丽 οετ ·-ΐ

⁹ W (.V) 6Z-ΐ

3W 9W 3W 9W (OHD) H 8ZI- -τ

9

Z. 0 / 00df / X3d Z8S19 / 00 Ο 1

 Dimension Boz)

 1-151 NPh (Boz) Me Me Me Me Me

1-152 N (4-F- Ph) (4-OH-3, o-di- Me Me Me Me Me Bu-Boz)

 1-153 NBz (Boz) Me Me, Me Me Me

1-154 NBz 4 F-Boz) Me Me Me Me Me

1-155 N (4- F-Bz) 4-OH-3, o-di-Me Me Me Me Me

I Bu-Boz;

 1-156 OH Me t DU H Π l-lo / Me Me Me Me Me Me

1-158 H H H H H H H

1-159 OH H H H H H

 J

 1-160 OH Et H H H H

1-161 OH Et Me Me Me Me

1-162 OH Pr Me Me Me Me

1-163 'OH iPr Me Me Me Me

 OH Bu Me Me Me Me

1-165 Eight iBu Me Me e Me

1-166 UH Pn Me Me Me Me

1-167 Un lrn Me Μθ ΜΘ Θ

1-168 UH Me n t DU Π Me

1-169 UAc Me H t DU Me

1-170 0-Prn Me H t Bu H Me

1-171 OCOH Me H t Bu H Me

1-172 0-Byr Me H t Bu H Me

1-173 0-Boz Me H t Bu H Me

1-174 0 (4-F-Boz) Me H t Bu H Me

1-175 0 (3— CF ₃ — Boz) Me H t Bu H Me zs / oodf / I: M SS91〇

CD QJ

S CQ S S S

S S S S

 α

 CQ Q CQ CQ OQ CQ m cQ CQ n Q Q CQ CO C CO

 L S S S

S S S

 oo

 s s s

S O

SO

H

⁸ N ³ W ⁹ W 0 £ Zl

⁹ W ^d Vi ^X HN ZZ- \

⁹ W (zg) ngN SZZ-l

^Θ Ν ^a W ^S W ^j dN LZZ- \ eW ^e W ³ W ^a W ( ^Z0 9-I3-S) ⁹ IVN 9ZZ-1

⁹ W ^a W ^Θ Ν ^θ ίϊ ^e W ( ^z a- ⁿ 9 -ΪΡ-9 'Z-tiO-) HN ZZ-1

 (zog

⁹ W ⁹ W ⁹ W _ ⁿ 81 -TP-S HO-HN ZZ-l aw aw 3) ⁹ WN £ ZZ-l

 HN zzz- \

( ^zo e) HM \ zz- \

⁸ W ³ W (° V) HN QZZ-l

⁹ W ^a W ^{3 9} W ¾N 6Ϊ2-Ϊ eW ^s Vi ³ Vi ^a W (zog-ng '-ip-g £ -W0-) 0 812-ΐ

⁹ W ^Q Vi ^a W ³ W ° V0 L \ Zl

H ⁿ 9 H ³ W HO 9ΪΖ-Ϊ

H H HO

qd-o ⁹ ws HHHH HO \ Zl

4d-0 4 ³ W HO ZlZ-l

Md-o ⁹ we HO z \ z- \

^ d- d3-HO

^ d ⁹ HO 012-ΐ zg- d- ε HO 60-ΐ

 HO 802-ΐ u- aw HO LOZ-l zg HO 902-ΐ

 HO 0Ζ-1 ng 9 HO fOZ-l

6V

LlZZO / OQdt / lDd J8S 19/00 OAV V1

-16 CH ₂ ϋ LH u 7-17 CH ₂ 0 CH 0 8-18 CH ₂ 0 CH s 0-19 CH ₂ s CH 0 0-20 CO 0 CH 0 0-21 CHOH 0 CH 0 0-22 Holo Thousand 0 CH 0 0-23 ONOH 0 CH (J u-24 C = N0Me 0 CH 0 u-25 ONOBz 0 CH ϋ u-26 C = N0Ac 0 CH (J u-27 C = N0Boz 0 CH 0 0-28 C = N0C0Bz 0 CH 0 u-29 C = N0Ph 0 CH 0 ϋ-30 ON0 (4-F-Ph) 0 CH 0 0-31 C = N0Pn 0 CH 0 ϋ-32 C = N0C0 awake e 0 CH 0 0 -33 C = N0C0NHPr 0 CH 0 0 8 -34 C = N0C0NHPh 0 CH 0 0-35 C = N0C0 HBz 0 CH 0-36 C = N0C0NMe ₂ 0 CH 0 0 8

-37 C = N0C0NMe- (iPr ϋ CH ϋ (J-38 ONOCONMe-(Ph) 0 CH 0 0-39 ONOCONEt- (Bz) 0 CH 0 0-40 C = N0C0 Ph- (Bz) 0 CH 0 0- 41 C = N0C0NPh- (B oz) 0 CH 0 0-42 CH ₂ 0 N 0 0-43 CO 0 N 0 0 -44 CHOH u! NU υ -45 Daiyu V 1 U Ό

 Eight -46 C: N0H 0 N u U

1-47 ONOMe 0 Nu (J

1-48 C = N0Bz 0 N 0

1-49 ONOAc n

 0 u u

1-50 C = N0Boz 0 N (J

1-51 ONOCOBz 0 Nu

1-52 C = N0Ph u N U

 One c /, 1> i ヽ

 1-53 Shiichi N0 (4-triode h) u u U

1-54 C-N0Fn u IN u π U eight

 1-55 L- OCUNH e u IN u u eight

 1 1 56 C = 0C0NHFr N u u

1-57 C = N0C0 HPh 0 N U eight

1-58 C = N0C0NHBz 0 0

 Eight

1 1 59 C = N0C0NMe ₂ 0 N 0

1-60 C = N0C0NMe- (iPr) 0 N 0 0 l-o 1 C-NO NOMe-(rn u N u

1-D2 C = 0C0NEt- (Bz) 0 u l-o3 C2 NOCONPh-(Βζ) ϋ N u U

1 fc »4 shi NO (JJN h— (B o z) U N u U 丄 ゎ 0 c¾ U shi ML) u

1 c LH U

1-67 CH ₂ 0 CH 0 0

1-68 CH ₂ 0 CH 0 0

1-69 C¾ 0 CH 0 0

1-70 CH ₂ 0 CH 0 0

1-71 CH, 0 CH 0 0 ooooooooooooooooooooo ooooooooooooooooooooooooooooooi; m: pi: pi::

 o o

 CO

 Ten

 o o o o o o o o o o o o o o o o o o o o

CJ

6 8-

o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o

DZ;;:; o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o

,,,,

 Two—I '' ■■ 【丄 レ 1! ~ Ί ((

Dimensions Dimensions Dimensions One — — — —

IIIIII i I 1 I t IIIIII t IIIIIIIIII

_{- 128 CH 2 0 CH 0 u} -129 CH 2 0 CH 0 0-130 CH 2 0 CH 0 0-131 CH 2 0 CH 0 0 - 132 CH 2 0 CH 0 0-133 CH 2 0 CH 0 0-134 CH ₂ 0 CH 0 0-135 CH ₂ 0 CH 0 ϋ-136 CH ₂ 0 CH 0 ϋ-13 / CH ₂ ϋ CH u υ 138 CH ₂ 0 CH u υ -139 c¾ 0 CH 0 0 -140 0 CH 0 1 141 c¾ 0 CH 0 0-142 CH ₂ 0 CH 0 0 1 143 CH ₂ 0 CH 0 0 1 144 C¾ 0 CH 0 0 1 14 iD CH ₂ 0 CH 0 0-146 CH ₂ 0 CH 0 0-147 CH ₂ 0 CH 0 0 1 148 0 CH 0 0 4y 0 CH 0 0 bU u H (J υ-151 c 0 CH 0 0-152 c¾ 0 CH 0 0-153 c 0 CH 0 0-154 c 0 CH 0 0 -155 CH ₂ 0 CH 0 0 0 0 HD 0 ¾D ε8ΐ-ΐ

0 0 HO 0 28ΐ-ΐ

0 0 HD 0 ΐ8ΐ-ΐ

0 0 HD 0 H3 08ΐ-ΐ

0 0 HD 0 6 /, ΐ-Τ

0 0 HO 0 8 ΐ-ΐ

0 0 HO 0 ¾3 ΖΖ ΐ-ΐ

0 0 HD 0 9Ζ.Ϊ-Ϊ

0 0 HO 0 ¾3 S I-ΐ

0 0 HD 0 ^ Τ-ΐ

0 0 HD 0 £ 11-1

0 0 HD 0 Ζί Ι-1

0 0 HD 0 ¾3 UT-ΐ

0 0 HO 0 ¾0 ΟΖΐ-ΐ

0 0 HD 0 ¾D 69ΐ-ΐ

0 0 HD 0 ¾0 89ΐ-ΐ

0 0 HD 0 Ζ.9Ϊ-Ϊ

0 0 HO 0 ¾3 99ΐ-ΐ

0 0 HD 0 ¾3 S91-T

0 0 H3 0 ¾3 9ΐ- ΐ

0 0 HD 0 ¾3 Ε9Τ-Τ

0 0 HO 0 ¾3 29ΐ-ΐ

0 0 HD 0 ¾0 Ι9Ι-Ι

0 0 HO 0 ΐ 09ΐ-ΐ

0 0 HD 0 63ΐ-ΐ

0 0 HO 0 ¾3 85ΐ-ΐ

0 0 HO 0 ¾3 Ι9ΐ-ΐ

0 0 HD 0 ¾3 99ΐ-ΐ

99

LUZO / OOdf / IDd J8S19 / 00 OAV ooooooooooooooooooooo ooooooooooooooooooooooo oooooooooo

o o o o o o o o o o o o o o o o o o o o o o o o o o o o o

οο οο οο οο οο

o sn—

o

例示 R1 R2 R3 R4 R5 R6 化合

Example R1 R2 R3 R4 R5 R6 Compound

 Object number

 Ten thousand

 2-1. OH Me Me Me Me Me

2-2 OH Me Me Me Me Me

2-3 OH Me Me Me Me Me

2-4 OH Me Me Me Me Me

2-5 OH Me Me Me Me Me

2-6 OH Me Me Me Me Me

2-7 OH Me Me Me Me Me

9 ώ_δ

 Ο OH Up Up

 lYl c Mc Mc Mc

2-9 OH Me Me Me Me Me -10 OH Me Me Me Me Me -11 OH Me Me Me Me Me -12 OH Me Me Me Me Me -13 OH Me Me Me Me Me -14 OH Me Me Me Me Me- 15 OH Me Me Me Me Me -16 OH Me Me Me Me Me -17 OH Me Me Me H Me -18 OH Me Me Me Me Me Un ΜΘ ΜΘ ΜΘ ΜΘ ΜΘ

9_ n Un Θ ΜΘ Θ Θ ΜΘ

Z Z 丄 Un jvie MoΘ

 Δ ΔΔ Un Θ Θ ΜΘ Me NIG

 \ H

 Z Ζό Un θ Μθ Me ΜΘ ΜΘ

0 0

 Un Me Me Me ΜΘ ΜΘ

 H

M 1 Un Me Me Me Μθ ΜΘ

Z O Un ΜΘ ΜΘ ΜΘ θ ΜΘ

 Un ΜΘ Μθ Θ ΐνΐθ M6

Un ΜΘ ΜΘ Μθ ΜΘ 9 9 a Un Μθ ΜΘ ΜΘ θ θ n Uun Θ ΜΘ ΜΘ Μθ ΜΘ 丄 j j Une Me Θ Μθ θ

 ru

Ό UnΔ Un ΜΘ ΜΘ ΜΘ Μθ ΜΘ rum ο_ ο

 Un β Θ JV1G e

9— ^ ± Un Μ u _Q θ Θ Θ Μθ Mem cm Μθ ΜΘ ivie Μθ

 D Un Μθ ΜΘ Me Μθ Θ _ 7

 I Un ΜΘ Me ΜΘ Μθ Θ 5 Un Me Me Me Me Me

9

Un Θ Me ΜΘ Me Μθ

 H

 Un me Me θ ΜΘ Θ

0—441 丄 un Μθ ΜΘ Μθ Μθ Θ

2-42 0H Me Me Me Me Me

2-43 OH Me Me Me Me Me

2-44 OH Me Me Me Me Me

2-45 OH Me Me Me Me Me

2-46 OH Me Me Me Me Me VS19 /

2-75 0 (3-C Boz) Me Me Me Me Me

L O U \ Γ DO no p, p

 ti JVlc I UVlpc

IVlt; Up MpΔ 9-7 i 7

IVlt; Up Mp

9_

 / OQ Π UΓshΠ UΓshΙ PV. P Up

 IVlti fci

 9_7Q (4: — UDfUl— ', 0 c_ UH η-t I R5nU- Μϋ IVlc IVlc U IVlp

 , "T; MP

ΓΠ ノ

ώ ου ri u shi ^ t r IVlfci IVlc MP

9—CI

U then U then Π ₂ Μβυ rn) ΜΘ Me IVlc lviu

2-82 0C0CH ₂ (4-Me-Ph) Me Me Me Me Me _οο

 ο U then U then V n) ΜΘ M ΜΘ ΜΘ

u then u n ₉ ivieu rnno ΐνΐθ 1V1G JVlfci IVlfci IVlt? Ό ₉ rnno IVlfci IVlc M IVloti IVlt? ώ ου ! \ τ: Li Π 0, Ο Ui IVlt? Li IVlc IVlc IVlc

ΓΠ ノ

 u

 π IVlti JVIG IVlt? IVlfci _QA

 Ό) ΜΘ ΜΘ ΜΘ ΜΘ ΜΘ ΜΘ

9-Q1 丄 pJ I Me ΜΘ ΜΘ e

 Q

 Γ 1 Θ MG M ivioe ΜΘ

Γ n Θ ivie ΜΘ

 1 DZ Θ Θ Θ Θ ΜΘ

2-96 ¾ Me Me Me Me Me

2-97 NH (Me) Me Me Me Me Me

2-98 NH (Et) Me Me Me Me Me

2-99 NH (Pr) Me Me Me Me Me-100 H (iPr) Me Me Me Me Me

9W ^z (zg- o E) N IZ \ -Z

 (zg-d-) HdN 921-2

(zg)

3W ( ^z Hd- ^) 3 圆

9W 3W (zg) 3 Awakening \ Z \ -Z

9W 3W 3W (_0-& U-Z

 9W (qd-¾3-e) awake LU-Z

9W (qd-iD-e) HN

 9W 91V (¾) HN

9W 3W ^Z ("N) N

( ³ a)-^ dN ou-z

(.0) · ¾Ν 601-2

 (¾) LO¾Ν-Z

(ng) J-M 901-Z

 01-Z

9W ( ^X H) W \ -Z

 3) 9WN £ 0 \ -Z 顺 ZOl-Z

(.0) HN ΐΟΐ-2 ε9

Ζ, ΠίΟ / OOdf / XDd Z8S19 / 00 OAV ,

 -129 NH (Ac) Me Me Me Me Me-.130 NMe (Ac) Me Me Me Me Me- (Ac) Me Me Me Me

 --134 NPh (CHO) Me Me Me Me Μβ

2- -135 NPh (Ac) Me Me Me Me Me

2- -136 NPh (Byr) Me Me Me Me Me

2- -137 N (Hxn) (3-MeO-Ph) Me Me Me Me Me

2- -138 N (Byr) (4-F-Bz) Me Me Me Me Me

2- -139 N (Hxn) (3-Br-Bz) Me Me Me Me Me

2- -140 NH (Boz) Me Me Me Me Me

2- -141 NH (4- F-Boz) Me Me Me Me Me

_{2- -142 NH (4-N0 2} -Boz) Me Me Me Me Me

2- -143 NH (4-NH ₂ -Boz) Me Me Me β

2- -144 NMe (Boz) Me Me Me Me Me o- -145 NH 4- (JH-3, 5-di-- t DU-DOZ Me Me Μθ Μβ Me

2- -146 NMe (4-OH-3, 5-di-t Bu— Me Me Me Me Me

 Boz;

 2- -147 NEt (4-OH-3, 5-di-t Bu-Me Me Me Me Me Boz ヽ)

 2- -148 NPr (4-OH-3, 5-di-t Bu- Me Me Me Me Me ヽ

 Boz)

 2--149 NBu (4-OH-3, 5-di-t Bu- Me Me Me Me Me

 Boz)

 2--150 NHx (4-0H-3, 5-di-t Bu- Me Me Me Me Me

 Boz)

2- -151 NPh (Boz) Me Me Me Me Me 2-152 N (4-F-Ph) (4-0H-3, 5— di— t Me Me Me Me Me

DU DOZJ

 丄; I DZ VDOZ ^ Θ Μθ Mo U 丄 4 D,

 1 \ 1 I

 DZ Γ DOZ ^ ΜΘ ΜΘ 1V1G Ινΐϋ _i

 丄 00 i \ ^ Γ DZy, 4 Un J D Ul L Ινΐθ IVlt; IVlt;

 DU DOZ)

 u u

 Z-lOO Un me Π I DU n u Π

 Me ΜΘ ΜΘ ΜΘ ΜΘ Mo u u u u

 loo u

 n n Π n n n rr u u u

Un n Π Π n Π

 u u — 丄 btJ UH bt Π Π Π Π »t» l Un t ΜΘ ΜΘ ΙνΙΘ ΜΘ

0

 Un rr Me ΜΘ Μθ Θ-ib Un ■ lI Drr Me Me ΜΘ Me ώ) t) ^ ru

 UH DU Θ ΜΘ Θ ΜΘ

 n Uun i l RDiUi jvie Θ 1V1G n uun MB Mo IVlc

L Ό ί Un i Pn IVlfci M M IVlti u

 Un IJ 丄 00 ΜΘ Π L DU Π IVlc u

 丄 ゎ y UAc Me Π L DU n ΜΘ u u

 丄 u rrn θ Π I D RUi u

 n e u u 丄 / 丄 U ΜΘ Π t3U Π ΜΘ 79

 1 ί ΜΘ Π L DU Π ΜΘ

2-173 0-Boz Me H t Bu H Me

2-174 0 (4- F- Boz) Me H t Bu H Me

2-175 0 (3- CF ₃ — Boz) Me H t Bu H Me

2-176 0-Bo z Me H t Bu Me Me

2-177 0 (4-CF ₃ -Bo z) Me H t Bu H Me / l〇AV

^ ¾ ≤ S a) ω ω ssss

W fc713¾ 一 SSI9 / O.-

in c

 2-19 s H s H H n D i 丄 l 丄 r \ Λ 1 1

Δ ~ ΖΌ (J U then M U U 丄 丄

O 1

 One l then HD l U then H u u 丄 丄 — Mouth U then M u U 丄 I

O Q

 Shiichi I UH U Shi n u υ 丄 丄 1

 _ 4 Shiichi INUMe U Shi H u υ 丄 丄

 A

 Shii] Ui5z Shi H u U 1 丄-b Shii IN U Ac U In n u 11 丄 _ _ ί Shi— INUtSOZ U In u υ 丄 丄 o o n 1 1

 Shiichi J DLDhSz U Shih A

 u Li 丄 丄 y Shiichi i U n A

 U In u υ 丄 丄 η— 1Γ (A C D

 U M u υ 丄 丄 Q 1 n

 j 丄 し 一 IN Π U U υ 丄 丄

1-61 Shiichi (J and DJ HMe U and H U υ 丄 丄

O Q Q

 O shi 1NU shi UlNH Γ U shi M U Π υ 1 丄 1 丄

O Q

 _ 4l Shiichi INULDJ H ^ J u Λ 1 1

 M M υ Ιί 丄 丄

P— ΜΠΡΑΚΠ4Π r. N u A o Π u υ 丄 丄

 n

 O Shi 1 MU 1 UlMJWe ^) U Π u 丄 丄 (

u し Π π u υ 丄 丄 Iwie l rx) U

u Π π π u υ 丄 丄

 n

UiNct D u n

 Π u 丄 丄 r n

 Shiichi JNU DlNri— \ D U Shi H u Ιί 丄 1

 r

 Z 丄 一 u uw n (, D o z) U u u υ 丄 丄

2-42 CH ₂ 0 N 0 0 1 1

2-43 CO 0 N 0 0 1 1

2-44 CHOH 0 N 0 0 1 1

2-45 ¾ ,. Mouth.Hand 0 N 0 0 1 1

2-46 C = N0H 0 N 0 0 1 1 -47 C = N0Me 0 N 0 0-48 ONOBz 0 N 0 0-49 C = N0Ac 0 N 0 0-50 ONOBoz 0 N 0 0-51 C = N0C0Bz 0 N 0 0-52 C = N0Ph 0 N 0 0 -53 ON0 (4-F-Ph) 0 N 0 0 -54 ONOPn 0 N 0 0-55 C = N0C0 麵 e 0 N 0 0-56 C = N0C0NHPr 0 N 0 0-57 C = N0C0NHPh 0 N 0 0 -58 C = N0C0 thigh z 0 N 0 0-59 C = N0C0NMe ₂ 0 N 0 0-60 C = N0C0NMe- (iPr) 0 N 0 0-61 ONOCONMe- (Ph) 0 N 0 0-62 ONOCONEt- ( (Bz) 0 N 0 0-63 C = N0C0NPh- (Bz) 0 N 0 0-64 C = N0C0NPh- (Bz) 0 N 0 0-65 C 0 CH 0 0-66 C 0 CH 0 0-67 C 0 CH 0 0-68 C¾ 0 CH 0 0-69 C 0 CH 0 0-70 CH ₂ 0 CH 0 0-71 C 0 CH 0 0-72 CH ₂ 0 CH 0 0-73 CH ₂ 0 CH 0 0-74 CH ₂ 0 CH 0 0 Z ¾ u nn nn U Η ₂ u H H uu — / LH ₂ un

 Then H U u

2- / 0 CH ₂ u then HU u

0 CH ₂ U then H U U

H H ₂ j し J1 u U 0 丄 U U Π n U π U ¾ U ru

 0

9_QQ

Rj π Π n ri Q Q M M ₉ u π u π U 00 υ H HUU

0—oc

 00 U then M u U

Z Η ₂ π U u υ 00 and H ₂ U MU u

H ₂ U then M u π u _Qn π ru

 ¾ ¾ n n n u

9

y 丄 H ₂ π n

U then n U π u then h ₂ π U n π U nu

9

 Then π u then n n U n u n

 U u Π π U n リ Π π u u n u ru

 A π

 Pi u

2-98 C¾ 0 CH 0 0

2-99 C¾ 0 CH 0 0 -100 C 0 CH 0 0 -101 CH ₂ 0 CH 0 0 -102 CH ₂ 0 CH 0 0

o o o o o o o o o o o o o o o o o o o o o o o

ooooooooooooooooooooo ooooooooooooooooooooooo oooooooooo

ー 丄 oo ¾ U し U

Ζ-Ι όΖ then H ₂ U then H u I)

 r

Shi H ₂ U Shi H uu

2- 134 H ₂ u Ln U u

2-135 shi H ゥ u shi H π u U

2-136 shi H ₂ L) shi M uu

2-137 shi H ₂ U shi H U U

 Then i ヮ U then li u u

2- 139 U then li n u n U

2-140 shi H ₂ U shi MU π U

2-141 then H ₂ U then n π U

2-142 then H ₂ U then n π UU

2-143 shi H ₂ U shi π UU

2-144 u then u u

2-145 Mr. ϋ ₂ U and MU u

2- 14b CH ₂ u then HU u

2-147 CH ₂ U then HU u

2-148 shi H ₂し shi li π uu

2-149 Shi U U U

2-150 then H2 u then n u u

2-151 n n ¾ U In U u

2-152 shi J¾ shi 11 π u u

2-153 ¾ u J Ji u u

2-154 0 CH 0 0

2-155 0 CH 0 0

2-156 CH ₂ 0 CH 0 0

2-157 c¾ 0 CH 0 0

2- 158 CH ₂₀ CH 0 0

n ^ ^ ^ ^ ^ ^ ^ ^

o o o o o o o o o o o o o o o o o-o o o o o o o o o o

<n o o n n o o o o o o: e r, 3: n: n: n: e n n:

Oo 〇 〇 〇 ooooo 〇 ooo 〇 oo 〇 oo 〇 〇 ooooooooooooooooooooo oooooooooo

S Q S S Q Q S S S Q Q Q β β β β β S β S S S S S S

Ο 〇 〇 〇 〇 〇 〇 ο 〇 ο ο ο 〇 〇 〇 ο 〇 ο 〇 〇 ο ο ο ο ο 〇 ο ο ο ο ο

ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο

例示 R1 R2 R3 R4 R5 R6 化合

Example R1 R2 R3 R4 R5 R6 Compound

 Object number

 Mouth

3-1 OH Me Me Me Me Me

3-2 OH Me Me Me Me Me

3-3 OH Me Me Me Me Me

3-4 OH Me Me Me Me Me

3-5 OH Me Me Me Me Me

3-6 OH Me Me Me Me Me

3-7 OH Me Me Me Me Me

3-8 OH Me Me Me Me Me

3-9 OH Me Me Me Me Me 丄 U UH Me Me Me Me Me

3-1 1 OH Me Me Me Me Me

3-12 OH Me Me Me Me Me

3-13 OH Me Me Me Me Me

3-14 OH Me Me Me Me Me

3-15 OH Me Me Me Me Me

3-16 OH Me Me Me Me Me

3-17 OH Me Me Me H Me

3-18 OH Me Me Me Me Me

3-19 OH Me Me Me Me Me

SS9〇Λν1 / 1 /

0

S S S S S S S

 a> a> ω

 S S S

CD

ssss

£ —

-103 NMe (Et), Me Me Me Me Me-104 NEt (Hx) Me Me Me Me Me-10b NPr ₂ Me Me Me Me Me-106 NPr (Bu) Me Me Me Me Me-107 NPr (Pn) Me Me Me Me Me-108 NPr (Hx) Me Me Me Me Me-109 NPr (0c) Me Me Me Me Me-110 NPr (Dc) Me Me Me Me Me-111 NBu ₂ Me Me Me Me Me-112 NBu ( Hx) Me Me Me Me Me-113 N (Pn) ₂ Me Me Me Me Me-114 (Nn) ₂ Me Me Me Me Me-115 NH (Ph) Me Me Me Me Me-116 H (3-Cl-Ph ) Me Me Me Me Me-117,

NMe (3-CF ₃ —Ph) Me Me Me Me Me-118 NEt (Ph) Me Me Me Me Me-119 NEt (4-MeO-Ph) Me Me Me Me Me-120 NPh ₂ Me Me Me Me Me- 121 NMe (Bz) Me Me Me Me Me-122 NMe (4-F-Bz) Me Me Me Me Me-123 NEt (Bz) Me Me Me Me Me-124 NPr (4-F-Bz) Me Me Me Me Me-125 NPh (Bz) Me Me Me Me Me-126 NPh (4-F-Bz) Me Me Me Me Me-127 N (3-Me0-Bz) ₂ Me Me Me Me Me-128 NH (CHO) Me Me Me Me Me-129 H (Ac) Me Me Me Me Me-130 NMe (Ac) Me Me Me Me Me HH ng 1 H HO 99ΐ- -ε

 (zog—ng

¾ -ΐρ-s' ε- HO- (zg-d-) N S9I- -ε s _W f l- -ε

 (zog—ng

 aw 1-TP- S 'ε- HO- (Hd-d-f) M S9T- -ε

 3W 191- -ε

9W (zog one ng; -τρ-g 'ε- H0_t ^ HN 09ΐ--£

9W 9W (zog—ng a -ip-g 'ε-HO-) "HN 6 \--£

9W (zog— ng i -τρ-g 'ε- HO- ΐ Ν S l--£

9W (zog—ng i -ip-g 'ε-HO-) ^ HN in- -ε

 SW (zog—; -τρ-g 'ε- HO-) s 丽 9n- -ε

9W (zog-ng: ^ -τρ-g 'ε-ΗΟ- ^ Η n- -ε

3 _W 9W 9W (zog) 3 n- -ε

9W 9W (zog— ¾N—) H £ n--ε

3W (zoe-¾-^) HN zn--ε aw (zog—) HN m--ε

 (zog) HN on--ε

 -ε

(zg-d- ^) (^ 9) M S £ \--ε

9W 31 (-o-ε) (uxH) N L £ \--ε

9W (^ 8) d 9 l- -ε

9W (;. V) qdN SET- -ε

 (OHO) HdN ει--ε

(.V) εετ. -C

3W (OHO)-ε

9 ^ 9W -ε

28

LlZZO / OOdf / XDd Z8S19 / 00 OW

qd-o ⁹ we 91S 9W ³ W HO ΖΙΖ- £

91V 3W 91 HO U Z- £

zg- tsu- ε ⁹ W HO 80S- ε zg- 9W 3W HO L0Z- £ za HO 902-ε

⁹ N 9W HO 0Ζ-

 HO

 D 9W HO

 HO

 ^ ι H H HO ΟΟΖ-ζ

H H H HO 66ΐ- ε zg- j- HO 86ΐ-ε

 HO L6 \-£

HO 961-C d d HO S6I- ε

H H HO 6ΐ- ε

H H d d -id HO εβΐ-ε

HH (2og- ^£ j0- £)

 H H (zog— j— π T 6T-C

H ng 1 H (zog) aHN 061-C

9W H H (zog-¾) —ε) 3 clients 68 顧 -ε

3W H ng a H (zog-d-e) a 88ΐ-ε

H ng a H (zog— ^e j—)

 H ng a H (zog—j—) 3 rigid 98T-C

H H (zog- ^ 3- ε) ΗΝ 98ΐ-ε 8

UO / OOdfAL d Γ85Ι9 / 00 OAV

o o o o o o o o o o o o o o o o o o o o o o o o o o o o o-^ → o n n o o o n n

 ί 1> ■ L> I> f

 o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o

A CNOH -54 C = N0Pn 0 N 0 0-55 C = N0C0NHMe 0 N 0 0-56 C = N0C0 HPr 0 N 0 0-57 C = N0C0 HPh 0 N 0 0-58 C: N0C0 Fiber z 0 N 0 0- 59 C = N0C0NMe ₂ 0 N 0 0-60 C = NOCONMe-(iPr) 0 N 0 0-61 C: = N0C0 band e_ (Ph) 0 N 0 0-62 C: = NOCONEt- (Bz) 0 N 0 0-63 C: = N0C0NPh- (Bz) 0 N 0 0-64 C: = NOCONPh- (Bz) 0 N 0 0-65 CH ₂ 0 CH 0 0-66 C 0 CH 0 0-67 CH ₂ 0 CH 0 0-68 C¾ 0 CH 0 0-69 CH ₂ 0 CH 0 0-70 C¾ 0 CH 0 0-71 CH ₂ 0 CH 0 0-72 CH ₂ 0 CH 0 0-73 CH ₂ 0 CH 0 0-74 CH ₂ 0 CH 0 0-75 C¾ 0 CH 0 0-76 CH ₂ 0 CH 0 0-77 CH ₂ 0 CH 0 0-78 CH ₂ 0 CH 0 0-79 CH ₂ 0 CH 0 0-80 CH ₂ 0 CH 0 0-81 CH ₂ 0 CH 0 0 U n U HJ u HJ

 u u HJ U ° u HJ

nuu nJ π u ⁶ u HJ

 U U u nJ u c nJ

 U ri 1 n u nJ I o π U u HJ u HJ U L—

U U HJ u HJ

 U u U HJ u HJ 6U l 1 t

U U H uJ U HJ L U l t

 rv

 U U HJ U HJ UU L-t

UU HJ π U HJ 00 ^_ tn U u HJ U HJ

 n U u HJ π u nJ LO

U U HJ u HJ

 U U nJ u oor

 U U HJ U HJ

 π U n

 U HJ U oO o U u r

 HJ U HJ GO

 u n u U

 U u nJ U n J

 π u u U U nJ Όο o u u HJ U HJ oo o

O c

U υ HJ U HJ

 U u HJ U HJ

 0 0 H3 0 HD S8- £

0 0 HO 0 8-ε

0 0 H3 0 C C8-ε

0 0 HO 0 Ζ8- £

68

^ ^ ^ ^ ^ ^ Ζ, ΙΖΖΟ / OOdf / IDd Z8SI9 / 00 OAV

^ ^ ^ ^ ^ ^

〇 o o o o o o o o o o o o o o o o o o o o 〇 〇 〇 〇 〇 o o o n n n o o o o o o o n o o o o o o o

 '· 丄 <> — one

 C

ooooooooooooooooooooo ooooooooooooooooooooooo oooooooooooooo

CD

00 s ^ s s s s ^ ^ ^ s s s s s s s ^ Q Q s s s s s s s s s n

00 s ^ ssss ^ ^ ^ sssssss ^ QQ sssssssss

o o o o o o o o o o o o o o o o o o o o o o o o o o o n o o o o n

e 3 S ooooooooooooooooooooo ooooooooooooooooooooo oooooooooooooo

GO CO O O CO o c CO O 0 O O o

 I 1 1 1 1 1 1 1 1 1 1

 -J-1 -J-G o to o Π ^ CO t— 'o 00 θ5

Q β Q Q β β β β β β β Q β β β S S S β S S β β Q S

Ο 〇 ο ο ο ο ο 〇 ο ο 〇 ο ο 〇 ο 〇 ο ο ο ο ο ο ο ο ο 〇 〇 ο ο ο ο ο ο ο n n o

 I '

(ooooooooooooooooooooo ooooooooooooooooooooo oooooooooo

t t

 t

o O

o o o o o o 〇 O Q 〇 O O 〇 o o o o 〇 o o o o o o o o o o

2 ^ o

 C

ooooooooooooooooooooo oooooo C ooooooooooooooooooooo ooooo

o o o o o o o o o o o 〇 〇 o O o O

 Φ ω QJ

S ^ S

 ω ω a> ω ω

: S

 ω

 S: S

;; ΙΠ ^

 〇 o 〇 O 〇 〇 o o o o 〇 〇 o 〇 o o o o o o o o o o o

2 inch

¾ 2 ふ —] --- -29 OH Me Me Me Me Me H 0-30 OH Me Me Me Me Me Me 0-31 OH Me Me Me Me Me Et 0-32 OH Me Me Me Me Me Pr 0-33 OH Me Me Me Me Me iPr 0 -34 OH Me Me Me Me Me Bu 0-35 OH Me Me Me Me Me CH 2 CF 3 0 - 36 OH Me Me Me Me Me CH Wa _{CHF 2 0-37 OH Me Me Me Me} Me CH CH F 0-38 OH Me Me Me Me Me Ph 0-39 OH Me Me Me Me Me 4-F-Ph 0-40 OH Me Me Me Me Me 3- CF ₃ -Ph 0-41 OH Me Me Me Me Me 4-F-Bz 0-42 OH Me Me Me Me Me 3-Cl-Bz 0-43 OH Me Me Me Me Me 3, 4-di-F-Ph 0-44 OH Me Me Me Me Me 2-MeO-Ph 0-45 OH Me Me Me Me Me 4-OH-3, 5-0 di-Me-Bz-46 OH Me Me Me Me Me 4-0H-3, 5-0 di-tBu-Bz-47 OH Me Me Me Me Me H 0-48 OH Me Me Me Me Me Me 0-49 OH Me Me Me Me Me Et 0-ςη O li H n mQ Θ MU _Q G ΜΘ ΜΘ ΓΓ n u-51 OH Me Me Me Me Me iPr 0-52 OH Me Me Me Me Me Bu 0-53 OH Me Me Me Me Me CH ₂ CF ₃ 0-54 OH Me Me Me Me Me CHoCHF 0 ο ο ο ο ο ο ο ο 〇 〇 ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο

OH

ώ I 亍

ω a> 0) 0) ： S S S S 9ふ

ω a> 0) 0): SSSS 9

0) 0) 0 0) ω ω 0) ω ω

9

 0) o 0)

0) u

 : S

 ω 0) ω

 : S: s

9 files o o o 〇 o o o 〇 〇 o 〇 〇 o o o o o o o o 〇 o 〇 〇

U n o o

 CD CO

 I I I I I I I I

 Dimensions Dimensions Dimensions Dimensions Dimensions

Fu

 9 inch

 Fu

Six minutes

08 --81 OH Me Me Me Me Me JU- -82 OH Me Me Me Me Me 2-MeO-Ph 0- -83 OH Me Me Me Me Me 4-OH-0

 3 o-di-Me-

D „

 DZ

--84 OH Me Me Me Me Me 4-UH-, o- U

 d it u-DZ- -85 OH Me Me Me Me Me 4- r-rn U- -86 OH Me Me Me Me Me c U- -87 OH Me Me Me Me Me H U- -88 OH Me Me Me Me Me Me U- -89 OH Me Me Me Me Me bt U- -90 UH Me Me Me Me Me rr n U

-91 eight OH Me Me Me Me Me irr

--92 OCHO Me Me Me Me Me D

 D, U, U

8--93 OAc Me Me Me Me Me shi 3 ◦--94 0 (Hxn) Me Me Me Me Me rt ₉ shi U- -95 OCO-cHx Me Me Me Me Me shi n ₂ shi ii ₂ r

 ,

--96 OCO-Ada (l) Me Me Me Me Me Ph u- -97 OBoz Me Me Me Me Me 4 卜 1 Ph U "-nyoo LK4 1 toe Boz Me Me Me Me Me U--yy U (4 -MeO-Boz) Me Me Me Me Me 4-r-DZ U— 1UU U (4-tBu-DOZ Me Me Me Me Me «3—shu βζ U- 101 0 (4- iPrO-Boz) Me Me Me Me Me 3, 4-di-F-Ph 0- 102 0 (3- CI- Boz) Me Me Me Me Me 2-Me0-Ph 0- 103 0 (3- F- Boz) Me Me Me Me Me 4 -OH-3,5- 0 di-Me-Bz- 104 0 (4-OH- 3,5-di-Me Me Me Me Me 4-0H-3, 5-0 tBu-Boz) ai ^_ CDU DZ -105 OCOBoz Me Me Me Me Me 4-1 Br-U -106 OCOCI ^ (4-0H- Me Me Me Me Me r rn u

3, 5-d i -tBu-Ph)

 ,,

 -107 OCOCH, (4-F-Ph) Me Me Me Me Me SDU

-108 0C0CH ₂ (4-MeO- Me Me Me Me Me tBu u

 Ph)

-109 0C0CH ₂ (4-Me-Ph) Me Me Me Me Me 1DU U-1 10 0C0CH ₂ (3-F-Ph) Me Me Me Me Me π π U

,

-1 1 1 0C0CH ₂ (2-MeO- Me Me Me Me Me h U

 Ph)

-1 12 0C0CH ₂ (2-Me-Ph) Me Me Me Me Me ΠΧ u -1 13 OCOCHj (4-OH-Me Me Me Me Me rlx υ

3, 5-di-MeO-Ph)

4-1 14 0C0CH ₂ (4-0H- Me Me Me Me Me Hx 0

3, 5-di-Me-Ph)

4-1 15 0C0CH _2- (3, 5-di-Me Me Me Me Me then J ^ U

 F-Ph) and M. Π Π 2

 c one

4-116 H Me Me Me Me Me 3, 4, 5-tr i1 u

 Me (J-DZ

 4-1 17 Me Me Me Me Me Me π U

4-118 Et Me Me Me Me Me Me u

 4-123 Ν¾ Me Me Me Me Me CH0CF3 0

4-124 NH (Me) Me Me Me Me Me CH CHF 0 0)

 S

 0)

s

Q)

s

0 m ³ N ⁹ w -S 'ε-ΗΟ-^) ΗΝ ZLl-

0 (zoe) s thigh ILl-

0 9W (zog-¾-1z) HN 0L \-

0 69l-f

0 aw (zog-j-^) HN l- ^

0 ngs (zog) HN L9l-

(zg

 0 aw -jg-ε) (UXH) N 991- f

0 n 9--(^ 8) 39Ϊ-

S '£- -f 、^UAMノ 9ΐー zg-θ^-τρ 0-

S '£--f, ^UA M 9ΐ- zg-θ ^ -τρ

 0 -9 '£ -UO- Z9l-

0 9W (° V) Hd

 0 Md-H-TP-i '' £ 9N (OHO) HdN-

0 zg- D- ε 9N 3W (3V) 1HN 091-1-

0 zg-d- (0H3) ^ HN 69ΐ-ί-

0 S5l-

0 Md-J- †-(3V) L l-

0 Md 9W (.V) HN

0 ¾H3¾3 ^s (zg_o-

0 (zg-H-t) MdN esi-i-

0 ng ^(z e) qdN

 0 (z -j-f ") -id I l-f

0 d (zg) 1HN 09T-f-

0 3 3 _W (zg- jt 3 6H-f

LOL

LlZimOd £ / lDd J8S19 / 00 OAV . Q Up

 4 117 i o-ヽ. Vie Π J iVlfc: M IVlP Up

 c Hx o

Ul

One u ₀ Up

 丄 / 4 I E L, ^ 1: — Π UΙn — Q, 0 ΜΘ lt IVlt? 1 0 αι L RD, U, β β DOZ

1 -1 丄 7 Χί-ί 0 Γ ^ (Λ—Γ U \ ΙnΑ— ό., 0 1 Ινΐθ iVlc IVlt! J o

 A- 0 Π, O ίνΐθ iVlc IVlfc IVlt- U j j 'J o i-i + t Do, u, ― D

 DOZ No

 77 nx no un IViU Me 1V1 Ho

Q ^

, 0— a <^ _η l'— I ¾D, U

 DU no

 Up Up

 丄 / 0 ΠΓΠ DOL IVIti e o

-17Q IN ΓΠ ノ ¾ IVlc IVlc iV lrlfc- Fto

 -J, J u

 DL DLZ

p MP o 丄 0丄 IViti Mc IVlU IVIfc i Pr o

p MP o 丄 0 丄 IViti Mc IVlU IVIfc i Pr o

_ι ₀

 Vie ο IN ^ t Γ ノ Θ 丄 vie fc? Mfc IVIfc? R DiUi

 nU— Q i— LDUDOZ

丄 ο un u Π u Π し shi ⁿ 2 shi ^F 3 o

-1 QA M

 丄 04 Mfc: 1V1pU! VltJ 2 o

A ~ O * J u n u Π U Π Π u n H n ^ 2 n \ j

4- -186 OH H H H H H Ph 0

4- -187 OH Et H H H H 4-F-Ph 0

4- -188 OH Et Me Me Me Me 3- CF ₃ -Ph 0

4- -189 OH Pr Me Me Me Me 4-F-Bz 0

4- -190 OH iPr Me Me Me Me 3-Cl-Bz 0 1 iy 1

 Un DU ΜΘ Θ ΜΘ,: U 丄 Factory i ll n

, 1 Mr.

 --ly UH lDU Me Me ΜΘ ΜΘ

 4-UH rn Me Μβ Θ ivie: Re リ 0, n

·-± リ Π , J Πリ al iviy DZ

·-± Π, J Π

 a 1 † XRDiUi— D R7Z

1 Q ^: Un u U

 4 Μθ n ^ U Π IVlt; ~ ± 1 -Π DI-, O Factoryh Ho

1 u

 UAc D

 Me n DU Π θ ά Γ r n π

.1 1J

 4-Urrn Me n tDU Π ivie bDU

4 Π Li Shu JiΠU

 One u u

 4 yy utsyr θ Π LDll Π I MVlt ,; 丄 R DlUl π

_9ΠΠ _Q

 UDOZ Π t RDnU u Π Up i ll π u One P one Ru

U DOZ Θ Π L RDlUl u Π 0 u ₃ u

 BOZJ MB Π u Π lVlc re u

UDOZ Θ Π and £) U u Π ivlt o Ί U 4 and * ₃ οζ; u

Me Π LD uu _v

Ινΐθ rしu rし ；）一 πリ ru pup し ₂し ί1Γ₂ uDU Π nx nx

Ινΐθ r then ur;) 1 π ri ru pup then ₂ ί1Γ ₂ u

 UD INn AC Me u Π ΜΘ 4 0 Γ1 υ

 IVIBU DZ

_9Π7 ΜΘ Π LDU u Π Me Π

z τl:--90Q 1ΝΠ Γ DOZ iVlti u Π H n

4- -210 NH (4-CF ₃ -Boz) Me H tBu H Me Pr 0

4- -211 NH (3-F-Boz) Me H tBu H Me iPr 0

4- -212 NH (3-CF ₃ -Boz) Me H tBu H Me Bu 0

04- -213 NMe (4-F-Boz) Me H tBu H Me

0

4- -214 Marauder e (4- CF ₃ -Boz) Me H tBu H Me CH ₂ CHF ₂ 0

-258 ΟΒζ Me Me Me Me Me tbu U ι \ Η (4 一 1 卜₃ -ϋοζ) Me e Me Me Me ■ i RI I Π-260 NMe (3, o— di—shi 丄 ichi Me Me Me Me Me Crr υ

 D ヽ -261 ΝΗ (3, 4 di-F- Me Me Me Me Me CDU U

 Boz)

-262 NH (2, 4-MeO- Me Me Me Me Me cpn U

 ヽ

 Boz)

-263 NH (3, 4, 5-tri- Me Me Me Me Me cHx 0

 (MeO-Boz)

-264 NHx (4-N0 ₂ -Boz) Me Me Me Me Me CH ₂ CH ₂ — 0

CH, CHF ₀ -265 NH (4-OH-3,5-Me Me Me Me Me 3, 4, 5-tri-0 di-Me-Boz) MeO-Bz Ex.XYZQ mnq

Compound

Object number

 Mouth

4-1 CH ₂ 0 CH 0 1

4-2 CH ₂ 0 CH 0 1

4-3 CH ₂ 0 CH 0 1

4-4 CH ₂ 0 CH 0 1

4-5 CH ₂ 0 CH 0 1

4-6 CH ₂ 0 CH 0 1

4-7 CH ₂ 0 CH 0 1

4-8 CH ₂ 0 CH 0 1

4-9, C 0 CH 0 1

-38 CH ₂ 0 CH 0 3-39 CH ₂ 0 CH 0 4-40 CH ₂ 0 CH 0 δ-41 CH ₂ 0 CH 0 6-42 CH ₂ 0 CH 0 7-43 CH ₂ 0 CH 0 8-44 C¾ 0 CH 0 8-45 CH ₂ 0 CH S 1-46 CH ₂ S CH 0 1-47 CO 0 CH 0 1-48 CHOH 0 CH 0 1-49 Small □ Hand 0 CH 0 1-50 C = N0H 0 CH 0 1-51 C = NOMe 0 CH 0 1-52 ONOBz 0 CH 0 1-53 C = N0Ac 0 CH 0 1-54 C = band oz 0 CH 0 1-55 ONO-COBz 0 CH 0 1-56 C = N0Ph 0 CH 0 1 -57 ONO-(4-F-Ph) 0 CH 0 1-58 ONO- Pn 0 CH 0 1-59 C = N0-C0NH (Me) 0 CH 0 1 1 60 C = N0- CONH (Pr) 0 CH 0 1-61 C = 0-C0NH (Ph) 0 CH 0 1-62 C = N0C0NH (Bz) 0 CH 0 1-63 C = N0C0NMe ₂ 0 CH 0 1-64 C = N0- COO e- (iPr) 0 CH 0 1-65 ONO-CONMe (Ph) 0 CH 0 1 -66 C = N0- CONEt- (Bz) 0 CH 0 1-67 C = N0-C0NPh- (Bz) 0 CH 0 1-68 C = 0-C0NPh- (Bz) 0 CH 0 1-69 CH ₂ 0 N 0 1-70 CO 0 N 0 1-71 CHOH 0 N 0 1-72 Bond 0 N 0 1-73 C = N0H 0 N 0 1-74 O Band e 0 N 0 1-75 C = N0Bz 0 N 0 1-76 C = N0Ac 0 N 0 1-77 C = N0Boz 0 N 0 1-78 C = N0C0-CH ₂ Ph 0 N 0 1-79 C = N0Ph 0 N 0 1-80 C = N0 (4- F-Ph) 0 N 0 1-81 C = N0-Pn 0 N 0 1-82 C = N0-C0NH (Me) 0 N 0 1-83 ONO-C0NH (Pr) 0 N 0 1-84 C = N0 -C0NH (Ph) 0 N 0 1-85 C = N0-CONH (Bz) 0 N 0 1-86 C = N0-CO ban e ₂ 0 N 0 1-87 C = N0-C0NMe- (iPr) 0 N 0 1-88 C = N0- CONMe-(Ph) 0 N 0 1-89 C = N0- CONEt (Bz) 0 N 0 1-90 ONO- CONPh- (Bz) 0 N 0 1-91 C = N0C0- NPh (Bz) 0 N 0 1-92 C 0 CH 0 1-93 CH ₂ 0 CH 0 1 ΐ 0 Η3 0 ¾3

 ΐ 0 Η3 0 ¾3

 ΐ 0 HD 0 ¾D 6Π-ΐ ^ ΐ 0 Η3 0 ¾D 8Π-

I 0 HD 0 ¾0 ΖΠ-ΐ-

I 0 HD 0 ¾3 9Π- ^ ί 0 Η3 0 ¾D ΐ Ι- ^ ΐ 0 Η3 0 ¾0 ΐ ΐ- ΐ 0 Η3 0 ¾3 επ- ΐ 0 Η3 0

 ΐ 0 HD 0 m-

1 0 Η3 0 tsu O U-f ΐ 0 Η3 0 ¾D 601-ΐ- ΐ 0 Η3 0 ¾D 801- ^

I 0 HD 0 ¾D L0 \ ~ f ΐ 0 HD 0 ¾3 90ΐ-ΐ ΐ 0 ΗΟ 0 ¾3 SOT- ΐ 0 Η3 0 ¾3 ΚΠ-

I 0 Η3 0 ¾3

 1 0 ΗΟ 0 soi-t- ΐ 0 Η3 0 ¾ ΙΟΐ- ^ ΐ 0 ΗΟ 0 ¾ ΟΟΐ-ί- ΐ 0 Η3 0 66- ΐ 0 Η3 0 ¾3 86-f- ΐ 0 Η3 0 ¾3 L6-f ΐ 0 Η3 0 ¾3 96- ΐ 0 Η3 0 6-f

I 0 ΗΟ 0 f6-f

O i l

LlZZQIOMr / LDd Z8S19 / 00 O o

ο ο o o O

ο ο oo O

ΐ 0 HO 0 0Z- ΐ 0 HO 0 fOZ- ΐ 0 Η3 0 pcs £ OZ- ΐ 0 Η3 0 ZOZ-f ΐ 0 Η3 0

 ΐ 0 Η3 0 O OOS-ΐ 0 Η3 0 m- ΐ 0 Η3 0 ¾

 ΐ 0 Η3 0 ¾ L6l- ΐ 0 Η3 0 961-t ΐ 0 HD 0 6l-f ΐ 0 Η3 0

 Τ 0 HD 0 ¾D

 ΐ 0 Η3 0 Z6l- ΐ 0 ΗΟ 0 Ϊ6 Ϊ- ΐ 0 Η3 0 ¾ 06ΐ-ΐ 0 Η3 0 ¾D 681-ΐ- ΐ 0 Η3 0 881-ΐ- ΐ 0 Η3 0 L8l-f ΐ 0 Η 0 98l-

I 0 HD 0 88l- ΐ 0 Η3 0 ¾D

 ΐ 0 HD 0 ¾3 £ 8l- ΐ 0 Η3 0 ¾3 Z8 \ -f ΐ 0 Η3 0 ¾3 \ Sl-f

I 0 HD 0 08l-f ΐ 0 HD 0 6Ll- ΐ 0 Η3 0 8Ll-f ε

ΙΙΓΖΟ / OOdf / IDd u

9— s s- -262 CH, 0 N 0 1 1 1

-263 CH ₂ 0 0 1 1 1

-264 CH ₂ 0 N 0 1 1 1

—265 CH ₂ 0 N 0 1 1 1

例示 R1 R2 R3 R4 R5 R6 R7 R8 化合

Example R1 R2 R3 R4 R5 R6 R7 R8 Compound

 Object number

 Number

 5-1 OH Me Me Me Me Me H H

5-2 OH Me Me Me Me Me H Me

5-3 OH Me Me Me Me Me H Et

5-4 OH Me Me Me Me Me H Pr

5-5 OH Me Me Me Me Me H iPr

5-6 OH Me Me Me Me Me H Bu

5-7 OH Me Me Me Me Me H iBu

5-8 OH Me Me Me Me Me H sBu

5-9 OH Me Me Me Me Me H Pn

5-10 OH Me Me Me Me Me H Hx

5-1 1 OH Me Me Me Me Me H Ph

5-12 OH Me Me Me Me Me H 4-F-Ph

5-13 OH Me Me Me Me Me H 4-CF -Ph 0 4 Un ΐνΐθ H Bz o ^— 1 o Un Θ IVIG IVlfc? N 4-F-Ph

5-16 Un Me iVlfci Un

 5-17 u

Un θ ΜΘ Me ₀ Θ Π cPr

5-18 n

 Un Θ vie IVl i 1-1 cPn

5-19 ivie Ac

5-21 S0 _? Me

5-22 OH iVit: ivit; λ SO Et

5-23 OH S0 ₂ Pr

5-24 un ΜΘ ίνιθ Θ IVlti u Π SO Ph

5-25 Un ΜΘ Μθ Me ΜΘ ΜΘ u Π S0 ₂ (4-Cl-Ph)

5-26 u

Un ΜΘ Μθ Θ ΜΘ Θ Π CONH,

5-28 OH Me Me Me Me Me H CO Marauder e ₂

5-29 un Ινίθ ινΐθ u n CONH (Et)

5-30 OH Me Me Me Me Me H CONH (Bu)

5-31 un CONH (Ph)

5-32 OH Me Me Me Me Me H CONH (4-F- Ph)

5-33 OH Me Me Me Me Me H LONH (4- to Bok ₃ -

 Ph)

5-34 un n CONH (2, 3- di-Cl-Ph)

5-35 OH Me Me Me Me Me H CONEt (4-F- Ph)

5-36 OH Me Me Me Me Me H CONH (Bz)

5-37 OH Me Me Me Me Me H CONH (4-F- Bz) —38 OH Me Me Me Me Me C0NH (4-CF _3-

Bz)-39 OH Me Me Me Me Me CONH (4-OH- 3, 5-di-tBu-

Bz) -40 OH Me Me Me Me Me H (J ₂ Me-41 OH Me Me Me Me Me Me CUBz-42 OH Me Me Me Me Me Et Hx-43 OH Me Me Me Me Me Pr Prn-44 OH Me Me Me Me Me iPr Byr-45 OH Me Me Me Me Me Bu Pnto-46 OH Me Me Me Me Me CH 2 CF 3 Hxn-47 OH Me Me Me Me Me CH, CH-F 2 4-F-Boz-48 OH Me Me Me Me Me CH ₂ CH ₂ -F 3-F-Boz-49 OH Me Me Me Me Me Ph 2-F-Boz-50 OH Me Me Me Me Me Me 4-F-Ph 2-MeO-Boz- 51 OH Me Me Me Me Me 3-CF ₃ -Ph 3-MeO-Boz-52 OH Me Me Me Me Me 4-F-Bz 4-MeO-Boz-53 OH Me Me Me Me Me Me 3-Cl-Bz 2 -CF3-B0Z-54 OH Me Me Me Me Me H 3-CF3-B0Z-55 OH Me Me Me Me Me Me 4-CF3-B0Z-56 OH Me Me Me Me Me Et 2-F-4-CF3-

Boz-57 OH Me Me Me Me Me Pr 4-OH-3, 5-di-Me-Boz-58 OH Me Me Me Me Me iPr 4-OH- 3, 5-di -tBu-Boz -59 OH Me Me Me Me Me n,,

 DU 4 One UH-o-di-tBu-Boz

5 - 60 OH Me Me Me Me Me CH 2 Cr 3 4 one OH - 3, o- di - tBu - Boz b- l UH Me Me Me Me Me and _{H 9 LH- h 2 4-Un} _, 0

Ul - tDU DOZ co UH Me Me Me Me Me to t "to ₂ t

 0, o αΐ Μθ

DZ) o ^_ bo UH u

 Me Me Me Me Men

 rn Π o o4 Un Me Me Me Me Me r * DU Me

 D

b-bo UH Me Me Me Me J J 1 ₃ -bt b-bb UH Me Me Me Me Me 4-r -DZ rr

5-o7 OH Me Me Me Me Me 3-C 丄 Bz iPr

5-Do OH Me Me Me Me Me Hu

5-69 OH Me Me Me Me Me Me lBu

D- / L) Un Me Me Me Me Me bt sBu b— / 1 On Me Me Me Me Me Pr Pn

C_7 ί Δ0 Un Me Me Me Me Me irr Hx r_7 Q Un Me Me Me Me Me D

 D, U, Ph

Un Me Me ΜΘ Me Me し し r ₃ 4-F-Ph i Un Me Me Me Me Me し H ₂し Π 一

Un Me Me Me Me Me and tt ₉ teeth ₂ one Γ Bz

5-77 OH Me Me Me Me Me Ph 4-F-Ph

5-78 OH Me Me Me Me Me 4-F-Ph 4- CF ₃ -Ph

5-79 OH Me Me Me Me Me 3-CF ₃ -Ph cPr

5-80 OH Me Me Me Me Me 4-F-Bz cPn

5-81 OH Me Me Me Me Me 3-Cl-Bz Ac 5—82 OH Me Me Me Me Me 3, 4-di-Boz

 F-Ph

5-83 OH Me Me Me Me Me 2 -MeO-Ph SO, Me 5-84 OH Me Me Me Me Me 4 - 0H_ S0 2 Et

 3, 5-di-

Me-Bz

 5-85 OH Me Me Me Me Me 4-OH-S0. Pr

 3, 5-di-tBu-Bz

5-86 OH Me Me Me Me Me H S0 ₂ Ph

5-87 OH Me Me Me Me Me Me S0 2 (4- CI - Ph)

5-88 OH Me Me Me Me Me Et C0NH ₂

5-89 OH Me Me Me Me Me Pr CONH (Me)

5-90 OH Me Me Me Me Me iPr C0NMe ₂ u 丄 D,,

 Un ΜHΘ ΜΘ ΜΘ Θ DU DU

5-92 OH Me Me Me Me Me CH ₂ CF ₃ CONH (Bu)

5-93 OH Me Me Me Me Me CH CH ^— F ₉ CONH (Ph)

5-94 OH Me Me Me Me Me CH CH CH ー F CONH (4-F-

Ph)

5-95 OH Me Me Me Me Me Ph C0 H (4-CF _3-

Ph)

5-96 OH Me Me Me Me Me 4-F-Ph CONH (2, 3- di-Cl-Ph)

5-97 OH Me Me Me Me Me 3-CF ₃ -Ph CON (Et)-

(4-F-Ph)

5-98 OH Me Me Me Me Me 4-F-Bz CONHBz

5-99 OH Me Me Me Me Me 3-Cl-Bz CONH (4-F-

Bz) V VJ OH π IVltr Up IVIc IVl:, U ΓΠΜΗ -CF _

 Γ i ll υ <

OH π Up, Up

iVlti Δ .VI i ll Η π

 , O I

 D

\ JO ΠH Mo _{0 0}

 ~ mc IVlc JVlti 4 Π \ J VJD i

 , «J HI

 † n

 -104 OH Vlt; VI IVlt; τ J Γ i

-10ή OH IVlt; IVlti 1 1 1

-106 OH 1V1 Up IVlt; Up M ivit- 11 Rvr--107 n Up, IVlc Mfci JViti ΓΙ1 ϋ

-1 OR n p, MG β I nxn

-1 OH Up,

n IVlU IVlt? Mc l ζΐ_ρ_η _Π7

-110 _R0

 π ινΐθ Me · P Γ-Γr Γ D

 iVic IVlfcr IVlt? DU Γ DU.

-11 OH M mPe vie 1V1 I MVlPt: '3 1V1 UUZ OH 1V1 ivit: IVifc: Up lvic ΓΗ Π ΓΗ-F O IVlfcrw DU / i

5- -114 OH Vie IVlt; 1V1U M ru r _p T; M

5- -115 OH IVlpt- ivipt; MP IVlc ivit; Γ 11 9-ΓΡ -Ro

5- -116 OH MP Up IVJPc IVlfci Up

 τ: Γ ΓΠ

 5- -117 OH IVlti Up VI Up Up Q-PP

δ- ■ 118 OH Me Me Me Me Me 4-F-Bz 2-F-4-CF3-

Boz

5- -119 OH Me Me Me Me Me 3-Cl-Bz 4-0H-3, 5-di-Me-Boz

120 OH Me Me Me Me Me 3, 4-di-4-0H-3, 5- F-Ph di_tBu-Boz

5-121 OH Me Me Me Me Me 2-MeO-Ph 4-0H-3, 5-di-tBu-Boz

5-122 OH Me Me Me Me Me 4-0H- 4-OH-3 5- 3, 5-di-di-tBu-Boz

Me-Bz

 5-123 OH Me Me Me Me Me 4- OH- 4-OH- 3 5- 3, 5-di-di-tBu-Boz tBu-Bz

 5-124 OH Me Me Me Me Me 4-Br-Ph CO (4-OH- 3, 5-di-Me- Bz)

5- -125 OH Me Me Me Me Me 2-F-Ph H

5- -126 OH Me Me Me Me Me H H

5- -127 OH Me Me Me Me Me Me Et

5- -128 OH Me Me Me Me Me Et Pr

5- -129 OH Me Me Me Me Me Pr iPr

5- -130 OH Me Me Me Me Me iPr Bu

5- -131 OCOH Me Me Me Me Me Bu iBu

0 "-132 OAc Me Me Me Me Me CH ₂ -CF sBu

0 "-133 OCOHx Me Me Me Me Me CH CHF Pn

5- -134 OCO-cHx Me Me Me Me Me CH2CH9F Hx

5- -135 OCO-Ada (l) Me Me Me Me Me Ph Ph o- -136 OBoz Me Me Me Me Me 4-F-Ph 4-F-Ph

5- -137 0 (4- F-Boz) Me Me Me Me Me 3-CF ₃ -Ph 4-CF ₃ -Ph

5- • 138 0 (4-MeO-Boz) Me Me Me Me Me 4-F-Bz Bz

5- ■ 139 0 (4-tBu- Boz) Me Me Me Me Me 3-Cl-Bz 4-F-Ph

5- 140 0 (4-iPr-Boz) Me Me Me Me Me 3 4-di- 4-CF ₃ -Ph F-Ph one ο DU J no Up Up MP 2-MeO-Ph cPr AO Up

U «J DO Me IVlt: Up 4-0H- _c p _n

Q = 1-Hn-

 No 3 5

 tBu-Bz

 OPOR D / Up Me 4 ichi Br— Ph Boz s— J OCO (A ^ O-jn j Up Mp A / Ip 2- -ph SOMe a tDU DZ

No P 1 _s Bu SOEt

■ 147 OCO (4-MeO-Bz) Up Me tBu S0 ₂ Pr

■ 148 OCO (4-MeBz) Up Up ¥ 1 iBu S0 ₂ Ph c; -1 -149 OCO (3-F-Bz) i P 1n S0 „(4-Cl―

 Ph)

■ 150 OCO (2-MeO-Bz) Up Up HY CONH

-151 OCO (2 Up Up

 -Me— Bz) iVlc IViti IVJc HY Γ0ΝΗ- (UP)

-152 OCO (4-OH-3, 5-Up VICT H 11YΛ CO ban e di-MeO-Bz)

 5- -153 OCO (4-OH- 3 5- Me Me Me Me Me Hx CONH (Et) di-Me-Bz)

 -154 OCO (3, 5-di- F-J MP MP CH CH CH 1 CONH 11 (Bu)

 Bz) CH-F,

5- -155 H Me Me Me Me Me 3, 4, 5- CONH (Ph) tri-MeO-

Bz

5- -156 Me Me Me Me Me Me H CONH (4-F-

3 5-di-tBuBz

 5- • 174 NPr (Hx) Me Me Me Me Me 4-Br-Ph 2-MeO-Boz

5--175 NPr (Oc) Me Me Me Me Me 2-F-Ph 3-MeO-Boz

5- 176 NPr (Dc) Me Me Me Me Me sBu 4-MeO-Boz δ- • 177 NBu ₂ Me Me Me Me Me tBu 2-CF ₃ -Boz

5-■ 178 NBu (Hx) Me Me Me Me Me iBu 3-CFj-Boz δ- 179 N (Pn) ₂ Me Me Me Me Me Pn 4-CF3-B0Z

5- 180 N (Nn) J Me Me Me Me Me Hx 2-F-4-CF3-

Boz

5--181 NH (Ph) Me Me Me Me Me Hx 4-OH-3, 5- di_Me- Boz δ-182 NH (3-Cl-Ph) Me Me Me Me Me Hx 4-0H-3, 5 -di-"tBu-Boz

5- -183 NMe- Me Me Me Me Me Hx 4- OH-3, 5-

(3-CF ₃ -Ph) di-tBu-Boz

5- -184 NEt (Ph) Me Me Me Me Me CH ₂ CH ₉ CH 4-0H-3, 5-

CHF ₂ di— tBu-Boz δ- -185 NEt-(4-MeO-Ph) Me Me Me Me Me 3, 4, 5-4-0H-3, 5-tri-MeO- di-tBu-Boz

Bz

 5- -186 N (Ph 2 Me Me Me Me Me H CO (4-OH-

3, o-di— Me—

Bz)

5- -187 NMe (Bz) Me Me Me Me Me Me H

5- -188 NMe (4-F-Bz) Me Me Me Me Me Et Me

5- • 189 NEt (Bz) Me Me Me Me Me Pr Et

5- • 190 NPr (4-F-Bz) Me Me Me Me Me iPr Pr

 NMe {Ac) Me Me Me Me Me 4: ΓΓ flA

5> J--〗 Q7 NMe rm) Me Me Me Me ΜΘ 0 then _{: 3} Γ rn

5-198 ΜΘ Me ΜΘ ΜΘ 4 Γ D <τ: Γ Γ 1

\ yp-t- (ヽ_Q p

 ΜΘ Μθ ίνιθ JVl6 «J D-h

5-200 Γ Θ Θ Θ U Me U

5-201 yrn i \ C θ u _a

 Me IVIU 9- IVlΡtrW Γ i J

 5-202 1ΝΓΠ Dj J-no iVlfci IVl; IVlc ivlc v 4-OH — 4-ΓΡ — Ph

 , □ Ul

 IVlti DZ.

 5-203 N (Hxn) (3- MeO-Θ ΜΘ e Me IVlti T Π Γ

 Ph), 0 u

 DU D /,

 5-204 N (Byr) (4-F-Bz) ΜΘ ΜΘ Θ Θ ΜΘ Di rfl urn

5-205 Ν (Ηχη) (3-Br- Bz) u _a

M6 mQ y Μ _Q θ Θ 9-1 P— rt

5-206 H (Boz) ΜΘ ΜΘ Μθ ΜΘ ΜΘ SDU

5-207 NH (4-F-Boz) Mo ΜΘ Μ ₀ θ jvie t D RnU O 2 ^ 1

_{5-208 NH- (4-N0 2 -Boz} ) iViti lVlti Up Up uu 2

5-209 NH (4-NH ₂ -Boz) Me Me Me Me Me Pn S0 ₂ Pr

5-210 NMe (Boz) Me Me Me Me Me Hx S0 ₂ Ph

5-211 NH (4- OH- 3 5- di- Me Me Me Me Me Hx S0 2 (4-Cl-Ph) tBu-Boz)

5-212 NMe (4-OH-35-Me Me Me Me Me Hx C0NH,

) HO-Top OH Ft HHHH 4-F-Ph SO.Me

OH FT VIC M TIPC 3-CF, _Ph COBz ή 一 228 OH 1 U Ϊ1p VIC Me 4-F-Bz cHx

 1

 OH i ll Up Up Up 4 OH— Hxn

OH i Pn 11 Up M VIPC 4-0H- 4_p

 Ί 5— di—

 tBu-Bz

 5-234 OH Me H tBu H Me 3-F-Boz

5-235 OAc Me H tBu H Me 2- -ph 2-F-Boz

5-236 OPrn H 1J H Ϊ1 c i i 2-MeO-Boz

me H †Rii H + 11 3-MeO-Boz 5—9

me H † Rii H + 11 3-MeO-Boz

OR L) v yr H n H MP 4-MeO-Boz

 5-241 0 (3-CF 1 -Boz) MP H 1 † Ri] H 1 "H 4-CF3-B0Z

5-242 OBoz Me H tBu H Me Hx 2-F-4-CF3-

Boz

5-243 0 (4- CF ₃ -Boz) Me H tBu H Me Hx 4-OH- 35-di— Me-Boz

4- OH - 3 5 -5-244 NH ₂ Me H tBu H Me

4- OH-35-

CHF ₂ di-tBu-Boz

5-245 NH (Ac) Me H tBu H Me 3, 4, 5- 4-OH 3 5-

All

 D o Un Me Π DU Π rn Π Γ 3 ΓΠΜΗ (V9.,

LI M

 Γ l il

D- o4 U (4-UH-, o-di-Me Me Me Me Me Me tt ₂ Shii Ui, Hi5Z tBu-Boz;

o- oo. \ ri ₉ Me Me Me Me ΜΘ rn then r

 DZ

 5-287 ΝΉ (Boz) ΜΘ ινΐθ JV1G JVJt? ". I ll H n u

5-288 NHMe — P

 Me Me Me Me Μθ 4 Γ 一 DZ n

5-289 NMe (Et) jvie e Mo Q-Π- ₇ IVlti

5-290 H (4-0H-3, 5-di- Θ Θ ΜΘ ΜΘ Θ CI 4 CI-Pt tBu-Boz) Γ

 5-291 NH (4-0H-3, 5-di-Me Μθ Μθ Θ ΜΘ Z 9— Μ Mα6ΠU— rn Γ tBuBz)

 5-292 Me (3-Cl-Boz) i__ΠΪ-ί—

 Me Me Me Me Θ lri

 o, o ai

 ΜΘ DZ

5-293 Pr ₂ —

 Me Me Me Me Me 4 Π Π 4

 Un DU Rn— R

 5-294 NBu (Bz) Me Me Me Me Me 4-Br-Ph iBu

5-295 NMe (Hx) Me Me Me Me Me 2-F-Ph sBu

5-296 Ac ₂ Me Me Me Me Me sBu Pn

5-297 OBz Me Me Me Me Me tBu Hx

5-298 NH (4-CF ₃ -Boz) Me Me Me Me Me iBu Ph -299 NMe (3, 5-di-CI-Me Me Me Me Me cPr 4-F-Ph Boz)

-300 NH (3, 4-di-F- Me Me Me Me Me cBu 4- CF- Ph

 Boz)

-301 NH (2,4-di-MeO- Me Me Me Me Me cPn Bz

 Boz)

-302 H (3,4, 5-tri- Me Me Me Me Me cHx 4-F-Ph

 (MeO-Boz)

-303 (Hx) (4-N0 2 - Me Me Me Me Me CHCH 2 CH 4-CF, -Ph

Boz) CHF ₂

-304 NH (4- OH-3, 5- di_ Me Me Me Me Me 3, 4, 5-cPr

 Me) Boz tri-MeO- Bz Example X Y z Q m n q

Compound

Object number

 Mouth

5-1 CH ₂ 0 CH 0 1 1 1

5-2 CH ₂ 0 CH 0 1 1 1

5-3 CH ₂ 0 CH 0 1 1 1

5-4 CH ₂ 0 CH 0 1 1 1

5-5 CH ₂ 0 CH 0 1 1 1

5-6 CH ₂ 0 CH 0 1 1 1

5-7 CH ₂ 0 CH 0 1 1 1

5-8 CH ₂ 0 CH 0 1 1 1

5-9 CH ₂ 0 CH 0 1 1 1

5-10 CH ₂ 0 CH 0 1 1 1 S— 1 o 1 π ΓΗ 0 1 1 1

5—1 ^ J ru n ΓΗ nil]

 ■ J ru 0 H i l l ー 1 ru Π9 re ru π 0 1 1 1 ー 17 ru Π2 u run 0 w 1 1 1

0 0 ru 0 1 1 1

U U nu 1 1 Q V V ru n π u 1 1 n, n ru Π Π u 1 1 1 0 1 91 M M ₂ nu ru Π Π u 1 1 1

J ΔΔ then M ₂ nu run 0 u 1 1 1 and n ₂ re n 0 VJ 1 1 1 rui n ru 0 1 1 1

 0 0 1 1 1

5-26 then n ₂ ΓΗ 0 1 1 1

5-27 0

^N 2 Ω vj 1 1 1

5-28 r shi u 11 ₂ nu ru π nu 1 1 1

5-29 shi ₂ nu π Π U 1 1 1 shi n ₂ uu π Π υ 1 1 1

5-31 0 ΓΗ 0 1 1 1

5-32 shi 12 ni 0 1 1 1

5-34 CH ₂ 0 CH 0 1 1 1

5-35 C 0 CH 0 1 1 1

5-36 C¾ 0 CH 0 1 1 1

5-37 CH ₂ 0 CH 0 1 1 1

5-38 CH ₂ 0 CH 0 1 1 1 Ό r shi u Π. Π r shi unn 1 丄 1 丄 1 丄 one / in sh! u then n Π \ J 1 丄 1 丄 1 丄

 ru

u: 丄 Π;) n u r then u n 0 u 1 丄 丄 1 丄 1 r then u π r then u n 0J 1 1 1 ru 0 0 w 1 1 1

D4: r u u π 'r r u n 0 1 1 1

 ru n V then u n 0 \ 1 丄 1 丄 1 丄

0 40 shi 1 nur shi un Π U 1 i 1l 1l o 4/1 1 shi H ₉ u shi ϋ 1 U 1

 丄 丄 丄 A o

M M ₉ U li Π U 1 1 1 丄 1 丄 o 4y MU n Π u 1 丄 丄 1 1 丄 o ou π u n n Π υ 1 丄 1 丄 1 丄 H2 ur u u Π Π υ 1 丄 1 丄 1 丄 r shi u rt ₂ nu ru 0 1 丄 1 丄 1 丄 fH 0 shi 0 1 1 1 shi ⁿ 2 shi n 丄 丄 丄 shi ₂ r nnu 1 丄 1 丄 丄 1

0 0 し rt ₂ nu un unu 丄 丄 O o O i ¾ J ¾ n U pu Π u 1 丄 Upper〗 1 丄 ϋ r θ r u u π u ru Π u 1 丄 1 丄 1 丄 ru π 0 U 1 丄 1丄 1 u u Π 丄

0 DU n Π 1

And ¹ ¾ u and Π u丄1丄1丄ru

 O し shi l u shi Π u 1 丄 11 1 丄

5-62 CH ₂ 0 CH 0 1 1 1

5-63 CH ₂ 0 CH 0 1 1 1

5-64 CH ₂ 0 CH 0 1 1 1

5-65 CH ₂ 0 CH 0 1 1 1

5-66 CH ₂ 0 CH 0 1 1 1 ob / shi unn 1 丄 o bo shi H ₂ U shi nr \ 9

 U

 3 w y Q

 Then n u n

 U

 One 7Γ »n u ru

 Π u -t1 0-1 7 l 1 丄 f f n u r u u n ri u

0 / z then H ₂ nu then Π n U

0 / shi M ₂ nun U o

0/4 then H ₂ u then H u 4

5—o then u then 11 u 0

D I u then H u then u z

 _77

0 (then M ₂ u then H u

oo then H ₂ U then HU

0 {y then l ₂ n U then 11 u

 0 oU then U u 0 iD 丄 U ¾ U then H n u 7

0 C5Z ¾ U then H u O Q

0 o u.

Then H ₂ U then M o Q

 π ru c

 0 04 then U then n

 0 oO then n π u

 0 U U U H H H n U

 C_Q7 then ur \ u U then Hu

 0 OO U then hi u

 D Qy shi-one ΠΙ-J U shi M U

 5-90 C = N0Me 0 CH 0

 5-91 C = bandz z 0 CH 0

 5-92 C = N0-Ac 0 CH 0

 5-93 C = N0- Boz 0 CH 0

5-94 ON0-C0CH ₂ -Ph 0 CH 0 5-95 C = 0-Ph 0 CH 0 1 1 1

5-96 Ν = -0-(4 dimensions-Ph) 0 CH 8 0 1 1 1

5-9 / u LH (J 丄 丄 丄

5-98 C = N0-CONHMe ϋ CH (J 丄 丄 丄

0-99 shiichi NO—shi OJNHPr (J CH (J 丄 丄 丄

5-100 C = N0-CONHPh u then H U 1 丄 丄

 C = N0-CONHBz 0 CH U 丄 丄 1

5-102 C = N0-CO marauder e ₂ 0 CH 0 1 1 1

5-103 C = N0-CO ban e (lPr) 0 CH U 1 1 1 C

 5-104 C = N0-CONMe-(Ph) 0 CH 0 1 1 1

5-105 C = N0- CONEt- (Βζ) 0 CH 0 1 1 1

5-106 C = N0-C0NPh- (Bz) 0 CH 0 1 1 1

5-18 0 ¹ 7 C = N0-CONPh— (Bz) 0 uH (Jill

 Eight

5-108 CH ₂ 0 N 0 1 1 1

5 `` -109 CO 0 N 0 1 1 1

" Eight

 3-110 CH 8OH 0 N U 1 1 1

5-丄 11 beef u IN 丄 丄 丄

5-112 C = N0H u N (J i l l

; 3-丄 13 shi — NOMe (J 1 u 丄 丄 丄

"

 5-114 C = N0Bz 0 N 8 0 1 1 1

5-115 C = N0Ac ϋ N (J i l l

"

 5-116 C = N0-Boz 0 N 0 1 1 1

5-11 / C = N0C0Bz 0 N 0 1 1 1

5-118 C2 NOPh 0 N 0 1 1 1

5-119 C = N0- (4-F-Ph) 0 N 0 1 1 1

5-120 C = N0-Pn 0 N 0 1 1 1

5-121 C = N0- CONHMe 0 N 0 1 1 1

5-122 C = N0-CONHPr 0 N 0 1 1 1 Two or

 Shiichi ί \ ϋ 一 し (JlNhhh U IN U 1 丄 1 丄 1 丄

 r

o— 丄 4 shi Fs — shi DlNl tSz U IN U 1 1 丄

1ヽ U 丄 丄 丄'One one 一 Λϋ— し DlNMe UU 丄 1 1 丄 1 丄-丄 t> Me

1 ヽ U 丄 丄 丄

0-丄 / し 一 \ U し UiN me) rn U IN Π U 1 丄 1 丄 1 丄

し一 INUUJ jN U 丄 1丄 1丄 IN Π U 1 丄 丄 o-丄

Shiichi INUUJ jN U 丄 1 丄 1 丄

JN U 丄 丄 丄 o - 1 Ji CH₂ π U し 11 Π U Ί丄 1丄 1丄 し H₂ U し hi U 丄 丄 丄1 1 1 INU

JN U 丄 丄 丄 o-1 Ji CH ₂ π U then 11 Π U Ί 丄 1 丄 1 丄 then H ₂ U then hi U 丄 丄 丄

0-丄 CH ₂ U then H u 丄 丄 丄

 r

0-104 CH ₂ U then U 丄 丄 丄

CH ₂ U then U 丄 1 丄 u 1

D ^_ lb V Lli U 1 I 1

 n

 0 丄 / ¾ ¾ u n n 丄 u 1 丄 1 丄 1 丄

LH ₂ u Π U 1 丄 1 丄 1 丄 1 1 u u Π u 丄 丄 丄

; -1

Shi H ₇ u Shi M u 丄 丄 丄

0 丄 ^: 丄 1

 U u u u 丄 1 丄 1 丄 ο 丄 4 ci¾ u 1 1 1

 M M υ 丄 丄 丄

3 丄 4 U then D 1i 1l 1i

0 144 c¾ Ό li U 1 丄 丄 ー 1

 U Π 1 Ί 1 Shishi M U 丄 丄 1

5-146 CH ₂ 0 CH 0 1 1 1

5-147 CH ₂ 0 CH 0 1 1 1

5-148 CH ₂ 0 CH 0 1 1 1

5-149 CH ₂ 0 CH 0 1 1 1

-179 rし π V し n u 丄 丄 丄 o 5-150 C¾ 0 CH 0 1 1 1

-179 r then π V then nu 丄 丄 丄 o

Un nur then un ΠJ 丄 丄 181-181 r then uu then n Π 丄 丄 丄 -182 then u then Π u 丄 丄 丄-183 r then πu ₉ nur then unu 丄 丄 184-184 then;) nur then unu 185 丄 丄 -185 r then πu ur then u Π w 丄 丄 丄 -186 then π ₂ nur then u Π u 丄 丄 丄 -187 then n ₂ u then Π u 丄 丄 丄 -188 then H ₉ u then Π Π u 丄 丄 丄-189 then π ₂ nu then u Π 丄 丄 190-190 then π ₂ u then u u 丄 丄 丄 -191 r

H H ₂ U u u Π Π u 丄 丄 丄-192 H H ₂ U r u u Π Π V 丄 丄 -193 r u u Π 9 U r u u Π η U 丄 丄 丄 -194 r Π u9 π U r Un Π U

-195 π

丄 丄 丄-199 し u rしu Π Π 丄 丄 丄-200 ru n U U r un un π 丄 丄 丄 丄 -196 n n ₂ π U r u u Π W 丄 丄 197 197 197 n n 丄 丄 丄-198 n n ₂ r r u u Π

丄 丄 丄 -199 shi urushi u Π Π 丄 丄 丄 -200 ru n

U u Π Π u 丄 丄 丄-201 M M ₂ H HU 丄 丄 丄 -202 CH ₂ 0 CH 0 1 1 1-203 CH ₂ 0 CH 0 1 1 1-204 CH ₂ 0 CH 0 1 1 1-205 CH ₂ 0 CH 0 1 1 1-206 CH ₂ 0 CH 0 1 1 1 o- UD Π 1 1

CH ₂ U OH 丄 丄 1 丄

 r

o-2Uo then H ₂ U then U 1 丄 丄 1 丄

 Π

 U U 11 u 1 丄 1 丄 1 丄

0-丄 (J then U then 11 Π u 1 丄 1 丄 1 丄 one once H ₂ then H Π u 1 丄 1 丄 1 丄

Shi H ₂ U Shi H Li 丄 丄 丄 1 1l J Shi HU Π

 H H 1 丄 1 丄 1 丄

0—14 then H ₂ u then Dili r-

H H ₉ U M M π D 1 丄 1 丄 1 丄 b-lb Li U HD HD 丄 丄 丄 r \

b-2 丄_Q U then M u 1 丄 丄 1 1 丄 br— οΐ8 CH ₂ V then HD 丄 丄 丄

CH ₂ U then HU 丄 丄 丄

CH ₂ ϋ HD HD ili rr on iiib H H H ₂ Ό し MU 1 1 1

CH ₂ u then H π U 1 丄 1 丄 1 丄

 Π

 Then V then li U 1 丄 1 丄 1 丄 _0

 し U し 11 Π 丄 1 丄 丄 1 1 Π Π V υ υ 丄 丄 丄

0 U Π

ΔΔΌ then n ₂ then rt D i Τ 1l Ίi

0 m I tt ₂ U n U 1 丄 丄

0 Zor

し M (J 丄 丄 丄U U 11 1) 丄 丄 丄

M (J 丄 丄 丄

5-230 CH ₂ 0 CH 0 1 1 1

5-231 CH ₂ 0 CH 0 1 1 1

5-232 CH ₂ 0 CH 0 1 1 1

5-233 CH ₂ 0 CH 0 1 1 1

5-234 CH, 0 CH 0 1 1 1 Dimension 1

CH ₂ 0 then H 1 1

 (J 丄 丄 丄 ii

-236 s H (J s HU 丄 1 丄 -237 tn ₂ U s hi υ 丄 丄 i-238 LU s HU 丄 丄！ -239 s! "U s U 1 i 丄 丄

CH ₂ U H H 丄 丄 丄 i-241 CH ₂ u Π

 M (J 1 1 1

丄 丄 丄 —242 CH ₂ u then U 丄 丄 丄 -243 then H ₂ U then J1 Π U 丄 丄 丄 -244 CH ₂ U then H (J il l-245

Then l ₂ (J then HU 1 1 1

丄 丄 丄 -246 CH ₂ (J LH Dil i-247 CH ₉ ϋ CH (J ill

1 1 1-248 CH ₂ 0 CH U 1 1 1-249 1 1

And H ₉ u and H (J il 1l-250 CH 2 U and H (J 1i l 1 1l- 251 U 1 1

H H ₂ ϋ D il 1i-252 H H u Π 1 1 1

 H H ϋ 丄 1 I-253 U U H H U 1 1 1

丄 丄 丄 -254 Shi H ₂ u Ln Π U 1 1 1

 丄 丄 丄 -255 n

 U U H H 丄 H 丄

丄 丄 丄-257 し H₂ u し H Λ U 11 11 11-258 CH₂ 0 CH 0 1 1 1-259 CH₂ 0 CH 0 1 1 1-260 CH₂ 0 CH 0 1 1 1-261 CH₂ 0 CH 0 1 1 1-262 CH₂ 0 CH 0 1 1 1 CH₂ U H u 1 1 1

丄 丄 丄 -257 then H ₂ u then H Λ U 11 11 11-258 CH ₂ 0 CH 0 1 1 1-259 CH ₂ 0 CH 0 1 1 1-260 CH ₂ 0 CH 0 1 1 1-261 CH ₂ 0 CH 0 1 1 1-262 CH ₂ 0 CH 0 1 1 1 CH ₂ UH u

 1

H ₂ UMD ili

 n 1

H ₉ UHU 1 1 1 o- bb CH ₂ u 1 1

 M D

H ₂ UHU 1 1 I 1 i

 1

M ₂ UU 1 1 1

Ό n u

τπ H ₂ U nu

 1 o U M u

1 1 o ί H ₉ UHD ilib— o CH ₂ U 11 U ill

CH ₂ u H

CH ₂ 1

 LH D i u 1

5-276 H U L

/ ί CH ₂ u HD

 Ζί U 11 U 1

 J¾ U H u 1

D Zou U H u

H ₂ L) HU ¾ UU 1

5-283 M

H ₂ UU 1

 5-284 LH U IN υ

5-285 H H ₂ U IN υ

5-286 CH ₂ 0 N 0 1 1 1

CH ₂ 0 0 1 1 1

5-288 CH ₂ 0 N 0 1 1 1

5-289 CH ₂ 0 N 0 1 1 1

5-290 CH ₂ 0 N 0 1 1 1

O7 NB0222- Own 6 c2 2—

-28 C = N0C0Bz -29 C = N0Ph -30 ONO (4-F-Ph) -31 C = N0Pn -32 C = N0C0 HMe -33 ONOCONHPr -34 C = N0C0NHPh -35 C = N0C0NHBz -36 C = N0C0NMe 2 -37 C = N0C0N (Me) iPr -38 ONOCON (Me) Ph -39 C = N0C0N (Et) Bz -40 C = N0C0N (Ph) Bz -41 C = N0C0N (Ph) Boz -1 C = N0CH, C00Me -2 C = N0CH ₂ C00Et

-4 C = N0CH ₂ C00iPr -5 C = N0CH, C00tBu -6 C = N0CH ₂ C00Ph -7 C = N0CHC00Bz

例示化合物番号 R7 Rl l

Illustrative compound number R7 Rl l

4-1 H 0 H 4-2 Me 0 H 4-3 Et 0 H 4-4 Pr 0 H 4-5 iPr 0 H 4-6 Bu 0 H 4-7 CH ₂ CF ' ₃ 0 H 4-8 CH ₀ CHF ₂ 0 H 4-9 CHQCHTF 0 H 4-10 Ph 0 H 4-1 1 4-F-Ph 0 H 4-12 3-CF ₃ -Ph 0 H 4-13 4-F-Bz 0 H 4 -14 3-Cl-Bz 0 H 4-15 H s H 4-16 Me s H 4-17 Et s H 4-18 Pr s H 4-19 iPr s H 4-20 Bu s H

4-22 CH CHFos H 4-23 CH ₉ CH. F s H 4-24 Ph s H 4-25 4-F-Ph s H 4-26 3— CF ₃ — Ph s H 4-27 4-F-Bz s H

df / ultl one Z8SI O0

00 〇

Sa

o

3] 2—— Md〇AV

ο ο ο

I

 Dimension

oo n co co co

£ 0.1

£ 0. -Party 03 1 O

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).

上記式中、 R¹乃至 R⁶、 X， Y， Z， A、 Q， n及び qは、 前述したものと同意 義を示し、 R^laは、 R¹の基の定義に含まれるアミノ基及び Z又は水酸基が、 保護 されていてもよいァミノ基及びノ又は水酸基である他、 R¹の基の定義における基 と同様の基を示し、 X^aは、 Xの基の定義に含まれるヒ ドロキシィミノ基及びノ又 は水酸基が、保護されていてもよいヒ ドロキシィミノ基及び Z又は水酸基である他、 Xの基の定義における基と同様の基を示し、 A^aは、 式

(IV)

In the above formula, R ^{1 to} R ⁶ , X, Y, Z, A, Q, n and q have the same meanings as described above, and R ^la is an amino group and a group included in the definition of the group of R ^1. Z or hydroxyl groups, other is optionally protected Amino groups and Roh or hydroxyl even though, indicate the same groups in the definition of group R ^1, X ^a is human Dorokishiimino included in the definition of X the group The group and the hydroxyl group are the same as the groups in the definition of the group X except that the group is a hydroxyimino group and a Z or a hydroxyl group which may be protected, and A ^a is ^a group represented by the formula:

 (II-a) (II-b) (II-c) (II-d)

(In the formula, T r represents the bird whistle two Rumechiru group, m represents the same meaning as those described above, the B and R ^{7 a} B and R ⁷ described above may be "protected later A hydroxyl group, an optionally protected thiol group and an optionally protected amino group, and have the same meanings as the groups in the definition of B and R ⁷ groups, and R ¹¹ is described below. Shows "protecting group for carboxyl group" :).

In the above, R ^la and "protecting group" of the "optionally protected good I Amino group" in the definition of B and R ^{7 a} is in particular if the protective group of Amino groups used in the field of organic synthetic chemistry Examples include, but are not limited to, halogeno C ₂ -C ₇ alkylcarbonyl groups such as the aforementioned C i -C ₇ aliphatic acyl group, chloroacetinol, dichloroacetylenole, trichloroacetyl, ^ “Aliphatic acyls” such as c ₂ —c ₇ alkylcarbonyl groups substituted by C 1 -c ₆ alkoxy such as toxicacetyl; the above-mentioned C ₇ —C „aromatic acyl groups, 2-bromobenzoyl, halogeno C ₇ Unaryo of Benzoiru - C "aromatic Ashiru group, 2, 4, 6-trimethylbenzoyl I le, 4 one toluoyl C ₇ such substituted with C ₆ alkyl as - C" aromatic § Shi Group, 4 one Anisoiru of such C i one C ₆ C ₇ substituted alkoxy - C "aromatic Ashiru group, 4 twelve Torobe Nzoiru, C ₇ substituted in two Toro, such as 2-two Torobenzoiru — C „Aromatic acyl group, C ₂ — such as 2- (methoxycarbonyl) benzoyl — C ₇ substituted by C ₇ alkoxycarbonyl — C,, Aromatic acyl group or 4-phenylbenzene C ₆ — like aryl. “Aromatic acyls” such as C ₇ — C n aromatic aryl group substituted with aryl; C ₂ —C ₇ alkoxycarbonyl group, 2, 2, 2 —Trichloro mouth ethoxycarbel, “Alkoxycarbels” such as C ₂ —C ₇ alkoxycarbonyl group substituted by halogen such as trimethylsilylethoxycarbonyl or tri-C ₆ alkylsilyl; vinyloxycarbonyl Or Aryl Kishikarubo "alkenylcarbonyl O alkoxycarbonyl such" as El: benzyl O alkoxycarbonyl, 4 1 to 2 C ₆ alkoxy or 1 to 2, such as methoxybenzizoleoxycanolebonyl, 3,4-dimethoxybenzinolexcanolevonyl, 2-ditrobenzoyloxycarbonyl or 4-12 trobenzoyloxycarbonyl “Aralkyloxycarbonyls” which may be substituted on the aryl ring by nitro; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t_butyldimethylsilyl, methyldiisopropylyl, methyldi-tert-butylsilyl, triisopropyl Groups selected from tri-C—C ₆ alkylsilyl groups such as silyl, aryls such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl or phenyldiisopropylsilyl and 1 C ₆ alkyl 3-substituted silyl "Silyls" such as benzyl, phenethyl, 3-phenylphenyl, naphthylmethyl, jS-naphthinolemethinole, diphenylmethyl, triphenylenolemethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, etc. C, —C ₆ alkyl group substituted with 4 aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methylbenzyl Methoxy pheninolesiphenylenolemethinole, 2-nitrobenzizole, 4-nitrobenzinole, 4-chlorobenzinole, 4-bromobenzinole, 4-cyanobenzinole, 4-cyanobenzinolephenylmethyl, bis (2- Nitorofue - Le) C, such as methyl or piperidines Roniru -! C ₆ alkyl, C One C ₆ alkoxy, nitro, halogen, Xia 1 to 3 of § Li that Ariru ring is substituted in - "Araru kill such" such as one C ₆ alkyl group substituted with Le group; or N, N-dimethylaminomethylene, benzylidene, 4-main butoxy A "substituted methylene group forming a Schiff base", such as benzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene or (5-chloro-2-hydroxyphenyl) phenylmethylene; And preferably a c, -C ₇ aliphatic acyl group, a C ₇ -C „aromatic acyl group or a C ₂ -c ₇ alkoxycarbonyl group, more preferably a C ₂ -C ₇ alkoxycarbonyl group. And particularly preferably a t-butoxycarbonyl group.

In the above, R ^la, "protecting group" of X ^a and B and R ⁷ "optionally protected human Dorokishiimino group and Roh or hydroxyl group" in ^a is in the field of organic synthetic chemistry There is no particular limitation as long as it is a protecting group for a hydroxyl group to be used. For example, c ₂ -c ₇ substituted with a carboxy such as the aforementioned c, 1C ₇ aliphatic acyl group, succinoyl, glutaroyl, and adiboyl Alkylcarbonyl groups, halogeno such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl c ₂ — c ₇ Alkyl forces C ₂ -C substituted with a luponyl group or C i-Cs alkoxy such as methoxyacetyl ₇ "aliphatic Ashiru such" such as an alkylcarbonyl group; the aromatic Ashiru group, 2-Buromobenzoiru, 4 _ black hole halogeno C ₇ such as Benzoiru - C _u aromatic Zokua sills group, 2, 4, 6 _ trimethyl Benzoiru, such as 4 _ toluoyl C - C ₆ has been C ^ -C u aromatic Ashiru group substituted with § alkyl, 4-ten ₆ § Rukoki like Anisoiru In substituted C ₇ -C "aromatic Ashiru group, 2-carboxyethyl benzo I le, 3 _ carboxybenzotriazole I le, 4 one carboxybenzoyl I C ₇ substituted by carboxy, such as Le - C" aromatic Ashiru Nitro-substituted CT-CU aromatic acyl groups, such as 412 trobenzoyl, 2-trobenzoyl, and C ₂ -C ₇ alkoxy carbonyls, such as 2- (methoxycarbonyl) benzoyl substituted C ₇ - C u like aromatic Ashiru group or a 4-phenylalanine-benzo I le C ₆ - C _w § C ₇ substituted by Li Ichiru - C "," aromatic and aromatic Ashiru group Acetyls ”; tetrahydrodropyran-2-yl, 3-bromotetrahydrodropyran-1-yl, 4-methoxytetrahydrodropyran-4-yl, tetrahydroxydrophiopyrane-2-yl, 4-methoxytetrahydrodropyropyrane-1-yl Such as "tetrahydrobilanyl or tetrahydrothiopyranyl";"tetrahydrofuranyl or tetrahydrothiofuranyl" such as tetrahydrofuran-12Tl or tetrahydrothiofuran-12-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, Tri C, 1 C ₆ alkylsilyl groups or diphenylmethylsilyl, such as butyldimethylsilyl, methyldiisopropylyl, methyldi-tert-butylsilyl, triisopropylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropyl "silyl ethers", such as three-substituted silyl group in good UNA Ariru and C ₆ alkyl from selected groups of silyl; main Tokishimechiru, 1, 1-dimethyl - 1-main Tokishimechiru, E DOO Shimechiru, propoxymethyl, iso-propoxymethyl, butoxymethyl, t- Butoxymethyl, such as (C -! C ₆ alkoxy) methyl group, 2- main Tokishietokishi substituted with C i-Ce alkoxy, such as methyl (C -! C ₆ alkoxy) methyl group or a 2, 2, 2 -"Alkoxymethyls" such as halogeno (Ci- Ce alkoxy) methyl such as trichloroethoxymethyl and bis (2-cycloethoxy) methyl; such as 1-ethoxyhexyl and 1- (isopropoxy) ethyl (C “C ₆ alkoxy”) “Substituted ethyls” such as acetyl group or halogenated thiol group such as 2,2,2-trichloromethyl; benzyl, _α -naphthylmethyl,] 3-naphthylmethyl, diphenylmethyl , triphenylmethyl, one naphthyl diphenyl methyl shed, from 1-3 § re like 9-Anse Rirumechiru - is C ₆ alkyl group or substituted Le group 4- Tylbenzyl, 2,4,6-trimethynobenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzinole, 4-nitrobenzyl , Such as 4-benzole, 4-b, lomobenzil, 4-cyanobenzyl, methyl, piperonyl. ,one. “Aralkyls” such as 1 to 3 aryl groups substituted with 1 to 3 aryl groups in which the aryl ring is substituted with 6 alkyl, —C ₆ alkoxy, halogen, or cyano; the aforementioned C ₂ —C ₇ alkoxy Such as a carbonyl group, a halogen such as 2,2,2-trichloromouth ethoxycarbonyl, or 2-trimethylsilylethoxycarbonyl or a C ₂ -C ₇ alkoxycarbonyl group substituted with a tri C _t -C ₆ alkylsilyl group; “Alkoxycarbonyls”; “alkenyloxycarbonyls” such as benzyloxycarbonyl and aryloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzylo One or two Cs, such as xyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-12 trobenzyloxycarbonyl ! —Ce is an “aralkyloxy radical” in which the aryl ring may be substituted with alkoxy or nitro, preferably a C 1, —C ₇ aliphatic acyl group, —Cu aromatic An acyl group, a C ₂ -C ₇ alkoxycarbonyl group or a (〇, 10 ₆ alkoxy) methyl group, more preferably a c ₇ —c „aromatic acyl group or a (c, —c ₆ alkoxy) methyl group And particularly preferably a benzoyl group or a methoxymethyl group.

In the above, "coercive in" optionally protected thiol group "in B and R ^{7 a} The protecting group is not particularly limited as long as it is a protecting group for a thiol group, which is used in the field of synthetic organic chemistry. Examples of the protecting group include, but are not limited to, the Ci 1 c ₇ aliphatic acyl group, "aliphatic Ashiru such" of c ₇ Al kill carbonyl group - c substituted with c ₆ alkoxy _{2 -;} c, such as a group or menu Tokishiasechiru - carboxy that is substituted with c ₂ -c ₇ alkyl carbonitrile as A halogeno such as the above-mentioned 〇 ₇ -〇 „aromatic sacyl group, 2-bromobenzoyl, 4-chlorobenzoyl C ₇ „ aromatic ァ syl group, 2, 4, 6-trimethyl benzoyl, 4-toluoyl C ₇ is substituted with a one C ₆ alkyl - C "aromatic Ashiru group, C ₇ substituted with C i-Cs alkoxy, such as 4-Anisoiru - C" aromatic Ashiru group, 2-carboxybenzoyl I le , 3-cal Carboxy-substituted C ₇ — C _u such as boxybenzoyl, 4-carboxybenzoyl, N ₇ -substituted C ₇ — C „such as aromatic acetyl group, 4-nitrobenzoyl, 2-nitrobenzoyl Aromatic acyl group, C ₂ —C ₇ such as 2- (methoxycarbonyl) benzoyl C ₇ —Cu Aromatic acyl group substituted with C ₇ alkoxycarbonyl or C ₆ such as 4-phenylbenzoyl — C ₇ —C substituted with C _{1 ()} aryl “Aromatic acyls” such as aromatic acyl groups; Tetrahidropiran-1-yl, 3-Bromotetrahydropiran-2-yl , 4 main Tokishitetorahi Doropiran one 4-I le, Te Torahi Dorochiopiran one ₂ ^ le or ₄ - main Tokishitetorahi Dorochiopiran -

"Tetrahydropyrael or tetrahydrothiopyranyls" such as 4 ^^-yl; "tetrahydrobranyl or tetrahydrothiofuranyls" such as tetrahydrofuran-1-yl or tetrahydrofurothiofuran-2-yl; trimethylsilyl, triethylsilyl, Tri-c, -c ₆ alkylsilyl groups such as isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl, triisopropylsilyl or diphenylmethylsilyl, diphenylbutylsilyl, “Silyls” such as aryl groups such as diphenylisopropylsilyl and phenyldiisopropylsilyl and silyl groups substituted by three groups selected from C ₆ alkyl; methoxymethyl, 1,1-dimethyl-1-yl 1—Metoki Methylcarbamoyl Honoré, ethoxymethyl, propoxymethyl, iso-propoxymethyl, butoxymethyl, such as t- butoxymethyl (C, _ C ₆ alkoxy) methyl group, 2- main Tokishieto Substituted with C i-Ce alkoxy, such as Kishimechiru (C _t one C ₆ alkoxy) methylation group or 2, 2, 2-trichloromethyl E butoxy methyl, bis (2-Kuroroetokishi) method halogeno such as chill (C —Ce alkoxy) “Alkoxymethyls” such as methyl; one to three amino acids such as benzyl, α-naphthylmethinole, jS-naphthylmethinole, diphenylmethyl, triphenylismethinole, α-naphthinolesphenizolemethyl, and 91-anthrinolemethinole C, C ₆ alkyl or 4-methylbenzyl substituted with a real group, 2,4,6_trimethinolebenzyl, 3,4,5_trimethinolebenzyl, 4-methoxybenzyl , 4-Methoxyphenyldipheninolemethyl, 2-Nitrobenzyl, 4-Nitrobenzinole, 4-chlorobenzinole, 4-Bu, Lomo 1 to 3 aryl substituted with C, 1 C ₆ alkyl, c ₆ alkoxy, nitrogen, cyano, etc., such as benzyl / le, 4-cyanobenzyl, methyl, and piperonyl An “aralkyl” such as a C i -C ₆ alkyl group substituted with a benzyl group; the above-mentioned C ₂ -C ₇ alkoxycarboyl group, 2,2,2-trichloromouth ethoxycarbonyl, 2-trimethylsilylethoxycarbonyl “Alkoxycarbonyls” such as C ₂ —C ₇ alkoxycarbonyl groups substituted with halogen or tri C — C ₆ alkylsilyl groups such as; carbonyloxy or aryloxycarbonyl “Alkenyl / reoxycarbonyls”; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethylbenzyloxycarbonyl, 2-nitroben Aryl rings may be substituted with one or two C! -Ce alkoxy or nitro, such as methoxycarbonyl or 412 trobenzyloxycarbonyl; ”, And preferably, the same. D substituted with one to three aryl groups such as an aliphatic acyl group, c ₇ —c „aromatic acyl group, c ₂ —c ₇ alkoxycarbonyl group, diphenylmethyl, triphenylmethyl, etc. —C ₆ alkyl group or (1-C ₆ alkoxy) methyl group, and more preferably, C ₇ , —C ₆ substituted with C ₇ —C „aromatic acyl group or 1 to 3 aryl groups alkyl or (C -! C ₆ alkoxy) methyl group, preferably especially a Benzoiru group, Jifuenirumechiru group, triphenylmethyl group, or main Toki Shimechiru group.

In the above, the term “protecting group for carboxyl group” in the definition of R ¹¹ refers to an organic compound There is no particular limitation as long as it is a protecting group for the lipoxyl group used in the field of chemical chemistry; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl , N-bentyl, isobentil, 2-methylinobutyl, neopentyl, 1-ethylpropynole, n-hexynole, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl "Anolequinole group" such as 1,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl; Propaninole, 2—Propenisle, 1—Methinole 1 _Propeninole, 1—Methinole 1—Propeninole, 2 1-propynyl, 2-methynol 2- 2-propynyl, 2-ethyl-2-propynyl, 1-buteninole, 2-buteninole, 1-methyl-1-buteninole, 1-methyl-1-buteninole, 3-methyl-2-buteninole, 1-ethinole, 1-buteninole, 3-butur, 1-methinole, 1-buteninole, 2-methinole, 3_buteninole, 1-etchinole, 3-b, tennisle, 1_penteninole, 2_ Pentenore, 1-Methinole 2-pentenole, 2-Methinole 2-pentenyl, 3_pentenyl, 1-methyl-3-pentenyl, 2_methyl-1-pentenole, 4_pentenole, 1-methinole One such as 4-pentenyl, 2-methyl-7, 4-pentenole, 1—hexenyl, 2—hexeninole, 3—hexeninole, 4-hexenyl, 5-hexenyl Nyl group ”; Ethur, 2-Probul, 1-Methyl_2-Propvinyl, 2-Methynole-1-propynole, 2-Ethynole-1-propynyl, 2-Butinole, 1-Methinole-1-butyninole, 2 1-Methinole 2-butyninole, 1-ethizole 2-butynyl, 3-butul, 1-methyl-3-butul, 2-methyl-3-butchur, 1-ethyl-1 3-butyninole, 2-pentulle, 1-methynole 1 —Pentinole, 2—Methyl-1-pentynole, 3-pentynyl, 1—Methyl-3-pentynole, 2-methyl-3-pentynyl, 4-pentinole, 1-methyl-4-pentul Alkynyl groups such as, 2-methynole-1-pentynole, 2-hexynole, 3-hexynole, 4-hexynole and 5-hexyl; trifluoromethyl, trichloromethyl, dichloro Le Oromechi / Les, Jikuroromechinore, jib port Momechinore, off / Reoromechinore, 2, 2, 2-Application Benefits off zone Leo Roe Chino les, 2, 2, 2-trichloromethyl E Chino Le - 2- Buromoechinore, 2- Black "Halogenoalkyl groups" such as lochinore, 2-funoleolochinore, 2-odoethinole, 3-chloropropinole, 4-funolerobutinole, 6-dohexinole, 2,2-dibutene moetinolle; 2-hi "Hydroxyalkyl group" such as droxyshetyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl, and 4-hydroxybutyl: "aliphatic acylalkyl group" such as acetylmethyl Benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl,] 3-naphthylmethinole, dipheninolemethyl, triphenylenolmethinole, 6-phenylhexizole, 1-naphthyldiphenylmethyl, 9- “Alkyl groups substituted with one to three aryl groups” such as anthrylmethyl, 4-methylbenz 2,4,6—Trimethylbenzyl, 3,4,5—Trimethylbenzyl, 4-Methoxybenzyl, 4-Methoxyphenininoresifeninolemethyl, 2-Trobenzinole, 4-Nitrobenzinole, Such as 4-chlorobenzene, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenolenomethinole, bis (2-ditropheninole) methinole, piperonyl, and 4-methoxycanolepo-benzyl "Aralkyl groups" such as alkyl groups substituted with one to three aryl groups in which the aryl ring is substituted with an alkyl, alkoxy, nitro, nitro, logen, cyano, or alkoxycarbonyl group; trimethylsilyl , Triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t- Chirushiriru, triisopropoxide building silyl, there may be mentioned methyl di Hue El Siri Honoré, isopropyl di phenylene Rushiriru, butyl diphenyl silyl, the "silyl group" such as Fuenirujiisopu port Birushiriru, preferably, C -! C ₆ Alkyl group, or CT—C. A Ararukiru group, c, and more preferably - a c ₆ alkyl group, particularly preferably C - a c ₄ alkyl group.

 In the case of a compound having a group substituted with a group selected from the above-described or below-described substituent group α and / or substituent group γ, the compound may be protected with the above-described protecting group or the like, if desired, and subjected to a method described below. To remove the protecting group.

Step A1 is a step for producing a compound having the general formula (V), and in an inert solvent, phosphines (preferably tributylphosphine or triphenylphosphine) and azodicarboxylic acid compounds (preferably) The azodicarboxylate getyl Alternatively, the reaction is carried out by reacting a compound having the general formula (III) with a compound having the general formula (IV) in the presence of J which is 1,1-azodicarbodilpiperidine. 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, lignin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; Jethyl ether, diisopropyl ether, tetrahydrofuran; Ethers such as dioxane, dimethoxetane, and diethylene glycol dimethyl ether; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric acid triamide; or a mixed solvent of the above solvents; , Aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons And ethers or a mixed solvent of the above solvents (more preferably, aromatic hydrocarbons or ethers, and particularly preferably, toluene or tetrahydrofuran).

 The reaction temperature varies depending on the starting compound, the solvent and the like, but is usually from 120 ° C to 150 ° C (preferably from 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, etc., and dried over anhydrous magnesium sulfate. It is obtained by drying over anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the target compound obtained can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., using a method commonly used for separation and purification of organic compounds as appropriate. It can be separated and purified by elution.

Step A2 is a step of producing a compound having the general formula (I), and reacting the compound (V) with an acid in the presence or absence (preferably, in the presence) of an inert solvent, after removal of the bird whistle two Rumechiru group in a ^a, optionally R ^la, X ^a and B Oyo Amino group in the fine R ^7, human Dorokishiimino group, and removing the R ^{1 1} is a protecting group of the coercive Mamorumoto and Z or carboxyl group of a hydroxyl group and / or a thiol group:

The acid used in the first-stage reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction, and 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, camphors zolefonic acid, trifluoroacetic acid, organic acids such as trifluorophenolic acid, etc .; zinc chloride; Lewis acids such as tin chloride, boron trichloride, boron trifluoride, and boron tribromide; acidic ion-exchange resins: preferably inorganic acids or organic acids (particularly preferably hydrochloric acid, acetic acid or _c is a triflate Ruoro acetate)

 The inert solvent used in the first-stage reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, 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, and acetic acid Esters such as butyl and getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; methanol ^^ ethanol Λ ^, η-propanol, Isopropanol, η-butanol, isobutanol, t-butano Alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorbate; formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide. Such an amide; water; or water or a mixed solvent of the above solvents; preferably ethers, alcohols or water (particularly preferably, dioxane, tetrahydrofuran, ethanol or water). You.

The reaction temperature varies depending on the starting compound, the acid used, the solvent, and the like, but is usually from 120 ° C to the boiling point (preferably from 0 ° C to 100 ° C). The reaction time varies depending on the starting compound, the acid used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

In this step, the compound (V) is subjected to ^a catalytic reduction reaction in an inert solvent under atmospheric pressure or under pressure (preferably, under pressure) to remove the triphenylmethyl group in Aa. By removing R ^11, which is a protective group for amino, hydroxyimino, hydroxyl and / or thiol groups, and / or a carboxyl group in R ^la , X ^a and B and R ⁷ , the desired compound (I ) Can also be manufactured.

 The catalyst used in the above catalytic reduction reaction is not particularly limited as long as it is used in a usual catalytic reduction reaction, and examples thereof include palladium monocarbon, Raney nickel, rhodium aluminum monoxide, triphenylphenylphosphine rhodium monoxide, It is barium sulfate barium sulfate, palladium black, platinum oxide, or platinum black, and is preferably 5 mm palladium ash.

 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 solvents such as hexane, heptane, lignin, and petroleum ether Hydrocarbons; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; Jethyl ether, diisopropyl ether Ethers such as, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol— Nore, diethylene glycolone, glycerin, octano Alcohols such as cyclohexanol and methylacetosorb; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphate triamide; organic acids such as acetic acid and trifluoroacetic acid; or A mixed solvent of the above solvents; preferably, ethers, alcohols or organic acids (particularly preferably, alcohols). The reaction temperature varies depending on the starting compound, the catalyst used, the solvent, and the like, but is usually 0 ° C to 100 ° C (preferably 10 ° to 50 ° C).

The reaction time varies depending on the starting compound, the catalyst used, the solvent, the reaction temperature, etc. Usually, it is 30 minutes to 48 hours (preferably 1 hour to 24 hours).

 The removal of protecting groups for amino group, hydroxyl group and thiol group varies depending on the kind, but generally, methods well known in the art of organic synthetic chemistry, for example, TW Green, (Protective Groups in Organic Synthesis, John Wiley & Sons: JFW McOmis, (Protective Groups in Organic Chemistry), Plenum Press 方法 The method described here (this can be performed as follows.

 When the protecting group of the amino group is a silyl, usually, a compound that produces a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, pyridine hydrofluoride, or potassium fluoride 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 dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether. Such ethers are suitable.

 The reaction temperature and reaction time are not particularly limited, but are usually 0 to 50 °. For 10 to 18 hours.

 When the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group forming a Schiff base, the amino group is treated with an acid or a base 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, perchloric acid, phosphoric acid, An inorganic acid such as 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 carbonate such as lithium carbonate, sodium carbonate, or lithium carbonate. Salts; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxylated lithium; metal alkoxys such as lithium methoxide, sodium methoxide, sodium methoxide, and potassium tert-butoxide And ammonia such as concentrated aqueous ammonia and 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. For example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol Alcohols such as tert-butanol, isoamyl alcohol Λ ^, diethylene glycol, glycerin, octanole, cyclohexanol, methylcellulose sorb; ethethyl ether, diisopropyl alcohol, tetrahydrofuran, dioxane, Ethers such as dimethoxetane and diethylene glycol dimethyl ether; water; a mixed solvent of water and the above organic solvent; preferably ethers (particularly preferably dioxane).

 The reaction temperature and reaction time vary depending on the starting compound, the solvent, and the 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. And react for 1 hour to 10 hours.

 When the protecting group for the amino group is an aralkyl or aralkyloxycarbonyl, the protecting group is usually brought into contact with a reducing agent in an inert solvent (preferably, at room temperature in the presence of a catalyst at room temperature). Reduction) 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, lignin, and petroleum ether; Aromatic hydrocarbons such as tolune, benzene and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl Ethers such as toxetane and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octananol , Cyclohexano Alcohols such as methinoreserosolve; organic acids such as acetic acid; water; a mixed solvent of the above solvent and water; preferably alcohols, ethers, organic acids or water (particularly preferable). Represents 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. Na-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine rhodium monochloride, and palladium monosulfate are used.

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

The reaction temperature and reaction time varies depending on the starting material, catalyst, varies depending on the solvent or the like, usually, at o ° c to 1 0 0 ° C, is carried out from 5 minutes to 2 4 hours _c

 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.

 Such organic solvents include, for example, chloroform, dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride; nitriles such as acetonitrile, getylether, disopropylether, and tetrahylene. Ethers such as drofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide; And sulfoxides such as dimethyl sulfoxide; sulfolane; 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 the oxidation. Preferably, the oxidizing agent is persulfuric acid lime, sodium persulfate, ammonium-ammonium nitrate (CAN), 2,3-dichloromethane. One, 5-, 6-dicyano-p-benzoquinone (DDQ) is used.

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

 When the protecting group for the amino group is an alkenyloxycarbonyl, the protecting group for the amino group is usually substituted to form the above-mentioned aliphatic acyls, aromatic acyls, alkoxycarbonyls or Schiff bases. The reaction is performed 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 aryloxycarbonyl group, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly convenient. Can be carried out with few side reactions:

 When a silyl is used as a protecting group for the hydroxyimino group, hydroxyl group and thiol group, tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, fluorinated rim is usually used. Ability to treat with a compound that produces a fluorine anion such as, 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-toluenesulfone It can be removed by treating with an organic acid such as acid, camphorsulfonic acid, trinoleoracetic acid, and trifluoromethanesulfonic acid.

 In addition, when removing with a fluorine anion, the reaction may be accelerated by adding an organic acid such as formic acid, acetic acid or 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, it is dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl. Ethers such as ether; nitriles such as acetoetrile and isobutyronitrile; organic acids such as acetic acid; water;

 The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the solvent, and the like.Typically, the temperature is from o ° C to 100 ° C (preferably from 10 ° C to 50 ° C), from 1 hour to 24 hours. Implemented for 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 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 this reaction. Aliphatic hydrocarbons such as hexane, heptane, lignin, petroleum ether; toluene, Aromatic hydrocarbons such as benzene and xylene; esters such as ethyl acetate and propyl acetate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; Methanol, ethanol, _n -pronol, isopropanol, n-butanol, isobutanol, t-butanol, Alcohols such as isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorb; formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, and hexamyltriamide Amides: fatty acids such as formic acid and acetic acid; water; a mixed solvent of the above solvents; preferably alcohols (particularly preferably methanol).

 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.For example, palladium-carbon, palladium-black, Raney nickel, platinum oxide, platinum black, platinum black, Rhodium aluminum monoxide, triphenyl phosphine rhodium monochloride, palladium monosulfate barium, and preferably palladium monoash.

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

 The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from o ° C to 100 ° C (preferably from 20 ° C to 70 ° C), from 5 minutes to 4 minutes. 8 hours (preferably 1 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 an organic solvent, ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, getyl ether, Examples thereof include ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphate 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 the oxidation. Preferably, the oxidizing agent is persulfuric acid rim, sodium persulfate, ammonia cell silicate (CAN), 2, 3 —Dichloro-1,5,6-dicyano_p-benzoquinone (DDQ) is used.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent, etc. It is carried out at a temperature of 1 to 150 ° C. for 10 minutes to 24 hours.

 Also in liquid ammonia or like methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methylcellosolve It can also be removed by reacting alkali metals such as lithium metal and sodium metal at 178 ° C to 0 ° C in such alcohols.

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

 The solvent to be 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, carbon tetrachloride; or a solvent such as acetonitrile. Tolyls; mixed solvents of the above solvents. The reaction temperature and reaction time vary depending on the starting compound, solvent, etc.

Performed at 50 ° C for 5 minutes to 72 hours.

 When the reaction substrate has a sulfur atom, preferably, aluminum chloride sodium iodide is used.

 When the protecting group for the hydroxyimino group, hydroxyl group and thiol group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is 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. For example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; Alkali metal bicarbonates such as lithium hydrogen, sodium bicarbonate and potassium bicarbonate; lithium metal hydroxides such as lithium hydroxide, sodium hydroxide and hydroxylated water; lithium methoxide, sodium methoxide; Metal alkoxides such as sodium methoxide and potassium hydroxide; ammonia such as ammonia water and concentrated ammonia-methanol; preferably alkali metal hydroxides, metal alkoxides or Ammonia (particularly preferably, alkali metal hydroxides or metal alcohols) In Sid acids) is there.

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

 The reaction temperature and reaction time vary depending on the starting compound, the base used, the solvent, and the like, and are not particularly limited.However, in order to suppress a side reaction, the reaction is usually performed at -20 ° C to 150 ° C. It takes between 10 and 10 hours.

 When the protecting group for the hydroxyimino group or the hydroxyl group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group, usually, an acid is used in the solvent. It is removed by processing.

The acid to be used is not particularly limited as long as it is usually used as Brenstead acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or acetic acid or trifluoromethane. Brenstead acids, such as organic acids such as acetic acid, methanesulfonic acid, and p-toluenesulfonic acid: Lewis acids such as boron trifluoride, but strongly acidic cation exchange resins such as Dowex 50W Can be used. The solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples of the solvent include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; benzene, Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorine benzene, and dichloromethane ethene; ethyl formate, ethyl acetate, and propyl acetate Esters such as butyl acetate, butyl acetate, and getyl carbonate; ethers such as getyl ether, diisopropyl propyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and dimethyl glycol dimethyl ether; methanol, ethanol _n Alcohols such as monopropanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorbet; acetone, methylethylezol Ketones such as reketone, methyl isobutyl ketone, isophorone, and hexahexanone; water; a mixed solvent of the above solvents; preferably ethers (particularly preferably tetrahydrofuran) or alcohol (Particularly preferred is methanol).

 The reaction temperature and reaction time vary depending on the starting compound, the acid used, the solvent, etc., but are usually from 10 ° C to 200 ° C (preferably from 0 ° C to 150 ° C). Minutes to 48 hours (preferably 30 minutes to 10 hours).

 When the protecting group for the hydroxyimino group or the hydroxyl group is an alkenyloxycarbonyl group, the removal reaction is usually performed when the protecting group for the hydroxyl group is the above-mentioned aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group. It is achieved by treating with a base in the same manner as in the above condition.

 In the case of an aryloxycarbonyl group, use of palladium, triphenylphosphine, or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphate is particularly preferable. The removal method is simple and can be carried out with few side reactions.

 The above-mentioned reaction of contacting the compound (V) with an acid or the contact reduction reaction of the compound (V) simultaneously removes the amino, hydroxyimino, hydroxyl, and thio or thiol protecting groups. It may be done.

 In addition, the removal of the protecting group for the amino group, hydroxyimino group, hydroxyl group and Z or thiol group can be carried out in any order and the desired removal reaction can be carried out sequentially.

The carboxyl protecting group can be removed by treatment with an acid or 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 commonly used acid and does not inhibit the reaction. 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 carbonate such as lithium carbonate, sodium carbonate, or carbonated lime. Salts; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxylated lime; Metal alkoxides such as lithium methoxide, sodium methoxide, sodium methoxide, and potassium hydroxide; Ammonia water, ammonia such as concentrated ammonia and methanol are used.

 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, isopropanol, n-butanol and isobutanol. Alcohols such as butanol, t-butanol, isoamyl alcohol, diethylene glycolone, glycerin, octanomore, cyclohexanol, methyl sorb, dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dime Ethers such as toxetane and diethylene glycol dimethyl ether; water; a mixed solvent of water and the above organic solvent; preferably ethers (particularly preferably dioxane).

 The reaction temperature and reaction time vary depending on the starting compound, the solvent and the 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. Incubate for 1 hour to 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 to separate the organic layer containing the target compound. It is obtained by washing with water, etc., drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the target compound obtained is 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, and applying chromatography. By doing so, it can be separated and purified.

 (Method B)

In the method B, in the compound (I), A is a compound represented by the formula (II-a), (II-b) or (II This is a step of producing a compound (XII 1), (XIV) or (XII) which is a group having _c).

Wherein R ^{1 to} R ⁶ , R ^la , X, X ^a , Y, Z, Q, n, q and m are as defined above. D represents a halogen atom, E represents an oxygen atom or a sulfur atom.

 Step B1 is a step of producing a compound having the general formula (VIII), and reacting the compound (VI) 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). Bases used in the above reaction include, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate: alkali metal bicarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate, and hydrogencarbonate lime; hydrogen Alkali metal hydrides such as lithium hydroxide, sodium hydride and hydrogenation power; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and hydroxylation power; lithium methoxide; Alkali metal alkoxides such as sodium methoxide, sodium methoxide and potassium butoxide; triethylamine, tributylamine, disopropylethynoleamine, N-methylmorpholine, pyridine, 4- (N, N-dimethyl Tylamino) pyridine, N, N-dimethylaniline, N, N-getyl Nirin, 1,5-diazabicyclo [4.3.0] nona5_en, 1,4-diazabicyclo [2.2.2] octane (DAB CO), 1,8-diazabicyclo [5.4.0] Organic amines, such as —7-indene (DBU); and 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 present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; dimethylformamide, dimethylacetamide; Amides such as hexamethylphosphoric acid triamide; or a mixed solvent of the above-mentioned solvents; and preferably amides (particularly preferably dimethylformamide).

The reaction temperature at the time of reacting compound (VI) with a base depends on the starting compound, the base used, the solvent, and the like. Generally, the reaction temperature is from −50 ° C. to 200 ° C. (preferably from 0 ° C. to 120 ° C). The reaction time for reacting the 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 from 15 minutes to 24 hours (preferably from 1 hour to 10 hours).

 The reaction temperature at the time of reacting the compound (V I) with the compound (V I I) is usually from 20 ° C to 200 ° C (preferably from 0 ° C to 150 ° C).

 The reaction time for reacting the compound (V I) with the compound (V I I) is usually 30 minutes to 48 hours (preferably 1 hour to 24 hours):

 After completion of the reaction, the target compound (VIII) 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. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is removed. It is obtained by separating, 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 target compound obtained may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography, and applying a suitable eluent. Can be separated and purified.

 Step B2 is a process for producing a compound having the general formula (X) in an inert solvent in the presence of a catalyst such as sodium acetate, piperidinium acetate, piperidinium benzoate. Alternatively, in the absence (preferably in the presence), the reaction is carried out 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, lignin, 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; Esters such as butyl acetate and dimethyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, Soamiruaruko —Alcohols, such as diol, diethylene glycol, glycerin, octanol, cyclohexanol, methylcellosolve; nitriles, such as acetonitrile, isobutyronitrile; formamide, dimethylformamide, dimethylacetamide And amides such as hexamethylphosphoric triamide; or a mixed solvent of the above-mentioned solvents; preferably, amides (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. 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, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography, and using an appropriate eluent. Separation and purification can be achieved by elution.

 Step B3 is a step of producing a compound having the general formula (XI), and is carried out by performing a catalytic reduction reaction on compound (X) 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 the compound (X) with a metal hydride can be carried out according to the method disclosed in WO 93/309 A.

The step B4 is a step for producing a compound having the general formula (XII), and is carried out by performing a reaction for removing an amino group, a hydroxyimino group and / or a protecting group for a hydroxyl group in an inert solvent. The reaction for removing the amino group, the hydroxyimino group and the protecting group for the amino group or the hydroxyl group is carried out in the same manner as in the above-mentioned Method A, Step A2. Step B5 is a step of producing a compound having the general formula (XIII). In the compound (X), the amino group at R ^la and X ^a of the compound (X) in which E is a sulfur atom, This step is carried out by removing the protecting group for the hydroxyimino group and the Z or hydroxyl group.This step is performed in the same manner as the method for removing the protecting group for the amino group, the hydroxyimino group and the hydroxy or hydroxyl group in step A2 of the above-mentioned Method A. Will be

 Step B6 is a step of producing a compound having the general formula (XIV), and is carried out by performing a catalytic reduction reaction on compound (XIII) in an inert solvent. The catalytic reduction reaction is performed in the same manner as in the above-mentioned Method A, Step A2.

 This step is also carried out by reacting the compound (XIII) with a metal hydride. The method of reacting the compound (XIII) with the metal hydride can be performed according to the method disclosed in W093 / 1309A.

 (Method C)

 Method C is another method for synthesizing compound (I).

上記式中、 Ri乃至 R⁶、 R^la、 X、 X^a、 Y、 Z、 A、 Aa、 Q， n及び qは、 前述したものと同意義を示し、 B o cは t—ブトキシカルボ二ル基を示し、 Gは「保 護されていてもよいホルミル基」 または 「保護されていてもよいカルボキシル基」 を意味する。

In the above formula, Ri to R ⁶ , R ^la , X, X ^a , Y, Z, A, Aa, Q, n and q have the same meanings as described above, and B oc is t-butoxycarbonyl G indicates “protection” "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 organic synthetic chemistry. For example, dimethoxymethyl A methyl group substituted by the above-mentioned C ₆ alkoxy, such as diethoxymethyl, dipropoxymethyl, dibutoxymethyl, 1,3-dioxane-2-yl, 1,3-dioxolan-1-yl, 1 , 3—Dithiane 2—yl, 1,

3-dithiolan-12-yl, preferably dimethoxymethyl, ethoxymethyl, 1,3-dioxolan-1-yl or 1,3-dithiane-12-yl. In the above G, the “protecting group” of the “optionally protected carboxyl group” is not particularly limited as long as it is a protecting group for a carboxyl group used in the field of organic synthetic chemistry. Echiru, propyl, isopropyl, butyl, s- butyl, C, such as t one-butyl; - C ₆ alkyl group, benzyl, phenethyl, 3-Fuenirupu port pills, 1 one naphthylmethyl, Jifuenirumechiru, triphenylmethyl, 4 Mechi Rubenjiru , 4-Methoxybenzyl, 412-trobenzyl, 4-fluorobenzyl,

C) —C ₆ alkyl, such as 4-cyanobenzyl, C i—C ₆ alkoxy, nitro, nitrogen, or 1 to 3 C ₆ —C _{1 C)} aryl optionally substituted with cyano A C ₆ alkyl group, preferably a C ₆ alkyl group or a benzyl group.

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

 When G in the compound (XV) is a formyl group, the compound (XV) is reacted with the compound (XVI) in an inert solvent, and then the t-butoxycarbonyl group, which is a protecting group for the amino group, is converted to an acid. This is carried out by removing the ring, closing the ring, and further reacting with an oxidizing agent.

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

The inert solvent used for reacting the compound (XV) with the compound (XVI) is not particularly limited as long as it is inert to the reaction. For example, hexane, heptane, rig-mouth, Aliphatic hydrocarbons such as petroleum ether; Aromatic hydrocarbons such as benzene, toluene, and xylene: such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether One ters; methanol, ethanol, n-prono. Nol, isopropanol, ' _η -butanol, isobutanol, t-butanol, isoamino olea / record / re, diethylene glycol monosol, glycerin, otano monosol, cyclohexanol, methylcellosolve, etc. Alcohols; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; acids such as acetic acid and propionic acid; sulfoxides such as dimethylsulfoxide; sulfolane; Or a mixed solvent of the above-mentioned solvents; and preferably ethers (particularly preferably tetrahydrofuran).

 The reaction temperature at which the compound (XV) is reacted with the compound (XVI) varies depending on the starting compound, the base used, the solvent, and the like. Generally, the reaction temperature is 0 ° C to 200 ° C (preferably 10 ° C). C to 120 ° C.).

 The reaction time for reacting the compound (XV) with the compound (XVI) 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). Hours to 24 hours).

 The method for removing the t-butoxycarbyl group, which is an amino-protecting group, using an acid can be carried out by using an acid when the amino-protecting group in step A2 of method A is an alkoxycarboxy group. The method is performed in the same manner as the above method.

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; and ruthenium tetroxide. Ruthenium oxides; selenium compounds such as selenium dioxide; iron compounds such as iron chloride; osmium tetroxide, potassium osmate. • Osmium compounds such as dihydrate (K ₂ 0s0 ₄ '2H ₂ 0); silver compounds such as silver oxide; mercury compounds such as mercury acetate; lead oxide compounds such as lead oxide and lead tetraacetate Inorganic metal oxidizing agents such as potassium chromate, chromate-monosulfate complex, chromate compounds such as chromate-pyridine complex, and cerium compounds such as ammonium cellium nitrate (CAN); chlorine molecule, bromine Molecules, halogen molecules such as iodine molecules; periodic acids such as sodium periodate; ozone; hydrogen peroxide; nitrous acid compounds such as nitrous acid; potassium chlorite, sodium chlorite Chlorite compounds; inorganic oxidizers such as persulfate compounds such as potassium persulfate and sodium persulfate; reagents used for oxidation of DMSO (dimethyl sulfoxide and dicyclohexylcarbodiimide; Oxalyl chloride, complexes with acetic anhydride or phosphorus pentoxide, or pyridine-sulfuric anhydride complexes); combinations of peroxides such as t-butyl hydroperoxide with vanadium or molybdenum complexes; such as triphenylmethyl cation Stable cations; N-bromosuccinic acid imids such as imido and combinations of alkalis; oxolanes such as dimethyldioxysilane; hypochlorous oxide compounds such as t-butyl hypochlorite; Azodicarboxylic acid compounds such as azodicarboxylic acid esters; peracids such as m-chloroperbenzoic acid and perphthalic acid; disulfides such as dimethyldisulfide, diphenyldisulfide, dipyridyldisulfide and triphenylphosphide Nitrites such as methyl nitrite; methane tetrabromide Organic oxidizing agents such as tetrahalogenated carbons and quinone compounds such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ); and preferably halogen molecules (particularly preferably Iodine molecule).

 The solvent used in contact with the oxidizing agent is not particularly limited as long as it is inert to the reaction, but is preferably used in reacting compound (XV) with compound (XVI). Solvent.

 The reaction temperature and reaction time at the time of contact with the oxidizing agent are the same as the reaction temperature and reaction time at the time of reacting the compound (XV) with the compound (XVI).

When G in the compound (XV) is a carboxyl group, the compound having the general formula (XV) or a reactive derivative thereof (acid halides, active esters) in an inert solvent Or a mixed acid anhydride) and a compound having the general formula (XVI) or an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate or sulfate), and then a protecting group for an amino group The reaction is carried out by removing the t-butoxycarbonyl group using an acid and closing the ring.

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

 In the acid halide method, compound (XV) is converted to a halogenating agent (eg, thionyl chloride, thionyl bromide, oxalic acid chloride, oxalic acid dichloride, oxychlorine, phosphorus trichloride, pentachloride) in an inert solvent. To produce an acid halide, and the acid halide and the compound (XVI) or its acid addition salt in an inert solvent in the presence or absence of a base (preferably Is carried out in the presence of).

 Bases used in the above reaction include, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and carbon dioxide; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; hydrogenation Alkali metal hydrides such as lithium, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide, sodium hydride Alkali metal alkoxides such as methoxide and potassium t-butoxide; triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N —Dimethylaniline, N, N—Jetirani 1,5-Diazabicyclo [4.3.0] Nona-5-ene, 1,4-Diazabicyclo [2.2.2] octane (DABCO), 1,8-Diazabicyclo [5.4.0] — Organic amines such as 7-indene (DBU), 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. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether Ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; sulfolane; Are halogenated hydrocarbons, ethers or amides (particularly preferably, dichloromethane, chloroform, tetrahydrofuran or dimethylformamide).

 The reaction temperature varies depending on the starting compounds, reagents, etc., 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 carried out at a temperature of about 20 ° C. To 150 ° C, preferably, the reaction between the halogenating agent and the compound (XV) is 110 ° C to 100 ° C, and the acid halide and the compound (XVI) or a compound thereof. The reaction with the acid addition salt is between 120 ° C and 100 ° C.

 The reaction time varies depending on the starting compounds, reagents, reaction temperature, etc., but the reaction between the halogenating agent and the compound (XV) and the reaction between the acid halide and the compound (XVI) or an acid addition salt thereof are usually performed. 30 minutes to 80 hours (preferably 1 hour to 48 hours).

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

 The active esterifying agent used in the above reaction includes, for example, N-hydroxysuccinimide, 1-hydroxybenzotriazolone, N-hydroxy-1-5-noslevo ^ "nen-2,3 N-hydroxy compounds such as dicarboxyimide; disulfide compounds such as dipyridyl disulfide; carbodiimides such as dihexyl hexylcarbodiimide; carbonyldiimidazole; triphenylphosphine; It is suitably performed in the presence of such a condensing agent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. But not limited to, for example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane, 1,2-dichloroethane, carbon tetrachloride Halogenated hydrocarbons such as: ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxan, dimethoxetane, diethylene glycol dimethyl ether; ketones such as acetone; formami , Dimethylformamide, dimethylacetamide, amides such as hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; sulfolane; and preferably ethers or amides (particularly, Preferably, dioxane, tetrahydro Run or dimethylformamidine de).

 Examples of the base used in the above reaction include the same bases as those used in the acid halide method.

 The reaction temperature varies depending on the starting compounds, reagents, etc., but in the case of an active esterification reaction, it is usually —70 ° C. to 1.5 ° C. (preferably 110 ° C. In the reaction of the active ester with the compound (XV) or an acid addition salt thereof, the temperature is from −20 ° C. to 100 ° C. (preferably from 0 ° C. to 50 ° C.). .

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

 In the mixed acid anhydride method, the compound (XV) is reacted with a mixed acid anhydride in an inert solvent in the presence or absence (preferably, in the presence of a base) of the mixed acid anhydride to produce mixed acid anhydrides. Thereafter, the reaction is carried out by reacting the mixed acid anhydride with the compound (XVI) or an acid addition salt thereof in an inert solvent.

Bases used in the above reaction include, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and carbon dioxide; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; hydrogenation Alkali metal hydrides such as lithium, sodium hydride and hydrogenation power: Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and hydroxylation water; lithium methoxide Alkali metal alkoxides such as sid, sodium methoxide, sodium methoxide, potassium monobutoxide; triethylamine, tributylamine, disopropylethylamine, N-methylmorpholine, pyridine, 4_ (N, N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N-Jetylaniline, 1,5-diazabicyclo [4.3.0] Nona-1-ene, 1,4-diazabicyclo

[2.2.2] Organic amines such as octane (DAB CO) and 1,8-diazabicyclo [5.4.0] —7-pandacene (DBU), preferably organic amines

(Particularly preferably, triethylamine).

Mixed acid anhydride agent used in the above reaction is, for example, chlorocarbonate Echiru, carbonate one c ₄ Arukiruharai de like chloroformate isobutyl; Pibaroirukurori de yo una Ci-C ₅ alkanoyloxy Noi Le pays de; Shianohosuhon acid Jechiru di one c ₄ alkyl or di c ₆ as Shianohosuhon acid diphenyl - a c ₁₄ § Li one Rushianorin acid, preferably di one c ₄ alkyl or di c ₆ -c ₁₄ § Li one Rushianorin acid (especially Preferably, it is getyl cyanophosphonate).

 The inert solvent used in the production of mixed acid anhydrides is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include hexane, heptane, and rig ports. Aliphatic hydrocarbons such as benzene or petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; Ethers such as monoter, diisopropylether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, Amides such as hexamethylphosphoric acid triamide; amides such as dimethyl sulfoxide Sulfoxide such; sul Horan; are, preferably, ethers or amine earth (particularly preferably, the Tetorahi de port furan or dimethylformamidine de) is.

The reaction temperature in the reaction for producing mixed acid anhydrides varies depending on the starting compounds, reagents, etc., but is usually from -50 ° C to 100 ° C (preferably from 0 ° C to 60 ° C). is there. The reaction time for the reaction to produce mixed acid anhydrides depends on the starting materials, reagents, and reaction temperature. The force S that varies depending on the degree and the like is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours).

 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 inert solvent is the same as that 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 varies depending on the starting compounds, reagents, etc., but is usually from 130 ° C to 10 ° C (preferably 0 ° C). 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 varies depending on the starting compound, the reagent, the reaction temperature and the like, but is usually 5 minutes to 24 hours (preferably, 30 minutes to 16 hours).

In the case of using di-C ₄ alkyl cyanophosphoric acid or di c ₆ -c ₁₄ aryl-lucyanic acid in this reaction, the compound (XV) is directly reacted with the compound (XVI) in the presence of a base. It can also be done.

The method of removing the t-butoxycarbyl group which is an amino-protecting group using an acid is performed by using an acid in the case where the amino-protecting group in step A2 of method A is an alkoxycarbonyl. The removal is performed in the same manner as the removal method.

 A method for removing the t-butoxycarbyl group, which is a protecting group for an amino group, by using an acid to close the ring is described in the above-mentioned Method A, Step A2, when the protecting group for the amino group is an alkoxycarboxy group. The removal is performed in the same manner as the method of removing with use.

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, the compound ( After reacting the compound (XVI) with the compound (XV), the t-butoxycarbonyl group, which is a protecting group for the amino group, is removed using an acid, and the ring is closed.

In this step, after isolating and purifying the amide compound serving as an intermediate, the t-butoxycarbonyl group, which is a protecting group for the amino group, is removed with an acid in the same manner as in the above reaction, followed by ring closure. Also be done by _c Bases used in the reaction of reacting compound (XV) with compound (XVI) include, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and carbonated lithium; lithium hydrogen carbonate, sodium hydrogen carbonate, hydrogen hydrogen carbonate Alkali metal bicarbonates such as lithium hydride; alkali metal hydrides such as lithium hydride, sodium hydride, and lithium hydride; alkalis such as lithium hydroxide, sodium hydroxide, and hydroxylation lime Metal hydroxides; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium methoxide, potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N N-Dimethylaniline, N, N-Jetylaniline, 1,5-Diazabicyclo [4.3.0] Nona-1-ene, 1,4-Diazabicyclo [2.2.2] octane (DABC 0), 1 , 8-diazabicyclo [5.4.0] —organic amines such as 7-indene (DBU), preferably organic amines (particularly preferably triethylamine).

The inert solvent used in the reaction of the compound (XV) with the compound (XVI) is not particularly limited as long as it is inert to this reaction. For example, hexane, heptane, Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether Ethers; methanol, ethanol, n-prono. Alcohols such as phenol, isopropanol, _n -butanol, isobutanol, t-butanol, isoamino oleanolone, diethylene glycolone, g, reserin, octanolone, cyclohexanol, and methylcellosolve; Amides such as amide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric acid triamide; or a mixed solvent of the above solvents; preferably ethers or amides (particularly preferable). 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. C (preferably between 50 ° C. and 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 an amino group, with an acid to close the ring is performed in the case where the protecting group for the amino group in step A2 of Method A is an alkoxycarboxy group. The removal is performed in the same manner as the method of removing with use.

 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, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. 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 may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography, and using an appropriate eluent. Separation and purification can be achieved by elution.

The C 2 step is a step for preparing a compound having the general formula (I), R ^la and amino group in X ^a, human Dorokishiimino group and or a protecting group of the hydroxyl group and, Contact Keru amino group in A ^a, thiol The method for removing the group and the protecting group for Z or the hydroxyl group is performed in the same manner as the method for removing the amino group, the hydroxyimino group, the thiol group and the protecting group for Z 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. Then, an immiscible organic solvent such as water and ethyl ethyl ester is added, and the organic layer containing the target compound is added. It is obtained by separating, washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the obtained target compound can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., using a method commonly used for separation and purification of organic compounds as appropriate. Separation and purification can be achieved by elution.

 (Method D)

Method D is a compound of the formula (I) in which A has (II_d) and m is 1. This is a method for producing a compound (XIV) in which (XXIII) and A have (II-b) and m is 0.

Step D5

上記式中、 R¹乃至 R⁷、 R¹ \ R^{l a}、 R^7a、 X a、 X、 Y、 Z、 B、 D、 Q、 nおよび qは前述したものと同意義を示す。 第 D l工程は、 一般式 （XV I I I ) を有する化合物を製造する工程であり、 不 活性溶媒中、 塩基の存在下、 一般式 （V I ) を有する化合物を一般式 （XV I I ) を有する化合物と反応させることにより行われ、本工程は前記 B法第 B 1工程と同 様に行われる。

In the above formula, R ^{1 to} R ⁷ , R ¹ \ R ^la , R ^7a , X a, X, Y, Z, B, D, Q, n and q have the same meanings as described above. Step Dl is a step for producing a compound having the general formula (XVIII), and converting the compound having the general formula (VI) into a compound having the general formula (XVII) 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 carried out by using a catalytic reduction reaction or a common nitro group reduction method such as a zinc monoacetic acid method, a tin monoalcohol method or a tin monohydrochloric acid method.

 Step D3 is a step of producing a compound having the general formula (XX), and is accomplished by subjecting compound (XIX) to a Meerwein Arylation reaction. Meerwein

The Arylation reaction is described in Japanese Patent Application Laid-Open No. 55-22657 (US Pat. No. 4,258,193) and

S. Oae et al. [Bull. Chem. Soc. Jpn., 53, 1065 (1980) and the like. This 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 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. The same applies to.

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

The D 6 step is a step of producing the compound (XIV), after reacting the compound (XX) and Chio Urea, hydrolyzed, removing the protecting group of the optionally X a and R ^{1 a} It is performed by

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

After completion of the reaction, the target compounds (XXIII) and (XIV) of this reaction are collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and If present, remove it 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., and dry with anhydrous magnesium sulfate and anhydrous sodium sulfate. It is obtained by drying over anhydrous sodium bicarbonate or the like and distilling off the solvent. If necessary, the obtained target compound can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., using a method commonly used for separation and purification of organic compounds as appropriate. It can be separated and purified by elution.

Further, when the compounds (1), (XI1), (XIII), (XIV) and (XXIII) obtained by the methods A, B, C and D each have an amino group, it is more desirable. This allows alkylation, arylation, aralkylation or acylation of an amino group. These reactions are known or known methods or methods similar thereto [The Chemistry of the Amino Group, chapter 6, 1968, John Wiley & Sons _N The Chemistry of the Amino Group, chapter 2, 1970, John Wiley & Sons, and the like. ] Pico so easy Pico is manufactured. That is, alkylation or aralkylation of an amino group is carried out by, for example, a synthesis method in which a basic salt of an amine is reacted with an alkyl halide or an aralkyl halide, and allylation is carried out by reacting an amine with an aryl halide in the presence of a base. It can be performed by a synthesis method or the like.

 The starting compounds (IV), (VII), (IX), (XVII) and (XXI) are known or are easily produced according to known methods or methods similar thereto.

 The starting compounds (II1), (VI), (XV), (XXXI), (XXXII1), (XVI) and (XXXV) can also be produced, for example, by the following method.

 (Method E)

Method E is a process for producing compound (III) when compound (VI) or Q is an oxygen atom. Step E1

上記式中、 R^la、 R²乃至 R⁶、 X Y， Z、 G、 Q、 n、 q及び B o cは前述 したものと同意義を示す。

In the above formula, R ^la , R ^{2 to} R ⁶ , XY, Z, G, Q, n, q and B oc have the same meanings as described above.

 Step E1 is a step for producing a compound (VI) [(III); when Q = 0], by reacting a compound having the general formula (XXIV) with a compound (XVI) and using an acid. This is carried out by removing the t-butoxycarbonyl group, which is a protecting group for the amino group, and closing the ring. This step is a method of reacting the compound (XV) with the compound (XVI) in the step C1 of the method C, removing the t-butoxycarbonyl group, which is a protecting group for the amino group, using an acid, and closing the ring. The same is done.

In particular, when Z in the compound (XVI) is a nitrogen atom, the ring closure is preferably carried out in the absence of a solvent using the compound (XXIV) in a large excess. After completion of the reaction, the target compound (VI) [(III); when Q = 0] 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. Then, an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. Washed with water, etc., dried with 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 combined with a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds. It can be separated and purified by elution. (F method)

 Method F is a method for producing compound (XV).

(XXV) 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 In the method C, the meaning is the same as that described above for the explanation of G.).

 Step F1 is a step for producing a compound (XV), which comprises reacting a compound having the general formula (IV) with a compound having the general formula (XXV) in an inert solvent in the presence of a base. When the formyl group or carboxyl group in G is a protected formyl group or protected carboxyl group, the reaction is carried out by removing the protecting group, if desired.

 The base used in 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 an alkali metal. Hydrides (particularly preferably sodium hydride).

 The solvent 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 preferably the solvent is And amides and other mixed solvents (particularly preferably dimethylformamide).

 The reaction temperature when 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, and the like, but is usually from −50 ° C. to 200 ° 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 minutes. Time (preferably 1 hour to 10 hours). The removal of the protecting group of the formyl group or the carboxy group as desired depends on the type thereof, and generally, a method well known in the art of organic synthetic chemistry, for example, TWGreen, (Protective Groups in Organic Synthesis), John Wiley &Sons; JFW Mcomie , (Protective Groups in Organic Synthesis), Plenum Press.

Compounds in which G of the compound (XV) or G of the compound (XXV) is ^a carboxyl group or a protected carboxyl group are usually selected from compounds having ^a G or G ^a formyl group or ^a protected formyl group. It can be easily manufactured according to the method.

 After completion of the reaction, the target 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 insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water, 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 desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified.

 (G method)

Method G is a compound (XV) in which A a has (II—b ′) and m has the value 0 and the compound (XXXIII) or the A a force S (II−d ′) Is a method for producing a compound (XXI) wherein is 1.

(XVII) G ^a — (CH ₂ ) q-QH (XXVII)

 (XXVI)

 Step G2

G ^a- (CH ₂ ) qQ- ^ ^-H ₂

 (XXVIII)

上記式中、 R⁷、 R¹ \ R^{7 a}、 G G， D、 B、 Q及び qは前述したものと同 意義を示す。 第 G 1工程は、 一般式 （XXV I I ) を有する化合物を製造する工程 であり、 不活性溶媒中、 塩基の存在下、 一般式 （XV I I ) を有する化合物を一般 式 （XXV I ) を有する化合物と反応させることにより行われ、 本工程は前記 F法 第 F 1工程と同様に行われる。

In the above formula, R ⁷ , R ¹ \ R ^{7 a} , GG, D, B, Q and q have the same meanings as described above. The step G1 is a step for producing a compound having the general formula (XXV II), wherein the compound having the general formula (XV II) is synthesized in an inert solvent in the presence of a base. This step is carried out by reacting with a compound having the formula (XXVI), and this step is carried out in the same manner as in the above-mentioned Method F, Step F1.

 The G2 step is a step of producing a compound having the general formula (XXIII), and is performed by reducing the compound (XXVIII). This reaction is carried out 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.

 The G3 step is a step of producing a compound having the general formula (XXIX), and is achieved by performing a Meerwein Arylation reaction on the compound (XXIII).

The Meerwein Arylation reaction is 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), etc. . This is performed according to the method described in [1].

 Step G4 is a step of producing compound (XXX), which is performed by reacting compound (XXIX) with a compound having the general formula (XXI). This step is carried out by reacting a compound having the general formula (XX IX) with a compound having the general formula (XX I) in an inert solvent in the presence of a base. Is performed in the same manner as described above.

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.

 The G6 step is a step of producing the compound (XXXI I), in which the compound (XXIX) is reacted with thioperia and then hydrolyzed.

 The reaction of hydrolyzing the compound (XX IX) with thioperia is carried out according to the method described in JP-A-55-226577 (US Pat. No. 4,258,193). Will be

In the G 7 step method of removing the protecting group of the formyl group or carboxyl group in the definition of group G ^a is protecting the formyl group or carboxyl group in Method F It is performed in the same manner as the method for removing a group.

 After completion of the reaction, the target compounds (XXXI) and (XXXIII) of this reaction are 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. Then, an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water, etc., drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the obtained target compound can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds. It can be separated and purified by elution.

 (H method)

 Method H is a method for producing compound (XVI).

上記式中、 R^la、 R²乃至 R⁶、 X\ Y、 Z、 D、 B o c及び nは前述したものと 同意義を示す。

In the above formula, R ^la , R ^{2 to} R ⁶ , X \ Y, Z, D, B oc and n have the same meanings as described above.

The HI step is a step of producing the general formula (XXXVI), in which a compound having the general formula (XXXIV) is reacted with a compound having the general formula (XXXV) in an inert solvent in the presence of a base group. This step is performed in the same manner as the D method, step D1. The step H2 is a step of producing the compound (XVI), and is carried out by reducing the compound (XXXVI). This step is carried out in the same manner as the D method step D2. After completion of the reaction, the target compound (XVI) 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 to separate the organic layer containing the target compound. After washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc., the target compound obtained by distilling off the solvent can be obtained by a conventional method, if necessary. Separation and purification can be performed by appropriately combining ordinary methods commonly used for separation and purification of organic compounds such as crystallization and reprecipitation, and applying chromatography and eluting with an appropriate eluent.

 (I method)

 Method I is a method for producing compound (XXXV).

(XXXV) 上記式中、 R⁶、 Z、 D及び B o cは前述したものと同意義を示す。

(XXXV) In the above formula, R ⁶ , Z, D and Boc have the same meanings as described above.

 Step I1 is a step for producing a compound having the general formula (XXXVIII), which is carried out by protecting the amino group of the compound having the general formula (XXXVII) with a t-butoxycarbonyl group. Is generally well known in the art of organic synthetic chemistry, for example, according to TWGreen, (Protective Groups in Organic Synthesis), John Wiley &Sons; J ". FW Mcomie, (Protective Groups in Organic Synthesis), Plenum Press It can be carried out.

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, preferably ethers or amides (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 150 ° C to 200 ° C (preferably from 0 ° C to 120 ° C).

 The reaction time 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).

 After completion of the reaction, the target compound (XXXV) of the 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. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is removed. It is obtained by separating, 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 target compound obtained may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography, and applying a suitable eluent. Can be separated and purified.

 (J method)

Method J is a separate synthesis method for producing a compound (XLVI; compound (XXXVI) in which Xa is a carbonyl group).

 (XLIII)

(XLV) In the above formula, R ^la , R ^{2 to} R ⁶ , Y, Z, D, n and B oc have the same meanings as described above, and Ha 1 o is a chlorine atom, a bromine atom, an iodine atom or the like. Indicates a halogen atom.

 Step J1 is a step of producing the general formula (XLI), in which a compound having the general formula (XL) is reacted with a compound having the general formula (XXXV) in an inert solvent in the presence of a base. This step is performed in the same manner as in the D method, step D1. Step J2 is a step for producing a compound (XLII), which is carried out by subjecting the 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.

Solvents used for removal by oxidation are those that do not participate in this reaction. If it is, there is no particular limitation. Preferable examples of such an organic solvent include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, and methyl ether. And ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide, and sulfoxides such as dimethylsulfoxide.

 The oxidizing agent used is not particularly limited as long as it is a compound used for oxidation. Preferably, the oxidizing agent is persulfuric acid lime, sodium persulfate, ammonia cell silicate (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 0. C. to 150.degree. 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. Preferable examples of such an organic solvent include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetate nitrile, and ethyl ether. , Ethers such as tetrahydrofuran, dioxane, amides such as dimethylformamide, dimethylacetamide, amides such as hexamethylphosphoric triamide and sulfoxides such as dimethylsulfoxide, and aromatics such as benzene and toluene. Group hydrocarbons.

 The acid used is not particularly limited, but preferably, sulfuric acid, hydrochloric acid, bromic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid are used.

 The reaction temperature and reaction time vary depending on the starting compound, the acid catalyst, the solvent and the like, but the reaction is usually carried out at 0 ° C. to 150 ° C. for 10 minutes to 24 hours.

Step J3 is a step of producing a compound of the general formula (XLIII) in the presence of a base in an inert solvent in a step of producing a compound of the general formula (XLIII). This step is performed according to the D1 step of the D method. Step J4 is a step of producing the general formula (XLV I), in which the compound having the general formula (XL IV) is reacted with a compound having the general formula (XLV) in an inert solvent in the presence of a base. This step is carried out in the same manner as the method for synthesizing a chromanone derivative described in JP-A-60-51189:

 After completion of the reaction, the target compound (XLV 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. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is added. It is obtained by separating, 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 target compound obtained may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography, and applying a suitable eluent. Can be separated and purified.

 (K method)

 Method K is a separate synthesis method for producing compounds (XLVIII; compounds (I) excluding those in which X is a bond and carbonyl (> CO)).

上記式中、 R^{l a}、 R²乃至 R⁶、 A、 Q、 Υ、 Ζ及び ηは前述したものと同意義 を示し X bは前述した Xの定義のうち Xが結合及びカルボニル（>CO) であるも のを除いた基を示す。

In the above formula, R ^la , R ^{2 to} R ⁶ , A, Q, Υ, Ζ, and η have the same meanings as described above, and X b represents a bond and a carbonyl (> CO) Represents a group excluding

Step K1 is a step for producing a compound of the general formula (XLV III), Oximation reaction of ketone or reduction reaction of ketone usually performed on compound having the general formula (XLVII), and the obtained oxime form or alcohol form is optionally subjected to etherification reaction such as rubamoylation reaction or acylation. The reaction is performed. Further, alcohol compound obtained by the reduction can be a chromene body by acid catalyzed dehydration reaction, then it is possible to chroman body by a conventional catalytic hydrogenation _c

 After completion of the reaction, the target compound (XLVIII) 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. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water, 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 target compound obtained is eluted with an appropriate 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.

(Best mode for carrying out the invention)

 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.

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, and “Ph” indicates a fuunyl group, “HC1” or “HC1 saltj” next to a compound indicates that the compound is the hydrochloride salt, and “CH ₃ ” may be omitted from the methyl group.

502

Z.IZZ0 / 00df / I3d 38S 19/00 OAV s / ood O. one

cm

HZ

Z8S19 / 00 ΟΛ \ ilZZ JOO C / ID

19 / S-1 13d

o

実施例 1

Example 1

 5-{4-[6-(6-hydroxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) -1 1-methyl-1 H-benzoimidazole-1-2-ylmethoxy] benzyl } Thiazolidine-1,2,4-dione hydrochloride (Exemplary compound N Q. 2-1) N— {2 -— [4-1 (2,4-dioxothiazolidine-1-ylmethyl) phenoxyacetylamino] —5— ( 6-Methoxymethoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} -N-methylcarbamic acid t-butyl ester (Compound of Reference Example 3) 0.77 g of 4N hydrochloric acid One dioxane (15 ml) was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, dioxane was distilled off from the reaction mixture, ethyl acetate was added to the obtained residue, and the mixture was crystallized to obtain 0.32 g of the desired compound having a melting point of 16 (TC to 16 ° C). Was.

Example 2

 3— {4-[6 -— (6-hydroxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) -1-1-methyl-1 H-benzimidazole-1-2-ylmethoxy] Nil} — 2-— (2,2,2-trifluoroethyl) methyl ester propionate (Exemplified compound No. 7-34)

N— {2-[4 -— [2- (2,2,2-trifluoroethoxy) -1-2-methoxycarbonylethyl] phenoxyacetylamino] — ₅ _ (6-methoxymethoxy-1

2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl} N-methylcarbamic acid t-butyl ester (compound of Reference Example 6) 1.0 g, 4N hydrochloric acid Example using 4-dioxane 10 m 1 and 1,4-dioxane 10 m 1

The reaction was carried out at room temperature for 7 hours according to 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) to obtain an R f value of 0.28 (silica gel thin-layer mouth chromatography: _n - hexane: acetic acid Echiru 1: 1) purpose compound having 0. 7 2 g was obtained _c

Example 3 —3— {4-“6— (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) 1-1-methyl-1-H-benzimidazol —2-ylmethoxy] Phenyl} —2 -— (2,2,2-trifluoroethoxy) propionic acid (exemplified compound No. 4-7) _

 3— {4-[6-(6-hydroxy-1,2,5,7,8-tetramethylchroman-1

2-ylmethoxy) 1-methyl-1-H-benzoimidazolo-2-ylmethoxy] phenyl} —2- (2,2,2-trifluoroethoxy) methyl propionate (Example 2) Compound) To a mixture of 0.70 g of anhydrous tetrahydrofuran 7 ml of anhydrous tetrahydrofuran 7 ml of an aqueous solution of 0.13 g of lithium hydroxide monohydrate was added 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 aqueous sodium hydrogencarbonate solution, 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 resulting residue was purified by liquid chromatography [DIOL (filler trade name; Merck); ethyl acetate]. The R f value was 0.51 (“HPTLC : DIOL F254S "(MERCK); ethyl acetate) in an amount of 0.34 g.

Example 4

 2- (4-fluorobenzylthio) -1-3- (4- [6- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) 1-1-methyl-1H —Benzoimidazole-1-2-ylmethoxy] fuel) Methyl propionate (Exemplified compound No. 7-54)

N- {2- [4- [2- ( 4 one full O Robben Gino les Chio) Single 2 main Tokishikarubo two Ruechiru] phenoxyethanol methylcarbonyl § amino] - ₅ - (6-main Tokishime butoxy one 2, 5 , 7,8-Tetramethylchroman-2-ylmethoxy) phenyl} —N-methylcarbamic acid t-butyl ester (compound of Reference Example 11) 0.67 g, 1,4-dioxane 5 m 1 The reaction was carried out according to Example 1 using 2,4-dioxane and 4 ml of 4N hydrochloric acid. 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: 1,2: 1,3: 1) to obtain Rf = 0. Yellow oil with 32 (ethyl acetate: _n- hexane = 1: 1) 0.18 g of the desired compound in the form of was obtained.

Example 5

 2- (4-Fluorobenzylthio) 1-3- {4- (6- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) 1-1-methyl-1H-benzo Imidazoyl 2-ylmethoxy, phenyl} Propionic acid (Exemplified compound No. 4-27)

 2- (4-Fluorobenzylthio) -1-3- (4- [6- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H-base Methyl propionate (compound of Example 4) 0.15 g, 1,4-dioxane 2m1 and 1N sodium hydroxide aqueous solution 2.6m1 were used. The reaction was carried out according to Example 3. 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 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 to obtain 45 mg of the target compound as a yellow powder having a melting point of 97-100 ° C.

Example 6

 2— [Bis (4-fluorophenyl) methoxy] — 3— {4— [6— (6-hydroxy_2,5,7,8-tetramethylchroman-1-ylmethoxy) 1-1-methyl I 1 H-Benzoimidazole-21-Milmethoxy {phenyl} Methyl propionate (Exemplified Compound No. 7-57)

N- {2- [4- [2- [bis (4-fluorophenyl) methoxy] -12-methoxycarbonylethyl] phenoxyacetylamino] — 5 -— (6-methoxymethoxy) 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl} -N-t-butyl methylcarbamate (compound of Reference Example 33) 0.98 g, 1,4-dioxane 1 The reaction and after-treatment were carried out in the same manner as in Example 1 using 5 ml of 5 ml and 4 ml of 4N hydrochloric acid 1,4-dioxane solution, and the Rf value was 0.15 (silica gel thin layer chromatography). 0.23 g of the target compound as a tan oil having the following formula: ethyl acetate: _n- hexane = 1: 1) was obtained.

Example 7

 2-“Bis (4-fluorophenyl) methoxy] — 3— {4-[6— (6-hydroxy2,5,7,8-tetramethylchroman-2-ylmethoxy) 1-1-methyl

-1 H-Benzimidazole-l- 2-methoxy] phenyl] Propionic acid (Exemplified compound No. 7-2)

2- [bis (4-fluorophenyl) methoxy] — 3— {4— [6- (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) 1-1-methyl 1H-benzimidazole-l- 2 -ylmethoxy] phenyl} methyl propionate (compound of Example 6) 0.21 g, lithium hydroxide 'monohydrate 0.034 g After performing the reaction and post-treatment according to Example 3 using 2 ml of distilled water and 2 ml of tetrahydrofuran, liquid chromatography ("LiChroprep DIO-ji" (MERCK, registered trademark), ethyl acetate: _n -Hexane = 2: 1) and recrystallized with ethyl acetate, n-hexane and diisopropyl ether to give the desired compound as a brown powder having a melting point of 116 ° C to 126 ° C. 0.104 g was obtained.

Example 8

 3— {4-[6— (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-1-methyl_1 H—N-zimidimidazole-1-2-ilmethoxy] } -Ethyl 2-phenylthiopropionate (exemplified compound No. 7-106) N- {2- [4- (2-ethoxycarbonyl-12-phenylthioethyl) phenoxyacetylamino] — 5 _ (6-Methoxymethoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl} —t-butyl N-methylcanolebamate (Compound of Reference Example 16) 0 The reaction and after-treatment were carried out according to Example 1 using 73 g, 1 ml of ethanol and 5 ml of 1,4-dioxane solution of 4N hydrochloric acid, and the Rf value was 0.36 (silica gel thin layer). Chromatography, 0.48 g of the desired compound in the form of a white glass having ethyl acetate: n-hexane = 1: 1) was obtained. .

Example 9 3— {4-[6— (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-methyl-1-H-benzoimidazo-1-lu-2-ylmethoxy] phenyl } I-2-Fenylthiopropionic acid 'hydrochloride (Hydrochloride of Exemplified Compound No. 4-24)

 3 _ {4— [6— (6-hydroxy-1,2,5,7,8—tetramethylchromane)

2-ylmethoxy) 1 1-methyl-1H-benzoimidazole-1-2-ylmethoxy] phenyl} _ethyl 2-ethylthiopropionate (Compound of Example 8) 0.

46 g, lithium hydroxide monohydrate 0.12 g, distilled water 4 m1, tetrahydrofuran 5 m1 and N, N-dimethylformamide 3 m1 according to Example 3. After the reaction and post-treatment, the product was subjected to liquid chromatography ("LiChroprep DIO-ji" (MERCK, registered trademark), ethyl acetate: _n- hexane = 2: 1) to obtain a glassy product. Dissolve 0.25 g in 1 mL of dimethyl ether, add 3 ml of 4N hydrochloric acid solution in 1,4-dioxane at room temperature, stir for 30 minutes, and collect the resulting precipitate by filtration. 0.17 g of a milky white powdery target compound having a temperature of ° C to 124 ° C (softening point) was obtained.

Example 10

2-Hydroxydi-1--3- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-inolemethoxy) -1-methyl-1-H-benzoimidazo-1-1-2 f Lume Toxi] 7-83) N- {2-("4- (2-Hydroxy-1-2-ethoxycarbonylethyl) phenoxyacetylamino] _5_ (6-Methoxymethoxy) 1,2,5,7,8-Tetramethylchroman-12 f-methoxy) phenyl} -N-methylca / t-butyl levamine (compound of Reference Example 15) 0.7 g, ethanol 2 m1 and 4 The reaction and post-treatment were carried out in the same manner as in Example 1 using 5 ml of a 1,4-dioxane solution of normal hydrochloric acid, and the Rf value was 0.04 (silica gel thin-layer chromatography, ethyl acetate: _n- hexane). = 1: 1) 0.43 g of the desired compound in the form of a white glass having the formula:

Example 1 1

2-Hydroxy-1 3— ί4-[6-(6-Hydroxy-1 2, —5, —7, —8—tetrame Tylchroman-1-ylmethoxy-1-11-methyl-1H-benzoimidazole-12-fluoromethyI] propylic acid 'hydrochloride (Exemplary compound No. 4-1 hydrochloride)

2-Hydroxy-1 3— {4-[6- (6-Hydroxy_2,5,7,8-tetramethylchroman-1-ylmethoxy) -1 1-Methyl-1 H-Benzoimidazo-2-yl Toxyl] ethyl} ethyl propionate (compound of Example 10) 0.4 g, lithium hydroxide monohydrate 0.12 g, distilled water 4 ml and N, N-dimethylformamide 1 The powdery crude product 0.14 _§ obtained by performing the reaction and post-treatment according to Example 3 using 0 m 1 was suspended in 5 ml of 1,4-dioxane, and 4N hydrochloric acid was added. 5 ml of a 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 the target compound as a pale yellow powder having a melting point of 200 ° C or more (decomposition point).

Example 1 2

 2-Ethoxy 3— {4-[6- (6-hydroxy-1,2,5,7,8-tetramethynolechroman-2-inolemethoxy) -1-methyl-1 ri-benzimidazol-2-ylmethoxy] phen Nyl} ethyl propionate (exemplified compound o ._ 7-85) N- {2- [4- (2-ethoxy-l-ethoxycarbonylethyl) phenoxyacetylamino] — 5 -— (6-methoxymethoxy) 2,5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl} —t-butyl N-methylcarbamate (compound of Reference Example 23) 65 g, ethanol 2 m1 and 4 norm The reaction and after-treatment were carried out in the same manner as in Example 1 using 5 ml of a 1,4-dioxane solution of hydrochloric acid, and the Rf value was 0.2.

There was obtained 0.37 g of the desired compound as a pale yellow oil having 8 (silica gel thin layer chromatography, ethyl acetate: _n- hexane = 1: 1).

Example 13

2-ethoxy-1 3- {4-[6- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) -1 -methyl-1 H-benzoimidazoyl-2-ylmethoxy] Phenyl} propionic acid 'hydrochloride (Hydrochloride of Exemplified Compound No. 4-3) 2-Ethoxy 3- {4-[6-(6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1 1-methyl-1 H-benzoimidazo-1-2-ylmethoxy] Example 3 Using 0.35 g of ethyl ethyl propionate, 0.076 g of lithium hydroxide monohydrate, 5 ml of distilled water and 10 ml of N, N-dimethylformamide After the reaction and post-treatment according to the above, the product was subjected to liquid chromatography ("LiChroprepDIOL" (MERCK), ethyl acetate: _n- hexane = 3: 1), and the obtained glassy product 0 14 _§ was dissolved in 5 ml of 4N hydrochloric acid in 1,4-dioxane solution, and left at room temperature for 10 minutes. The residue obtained by distilling off the solvent was crystallized with getyl ether to give a melting point of 1. 2 2 ~ 1 3 2 ^{C C} pink powder purposed compound 0. 1 5 g of having (softening point) were obtained.

Example 14

 2- (4-Funoleo-benzyloxy) 1 3— {4-“6- (6-hydroxy-1,2,5,7,8-tetramethylchroman_2-ylmethoxy) 1-1-methyl-1 1H-benzoimidazo Rue 2-ylmethoxy] Fehl) Ethyl propionate (Exemplified compound No. 7-40)

 N- {2- [4-[2- (4-fluorobenzyloxy) _2-ethoxycarbonylylethyl] phenoxyacetylamino] -5- (6-methoxymethoxy-1,2,5,7 , 8-Tetramethylchroman-1-ylmethoxy) phenyl} -N-methylcarnoxamate t-butyl (compound of Reference Example 24) 0.6 g, ethanol 2 m1, and 4N hydrochloric acid The reaction and post-treatment were carried out according to Example 1 using 5 ml of a 1,4-dioxane solution, and Ri = 0.31 (silica gel thin-layer chromatography, ethyl acetate: n-hexane = 1: 1). 0.35 g of a light yellow glassy target compound having the following formula: was obtained. Example 15

 2-(4 Fluorobenzyloxy) 1 3-{4-"6-(6-Hydroxy-1. 2, 5, 7, 8-Tetramethylchroman _ 2-ylmethoxy) 1 1-Methyl-1 H-benzoimidazole-2-ylmethoxy] phenyl} propionic acid 'hydrochloride (Exemplified compound No. 4-13 hydrochloride)

2-(4-Fluorobenzyloxy) 1 3-{4-[6-(6-Hydroxy-1, 2 5,7,8-Tetramethylchroman-1-ylmethoxy) -11-methyl-1H-Benzoimidazoyl-2-ylmethoxy] phenyl) ethyl propionate (compound of Example 14) 0.33 g, After performing the reaction and post-treatment according to Example 3 using 0.063 g of lithium hydroxide 'monohydrate, 5 ml of distilled water and 1 Oml of N, N-dimethylformamide, Mouth chromatography ("LiChroprep DIO-ji" (MERCK, registered trademark), ethyl acetate: _n- hexane = ₃ : 1), 0.2 g of the obtained glassy product was treated with 4N hydrochloric acid 1 , 4-dioxane solution was dissolved in 5 ml and left at room temperature for 10 minutes.The residue obtained by distilling off the solvent was crystallized with getyl ether to give a melting point of 11 ° C to 120 ° C. 0.16 g of an off-white powdery target compound having a (softening point) was obtained.

47 (シリカゲル薄層 クロマトグラフィ一、 酢酸ェチル： _n—へキサン = 2 : 1) を有する無色ガラス状 の目的化合物 0. 53 gが得られた。 2—Ethylthio—3— {4—1—6— (6—Hydroxy-1,2,5,7,8—Tetramethylchroman—2—ylmethoxy) -1-Methyl-1 H—Benzimidazo—2—Irmet Nyl} Methyl propionate (Exemplified Compound No. 7-44) N— [2-Amino_5_ (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] — T-butyl N-methylcarbamate (compound of Reference Example 2) 1.45 g, 3- (4-carboxymethoxypropyl) — methyl 2-ethylethylthiopropionate (Compound of Reference Example 35) 0.86 g Using 0.35 g of anhydrous triethylamine, 0.57 g of getyl cyanophosphate and 50 ml of anhydrous tetrahydrofuran, the crude product obtained by performing the reaction and post-treatment according to Reference Example 3 was converted to 30 ml of methanol. Dissolve and add 30 ml of 4N hydrochloric acid in 1,4-dioxane Added at temperature and left for 1 8 hours. The solvent was distilled off, diluted with water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was subjected to column chromatography (silica gel, ethyl acetate: n-hexane).

There was obtained 0.53 g of the target compound as a colorless glass having 47 (silica gel thin-layer chromatography, ethyl acetate: _n- hexane = 2: 1).

Example 17

2-Ethylthio-3— _ {4— [6- (6-hydroxy-1,2,5,7,8-tetrame Tylchroman-1-ylmethoxy) 1-1-methyl-1-H-benzimidazole-12-ylmethoxy] fuel) Propionic acid hydrochloride (Hydrochloride of Exemplified Compound No. 4-17)

 2-Ethylthio-1-3- {4-1-1 [6- (6-Hydroxy-2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-1-methyl-1-H-benzimidazo-l-2T 2-methoxy Methyl propionate (compound of Example 17) 0.5

After performing the reaction and post-treatment according to Example 3 using 2 g, lithium hydroxide monohydrate 0.106 g, distilled water 2 m1 and N, N-dimethylformamide 1 Om1 The product was subjected to reversed-phase preparative high-performance liquid chromatography (〇DS, acetonitrile: water = 2: 1), and the obtained glassy product was dissolved in 4N ethyl acetate hydrochloride solution. Then, n-hexane was added to the residue, and the insolubles were collected by filtration to obtain 0.14 g of the target compound as a white powder having a melting point of 173 ° C to 177 ° C.

Example 18

 3_- {4— [6— (6-hydroxy-1,2,5,7,8-tetramethylchroman-12 methoxy) _ 1-methyl-1 H-benzimidazole _ 2—ylmethoxy] phenyl } —2— (4-Ditrophenoxy) ethyl propionate (Exemplified Compound No. 7-1 19)

N— {2- [4-(2- [4-nitrophenoxy] —2-ethoxycarbonylethyl) phenoxyacetylamino] —5— (6-methoxymethoxy-1,2,5,7,8-tetra Methylchroman-2-ylmethoxy) phenyl} -t-butyl N-methylcarbamate (Compound of Reference Example 30) 2.64 g, 25 ml of 1,4-dioxane 25 ml and 4N 1,4-dioxane The reaction and post-treatment were carried out according to Example 1 using 25 ml of the solution, and the Rf value was determined to be 0.19 (silica gel thin-layer chromatography, ethyl acetate: _n- hexane = 1: 1). This yielded 1 · 58 g of a yellow glassy target compound having

Example 19

3— {4-[6- (6-hydroxy2.5,7,8-tetramethylchroman-1-ylmethoxy) 1 1-methyl-1 H-benzimidazole-1-ylmethoxy] Phenyl} —2- (4-nitrophenoxy) propionic acid (Exemplified compound No. 7-9)

 3-{4-[6-(6-hydroxy-1,2,5,7,8-tetramethylchroman-1

2-ylmethoxy) 1-methyl-1H-benzoimidazole-1-2-ylmethoxy] phenyl} 2- (4-nitrophenoxy) ethyl propionate (compound of Example 18) 1.55 g After performing the reaction and post-treatment according to Example 3 using 0.27 g of lithium hydroxide monohydrate, 25 ml of distilled water and 25 ml of tetrahydrofuran, column chromatography ("LiChroprep DIO '(MERCK, registered trademark), ethyl acetate: _n- hexane = 4: 1) yielded 0.25 g of a yellow glassy target compound having a melting point of 135 ° C or more (softening point). Got:

Example 20

 3— {4— [6- (6-hydroxy-1 2'—5,7,8-tetramethylchroman_2-ylmethoxy) -1-1-methyl-1 H-benzimidazo-l-2 ilmethoxy] Nyl} —2— (4-N-nitrofurthio) ethyl propionate (Exemplary compound No. 7-121)

 N— {5— (6-Methoxymethoxy 2,5,7,8—Tetramethylchromane

20 (シリカゲル薄層クロマトグラフィー、 酢酸ェチル： n—へキサ ン =2 ： 3) を有する黄色ガラス状の目的化合物 0. 6 gが得られた。 2-ylmethoxy) 1 2— [4— [2— (4—2-nitrophenyl) 1-2-ethoxycarbonylinolethino] phenoxyacetylamino] phenyl} —N-methylcarbamine Using 1 g of t-butyl acid (compound of Reference Example 17), 5 ml of ethanol and 1 Om 1 of 4N hydrochloric acid in 1,4-dioxane, the reaction and post-treatment were carried out according to Example 1, and

0.6 g of the target compound as a yellow glass having 20 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 2: 3) was obtained.

Example 21

 3-{4-[6-(6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) 1! -Methyl-1_H-benzimidazo-l- 2-ylmethoxy] phenyl: 2- (4-ditrophenylthio) propionic acid hydrochloride (Hydrochloride of Exemplified Compound No. 7-1-11)

3— {4-[6— (6-hydroxy 2,5,7,8-tetramethylchromane) 2- (Ilmethoxy) 1-1H-Methyl-1H-Benzoid-Midazo-Iu 2-Ilmethoxy] phenyl} 1-2- (412-Trofurenylthio) Ethyl propionate (Compound of Example 20) 0. Reaction and after-treatment according to Example 3 using 58 g, lithium hydroxide 'monohydrate 0.11 g, distilled water 8 ml and N, N-dimethylformamide 15 ml After that, the mixture was subjected to liquid chromatography ("LiChroprepDIOL" (MERCK, registered trademark), ethyl acetate: _n- hexane = 10: 1), and the obtained glassy product 0.38 the g was dissolved in as tetrahydrofuran 5 m 1, 4 N hydrochloric acid 1, crystallized 4 Jiokisan solution 5 m 1 added was removed by distillation, and the _c solvent was allowed to stand for 10 minutes at room temperature the residue in Jechi ether, mp 0.35 g of the target compound as a yellow powder having a temperature of 130 ° C. to 138 ° C. (softening point) was obtained.

Example 22

 3-{4-[6— (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) 1-1-methyl-1 H-benzoimidazole-2-ylmethoxy ] Fehl) 1-Ethyl 2-phenoxypropionate (Exemplified compound No. 7-92) N— {2- [4- (2-Ethoxycarbonyl 2-phenoxicetyl) phenoxyacetylamino] _ 5 _ (6- Methoximethoxy 2,5,7,8-tetramethynolechroman_2-ylmethoxy) phenyl} —N-methylcarbamic acid t-butynole (compound of Reference Example 29) 0.58 g, ethanol 5 m 1 and The reaction and after-treatment were carried out in the same manner as in Example 1 using 1N 4N hydrochloric acid in 1,4-dioxane as in Example 1, and the Rf value was 0.13 (silica gel thin-layer chromatography, ethyl acetate: n- 0.39 g of the target compound in the form of a white glass having the following formula: xane = 1: 2) was obtained.

Example 23

 3-{4-[6- (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1 1: methyl-1H-benzoimidazole-1-2-ylmethoxy] phen } — 2-phenoxypropionic acid 'hydrochloride (Exemplified Compound No. 4-10 hydrochloride)

3— {4-[6— (6-hydroxy 2,5,7,8-tetramethylchroman-12-ylmethoxy) 1-l-methyl _ 1 H-Venzoi midazo 1-l 2-methyl [Phenyl] -1-ethyl 2-phenyloxypropionate (compound of Example 22) 0.37 g, lithium hydroxide monohydrate 0.076 g, distilled water 5 m 1 And N, N-dimethylformamide (10 ml), followed by reaction and post-treatment according to Example 3, followed by liquid chromatography (“LiChroprepDIOL” (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 of 1,4-dioxane (5 ml) and left at room temperature for 15 minutes. The residue obtained by distilling off the solvent was dissolved in 5 ml of tetrahydrofuran, and added dropwise to 250 ml of getyl ether with stirring. After stirring for further 20 minutes, the resulting precipitate was collected by filtration to obtain 0.22 g of an off-white powdery target compound having a melting point of 128 ° C to 135 (softening point). Example 24

 2-(4-cyanophenoxy)-3-4 1 [6-(6-hydroxy 2,5,7,8-tetramethylchroman-2-ylmethoxy) -1 -methyl-1 H-benzoimidazole-2- Ilmethoxy-phenyl) ethyl propionate (Exemplified compound No. 7-1 2 2)

N- {2- [4- [2- (4-cyanophenoxy) -1-2-ethoxycarbonylethyl] phenoxyacetylamino] —5- (6-methoxymethoxy-1,2,5,7,8-tetramethyi ^ / Chroman 12-ylmethoxy) pheninole) 1-N-methyl t-butyl bamate (compound of Reference Example 18) 0.57 g, 1,4-dioxane 3ml and 4N hydrochloric acid The reaction and post-treatment were carried out in the same manner as in Example 1, using 3 ml of 1,4-dioxane solution. _0.27 g of a white glassy target compound having a ¾ value = _0.38 (“HPTLC NH ₂ F _254S ” (MERCK), ethyl acetate: n—hexane = 3: 2) was obtained.

Example 25

 2- (4-cyanophenoxy) -1-3- (4-[6- (6-hydroxy-2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-methyl-1 H-benzoimidazo-2 Ilmethoxy] phenyl} propionic acid 'hydrochloride (Hydrochloride of Exemplified Compound No. 7-12)

2- (4-cyanophenoxy) -1-3- (4- [6- (6-hydroxy-1,2,5,7,8-tetramethinolechroman-1-inolemethoxy) 1-1_methizole-1H-benzo Imidazole-2-ylmethoxy] phenyl} ethyl propionate (compound of Example 24) 0.48 g, lithium hydroxide monohydrate 0.09 g, distilled water 5 ml and N After performing the reaction and post-treatment according to Example 3 using N, N-dimethylformamide 1Om1, liquid chromatography ("LiChroprepDIOL" (MERCK, registered trademark), ethyl acetate: _n- The resulting glassy product was dissolved in 5 ml of 1,4-dioxane, and 2 ml of a 4N hydrochloric acid solution of 1,4-dioxane was added at room temperature. Let stand for minutes. This solution was added dropwise to 100 ml of getyl ether while stirring. The mixture was further stirred for 15 minutes, and the resulting precipitate was collected by filtration to obtain 0.33 g of a light red powdery target compound having a melting point of 142 ° ^{C. to} 144 C (softening point).

Example 26

 _3_-{4-1- [6-(6-hydroxy, 5,7.8-tetramethylchroman-1-ylmethoxy) -1 1-methyl-1 H-benzimidazole-1-2-ylmethoxy] fuel )-2- (4-Methylphenylthio) ethyl propionate (Exemplified compound N Q. 7-127)

N- {2- [4- [2-ethoxycarbonyl_2-2- (4-methylphenylthio) ethyl] phenoxyacetylamino] -5- (6-methoxymethoxy-1,2,5,7,8 —Tetramethylchroman-2-ylmethoxy) phenyl} —t-butyl N-methylcarbamate (compound of Reference Example 19) 0.92 g, ethanol 4 ml and 4N hydrochloric acid 1,4-dioxane solution The reaction and post-treatment were carried out according to Example 1 using 10 ml, and Rfj [S = _0.31 ("HPTLC NH, _F254S " (MERCK), ethyl acetate: n-hexane = 1) 0.51 g of a white glassy target compound having the following formula: 1) was obtained.

Example 2 7

 2- (4-Methylphenylthio) -1-3- (4--6- (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy-1-methyl-1H-benzoimidazole) — 2-ylmethoxy] fuundyl} propionic acid .hydrochloride (Exemplified compound No. 7-17)

3— {4— [6— (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) 1 1—methyl-1 H— ^ ^ [Phenyl] —2- (4-methylphenylthio) ethyl propionate (compound of Example 26) 0.55 g, lithium hydroxide monohydrate 0.1 lg, distilled water 5 ml and After performing the reaction and post-treatment according to Example 3 using N, N-dimethylformamide 1 Om 1, liquid chromatography (“LiChropr mark DI0” (MERCK, registered trademark), ethyl acetate: n-Hexane = 2: 1), 0.3 g of the obtained glassy product was dissolved in 5 ml of 1,4-dioxane, and 2 ml of a solution of 4N hydrochloric acid in 1,4-dioxane at room temperature was added. The solvent was distilled off, and the residue was dissolved in 1,4-dioxane (5 ml) and added dropwise to 200 ml of getyl ether while stirring, and the mixture was further stirred for 30 minutes. and, when filtered resulting precipitate mp 1 1 8: ~ 1 2 2 C C off-white powdery target compound 0. 2 6 g with (softening point) It was _c

Example 2 8

 2- (4-chlorophenol) 3- (4) [6- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) 1-1-methyl-1-H —Benzoimidazo-1-yl-2-ylmethoxy] phenyl} ethyl propionate (Exemplified compound No. 7—130)

N— {2— [4- [2- (4-chlorophenethylthio) -1-2-ethoxycarbonylethyl] phenoxyacetylamino] —5 -— (6-methoxymethoxy 2,5,7,8 —Tetramethinolechroman-1-2-inolemethoxy) pheninole} 1-N-Methylenolenoic acid t-butyl phenol (Compound of Reference Example 20) 0.75 g, ethanol 4 m1 and 4N hydrochloric acid 1 conducting a reaction and post-treatment was carried out according to example 1 using 4 _ Jiokisan solution 1 0 m l, R f value = 0 3 3 ( "HPTLC H 2 F 254S" (MERCK), acetic Echiru:. n-to 0.5 lg of the target compound in the form of a white glass having the following formula: xane = 1: 1) was obtained.

Example 2 9 '

 2- (4-chlorophenylthio) — 3— {4- (6— (6-hydroxy-1-2.5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1-H— Benzoimidazoyl 2-ylmethoxy] phenyl} Propionic acid 'hydrochloride (Hydrochloride of Exemplified Compound No. 7-20)

2— (4-chlorophenol) 1 3— {4— [6— (6—hydroxy 2,5, 7,8-Tetramethylchroman-1-ylmethoxy) 11-methyl-11H-benzoimidazoyl-2-ylmethoxy] phenyl} ethyl propionate (compound of Example 28) 0.49 g, 0.09 g of lithium hydroxide monohydrate, 5 ml of distilled water and 1 Oml of N, N-dimethylformamide according to Example 3, followed by reaction and post-treatment. The mixture was subjected to liquid chromatography ("LiChroprepDIOL" (MERCK, registered trademark), ethyl acetate: _n- hexane = 2: 1), and 0.23 g of the obtained glassy product was treated with 1,4-dioxane 5 Then, 2 ml of a 4N hydrochloric acid solution in 1,4-dioxane 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 5 ml of 1,4-dioxane, and added dropwise to 200 ml of getyl ether while stirring. The mixture was further stirred for 30 minutes, and the resulting precipitate was collected by filtration to obtain 0.2 g of the objective compound as a pale yellow powder having a melting point of 120 ° C to 124 ° C (softening point).

Example 30

 2- (4-t-butylphenylthio) — 3— {4— [6 _ (6-hydroxy2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1H— Benzoimidazole-2- (inolemethoxy) phenyl] ethyl propionate (Exemplified compound No. 7-133)

4 2 ("HPTLC NH₂ F_254S" (MERCK)、 酢酸ェチル： n—へキサ ン = 1 ： 1) を有する白色ガラス状の目的化合物 0. 5 5 gが得られた。 N- {2-[4 -— [2- (4-t-butylphenylthio) _ 2 _ethoxycarbonylethyl] phenoxyacetylamino] 1 5— (6-methoxymethoxy 2,5,7,8 —Tetramethylchroman —2-inolemethoxy) phenyl} —N-Methylcarbamate t-butyl (compound of Reference Example 21) 0.75 g, ethanol 8m1 and 4N hydrochloric acid 1,4-dioxane solution The reaction and post-treatment were carried out according to Example 1 using 8 ml, and R

There was obtained 0.55 g of a white glassy target compound having ₄₂ ("HPTLC NH ₂ F _254S " (MERCK), ethyl acetate: n-hexane = 1: 1).

Example 3 1

2- (4-t-butylphenylthio) -1-3- (4- [6- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) 1-1-methyl-1H —Benzoimidazole—2-ylmethoxy] phenyl} Propionic acid 'hydrochloride (Hydrochloride of exemplified compound No. _7-23) 2-(4-t-butylpheninolethio) 1 3-{4-[6-(6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) 1 1 _methyl-1 H —Benzoimidazole-2-ylmethoxy] phenyl tn ethyl pionate 0.53 g, lithium hydroxide monohydrate 0.1 g, distilled water 5 ml and N, N-dimethyl After performing the reaction and post-treatment according to Example 3 using 15 ml of formamide, liquid chromatography ("LiChropr DI0, (MERCK, registered trademark)", ethyl ethyl acetate: n- The resulting glassy product was dissolved in 5 ml of 1,4-dioxane, 2 ml of 4N hydrochloric acid in 1,4 dioxane was added at room temperature, and the mixture was added to the mixture at room temperature. The residue obtained by distilling off the solvent was dissolved in 1,4-dioxane (5 ml) and added dropwise with stirring to 20 ml of getyl ether. The resulting precipitate was collected by filtration.The target compound was obtained as a pale yellow powder having a melting point of 134 ° C to 138 ° C (softening point).

24 g were obtained.

Example 3 2

 3— {4-[6— (6-hydroxy-1,2,5,7,8-tetramethinolechroman-12-ylmethoxy) _ 1-methyl-1H-benzoimidazole-2-ylmethoxy] Phenyl} -2- (4-methoxyphenylthio) ethyl propionate (Exemplified Compound No. 7-136)

N— {5— (6-Methoxymethoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) 1-2— [4— [2— (4-Methoxyphenylthio) 12— [Toxicanolebonylethyl] phenoxyacetylamino] feninole} t-butyl _N-methylcarbamate (compound of Reference Example 2) 0.7 g, ethanol 8 m1 and 4N hydrochloric acid 1 The reaction and work-up were carried out in the same manner as in Example 1 using 8 ml of a 1,4-dioxane solution, and the Rf value was _0.26 ("HPTLC NH ₂ F _254S " (MERCK), ethyl acetate: n- 0.5 g of a white glassy target compound having the following formula: xane = 1: 1) was obtained.

Example 3 3

3— {4— [6— (6-hydroxy-1,2,5,7,8—tetramethylchroman-1-ylmethoxy) 1—1methyl-1-H—Venzoimidazo—1 2-ylmethoxy] Hue Nil} — 2— (4-Methoxyphenylthio) propionic acid.Hydrochloride Product No. 7-26 hydrochloride)

3-{4-[6-(6-Hydroxy-1 5 7, 8-Tetramethylchroman-1-Remethoxy) 1 1-Methyl-1 H-Benzydazole-1-Remethoxy] Phenyl}-2 — (4-Methoxyphenylthio) ethyl propionate (compound of Example 32) 0.48 g, lithium hydroxide monohydrate 0.1 lg, distilled water 5 ml and NN-dimethylformamide After performing the reaction and post-treatment according to Example 3 using 15 ml, the mixture was subjected to liquid chromatography ("LiChroprepDIOL" (MERCK, registered trademark), ethyl acetate: _n -xane = 21). The obtained glassy product was dissolved in 14 ml of 14-dioxane, 2 ml of 4N hydrochloric acid solution in 14 ml of dioxane was added at room temperature, and the mixture was allowed to stand for 15 minutes. The residue thus obtained was dissolved in 5 ml of 14-dioxane, and added dropwise to 200 ml of dimethyl ether while stirring. The mixture was further stirred for 15 minutes, and the resulting precipitate was collected by filtration to obtain 0.22 g of a pinkish powdery target compound having a melting point of 122 ° C and 125 ° C (softening point).

Example 34

5-{4-[6-(6-hydroxy 1-4-oxo-2 5 7 8-tetramethylchroman-1-ylmethoxy)-1-methyl-1 H-benzoimidazo-1-2-ylmethoxy] benzyl} thiazolidine — 24—dione (Exemplary compound No. 2- 20)

N— {5— (6-acetoxy-4-oxo-1 2 5 7 8—tetramethylchroman-1-ylmethoxy) 1-2— [4— (24-dioxothiazolidine-15-ylmethyl) ) [Phenoxyacetylamino] phenyl} -t-butyl N-methylcarbamate (compound of Reference Example 41) 0.25 g, distilled water 5 m 1 and 4N hydrochloric acid 14-dioxane solution 30 m The mixture was left at room temperature for 5 days, then heated to reflux for 1 hour. The solvent was distilled off from the reaction mixture, water was added to the residue, the mixture was neutralized with sodium hydrogen carbonate, 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 obtained residue was subjected to reversed-phase preparative high-performance liquid chromatography (ODS, acetonitrile: (0.2% acetic acid + 0.2% triethylamine) aqueous solution = 11). R fi = 0.32 ("HPTLCDIOL F _954S " ( _MERK ), ethyl acetate: 0.18 g of a light yellow glassy target compound having n-hexane = 3: 1) was obtained. Example 35

 5— {4-1- [6-(6-hydroxy-1-4,2-oxo-1,2,5.7,8-tetramethylchroman-2-ylmethoxy) -1-1-methyl-1H-benzodimidazo-1--2-methoxy) Benzyl) thiazolidine mono 2,4-dione 'hydrochloride (Hydrochloride of Exemplified Compound No. 2-20)

 5-{4-[6-(6-hydroxy-1 4-oxo-1,2,5,7,8-tetramethyl chroman-2-ylmethoxy) -1-methyl-1 H-benzoimidazolu-2-ylmethoxy Benzyl} thiazolidine-1,2, -dione (compound of Example 34) A mixture of 0.17 g, 3 ml of ethyl acetate and 2 ml of 4N ethyl acetate hydrochloride solution was stirred at room temperature for 10 minutes. To the reaction mixture was added 5 Om 1 of n-hexane, and the mixture was stirred for 30 minutes.The resulting precipitate was collected by filtration.0.14 g of the desired compound was obtained as a pale yellow powder having a melting point of 150 ° C to 154 ° C. was gotten.

Example 36

5— {4-[6-(6-Hydroxy-1-methoxyimino _2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-Methyl-1H-Venzoimidazo-one 2-Ilme Toxy] benzyl} thiazolidine-1,2,2-one (Exemplified compound No. 2-24)

56 ("HPTし CDI0LF_254S" (MERK)、 酢酸ェチル： _n-へキサン = 3 ： 1) を有する淡紅色ガラス状の目的化合物 0. 22 gが得られた。 実施例 3 7 5— {4— [6— (6-hydroxy-1,4-oxo-1,2,5,7,8-tetramethylchroman-1-inolemethoxy) -1-methyl-1-H-benzoimidazole-21-ylmethoxy] benzyl} thiazolidine one 2, (the compound of example 34) 4-dione 0. 3 g, O-Mechiruhi Dorokishiruamin hydrochloride 0. 1 3 _§, a mixture of pyridine 0. 1 2 g of anhydrous methanol Ichiru 1 5 m l at room temperature After stirring for 1 hour, the mixture was left for 20 minutes. The mixture was further refluxed for 4 hours and left overnight. The solvent was distilled off, and the residue was subjected to reverse phase preparative high performance liquid chromatography (ODS, acetonitrile: (0.2% acetic acid + 0.2% triethylamine) aqueous solution = 6: 4), and R

0.22 g of the desired compound in the form of a pink glass having 56 ("HPT-CDI0LF _254S " ( _MERK ), ethyl acetate: _n- hexane = 3: 1) was obtained. Example 3 7

 5- {4-[6—_j6—Hydroxy-1- 4-imethoxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-methyl-1-H-benzoimidazole—2-ylme Toxy] benzyl} thiazolidine-2,4-dione 'hydrochloride (Hydrochloride of the exemplified compound No. 2-24)

 5-{4-[6— (6-hydroxy 4-methoxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1 1-methyl1-1 H-benzoimidazo-2 —Ilmethoxy] benzyl} thiazolidine-1,2,4-dione (compound of Example 36) 0.2 1 g, 5 ml of ethyl acetate and 10 ml of 4N ethyl acetate hydrochloride solution were mixed with 10 ml of ultrasonic waves. Irradiated for minutes. The solvent was distilled off, and the obtained residue was crystallized with getyl ether to obtain 0.2 g of a light yellow powdery target compound having a melting point of 140 ° C to 144 ° C (softening point). Was.

Example 3 8

 5— {4— [6-(4-benzyloxyimino-6-hydroxy-1,5,7,8-tetramethylchroman-1-ylmethoxy) -1 1-methyl-1 H-benzoimidazole-2 —Ilmethoxy] benzyl} thiazolidine-1,2, dione (Exemplified compounds No. 2-25)

5-{4-[6- (6-hydroxy-1-4-oxo-2,5,7,8-tetramethynorecroman-1-2-ylmethoxy) -1 1-methinole 1 H-benzoimidazogray 2-ylmethoxy] Benzyl} thiazolidine-2,4-dione (Compound of Example 34) 0.3 g, 0.24 g of 0_benzylhydroxylamine hydrochloride, 0.12 g of pyridine, and 15 ml of anhydrous methanol using Example 36 A light yellow glassy target compound having R fi = 0.58 ("HPTLC DIOL F _254S " ( _MERK ), ethyl acetate: n-hexane = 3: 1) 0.24 g obtained _c

Example 3 9

5— {4-1- [6 -— (4-benzyloxyminnow 6-hydroxy-2,5.7,8-tetramethylchroman-1-xy-) -_ 1-methyl-1 H-benzoimidazole-1 2 —Ilmethoxy] benzyl} thiazolidine-1 2,4-dione'hydrochloride (eg Compound No. 2-25 hydrochloride)

 5— {4— [6— (4-benzyloxyimino-6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-methyl-1-H-benzoimidazole-2- [Milmethoxy] benzyl} thiazolidine_2,4-dione (Compound of Example 38) 0.23 g, 5 ml of ethyl acetate, and 10 ml of 4N ethyl acetate hydrochloride solution were reacted according to Example 37. And after-treatment, melting point 135 ° C ~ 142 ° C

0.2 g of a light yellow powdery target compound having a (softening point) was obtained.

Example 40

 5-{4-[6-(6-Hydroxy-1- 4-Hydroxyimino _ 2,5,7,8-Tetramethylchroman-2-ylmethoxy) -1-Methyl-1H-Venzoimidazo1-2 —Ilmethoxy] benzyl} thiazolidine-1, 2,4-dione (Exemplified compound No. 2-23)

 5— {4— [6— (6-hydroxy-1,4-oxo-2,5,7,8-tetramethynolechroman-1-ylmethoxy) -1-methyl-1-H-benzoimidazo-l-2-ylmethoxy Benzyl} thiazolidine-2,4-dione (Compound of Example 34) 0.6 g, hydroxylamine hydrochloride 0.21 g, pyridine 0.24 g, and a mixture of anhydrous methanol 30 ml 1 were stirred at room temperature for 1 hour. After that, it was left for 1.5 days. After heating under reflux for an additional 1 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 to stand for 2 days. The solvent was distilled off, and the residue was subjected to reverse phase preparative high performance liquid chromatography (ODS, acetonitrile: (0.2% acetic acid + 0.2%).

2% triethylamine) Aqueous solution = 1: 1), R = 0.36 ("HPTLCDI0L F _254S " ( _MERK ), ethyl acetate: n-hexane = 3: 1). 0.33 g of compound _c was obtained.

Example 4 1

5-{4-[6-(6-hydroxy-1-4, hydroxy7-1,2,5,7,8-te. Tramethylchroman 21-inolemethoxy)-1-methyl-1 H-benzoimidazole-2 —Ilmethoxy] benzyl} thiazolidine—2,4-dione ′ hydrochloride (Hydrochloride of Exemplified Compound No. 2-23) 5— {4-[6— (6-Hydroxy-1 4-Hydroxyimino _ 2,5,7,8—Tetramethylchroman 2— ^ f-Lumethoxy) -1 1-Methyl-1 H—Venzoimidazo 2-ylmethoxy] benzyl} thiazolidine-l, 4-dione (compound of Example 40) 0.32 g, 10 ml of ethyl acetate and 15 ml of a 4N solution of ethyl acetate hydrochloride in 15 ml of Example 3 were used. The reaction and after-treatment were carried out according to 7, to obtain 0.32 g of the target compound as a yellow powder having a melting point of 158 ° C to 16 ° C (softening point).

Example 4 2

 5— {4— [6— (4-ethoxycarbonylmethoximino-1 6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) 1—1methyl-1 1_H—nzomidazole I-2-ylmethoxy] benzyl} thiazolidine-1,2,4-dione (Exemplified compound No. 6-2)

3 2 ("HPTLC DIOL F_254S" (MERK)、 酢酸ェチル： n_へキサン = 3 ： 1 ) を有する淡黄色ガラス状の目的化合物 0. 2 5 gが得られた _c 実施例 4 3 5-{4-[6-(6-Hydroxy-4-oxo-1,2,5,7,8-tetramethylchroman-1 -Inolemethoxy) -1 -Methylenol 1 H-Benzimidazono-1- 2-Milmethoxy Benzyl} thiazolidine-1,2 dione (Compound of Example 34) 0.3 g, t_butyl p-aminosulfonate p-toluenesulfonate 0.48 g, pyridine 0.12 g and anhydrous methanol 15 m The mixture of 1 was stirred at room temperature for 1 hour and then left for 1.5 days. After further refluxing for 3.5 hours, the mixture was allowed to stand still. 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 left for 2 days. The solvent was distilled off, and the residue was subjected to reverse phase preparative high performance liquid chromatography-(ODS, acetonitrile: (0.2% acetic acid + 0.2% triethylamine) aqueous solution = 3: 2), and R

_C Example 4 3 in which 0.25 g of a light yellow glassy target compound having 3 2 ("HPTLC DIOL F _254S " ( _MERK ), ethyl acetate: n_hexane = 3: 1) was obtained.

 5— ”4— [6- (ethoxycarbonyl methoxyimino-1 6—hydroxy-1

5,7,8-Tetramethylchroman-1-ylmethoxy) 1-1-methyl-1H-benzoimidazo-1-ru-2-ylmethoxy] benzyl} thiazolidine-2,4-dione hydrochloride (Exemplified Compound No. 6-2 hydrochloride)

5— {4-[6— (4-ethoxycarbonylmethoximino) — 6—hydroxy 2,5,7,8-Tetramethylchroman-12-ylmethoxy) 1-1-methyl-1H-benzimidazole-12-ylmethoxy] benzyl} thiazolidine-12,4-dione (Example 42) The compound was subjected to the reaction and post-treatment in the same manner as in Example 37 using 0.24 g, 5 ml of ethyl acetate and 1 Om1 of a 4N ethyl acetate hydrochloride solution. 0.19 g of a light yellow powdery target compound having a 133 ° C (softening point) was obtained. Reference example 1

 N- [5- (6-Methoxymethoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) 1-2-2-trophenyl] -t-butylester N-methylcarbamate (raw material for Reference Example 2) )

 6-Methoxymethoxy 2,5,7,8-Tetramethylchroman-1-ylmethanol 1 5.OO g, N- (5-chloromethyl 1-2-nitrophenole) 1-N-methinorecanolebaminic acid t 0.78 g of sodium hydride (55% by weight) was added to a mixture of 5.1 g of monobutyl ester and 10 Om1 of dimethylformamide under ice cooling, and the mixture was stirred at room temperature for 3 hours. Stirred. After allowing the reaction mixture to stand for 晚, 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 a saline solution 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). R fi = 0.30 (silica gel thin-layer chromatography; hexane: ethyl acetate) = 3: 1).

Reference example 2

 N— [2-Amino-5— (6-Methoxymethoxy-1,2,5,7,8-Tetramethylchroman-1-Inolemethoxy) pheninole] 1-N-Methylcarbamic acid t-petit / Rester (Reference example) 3, raw materials)

N— [5- (6-Methoxymethoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) 1-2-2-trophenyl] —N-methylcarbamic acid t-butyl ester (Compound of Reference Example 1) 4.0 g, 10% palladium-carbon 0.4 g A mixture of methanol and 8 Om 1 was stirred under a hydrogen atmosphere at room temperature for 3 hours. After the reaction is completed, the catalyst is filtered off from the reaction mixture, and the filtrate is concentrated. The target compound having R = 0.12 (silica gel thin layer chromatography; hexane: ethyl acetate = 3: 1) is obtained. 3.77 g of the product were obtained.

Reference example 3

 N— {2-[4-(2,4 dioxothiazolidine-1-ylmethyl) phenoxy ^ tyla — 5— (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman 1— Ilmethoxy) phenyl} N-methylcarbamic acid t-butyl ester (raw material of Example 1)

N— [2_Amino-5— (6-Methoxymethoxy 2,5,7,8-Tetramethylchroman-1-ylmethoxy) phenyl] —N-Methylcarbamic acid t-butyl ester (Compound of Reference Example 2) 0. 60 g, 4- (2,4-dioxothiazolidine-1.5 f-methyl) In a mixture of 0.34 g of phenoxyacetic acid and 10 ml of anhydrous tetrahydrofuran, under ice-cooling, triethylamine 0.2 Om 1 and getylcyano Phosphonate (0.22 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After allowing the reaction mixture to stand for a while, 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 a saline solution 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). R = 0.30 (silica gel thin-layer chromatography; hexane: acetic acid) 0.81 g of the desired compound having the following formula: ethyl = 1: 1) was obtained.

Reference example 4

 3- [4- (t-Butoxycarbonylmethoxy) phenyl] — 2- (2,2,2-trifluoroethoxy) propionic acid methyl ester (raw material for Reference Example 5)

3- (4-Hydroxyphenyl) -1-2- (2,2,2-trif / reo-ethoxy) methyl propionate 3.40 g, 60 ml of acetone in a mixture of cesium carbonate 5.9 at room temperature 7 g 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 extracted with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain RH = 0.50 (silica gel thin-layer chromatography). 1; n-hexane 'ethyl acetate = 3: 1) The target compound having 4.2 g was obtained ₌

Reference example 5

 3- (4-carboxymethoxyphenyl) 1-2- (2,2,2-trifluoroethoxy) methyl propionate (raw material of Reference Example 6)

 3- [4- (t-Butoxycarbonylmethoxy) phenyl] — 2- (2,2,2-Trifluoroethoxy) methyl propionate (compound of Reference Example 4) 4.

To a mixture of 0.5 g and 1,4-dioxane 40 m 1 was added 4N dioxane hydrochloride 4 Om 1 at room temperature, and the mixture was stirred at room temperature for 5 days. After completion of the reaction, 4N-hydrochloric acid-1,4-dioxane was distilled off from the reaction mixture, and crystallization gave 3.63 g of the target compound having a melting point of 75 ° C to 81 ° C. .

Reference example 6

 N— {2— [4-1-1 [2-Methoxyquinone 2- (2,2,2-trinophenol) ethoxy] phenoxyacetylamino] — 5— (6-methoxymethoxy-1,2, _5, 7,8-Tetramethylchroman-2-ylmethoxy) phenyl} -N-methyl t-butyl rubbamate (raw material of Example 2)

N— [2-Amino-5_ (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —N-methylcarbamic acid t-butyl ester (Compound of Reference Example 2) 0.80 g, 3- (4-carboxymethoxyphenyl)-2- (2,2,2-trifluoroethoxy) methyl propionate (compound of Reference Example 5) 0.59 g Triethylamine 0.18 g, getyl cyanophosphonate 0.29 g and anhydrous tetrahydrofuran 2 O m 1 were used.The reaction and after-treatment according to Reference Example 3 gave R n = 0. 1.09 g of the desired compound having 56 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 1: 1) was obtained. Reference Example 7

 3- (4-hydroxyphenyl) -1-methyl 2-mercaptopropionate (raw material for Reference Example 8)

 5-1- (4-acetoxybenzyl) 1,3-trimethylmethylthiazolidine 1,4-dione 87.9 g of toluene 1.59 1 solution of 28% sodium methoxide methanol solution 36 8 g on ice The solution was added dropwise under cooling. After stirring at room temperature for 2 hours, the reaction solution was adjusted to pH = 2 by adding tetrahydrofuran 11 and ice water. 0.81 and 10% hydrochloric acid. Unwanted substances in the organic layer of the reaction solution were removed by filtration, and the mother liquor was washed with a 5% aqueous solution of citric acid and a saturated saline solution, 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 (1st time: ethyl acetate: n-hexane 2 1: 6, 1: 5, 1: 4, 2nd time: ethyl ethyl sulfate: n-hexane) = 1: 6, 1: 5) yielded 0.33 g of an orange oily target compound having R f = 0.35 (dimethyl acetate: n-hexane = 1: 4) .

Reference Example 8

 Methyl 2- (4-fluorobenzylthio) -3- (4-hydroxyphenyl) propionate (raw material for Reference Example 9)

3- (4-Hydroxyphenyl) -1-methyl 2-mercaptopropionate (Compound of Reference Example 7) Triethylamine 0.14m1 and 4-fluorobenzylbromide in a solution of 20Omg of 4ml of anhydrous tetrahydrofuran 0.12 ml was added, and the mixture was 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 a saturated saline solution 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: 1) to obtain R f = 0.44 (ethyl acetate: _n 0.26 g of the target compound as a colorless oil having _ hexane = 1: 2) was obtained.

Reference Example 9

3— (4— t—butoxy canoleboerme toxic) (Dilthio) methyl propionate (raw material for Reference Example 10)

Methyl 2- (4-fluorobenzylthio) -1- (4-hydroxyphenyl) propionate (compound of Reference Example 8) 0.20 g, t-butyl bromoacetate 0.13 m, anhydrous N, N —Reaction was carried out according to Reference Example 4 using 4 ml of 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). R f = 0.21 (ethyl acetate) : the n- hexane = 1: 9) colorless oil-like target compound with 0. 25 g was obtained _c

Reference example 10

 3- (4-carboxymethoxyphenyl)-2- (4-fluorobenzylthio) methyl pionate (raw material for Reference Example 11)

3- (4-t-butoxycanoleboninolemethoxyphenyl) -2-((4-fluorothienylbenzoylthio) methyl propionate (compound of Reference Example 9) 4.00 g, 1,4-dioxane 10m 1 and 4 The reaction was carried out according to Reference Example 5 using 40 ml of normal hydrochloric acid 1,4-dioxane. The solvent was distilled off from the reaction mixture under reduced pressure to give 4.53 g of the desired compound as a pale orange oil having R f = 0.12 (ethyl acetate: _n- hexane = 1: 2). A mixture of dioxane) was obtained.

Reference example 1 1

 N— {2— [4— [2— (4-Funoleo benzylthio) -1-2-methoxycarbinolethiol] phenoxymethylcarbonylamino 1—5 -— (6-Methoxymethoxy-1,2,5, 7,8-tetramethylchroman-1-ylmethoxy) phenyl} -N-methyl t-butyl ester of rubambanic acid (raw material of Example 4)

3- (4-carboxymethoxyphenyl) -2- (4-fluorobenzylbenzyl) methyl propionate (compound of Reference Example 10) 586 mg, N- [2-amino-1-5- (6-methoxymethoxy) 1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] 1-N-methylcarbamic acid t-butyl ester (Compound of Reference Example 2 The reaction was carried out according to Reference Example 6 using 500 mg of triethylamine, 0.42 ml of anhydrous tetrahydrofuran, 1 Om1 of anhydrous tetraethylamine and 0.23 ml of getyl cyanophosphate. 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) to give 0.69 g of the target compound as a yellow oil having R f = 0.63 (ethyl acetate: n—hexane _{= 1} : 1).

 Reference example 1 2

 4-Ethyl hydroxyphenyl lactate (raw material for Reference Example 13)

 30 g of 4-hydroxyphenyl lactic acid, 50 ml of absolute ethanol and 4 N hydrochloric acid 1,

A mixture of 4 dioxane solutions 1 O Oml was left overnight at room temperature: After the solvent was distilled off, the mixture 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 to obtain 35.7 g of the objective compound as a pale yellow oil having an Rf value of 0.78 (silica gel thin-layer chromatography, ethyl acetate).

 Reference Example 1 3

 3- (4-t-Butoxycarbonylmethoxyphenyl) _2-Ethylhydroxypropionate (raw material for Reference Examples 14 and 25)

3 (シリカゲル薄 層クロマトグラフィー、 酢酸ェチル： _n—へキサン = 1 ： 4) を有する淡黄色油状 の目的化合物 28 gが得られた。 4-hydroxyethyl lactate (compound of Reference Example 12) 35.6 g, bromoacetic acid t-butyl ester 58.2 g, cesium carbonate 83 g, and acetone 70 Om 1 Reaction and post-treatment,

28 g of the target compound as pale yellow oil having 3 (silica gel thin-layer chromatography, ethyl acetate: _n- hexane = 1: 4) was obtained.

 Reference example 1 4

 3- (4-Carboxymethoxyphenyl) -1-ethyl 2-hydroxypropionate (raw material for Reference Example 15)

3- (4-t-butoxycarbonyl main Tokishifueniru) one 2-arsenate Dorokishipuropio phosphate Echiru (compound of Reference Example 1 3) 1 8 ₈ and 4 N hydrochloric acid 1, 4 one Jiokisan solution The reaction and after-treatment were carried out according to Reference Example 5 using ₁₅₀ m 1, and the value = _0.35 (“HPTLC DIOL F _254S ” ( _MERK ), ethyl acetate: n_hexane = 1: 2) Thus, 17.5 g of a brown oily target compound having the following formula: was obtained.

Reference example 1 5

N- {2- [4 -— (2-ethoxycarbonyl-l-hydroxyl-phenoxyacetylamino)] — 5- (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) Phenyl} -t-butyl N-methylcarbamate (Example 10; raw material of Reference Examples 16 to 24)

N- [2-Amino-5- (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -t-butyl N-methylcarbamate (Compound of Reference Example 2) 1 6 g, 3- (4-carboxymethoxyphenyl) _2-ethyl hydroxypropionate (compound of Reference Example 14) 17.4 g, anhydrous triethylamine 4.86 g, getyl cyanophosphate 7. . Doing 8 2 g and reaction and treatment in accordance anhydrous as tetrahydrofuran 2 5 Om 1 to Yore ,, reference example 3, R ί value = 0 1 (shea Rikageru thin layer chromatography, acetate Echiru: _eta - 20.6 g of yellow glassy target compound having hexane = 2: 1) were obtained.

Reference Example 1 6

 N- {2 -— “4- (2-ethoxycarbonyl_2-phenylthioethyl) phenoxyacetylamino” —5 -— (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phen 2) 1-N-Methynolecarbamic acid t-butynole (raw material of Example 8)

N— {2-[4- (2-ethoxycarbonyl 2-hydroxyhexyl) phenoxyacetylamino] — 5— (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phene } —N-methylcarbamic acid t-butynole (compound of Reference Example 15) lg, thiophenol 0.22 g, 1,1 ′-(azodical ponyl) dipiperidine 0.53 g, tri-n-butylphosphine A mixture of 0.42 g and anhydrous toluene 2 Om 1 was stirred at room temperature for 3 hours, and then left standing. 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: 2), R fi = 0.75 (silica gel thin layer chromatography, ethyl acetate: n-hexane = 1: 1), white glassy target compound 0.75 g was obtained.

Reference Example 1 7

N- {2- [4-[2-ethoxycarbonyl-1- (4- (2-trophenylthio) ethyl] phenoxyacetylamino]] — 5- (6-methoxymethoxy-1,2,5,7, 8-Tetramethinolechroman-2-ylmethoxy) phenyl} -tert-butyl N-methylcarbamate (raw material of Example 20)

 N— {2-[4-(2-ethoxycarbonyl 2-hydroxitytyl) phenoxyacetylamino] — 5— (6—methoxymethoxy 2, 5, 7, 8, 8-tetramethylchroman-2-ylmethoxy) phenyl Nore} — N-methylcarbamic acid t-butynole (Compound of Reference Example 15) 1.5 g, 4-nitrothiophenol 0.78 g, 1,1 ′ — (azodicarboe) dipiperidine 1.5 g, tri_n —Reaction and post-treatment were carried out according to Reference Example 16 using 1.4 g of butylphosphine and 3 Om 1 of anhydrous toluene, and R f (jS = 0.47 (silica gel thin layer chromatography, ethyl acetate) : 44 g of pale yellow oily target compound having n-hexane = 1: 2) was obtained.

Reference Example 1 8

 N— {2- [4- [2- (4-Cyanogenoxy) _2-Ethoxycarbylethyl] phenoxyacetylamino] 2 5 _ (6-Methoxymethoxy-1,2,5,7,8 —Tetramethylchroman-2-ylmethoxy) phenyl} t-butyl N-methylcarbamate (raw material of Example 24)

N- {2- [4 -— (2_ethoxycanolebonyl_2-hydroxyshetinole) phenoxyacetylamino] — 5— (6—Methoxymethoxy-1,2,5,7,8—tetramethylchroman—2_ylmethoxy) Phenyl} -t-butyl N-methylcarnoxamate (compound of Reference Example 15) lg, 4-cyanophenol 0.36 g, 1,1 '-(azodicarbonyl) dipiperidine 0.76 g, tri-1 The reaction and post-treatment were carried out according to Reference Example 16 using 0.61 g of n_butylphosphine and 2 Om1 of anhydrous toluene, and Ri = 0.29 (thin layer chromatography on silica gel, ethyl acetate: n —Hexa Down = 1: 2) white glass target compound with 0. 5 7 g was obtained _c

Reference Example 1 9

 N_- {2-[4-— [2-ethoxycarbinyl 2 -— (4 _methylphenylthio) -butyl ”] phenoxyacetylamino — 5— (6-methoxymethoxy-1,2,5,7 1,8-Tetramethylchroman-1- (2-methoxy) phenyl Fe-t-butyl-1-methylcarbamate (raw material for Example 26)

 N— {2-[4- (2-ethoxycarbonyl-2—hydroxyxethyl) phenoxyacetylamino] — 5— (6—Methoxymethoxy 1,2,5,7,8—tetramethyl chroman 1—2-methylethoxy) N-N-methyl-butanol (1-compound of Reference Example 15) 1.2 g, 4-methylthiophenol 0.37 g, 1,1 '-(azodicarbonyl) dipiperidine 0.8 The reaction and post-treatment were carried out according to Reference Example 16 using 1 g, 0.65 g of tri-n-butylphosphine and 25 ml of anhydrous toluene, and R = 0.61 (silica gel thin-layer chromatography, 0.94 g of a white glassy target compound having ethyl acetate: n-hexane = 1: 2) was obtained. Reference Example 20

 N- {2-[4— “2— (4-cloth feninolethio) 1-2-ethoxy force / leponinoleethyl] phenoxyacetylamino] — 5-2 (6-meximethoxy 2,5,7, 8-Tetramethinolechroman-1-ylmethoxy) phenyl} -tert-butyl N-methylcarbamate (raw material for Example 28)

N- {2- [4 -— (2-ethoxycarbonyl-1-2-hydroxyxethyl) phenoxy acetylamino] —5 -— (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl Nore} -t-butyl N-methylcarbamate (Compound of Reference Example 15) 1.2 g, 4-chlorothiophenol 0.43 g, 1,1 '-(azodicarbonyl) dipiperidine 0.8 1 g Using 0.65 g of tri-n-butylphosphine and 25 ml of anhydrous toluene, the reaction and post-treatment were carried out according to Reference Example 16, and R f ί. = 0.54 (silica gel thin layer chromatography). There was obtained 0.777 g of a white glassy target compound having the following characteristics: chromatography, ethinol acetate: η _ hexane = 1: 2). Reference Example 2 1 N- {2-[4— [2— (4—t—buty.rufenylthio) -1 2-ethoxy z canolephonylletyl] phenoxyacetylamino] 1 5— (6 methoxymethoxy--2, Five,

7,8-tetramethylchroman-2-ylmethoxy) phenyl} — N-me: t-butyltinolecarbyl t-butyl (raw material for Example 30)

 N_ {2— [4 _ (2-ethoxycarbonyl-1 2-hydroxyshetyl) phenoxyacetylamino] -15- (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-12 lumethoxy) phenyl } -T-butyl N-methylcarbamate (compound of Reference Example 15) 1.2 g, 0.5 g of 4-t-butylthiophenol, 1,1 '-(azodicarbonyl) dipiperidine 0.8 1 g, tri Using 0.65 g of mono-n-butylphosphine and 25 ml of anhydrous toluene, the reaction and post-treatment were carried out according to Reference Example 16, and the Rf value was 0.61 (silica gel thin-layer chromatography, 0.78 g of a white glassy target compound having ethyl acetate: n-hexane = 1: 2) was obtained. Reference Example 2 2

 N- {2- [4 -— [2-ethoxycarbonyl-1- (4-methoxyphenylthio) ethyl] phenoxyacetylamino, -5- (6-methoxymethoxy-1,2,5,7

8-Tetramethylchroman 12-inolemethoxy) phenyl} 1-butyl N-methylcarbamate (raw material for Example 32)

 N- {2-[4--(2-ethoxycanoleponyl 2-hydroxyxetinole) phenoxy cetylamino]-5-(6-methoxymethoxy 2,5,7,8 -tetramethynochromone 1-2 -inolemethoxy) } -N-Methynolecanolenoamic acid t-butynole (compound of Reference Example 15) 1.2 g, 4-Methoxythiophenol 0.42 g, 1,

1 ′-(azodicarbonyl) dipiperidine 0.8 g, tri-n-butylphosphine 0.65 g and anhydrous toluene 25 ml were used to carry out the reaction and post-treatment according to Reference Example 16 to obtain R = 0.72 g of a white glassy target compound having 0.42 (silica gel thin-layer chromatography, ethyl acetate: _n- hexane = ι: 2) was obtained. Reference Example 23

N- {2-[4 -— (2-ethoxy-1 2 _ethoxycarbonelechinole) phenoxycetylamino] _— 5—— (6-methoxyethoxy-1,2,5—7,8—te Man-1-2f-methoxy) phenyl} -tert-butyl N-methylcarbamate (raw material for Example 12)

 N- {2- [4- (2-ethoxycarbonyl-12-hydroxyhexyl) phenoxy cetylamino] -15- (6-methoxymethoxy-2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl } —N-Methylenol t-butyl rubinate (compound of Reference Example 15) 1 g, 1.2 g of iodide chill, 1.1 g of silver oxide and 15 ml of anhydrous toluene for 2 hours Heated to reflux = allowed to stand at room temperature, and further heated to reflux for 7 hours. The insoluble matter was removed, the solvent was distilled off, and the residue was subjected to liquid chromatography (silica gel, ethyl acetate: n-hexane = 2: 5) to give a value of 1¾ £ = 0.51 (silica gel). Power gel thin layer chromatography, 0.46 g of the desired compound as pale yellow oil having ethyl acetate: n-hexane = 1: 2) was obtained.

Reference Example 24

 N- {2-"4-" 2-ethoxycarbonyl-1 2--(4-fluorobenzene), _-ethyl] phenoxyacetylamino]-5-(6-methoxymethoxy-2, 5,7, -Tetramethinolechroman-1-ylmethoxy) phenyl} -N-methylcarbamate t-butyl (raw material for Example 14)

N- {2-[4--(2-ethoxycarbonyl _ 2-hydroxyoxethyl) phenoxy sestylamino]-5-(6-methoxymethoxy 2, 5, 7, 8-tetramethyinolechroman 1 2 _ isthremetoxy) feninole } —N-Methinolecanolebamate t-butynole (compound of Reference Example 15) 1.5 g, 4-fluorobenzyl bromide 2.26 g, silver (I) oxide 1.63 g, The reaction and post-treatment were carried out according to Reference Example 23 using anhydrous toluene 2 Om1, and the Rf value was 0.80 (silica gel thin-layer chromatography, ethyl acetate: _n- hexane = 1: 2). 0.62 g of a light yellow oily target compound having the formula was obtained.

Reference Example 2 5

 3- (4-t-butoxycarbonylmethoxyphenyl) ethyl 2-phenyloxypropionate (raw material for Reference Example 27)

3- (4-t-Butoxycarbonylmethoxyphenyl) _2-Hydroxypropyl 1 g of chloromethanesulfonic acid chloride was added to a mixture of 2 g of ethyl ethyl onate (compound of Reference Example 13), 0.69 g of anhydrous triethylamine and 2 Om1 of anhydrous tetrahydrofuran under ice cooling, and the mixture was stirred for 1 hour. did. After distilling off the solvent, the residue was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline 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 was added 0.58 g of phenol and sodium hydride (55%, oil).

A mixture of 0.28 _§ and anhydrous ^^, N-dimethylformamide 1 Om 1 was stirred at room temperature for 30 minutes, added dropwise at room temperature, and further stirred for 7 hours. 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 ("LiChroprepi \ ¾" (MERCK), ethyl acetate: _n- hexane = 1: 6), and the R f value was determined.

_0.46 g of a colorless oily compound having _0.84 HPTLC NH ₂ F _254S "(MERCK), ethyl acetate: n-hexane = 1: 5) was obtained.

Reference Example 2 6

3- (4-t-butoxycarbonylmethoxyphene) 1 2- (4-diethoxyphenoxy) ethyl propionate (raw material for Reference Example 28)

3- (4-t-Butoxycarboxymethoxyphenyl) -1-ethyl 2-hydroxypropionate 1.8 g, 0.91 g of methyl methanesulfonate chloride, 0.61 g of anhydrous triethylamine, anhydrous Reference Example 2 using 40 ml of tetrahydrofuran, 0.77 g of a 4-to-two-mouth phenol, 0.24 g of sodium hydride (55%, oil) and 55 ml of anhydrous N, N-dimethylformamide The reaction and work-up were carried out according to 5 and the obtained crude product was subjected to column chromatography (silica gel, ethyl acetate: n-hexane = 1: 4), and the Rf value was 0.50 ( 2.15 g of the target compound as a pale yellow oil having silica gel thin layer chromatography, ethyl acetate: _n- hexane = 1: 3) was obtained.

Reference Example 2 7

3- (4-carboxymethoxyphenyl) -1-2-phenoxyb mouth pion roto-ethyl (reference material 29) 3- (4-t-Butoxycarbonylmethoxyphenyl) monoethyl 2-phenoxypropionate (compound of Reference Example 25) 0.43 g and 10 ml of 4N hydrochloric acid 1,4-dioxane solution 10 ml The reaction and after-treatment were carried out according to Reference Example 5, and a pale yellow oil having R ¾ = _0.43 ("HPTLC DIOL F _254S " ( _MERK ), ethyl acetate: n-hexane = 1: 3) was obtained. 0.38 g of the desired compound was obtained.

Reference Example 2 8

 '3-(4-Carboxymethoxyphenyl) — 2- (4-trophenoxy) ethyl propionate (raw material for Reference Example 30)

 3- (4-t-Butoxycarbonylmethoxyphenyl) 1-2- (4-2-Trophenoxy) ethyl propionate (compound of Reference Example 26) 1.86 g, 1,4-dioxane 20 m1 and The reaction and post-treatment were carried out according to Reference Example 5 using 60 ml of 4N hydrochloric acid 1,4-dioxane solution to obtain 1.44 g of the target compound as a reddish brown oil. Reference Example 2 9

 N- {2- [4 -— (2-ethoxycarbonyl-1-2-phenoxethyl) phenoxyacetylamino] _5— (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phen Nil) t-butyl N-methylcarbamate (raw material for Example 22)

 N— [2-Amino-5- (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —T-butyl N-methylcanolenomate (Compound of Reference Example 2) ) 0.45 g, 3- (4-carboxymethoxyphenyl) ethyl 2-ethylphenoxypropionate (compound of Reference Example 27) 0.37 g, triethylamine anhydride 15 g, getyl cyanophosphate Using 0.24 g and anhydrous tetrahydrofuran 1 Om1, the reaction and post-treatment according to Reference Example 3 gave R fi = 0.53 (silica gel thin-layer chromatography, ethyl acetate: n- 0.6 g of the target compound in the form of a white glass having the following formula: xane = 1: 2) was obtained.

Reference example 30

N- {2- [4-I (2- [4-Nitrophenoxy, 1-2-ethoxycarbonylethyl) -phenoxyacetylamino] _5— (6-Methoxymethoxy 2,5.7, 8 —Tetramethylchroman-1-ylmethoxy) phenyl} t-butyl N-methylcarbamate (raw material of Example 18)

 N- [2-Amino-5- (6-methoxymethoxy2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -t-butyl N-methylcarbamate (Compound of Reference Example 2) 1. 7 2 g, 3- (4-carboxymethoxyphenyl) 1- (4-nitrophenoxy) ethyl propionate (compound of Reference Example 28) 1.34 g, triethylamine anhydride 0.38 g, getyl cyanophosphate 0. Using 62 g and anhydrous tetrahydrofuran 5 Om 1, performing the reaction and post-treatment according to Reference Example 3, 1¾ value = 0.6 1 (silica gel thin-layer chromatography, ethyl acetate: n-hexane) 2.74 g of a yellow glassy target compound having the following formula: 1: 1) was obtained.

Reference example 3 1

 2- [bis (4-phnoleophenol) methoxy] — 3- (4-t-butoxycarbonylmethoxyphenyl) methyl propionate (raw material for Reference Example 32)

 3- (4-t-butoxycarbonylmethoxyphenyl) _2-methyl hydroxypropionate 3 g, 4,4'-difluorobenzhydryl chloride 4.61 g, silver (II) oxide 8.96 g and anhydrous toluene 6 Om1 and subjected to the reaction and post-treatment according to Reference Example 23 to obtain a crude product, which was then subjected to column chromatography (silica gel, ethyl acetate: n-hexane = 1: 9), followed by Reversed phase preparative high performance liquid chromatography (ODS, acetonitrile: water = 3: 1), R f value 39 (silica gel thin-layer chromatography, ethyl acetate: n-hexane = 1: 5) was obtained. As a result, 2.41 g of a target compound having a colorless oil was obtained.

Reference example 3 2

 2- [bis (4-fluorophenyl) methoxy] — 3- (4-carboxymethoxyphenyl) methyl propionate (raw material for Reference Example 33)

2- [bis (4-fluorophenyl) methoxy] — 3- (4_t-butoxycarbonylmethoxyphenyl) methyl propionate (Compound of Reference Example 31) 1.46 g, 1,4-dioxane 2 Om 1 The reaction and post-treatment were carried out according to Reference Example 5 using 20 ml of 1,4-dioxane solution and 4N hydrochloric acid to give 1.69 g of the target compound as a colorless oil. Obtained.

Reference example 3 3

 N- {2- [4- [2- [bis (4-fluorophenyl) methoxy] —2-methoxycarbonylethyl] phenoxyacetylamino, one 5- (6-methoxymethoxy—2 , 5,7,8-Tetramethylchroman-1-ylmethoxy) funinyl} -tert-butyl N-methylcarbamate (raw material for Example 6)

 N— [2-Amino-5- (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] —t-butyl N-methylcarbamate (Compound of Reference Example 2) 1 3 g, 2— [bis (4-fluorophenyl) methoxy] —3— (4-carboxymethoxyphenyl) 1.3 g of methyl propionate, 0.29 g of triethylamine anhydride, cyanophosphoric acid Using 0.46 g of getyl and 2 Om1 of anhydrous tetrahydrofuran, the reaction and post-treatment were carried out according to Reference Example 3.R f = 0.31 (silica gel thin-layer chromatography, ethyl acetate : 1.0 g of a yellow oil having the following formula: n-hexane = 1: 2) was obtained.

Reference example 3 4

 3- (4-t-Butoxycarbonylmethoxyphenyl) methyl 2-ethylthiopropionate (raw material for Reference Example 35)

A mixture of 1.29 g of 3- (4-hydroxyphenyl) -methyl 2-mercaptopropionate, 1.9 g of thiol iodide, 1.23 g of triethylamine and 30 ml of anhydrous tetrahydrofuran was added at room temperature for 2 hours. Stirred for 0 hours. The solvent was distilled off, diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in anhydrous acetone 2 O m 1, and 297 g of cesium carbonate and 1.78 g of t-butyl bromoacetate were added at room temperature. After the reaction and post-treatment, 1,53 g of a colorless oily target compound having an Rf value of 0.21 (silica gel thin-layer chromatography, ethyl acetate: _n- hexane _{= 1} : 5) was obtained. Was done.

Reference Example 3 5

Methyl 3- (4-carboxymethoxyphenyl) -2-ethyl thiopropionate Raw materials of Example 16)

 3- (4-t-butoxycanoleponinolemethoxyphenyl) methyl 1,2-ethynolethiopropionate (compound of Reference Example 35) 1.49 g, concentrated hydrochloric acid aqueous solution 2 m1 and acetic acid 10 m The mixture of 1 was stirred at 80 ° C for 3.5 hours. The solvent was distilled off, and the residue was washed with n-hexane to obtain 0.886 g of the desired compound as a crude product. This crude product was used immediately in Example 16.

Reference Example 3 6

 N- [5- (3,4-Dimethoxybenzyloxy) -1-2-trophenyl] -t-butyl N-methylcarbamate (raw material for Reference Example 37)

 Sodium hydride (55%, oily) 2.6 g of anhydrous toluene 100 ml suspension

A 100 ml solution of 3,4-dimethoxybenzyl alcohol 10 § in anhydrous ^^, N-dimethinoleformamide was added dropwise at room temperature, and the mixture was stirred for 40 minutes. Next, a solution of 11.5 g of t-butyl N- (5-chloro-2-phenyl-2-phenyl) -N-methylcarbamate in 100 ml of anhydrous N, N-dimethylformamide under ice-cooling was added. Was dropped. 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 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.

Reference Example 3 7

 N- (5-Hydroxy-1-2-2-phenyl) -1-N-methylcarbamic acid t-butyl (raw material for Reference Example 38)

N— [5— (3,4-Dimethoxypentinoleoxy) -1-nitrophenyl] —N-tert-butyl methylcarbamate (compound of Reference Example 36) llg, 2,3-dicyanone-5,6- A mixture of 9.1 g of 1,4-benzoquinone dichloride, 5 ml of distilled water and 50 ml of 1,2-dichloromethane ethane was stirred at room temperature for 7 hours. Further, 5 g of 2,3-dicyan-5,6-dichloro-1,4-benzoquinone was added, and the mixture was stirred at room temperature for 2.5 hours. -After standing, 300 ml of ethyl acetate and 5% sodium hydrogen carbonate were added to the reaction mixture. An aqueous solution of 50 Om 1 was added, and the _c- insoluble matter stirred for 10 minutes 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 tacrography (silica gel, ethyl acetate: n-hexane = 1: 2) to give a yellow powder having a melting point of 15 ° C to 15 ° C. 3.85 g of the title compound were obtained in the form of:

Reference Example 3 8

 N-Methyl-1-N- [2-nitro-5- (2-oxopropoxy) phenyl] -t-butyl diphosphate (raw material for Reference Example 39)

 N- (5-Hydroxy-l-l-l-2-to-n-phenyl) -t-butyl N-methylcarbamate (compound of Reference Example 37) 3.8 g, bromoacetone 3.2 g, cesium carbonate 7 g, and acetone The 100 ml mixture was 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 to obtain 4.65 g of a brown oily target compound having an Rί value of 0.17 (silica gel thin layer chromatography, ethyl acetate: η hexane = 1: 3).

Reference Example 3 9

 N— [5 -— (6-acetoxy-1-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) 1-2-2-trophenyl] —t-butyl N-methylcarbamate ( Raw material of Reference Example 40)

N-Methyl-N- [2-Nitro-5- (2-oxopropoxy) phenyl] t-butyl carbamic acid (compound of Reference Example 38) 4.1 g, acetic acid (3-acetyl-4-1H) A mixture of 3 g of hydroxy-1,2,5,6-triphenyl) phenyl ester, 0.9 g of pyrrolidine and 50 ml of anhydrous methanol was stirred for 7 hours under ice-cooling:-After standing, the solvent was distilled off. To the residue, ethyl ethyl acetate (20 mL) and 100 ml of a 2N aqueous hydrochloric acid solution were added, and the mixture was stirred 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 dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was subjected to liquid chromatography LiChroprepNH, "(MERCK), ethyl acetate: _n- hexane = 2: 5), followed by reversed-phase preparative high-performance liquid chromatography. ― (ODS, acetonitrile: (0.2% acetic acid + 0.2% triethylamine) aqueous solution = 13: 7), R f value = 0.71 (silica gel thin layer chromatography, ethyl acetate: 1.62 g of a brown glassy target compound having _n— hexane = 2: 5) was obtained.

Reference example 4 0

 N— [5— (6-Acetoxy_4_oxo- 1,2,5,7,8-Tetramethylchromane-12-ylmethoxy) -12-Aminophenyl] —N-Methylcarbamic acid t-butyl (Raw materials of Reference Example 41)

 N- [5- (6-acetoxy-4-oxo- 1,2,5,7,8-tetramethylchroman-l-ylmethoxy) -l-nitrophenyl] -t-butyl N-methylcarbamate (reference Example 3 9) 1.6 g, 10% palladium-carbon catalyst (0.2 g) and methanol 15 Om 1 were used for the reaction and post-treatment according to Reference Example 2 to obtain an R f 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.

Reference example 4 1

 N— {5— (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) -1 2-—4- (2,4-dioxothiazolidine-1 5- (methyl) phenoxyacetylamino] phenyl} -t-butyl N-methylcarbamate (raw material for Example 34)

N- [5- (6-acetoxy-4-oxo- 1,2,5,7,8-tetramethylchroman-12-ylmethoxy) -12-aminophenyl] -t-butyl N-methylcarbamate (Reference Example 4) Compound 0) 1.53 g, 4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetic acid 1.3 g, 1-ethyl-1 3- (3-dimethylaminobutyryl) carbodimid 0.9 g of hydrochloride (WS C 'HCl), 1-hydroxybenzotriazole · 0.7 g of monohydrate, 5 Om 1 of anhydrous tetrahydrofuran and anhydrous N, N-dimethylformamide The mixture of 20 ml was stirred for 1.5 hours at room temperature: after standing overnight, the solvent was distilled off, diluted with water and extracted with ethyl acetate. Extract the extract with 1N aqueous hydrochloric acid, 5% aqueous sodium bicarbonate (twice), and then with saturated saline Washed 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 R = 0.35 (silica gel). thin layer Kukomatogurafu I one, acetate Echiru: _n _ hexane = 3: 2) white glass target compound 1. 9 4 g were obtained with. Test example

Hypoglycemic action

 Blood was collected from the tail vein of KK mice (4-5 months) who developed diabetes, and their blood glucose levels were measured. Next, the mice were divided into groups (4 mice / group) so that the average of the blood glucose levels of the mice in each group was the same, and a powdered diet for mice adjusted to contain 0.01% of the test compound ( Mice (F-1, Funabashi Farm) for 3 days. A group of mice receiving the test compound was designated as a drug administration group. The group that received the powdered feed containing no test compound was used as a 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-1 (Dalco Roda-1, A & T). The blood glucose lowering rate was determined from the following equation.

Blood glucose lowering rate (%) =

 (Average blood glucose level of control group-average blood glucose level of drug-administered group) X 100Z Blood glucose level of control group

Test compound Blood glucose lowering rate (%)

 Compound of Example No. 1 6 6 7

 Compound of Example No. 3 3 5 7

 Compound of Example No. 5 3 4 9

 Compound of Example No. 9 3 6 7

From the above results, it was clear that the compound of the present invention exhibits an excellent blood glucose lowering effect. (Possibility of industrial use)

 The compound of the present invention having the above general formula (I), its pharmacologically acceptable salt and its pharmacologically acceptable ester are excellent in insulin resistance improving effect, hypoglycemic effect, anti-inflammatory effect, immunity Regulatory action, Aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, Lipid peroxide production inhibitory action, PPAR activation action, Anti-osteoporosis action, Leukotriene antagonism, Adipogenesis promotion action, Cancer cell growth suppression action, Has calcium antagonism, diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (for example, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc. ), Arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular disease (for example, ischemic heart disease, etc.), non-atherogenic atherosclerosis or ischemic heart disease Cell damage caused by the disease (eg, brain damage caused by stroke, etc.), gout, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, Psoriasis, eczema, allergic disease, asthma, GI ulcer, cachexia, autoimmune disease, knee inflammation), cancer, osteoporosis, cataract, etc.

 Further, the compound of the present invention having the above general formula (I), its pharmacologically acceptable salt and its pharmacologically acceptable ester, and a glucosidase inhibitor, an aldose reductase inhibitor, a biguanide agent, a statin Composition comprising at least one compound selected from the group consisting of a compound based on squalene, a squalene synthesis inhibitor, a fibrate compound, an LDL catabolic promoter and an angiotensin converting enzyme inhibitor (particularly preferred is the prevention of diabetes or diabetic complications). And / or therapeutic agents.) Are also useful.

 When the compound having the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable ester thereof are used as the above-mentioned therapeutic or prophylactic agent, Mix with appropriate pharmacologically acceptable excipients, diluents, etc., for example, tablets, capsules, granules, powders, syrups, etc., orally or by injection or suppositories, etc. Can be administered parenterally.

These preparations contain excipients (eg, lactose, sucrose, glucose, saccharides such as mannitol, sorbitol: corn starch, potato starch, alpha starch, Starch derivatives such as dextrin: Cellulose derivatives such as crystalline cellulose: Arabic gum; Dextran; Organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate Examples of such silicate derivatives include inorganic excipients such as phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; and 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 big gum, gay; boric acid; adipic acid: sulfuric acid Sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; sodium lauryl sulfate, lauryl sulfate such as magnesium lauryl sulfate; silicic anhydride, silica hydrate, etc. Silicic acids; and the above-mentioned starch derivatives.), Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the above-mentioned excipients) And disintegrants (for example, Cellulose derivatives such as hydroxypropylcellulose, carboxymethylcellulose, calcium / reoxymethylcellulose calcium, internally crosslinked carboxymethylcellulose sodium; chemically modified such as carboxymethylstarch, carboxymethylstarch sodium, crosslinked polyvinylpyrrolidone Starches and celluloses), stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as octabutanol, benzyl alcohol, and phenylethanol alcohol) Classes: Benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (eg, usually Examples thereof include a sweetener, an acidulant, a flavor, and the like, which are used), and a known method using additives such as a diluent.

The amount used depends on the symptoms, age, administration method, etc. For example, in the case of oral administration, the lower limit is 0.001 _mg / kg body weight (preferably 0.0 _mg / kg ₎ per dose. kg body weight), the upper limit is 500 mg / kg body weight (preferably, 50 mg / kg body weight). In the case of intravenous administration, the lower limit is 0.05 mg / kg Weight (preferably 0. 5 mg / kg body weight), and up to 50 mg / kg body weight (preferably 5 mg / kg body weight) is desirably administered once or several times daily depending on the symptoms.

Claims

The scope of the claims 1. The following general formula (I)

[In the above formula, R ¹ is a hydrogen atom, —C _s alkyl group, or one or three C ₆ — which may be substituted by a group selected from substituent group α. Ariru group, optionally substituted 3 1乃optimum with a group selected from the substituent group alpha C ₇ - C ₁₆ Ararukiru group, a hydroxyl group, Ashiru group Ashiruokishi group (said Ashiruokishi group, C _t one C ₇ aliphatic Ashiru group, optionally 1 to 3 substituents at Ru selected group from substituent group α C ₇ - C "aromatic Ashiru group, 1 to 3 optionally substituted with a group selected from substituent group monument Optionally substituted with one to five C ₈ -C ₁₂ araliphatic acyl groups, C ₄ -C 1 cycloalkylcarbonyl groups, or a group selected from substituent group α. Represents a 5- to 7-membered heteroaromatic carbonyl group having 1 to 3 heteroatoms selected from the group consisting of atoms, nitrogen atoms and sulfur atoms.), C, —C ₆ alkoxy group, or substituent group Amino group which may be substituted with one or two groups selected from the group consisting of May form together with the nitrogen atom 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.) R ² is a hydrogen atom, C _t one C ₆ alkyl group, or 1 group selected from Substituent Group monument乃optimum three optionally substituted C ₇ - shows the C ₁₆ Ararukiru group, RR ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a C! —Ce alkyl group, or a —C ₆ alkoxy group, R ⁶ is a hydrogen atom, a C, —C ₆ alkyl group, or a group selected from the group of substituents, Ce—C, which may be substituted one to three times. Aryl group, or a C-C ₁₆ aralkyl group which may be substituted by 1 to 3 groups selected from a substituent group; Q represents an oxygen atom or a sulfur atom, X is a bond, CH ₂ , CO, CHOR ⁹ or C 2 NOR ^{1 Q} (where R ⁹ and R ¹⁰ are a hydrogen atom, a C ₆ alkyl group (the alkyl group is the same or different 1 to 3 May be substituted with one or more Ci—C ₆ alkoxycarbonyl groups), a C ₆ —C _{1 ()} aryl group (the aryl group may be the same or different 1 Or 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 (the acyl group may be substituted by 1 to 3 C ₇ —C _{u, which} may be substituted with a group selected from a group consisting of an aliphatic C ₇ aliphatic acyl group and a substituent group << 1 to 3 C ₈ —C ₁₂ araliphatic acyl groups, C ₄ —C 1,! Cyclo, which may be substituted by 1 to 3 groups selected from an aromatic acyl group and a substituent group An alkylcarbonyl group, a group selected from the substituent group α having 1 to 5 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, which may be substituted 5 Or a 7-membered heteroaromatic carbonyl group, or a carbamoyl group which may be substituted by 1 or 2 groups selected from a substituent group.)  Α represents a group represented by the following general formula (II-a), (II-b), (II-c) or (Il-d),

 (Π-a) (Π-b) (Π-c) (Π-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 N—R ⁸ ; R ′ is a hydrogen atom, a C ₆ alkyl group, a C ₆ -C ₁₀ aryl group (the aryl group may be substituted with 1 to 3 identical or different substituents selected from the substituent group << C ₇ — (: ₁₆ aralkyl groups (the aralkyl groups may be substituted with the same or different 1 to 3 substituents selected from the substituent group Ω), or halogeno C ₆ Represents an alkyl group, R ⁸ may be substituted with 1 to 3 hydrogen atoms, a C ₆ alkyl group, or a group selected from a substituent group. Aryl group, C ₃ — C ,. A cycloalkyl group, a substituent group, a C ₇ -C ₁₆ aralkyl group, an acyl group which may be substituted by 1 to 3 groups selected from α, wherein the acyl group is Ci-C, an aliphatic acyl group, 1 to 3 groups which may be substituted with a group selected from the group of groups C _: one C _u aromatic acyl group, 1 to 3 groups which may be substituted with a group selected from the substituent group α ₈ -. C ₁₂ araliphatic Ashiru based on indicates to), substituent group] 1 to 2 substituents which may be the force Rubamoi Le group with a group selected from 3, C _s alkylsulfonyl group, a halogeno C - C ₆ alkynolesulfonyl group, which may be substituted with 1 to 3 C ₆ -C ₁₀ arylsulfonyl groups, or a group selected from substituent group _α , which is selected from substituent group _α. 1 to 3 optionally substituted c ₇ — c ₁₆ aralkylsulfonyl groups, Alternatively, when B represents N (R ⁸ ), the 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 one CH = or a nitrogen atom,  n represents an integer of 1 to 5,  q represents an integer of 0 to 5, Substituent group α represents a halogen atom, a hydroxyl group, C, - C ₆ alkyl group, halogeno C ₁ _C ₆ alkyl group, C _t one C ₆ alkoxy group, an amino group (said Amino groups are selected from substituent group / 3 The amino group may be substituted with the same or different 1 or 2 substituents selected from the above, 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. Or a saturated heterocyclic group having 1 to 3 heteroatoms.), C ₆ —C. Represents an aryl group, a cyano group, and a nitro group, Substituent group] 3 is C, one C ,. Ce—C, which may be substituted by 1 to 3 alkyl groups, groups selected from substituent group γ. Ariru group, 1 to 3 optionally substituted C ₇ -C ₁₆ 7 aralkyl group and Ashiru group (said Ashiru group with a group selected from Substituent group γ is, C, - C ₇ aliphatic Ashiru group, 1 to 3 C, 1C aromatic aromatic groups which may be substituted by 1 to 3 groups selected from substituent group γ, 1 to 3 substituted by groups selected from substituent group γ May be substituted with 1 to 5 C ₈ — c ₁₂ araliphatic acyl groups, c ₄ — c „cycloalkylcarbonyl group, and a group selected from substituent group γ. Represents 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.) Substituent group γ represents a halogen atom, a hydroxyl group, a monoalkyl group, a halogeno monoalkyl group, a Ci—Cs alkoxy group, a C ₆ alkylthio group, an amino group, and a nitrile group. ] Or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. 2. The following general formula (I ')

[In the above formula, X 'is CH ₂ , CO or C = NOR ¹⁰ (Wherein, R ^{1 Q} is a hydrogen atom, a C ₆ alkyl group (the alkyl group may be substituted with the same or different 1 to 3 C, —C ₆ alkoxycarbonyl groups) or C 1 "C ₁₆ represents an aralkyl group.) Indicates that A ′ represents a group represented by the following formula (II-b ′) or (II-d ′).

 (Π-d ')  (Π-b ') (In the above formula,  B 'represents an oxygen atom or a sulfur atom, R ⁷ is a hydrogen atom, a Ci—Ce alkyl group, C ₆ —. Aryl group (the aryl group may be substituted with 1 to 3 identical or different substituents selected from substituent group _α , and a C ₇ -C ₁₆ aralkyl group (the aralkyl group is Which may be substituted with 1 to 3 identical or different substituent (s) selected from group α), or halogeno C “C ₆ alkyl group.)] Or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. (Substituent group.) Halogen atom, hydroxyl group, Ci—C ₆ alkyl group, halogen Ci— (: ₆ alkyl group, C, —C ₆ alkoxy group, amino group (The amino group is The amino group may be substituted with one or two selected same or different substituents, 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. It may form a saturated heterocyclic group having 1 to 3 selected hetero atoms.), C ₆ — aryl group, cyano group and nitro group. 3. The substituted condensed imidazole derivative according to claim 2, wherein X and CH ₂ are CH ₂ , a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. 4. A substituted fused imidazole derivative, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof according to claim 2 or 3, wherein A ′ is a group represented by the formula (II-b,). . 5. The method according to claim 2, wherein A ′ is a group represented by the formula (II-d,), and B ′ is an oxygen group. A substituted condensed imidazole derivative which is an atom, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. 6. The substituted condensed imidazole derivative according to claim 2 or 3, wherein A ′ is a group represented by the formula (II-d,) and B ′ is a sulfur atom, or a pharmaceutically acceptable salt or Esters that are pharmacologically acceptable. 7. In any one of claims 2, 3, 5, and 6, wherein R ⁷ is a hydrogen atom, a C! -Ce alkyl group, a phenyl group (wherein the phenyl group is selected from the substituent group α). Or a benzyl group (the benzyl group may be the same or different 1 to 3 substituents selected from a group of substituents). A substituted imidazole derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, which is a substituted or unsubstituted halogeno C 1, —C ₆ alkyl group. 8. The method according to claim 2, wherein R ⁷ is a phenyl group (the 4-position of the phenyl group is one substituent selected from a substituent group). A benzyl group (position 4 of the benzyl group is selected from a substituent group α) A substituted condensed imidazole derivative, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, which may be substituted with one substituent) or a halogeno C 1, —C ₆ alkyl group. 9. The substituted condensed imidazole derivative according to any one of claims 1 to 8. 10. The pharmacologically acceptable salt of the substituted condensed imidazole derivative according to any one of claims 1 to 8. 11. The substituted condensed imidazo according to any one of claims 1 to 8. Pharmacologically acceptable hydrochloride of the derivative. 1 2. Pharmacologically acceptable esthetics / esters of the substituted condensed imidazole derivative according to any one of claims 1 to 8. 1 3. The methyl ester of the substituted condensed imidazole derivative according to any one of claims 1 to 8 1 4. The ethyl ester of the substituted condensed imidazole derivative according to any one of claims 1 to 8. 1 5. In claim 1, any one compound selected from the following, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof.  5— {4— [6— (6-hydroxy2,5,7,8-tetramethylchroman-12-ylmethoxy) _1-methyl-1 1-benzimidazole-1 2 f-lumethoxy] benzyl} thiazolidine One, two, four diones  3— {4-[6— (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) 1 1—methyl-1 H—benzoid Xish] fenyl} — 2— (2,2,2-trifluorotrifluoroethoxy) propionic acid  2- (4-Fluorobenzoylthio) 1 3— {4-[6— (6-hydroxy 1 2, 5,7,8-Tetramethylchroman-1-ylmethoxy) 11-Methyl-1H-Benzoimidazo-l-2-ylmethoxy] phenyl) Bropionic acid  3— {4-[6-(6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-methyl-1-H-benzoymidazole-1-2-ylmethoxy] } — 2-phenylthiopropionic acid 2- (4-Fluorobenzyloxy) -1-3- (4- [6- (6-hydroxy2,5,7,8-tetramethylchroman-2-ylmethoxy) 1-1-methyl-1H —Benzomidazo-1-yl-2-ylmethoxy] phenyl} bucopionic 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, and aldose, comprising the compound according to any one of claims 1 to 15 as an active ingredient. Reductase 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 the compound according to any one of claims 1 to 15 as an active ingredient. 19. A pharmaceutical composition for lowering blood glucose, comprising the compound according to any one of claims 1 to 15 as an active ingredient. 20.A diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, comprising the compound according to any one of claims 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, bone A preventive or therapeutic agent for arthritis, rheumatoid arthritis, allergic disease, asthmatic disease, GI ulcer, cachexia, autoimmune disease, otitis, 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 the manufacture of a pharmaceutical composition for improving insulin resistance. 23. Use of a compound according to any one of claims 1 to 15 for the manufacture of a pharmaceutical composition for lowering blood glucose. 24. Use of the compound according to any one of claims 1 to 15 for producing a pharmaceutical composition for preventing or treating diabetes.