WO2001005780A1

WO2001005780A1 - Coumarone analogues

Info

Publication number: WO2001005780A1
Application number: PCT/JP2000/004732
Authority: WO
Inventors: Takashi Fujita; Kunio Wada; Minoru Oguchi; Shinichi Kurakata
Original assignee: Sankyo Company, Limited
Priority date: 1999-07-16
Filing date: 2000-07-14
Publication date: 2001-01-25
Also published as: AU6016200A

Abstract

Novel coumarone analogues exhibiting excellent antitumor activities, which are compounds of general formula (1), salts of the same, or esters thereof, wherein R1 is hydrogen, C¿1?-C6 alkyl, or the like; R?2¿ is hydrogen, C¿1?-C6 alkyl, or the like; R?3, R4, R5 and R6¿ are each independently hydrogen, C¿1?-C6 alkyl, or the like; X is a single bond, -(C=O)-, -(C=NOR?7¿)-, or the like; R?7 and R8¿ are each independently hydrogen, C¿1?-C6 alkyl, C2-C6 alkenyl, or the like; A is -(C=O)- or -SO2-; U is -CH2- or the like; Y is -O- or -S-; Q is hydrogen, nitro, hydroxyl, or the like; k is an integer of 1 to 6; m and n are each independently an integer of 0 to 8; and Ar?1 and Ar2¿ are each a benzene ring or the like.

Description

TECHNICAL FIELD The present invention relates to a novel chroman analog having excellent tumor growth inhibitory activity, lipid peroxide production inhibitory activity, 5-lipoxygenase inhibitory activity, and / or hypoglycemic activity. BACKGROUND ART It is not known that the chemical structure of the chroman analog of the present invention is similar to that of the chroman analog of the present invention and that it has a tumor growth inhibitory activity, a lipid peroxide inhibitory activity, a 5-lipoxygenase inhibitory activity or a hypoglycemic activity. . The present inventors have proposed synthesis of a derivative having a novel chemical structure and excellent tumor growth inhibitory activity, lipid peroxide production inhibitory activity, 5-lipoxygenase inhibitory activity or hypoglycemic activity, and its pharmacology. As a result of many years of intense research on the activity, a novel chroman analog with a completely different chemical structure from known drugs has excellent tumor growth inhibitory activity, lipid peroxide production inhibitory activity, and 5-lipoxygenase inhibitory activity. The present inventors have found that they have activity or hypoglycemic activity and completed the present invention.

DISCLOSURE OF THE INVENTION The compound of the present invention is a compound represented by the following general formula (1), a pharmacologically acceptable salt or an ester thereof.

In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, an aralkyl group having 7 to 18 carbon atoms, and 1 to 6 carbon atoms. Aliphatic carbonyl groups, 7 to 15 carbon atoms, aromatic carbonyl groups, 8 to 19 carbon atoms, aralkyl carbonyl groups, 4 to 9 carbon atoms, cycloalkylcarbonyl groups, heteroaryl carbonyl groups, carbon atoms An alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms, an arylsulfonyl group having 6 to 14 carbon atoms, and carbamoyl A group or a substituting rubamoyl group;

R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms or an aralkyl group having 7 to 18 carbon atoms;

R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, and 7 to 18 carbon atoms Aralkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, halogen atom, nitro group, hydroxyl group, 1 to 6 carbon atoms 6 aliphatic aliphaticoxy groups, an alkylsulfonyloxy group having 1 to 4 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with halogen, an amino group, or any selected from <substituent group α> Represents an amino group substituted with a substituent of

X is a single bond, formula (C = 0) —group, formula — (C = NOR ⁷ ) —group, formula — (CHOH) —group, formula — CH (OR ⁸ ), formula — CH ₂ — A group or a formula — (C = NNR ⁹ R ^1Q ) —

R ⁷ and R ⁸ are the same or different and each represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, Alkenyl group having 2 to 6 carbon atoms, aryl group having 6 to 14 carbon atoms, aralkyl group having 7 to 18 carbon atoms, aliphatic acryl group having 1 to 6 carbon atoms, carbon number 7 to 15 aromatic acyl groups, aralkylcarbonyl groups having 8 to 19 carbon atoms, cycloalkylcarbonyl groups having 4 to 9 carbon atoms, heteroarylcarbonyl groups, 1 to 6 carbon atoms Alkylsulfonyl groups, arylsulfol groups having 6 to 14 carbon atoms, rubamoyl groups or rubamoyl substituents,

R ⁹ and R ^1Q are the same or different and each represent a hydrogen atom and an arbitrary substituent selected from the substituent group α>,

Α represents a formula— (C = 0) —group or a formula—S 0 ₂ —group,

U represents a —CH ₂ — group, a formula C (R ² ) —U, a formula C = CH group, or a formula X—U, a formula CH 2 CH group or a single bond;

Y represents a group represented by the following formula:

Q represents a hydrogen atom, a nitro group, a hydroxyl group, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms, and a carbon atom having 6 to 1 carbon atoms. 4 aryl groups, 7 to 18 carbon atoms aralkyl group, 1 to 6 carbon atoms alkoxy group, 6 to 14 carbon atoms aryloxy group, 7 to 18 carbon atoms aralkyloxy group, carboxyl Group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a cycloalkyloxy group having 4 to 9 carbon atoms, an oxygen atom (however, when Ar ¹ or Ar ² is a pyridine ring, An amino group or an amino group substituted with any substituent selected from the group consisting of:

k represents an integer of 1 to 6,

m and n are the same or different and each represent an integer of 0 to 8,

A r ¹ represents a benzene ring, a pyridine ring or a biphenylene group,

Ar ² represents an aryl ring, a heteroaryl ring or a nitrogen-containing heterocyclic ring.

However, in the above, the aryl ring, heteroaryl ring, or nitrogen-containing heterocyclic moiety may have 1 to 6 substituents at any position, and the substituent may be a <substituent group> 3 And> the same or different substituents arbitrarily selected from <Substituent group>

Alkyl group having 1 to 6 carbon atoms, aryl group having 6 to 14 carbon atoms, aralkyl group having 7 to 18 carbon atoms, aliphatic acyl group having 1 to 6 carbon atoms, carbon number 7 to 15 aromatic acyl groups, aralkylcarbonyl groups having 8 to 19 carbon atoms, cycloalkylcarbonyl groups having 4 to 9 carbon atoms, heteroarylcarbonyl groups, 1 to 6 carbon atoms Alkylsulfonyl group, arylsulfonyl group having 6 to 14 carbon atoms, sulfamoyl group, substituted sulfamoyl group, thiocarbamoyl group, substituted thiocarbamoyl group, rubamoyl group or rubamoyl group.

Substituents | 3>

Nitro group, hydroxyl group, halogen atom, alkyl group having 1 to 6 carbon atoms, alkyl group having 1 to 6 carbon atoms substituted with halogen, aryl group having 6 to 14 carbon atoms, carbon number of 7 to 18 Aralkyl groups, C1 to C6 alkoxy groups, C6 to C14 aryloxy groups, C7 to C18 aralkyloxy groups, carboxyl groups, C2 to C7 alkoxy groups Carboel group, cycloalkyloxy group having 4 to 9 carbon atoms, oxygen atom (however, Ar ¹ force; in the case of a pyridine ring, only when the nitrogen on the ring becomes an oxide), An amino group or an amino group substituted with an arbitrary substituent selected from substituent group α>. Further, the present invention is a medicine (particularly, a preventive or therapeutic agent for cancer or a preventive or therapeutic agent for diabetes) containing the compound (1) as an active ingredient.

Further, the present invention is a use for producing a medicament (particularly, a prophylactic or therapeutic agent for cancer or a prophylactic or therapeutic agent for diabetes) containing the compound (1) as an active ingredient.

Furthermore, the present invention is a method for preventing or treating cancer or a method for preventing or treating diabetes, comprising using an effective amount of the above compound (1) in mammals (particularly, humans). In R ¹ of the above formula (1), “an alkyl group having 1 to 6 carbon atoms” means, for example, methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, s-butyl Tyl, tert-butyl, n-pentyl, isopentyl, 2-methylinobutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3, 3- 1 to 1 carbon atoms such as dimethinolevbutinole, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl Examples thereof include six straight-chain or branched-chain alkyl groups, preferably having 1 to 4 carbon atoms, and more preferably a methyl group. In R ¹ of the above formula (1), “aryl group having 6 to 14 carbon atoms” means, for example, a carbon number of 6 to 14 such as feninole, indeninole, naphtinole, fenantreninole, and anthracenole. Aromatic hydrocarbon groups, and preferably a phenyl group. In R ¹ of the above formula (1), “an aralkyl group having 7 to 18 carbon atoms” includes, for example, benzyl, sodium naphthylmethyl, naphthylmethyl, indenylmethyl, phenanthrenylmethyl, anthracene Nylmethyl, diphenylmethinole, 1-phenyl, 2-phenyl, 1-naphthylethyl, 2-naphthinoleethyl, 1-phenylphenol, pill, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropynole, 2—Naphtinolepropine / le, 3—Naphtinolepropinele, 1—Feninolebuti / le, 2—Fune2

3-phenylbutyl, 4-phenylbutyl, 1-naphthinolebutynole, 2-'3-naphthylbutyl, 4-naphthylbutyl, 1_phenylpentinole, 2-phenylenopentenole, 3-phenylenopentinole, 4-phenylinopentenole, 4-phenylenopentenole , 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentinole, 4-naphthinolepentinole, 5-naphthylopentinole, 1-fueninohexenole, 2-phenynohexenole, 3 —Feninole hexinole, 4—Feninole hexinole, 5—Feninole hexinole, 6—Feninole hexinole, 1-naphthinolehexinole, 2 _Naphthinolehexyl, 3-Naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl, and 6-naphthylhexyl group can be mentioned. Group. In R ¹ of the above formula (1), the “aliphatic acyl group having 1 to 6 carbon atoms” includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, vivaloyl, hexanoyl, etc. Straight-chain or branched-chain alkylcarbonyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably an acetyl group. In R ¹ of the above formula (1), the “aromatic acyl group having 7 to 15 carbon atoms” is, for example, a group in which the above “aryl group having 6 to 14 carbon atoms” is bonded to a carbonyl group. And preferably a benzoyl group. In R ¹ in the above formula (1), the “aralkylcarbonyl group having 8 to 19 carbon atoms” is, for example, a group in which the “aralkyl group having 7 to 18 carbon atoms” is bonded to a carboel group. And preferably a furacetyl group. In R ¹ of the above formula (1), the “cycloalkylcarbon group having 4 to 9 carbon atoms” includes, for example, cyclopropylcarbonyl, cyclopentinolecarbonyl, cyclopentylcarbonyl, cyclohexylcarbol, cyclo Examples thereof include a saturated cyclic hydrocarbon monocarbonyl group having 4 to 9 carbon atoms such as heptylcarbol and cyclooctylcarbonyl, preferably a 3- to 6-membered group, more preferably It has 5 or 6 members. In R ¹ of the above formula (1), the “heteroarylcarbyl group” is a group in which the “aryl group substituted by a heteroatom” is bonded to a carboxyl group. Carbonyl, furylcarbonyl, pyrrolylcanoleboninole, imidazolylcarbinole, isotizazolylcarbonyl, isoxazolylcarbinole, pyridylcarbonyl, pyrazinylcarbonole, isobenzofuranylcarbonyl, indolinolecarboninole Such a nitrogen atom; and an optionally fused arylcarbonyl group substituted by an oxygen atom or a sulfur atom. The “halogen” in the “alkylsulfonyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogens” for R ¹ in the above formula (1) is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine. An atom can be mentioned, and it is preferably a chlorine atom. In R ¹ of the above formula (1), “C ¹ to C 6 alkylsulfoyl group, C ¹ to C 6 alkylsulfonyl group substituted with 1 to 3 halogens” is the same as “C ¹ to C 6 alkylsulfonyl group”. The “six alkylsulfonyl groups” are groups in which the above “lower alkyl group” is bonded to a sulfonyl group, for example, methanesulfonyl, ethanesulfonyl, n-prono ヽ. And sulfonyl. N-sulfonyl, n-butanes-no-honole, s-butanes-no-honore, s-butans-no-le-honore, tert-butane-sole-hon-no-le, n-pentans / le-ho-no-nore, iso-pentanes-no-re-hon-no-le, 2-methisole Pentane sulfonyl, n-hexanesulfoninole, 4-methylpentanesnorefoninole, 3-methylpentanesulfonyl, 2-methylpentanesulfonyl, 3,3-dimethylinobutanesulfonyl, 2,2-dimethylbutans / lefonyl, Linear or branched having 1 to 6 carbon atoms, such as 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3-dimethylbutanesulfonolene, and 2,3-dimethylbutanesulfonyl A chain alkane sulfol group can be mentioned, and it preferably has 1 to 4 carbon atoms. Yes, and more preferably a methanesulfonyl or ethanesulfol group. In R ¹ of the above formula (1), “an alkylsulfonyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogens” as a whole includes, for example, chloromethanesnolephonyl, 2-chloromouth ethanesnolejo Ninore, 2,2-dichloroethaneszolehonizole, 2,2,2-trichloro-mouth ethanesulfoninole, 3-chloro-mouth prono ヽ. Examples thereof include straight-chain or branched-chain alkane sulfol groups having 1 to 6 carbon atoms, such as snolehoninole, 4-bromobutanesulfonyl, 3-fluoropentanesulfonyl, and 6-fluoromouth hexansolephoninole. Preferably, it is a chloromethanesulfol group. The “arylsulfonyl group having 6 to 14 carbon atoms” for R ¹ in the above formula (1) is, for example, the above “aryl group having 6 to 14 carbon atoms” bonded to a sulfonyl group. And a phenylsulfonyl group. In R ¹ of the above formula (1), the term “substituent rubamoyl group” means a “substituent rubamoyl group in which a nitrogen atom is substituted with one or two substituents”. For example, the above "alkyl group having 1 to 6 carbon atoms", "aryl group having 6 to 14 carbon atoms", "aralkyl group having 7 to 18 carbon atoms", "fat having 1 to 6 carbon atoms" Group, an aromatic acyl group having 7 to 15 carbon atoms, an aralkylcarbonyl group having 8 to 19 carbon atoms, a cycloalkylcarbonyl group having 4 to 9 carbon atoms, Heteroarylcarbonyl group '', preferably, an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 1 to 6 carbon atoms, or an aromatic carbonyl group having 7 to 15 carbon atoms. A carbamoyl group substituted with a sil group, and more preferably a group having 1 carbon atom. 4 alkyl group is a force Rubamoiru group substituted by the number 1 to 4 aliphatic Ashiru group or several seven aromatic Ashiru group carbon atoms. In R ² of the above formula (1), the “alkyl group having 1 to 6 carbon atoms” includes, for example, the same groups as those described above for R ^1. It is one to four, more preferably a methyl group. In R ² of the above formula (1), the “aryl group having 6 to 14 carbon atoms” includes, for example, the same groups as those described above for R ¹ , preferably phenyl It is a group. In R ² of the above formula (1), “an aralkyl group having 7 to 18 carbon atoms” includes, for example, the same groups as those described above for R ¹ . It is a benzyl group. In R ³ , R ⁴ , R ⁵ and R ^e in the above formula (1), “an alkyl group having 1 to 6 carbon atoms” means, for example, the same groups as those described above for R ¹ It preferably has 1 to 4 carbon atoms, and more preferably is a methyl group. In R ³ , R ⁴ , R ⁵ and R ⁶ of the above formula (1), “an aryl group having 6 to 14 carbon atoms” means, for example, the same as the above-mentioned R ¹ . And preferably a phenyl group. In R ⁴ , R ⁵ and R ⁶ in the above formula (1), “an aralkyl group having 7 to 18 carbon atoms” means, for example, the same groups as those described above for R ^1. And preferably a benzyl group. In R ³ , R ⁴ , R ⁵ and R ⁶ of the above formula (1), “an alkoxy group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms and substituted with 1 to 6 carbon atoms” The "alkoxy group having 1 to 6 carbon atoms" in "," means, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, tert-butoxy, n-pentoxy, 2- Methylbutoxy, isopentoxy, neopentoxy, n-hexyloxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3 —Dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, and 2-ethylbutoxy groups. It is of 1 to 4 carbon atoms, more preferably a main butoxy or ethoxy alkoxy group. In R ³ , R ⁴ , R ⁵ and R ^s of the above formula (1), “an alkoxy group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms” Toximethoxy, 2-methoxyethoxy, ethoxymethoxy, 3-methoxypropoxy, 4-ethoxybutoxy, 5-methoxypentoxy, 6-ethoxyhexyl / reoxy groups, and preferably methoxymethoxy It is a toxic or ethoxy methoxy group. In R ³ , R ⁴ , R ⁵ and R ⁶ in the above formula (1), “halogen atom” means a fluorine atom, Examples thereof include a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom or a chlorine atom. In R ³ , R ⁴ , R ⁵ and R ⁶ in the above formula (1), the “aliphatic acyloxy group having 1 to 6 carbon atoms” means, for example, the aliphatic acyl group mentioned above for R ¹ Examples of the group include a group in which an oxygen atom is bonded to the same group as described above, preferably having 1 to 4 carbon atoms, and more preferably an acetyloxy group. In R ³ , R ⁴ , R ⁵ and R ⁶ in the above formula (1), “an alkylsulfonyloxy group having 1 to 4 carbon atoms” means that “an alkylsulfonyl group having 1 to 4 carbon atoms” is an oxygen atom. Such as methanesulfo-loxy, ethanesulfonyloxy, n-propanesulfoninoleoxy, isopropanesulfonyl / reoxy, n-butane snolephoninoleoxy, isobutane snolephoninolexy, s —Butanesulfonyloxy and tert-butanesulfonyloxy groups, and preferably a methanesulfonyl or ethanesulfonyl group. In R ³ , R ⁴ , R ⁵ and R ⁶ in the above formula (1), “an alkyl group having 1 to 6 carbon atoms substituted by 1 to 3 halogens” means 1 to 3 A halogen atom-substituted alkyl group having 1 to 6 carbon atoms, wherein the “alkyl group having 1 to 6 carbon atoms” refers to, for example, the same groups as those described above for R ^1. Examples of the “halogen-substituted alkyl group having 1 to 6 carbon atoms” include, for example, fluoromethyl, difluoromethinole, trifluoromethyl, chloromethinole, dichloromethinole, and trichloromethine. Nole, 2-fuzoleolochinole, 2-diphneoleolochinole, 2-chloroethinole, 2-dichloroethinole, 3-bromopropinole, 4-chlorobutinole, 5-fluoropentyl, 6-bromohexyl, etc. Bets can be, preferably, a preparative Rifuruoromechiru group. In R ⁷ and R ⁸ in the above formula (1), the “alkyl group having 1 to 6 carbon atoms” includes, for example, the same groups as those described above for R ^1. , Carbon The number is one to four, more preferably a methyl group. In R ⁷ and R ⁸ in the above formula (1), “an alkenyl group having 2 to 6 carbon atoms” includes, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl 1-methyl-1-propanol, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propynole, 1-buteninole, 2-buteninole , 1-Methyl-1-butenyl, 1-Methyl-1-butenyl, 3-Methyl-1-buteninole,

1 1 ethyl 1 2-buteninole, 3-butenyl, 1—methinole _ 3—buteninole, 2—methinole 1—3-buteninole, 1—ethinole 1—3-pteninole, 1—penteninole, 2—pentennole,

1—Methinole 2—Pentinole, 2—Methinole 1—Pentinole, 3—Pentinole, 1—Methinole 3—Pentinole, 2-Methinole 3—Pentenole, 4-Pentenole , 1-Methinole, 4-Pentinole, 2-Methinole, 4-Pentenole, 1-hexeninole, 2-hexenil, 3-hexeninole, 4-hexenur, 4-hexenul, 5-hexen / le A straight-chain or branched alkenyl group having 2 to 6 carbon atoms can be mentioned, preferably having 2 to 4 carbon atoms, and more preferably a 2-propenyl group. is there. In R ⁷ and R ⁸ of the above formula (1), the “aryl group having 6 to 14 carbon atoms” includes, for example, the same groups as those described above for R ^1. Is a phenyl group. In R ⁷ and R ⁸ in the above formula (1), the “aralkyl group having 7 to 18 carbon atoms” includes, for example, the same groups as those described above for R ^1. Is a benzyl group. In R ⁷ and R ⁸ in the above formula (1), the “aliphatic acyl group having 1 to 6 carbon atoms” includes, for example, the same groups as those described above for R ^1. Has 1 to 4 carbon atoms, and more preferably is an acetyl group. In R ⁷ and R ⁸ of the above formula (1), “an aromatic acyl group having 7 to 15 carbon atoms” Is, for example, the same groups as those described above for R ¹ , preferably having 7 carbon atoms, and more preferably a benzoyl group. In R ⁷ and R ⁸ of the above formula (1), “an aralkylcarbonyl group having 8 to 19 carbon atoms” includes, for example, the same groups as those described above for R ^1. Is a group having 8 carbon atoms, and more preferably a phenylacetyl group. In R ⁷ and R ⁸ of the above formula (1), the “cycloalkylcarbonyl group having 4 to 9 carbon atoms” includes, for example, the same groups as those described above for R ¹ . Preferably, it has 3 to 6 members, and more preferably, it has 5 to 6 members. In R ⁷ and R ⁸ of the above formula (1), the “heteroarylcarbonyl group” includes, for example, the same groups as those described above for R ¹ . In R ⁷ and R ⁸ in the above formula (1), the “alkylsulfur group having 1 to 6 carbon atoms” includes, for example, the same groups as those described above for R ¹ . It preferably has 1 to 4 carbon atoms, and is more preferably a methanesulfonyl or ethanesulfol group. In R ⁷ and R ⁸ of the above formula (1), the “arylsulfonyl group having 6 to 14 carbon atoms” means, for example, the same groups as those described above for R ^1. And preferably 6 carbon atoms. In R ⁷ and R ⁸ of the above formula (1), the “substituent rubamoyl group” includes, for example, the same groups as those described for R ¹ above. R ⁹ and R ^{1 in} the above formula (1). , An alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, an aralkyl group having 7 to 18 carbon atoms, an aliphatic group having 1 to 6 carbon atoms Acyl group '', `` aromatic acyl group having 7 to 15 carbon atoms '', `` carbon 8 to 19 aralkylcarbonyl groups "," 4 to 9 carbon cycloalkylcarbyl groups "," heteroarylcarbyl groups, "" 1 to 6 carbon alkylsulfonyl groups " Examples of the “group”, “arylsulfol group having 6 to 14 carbon atoms” and “substituted carbamoyl group” include the same groups as those described for R ¹ above. In Q of the above formula (1) and <substituent group>3>, the “aryl group having 6 to 14 carbon atoms” means, for example, the same groups as those described above for R ^1. It is preferably one having 6 carbon atoms, and more preferably a phenyl group. In Q and the substituent group 3> in the above formula (1), “halogen atom” means, for example, the same groups as those described above for R ³ , R ⁴ , R ⁵ and R ^6. Preferably, it is a fluorine atom or a chlorine atom. In Q of the formula (1) and the substituent group J3>, the “halogen-substituted alkyl group having 1 to 6 carbon atoms” includes, for example, the aforementioned R ³ , R ⁴ , R ⁵ and R ⁶ The same groups as those described above can be mentioned, and a trifluoromethyl group is preferable. In Q of the above formula (1) and <Substituent group 13>, the “aryl group having 6 to 14 carbon atoms” includes, for example, the same groups as those described above for R ^1. Preferably, it has 6 carbon atoms, and more preferably, it is a phenyl group. In Q in the above formula (1) and <Substituent group | 8>, “an aralkyl group having 7 to 18 carbon atoms” means, for example, the same groups as those described for R ¹ above. Preferably, it has 7 to 11 carbon atoms, and more preferably, it is a benzyl group. In Q and the substituent group / 3> in the above formula (1), the `` alkoxy group having 1 to 6 carbon atoms '' is the same as that described for R ¹ above. Is a group bonded to an oxygen atom, preferably has 1 to 4 carbon atoms, more preferably A methoxy or ethoxy group. In Q of the above formula (1) and <substituent group>3>, the “aryloxy group having 6 to 14 carbon atoms” refers to the “aryl group having 6 to 14 carbon atoms” described above for R ^1. The “group” is a group bonded to an oxygen atom, preferably has 6 to 10 carbon atoms, and is more preferably a phenyloxy group. In the formula (1), Q and the substituent group] 3>, the “aralkyl group having 7 to 18 carbon atoms” refers to the “aralkyl group having 7 to 18 carbon atoms” described above for R ^1. The "group" is a group bonded to an oxygen atom, preferably has 7 to 11 carbon atoms, and is more preferably a benzyloxy group. In the Q and the substituent group J3> in the above formula (1), the “alkoxycarbonyl group having 2 to 7 carbon atoms” includes, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxyl-ponyl, isopropoxy Carbonyl, n-butoxycarbonyl / s, s-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, 2-methylbutoxycarbonyl, isopentoxycarbol, neopentoxy Carbonyl, n-hexyloxycarbonyl, 2-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 4-methylpentoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl Ponyl, 3,3-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbol, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxy force / report, and 2-ethylbutoxycarbonyl group, preferably having 2 to 4 carbon atoms. And more preferably a methoxycarbonyl or ethoxycarbonyl group. In the above formula (1), Q and the substituent group) 3>, the “cycloalkyloxy group having 4 to 9 carbon atoms” includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, Cyclohexyloxy, Cycloheptyloxy, Cyclok Examples thereof include a saturated cyclic hydrocarbon monooxy group having 4 to 9 carbon atoms such as tiloxy, preferably 4 to 7 members, and more preferably 5 to 6 members. In Q of the above formula (1), <Substituent group H> and <Substituent group 13>, the “alkyl group having 1 to 6 carbon atoms” is, for example, the same as that described above for R ¹ The group is preferably a group having 1 to 4 carbon atoms, and more preferably a methyl group. In Ar ¹ of the above formula (1), the “aryl ring” is, for example, an aromatic hydrocarbon having 6 to 14 carbon atoms such as a benzene ring, an indene ring, a naphthalene ring, a phenanthrene ring, and an anthracene ring. And a benzene ring. In Ar ² of the above formula (1), the term “heteroaryl ring” refers to a ring in which at least one carbon atom on the aryl ring is substituted with at least one heteroatom, for example, a thiophene ring, a furan ring, 5- to 10-membered rings such as benzofuran ring, benzothiophene ring, pyrroyl ring, imidazo 1 / re ring, isoxazoline ring, pyridine ring, pyrazine ring, pyrimidine ring, indolin ring, quinoline ring, quinazoline ring And preferably contains one or more nitrogen atoms, and more preferably a pyridine ring, a pyrazine ring, a pyrimidine ring, a quinoline ring or an indoline ring. In Ar ² of the above formula (1), the “nitrogen-containing heterocycle” refers to a saturated heterocycle or a partially saturated heterocycle containing one or two nitrogen atoms, for example, an aziridine ring or an azolizine ring. And a 4- to 7-membered heterocycle such as a piperidine ring and a tetrahydropyridine ring, and a piperidine ring is preferable. In the substituent group α> in the above formula (1), the “substituted thiocarbamoyl group” refers to a “thiocarbamoyl group in which a nitrogen atom is substituted with one or two substituents”. Examples of the substituent include the above-mentioned "alkyl group having 1 to 6 carbon atoms" and " Aralkyl group of 14 to 14 carbon atoms, aralkyl group of 7 to 18 carbon atoms, aliphatic acyl group of 1 to 6 carbon atoms, aromatic aromatic group of 7 to 15 carbon atoms A "C8-C19 aralkylcarbyl group", a "C4-C9 cycloalkylcarbonyl group", and a "heteroarylcarbonyl group". A thiocarbamoyl group substituted by an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 1 to 6 carbon atoms, or an aromatic acyl group having 7 to 15 carbon atoms; It is a thiocarbamoyl group substituted by an alkyl group having 1 to 4 carbon atoms, an aliphatic acyl group having 1 to 4 carbon atoms, or an aromatic acyl group having 7 carbon atoms. In the above-mentioned (1) Substituent group <1>, the “substituted sulfamoyl group” refers to a “sulfamoyl group in which a nitrogen atom is substituted with one or two substituents”. Examples of the above include “the alkyl group having 1 to 6 carbon atoms”, “aryl group having 6 to 14 carbon atoms”, “aralkyl group having 7 to 18 carbon atoms”, and “1 to 6 carbon atoms”. An aliphatic acyl group, an aromatic acyl group with 7 to 15 carbon atoms, an aralkylcarbonyl group with 8 to 19 carbon atoms, and a cycloalkyl carboxy group with 4 to 9 carbon atoms. And a heteroarylcarbonyl group, preferably an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 1 to 6 carbon atoms or 7 to 15 carbon atoms. Sulfamoyl group substituted with an aromatic acyl group, more preferably It represents an alkyl group having 1 to 4 carbon atoms, 1 to 4 aliphatic carbon atoms Ashiru group or a sulfamoyl group substituted by the number seven aromatic Ashiru group carbon. In the above substituent group α> of (1), “aryl group having 6 to 14 carbon atoms”, “aralkyl group having 7 to 18 carbon atoms”, “aliphatic group having 1 to 6 carbon atoms” Group), an aromatic acyl group having 7 to 15 carbon atoms, an aralkylcarbyl group having 8 to 19 carbon atoms, a cycloalkylcarbonyl group having 4 to 9 carbon atoms, and a heteroarylcarbonyl. The “group”, “alkylsulfonyl group having 1 to 6 carbon atoms” and “arylsulfonyl group having 6 to 14 carbon atoms” have the same meaning as described above.

"Pharmacologically acceptable salt thereof" means that the compound (1) of the present invention can be converted into a salt. The salt is referred to as such a salt. Preferably, such a salt is an alkali metal salt such as a sodium salt, a potassium salt, a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, or aluminum. Metal salts such as salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenylglycine alkyls Estel salt, ethylenediamine salt, N-methyldalcamine salt, guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, black mouth pro-force salt, professional Power-in salt, diethanolamine salt, N-benzirufenethylamine salt, piperazine salt, tet Amine salts such as organic salts such as lamethylammonium salt and tris (hydroxymethyl) aminomethane salt; hydrohalic acids such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide Inorganic salts such as salts, nitrates, perchlorates, sulfates, and phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; benzenesulfonate; p. Organic acid salts such as arylsulfonic acid salts such as toluenesulfonic acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, tartrate salt, oxalate salt, maleate salt; And amino acid salts such as daricin salt, lysine salt, arginine; ^, ordinine salt, glutamate, and aspartate; and preferably fumarate , Maleate or hydrochloride, and more preferably, hydrochloride.

In addition, the compound (1) of the present invention may absorb water and leave adsorbed water or form hydrates when left in the air, and such salts are also included in the present invention. Is done. Further, the compound (1) of the present invention may absorb some other solvent to form a solvate, and such salts are also included in the present invention. ''"Ester" means the ester of the compound (1) of the present invention, which can be optionally converted to an ester. Such esters include "ester of hydroxyl group" and "ester of carboxy group". And an ester wherein each ester residue is a “general protecting group” or a “protecting group that can be cleaved in vivo by a biological method such as hydrolysis”. "General protecting group" means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and "a general protecting group" such as "ester of hydroxyl group". Examples include formyl, acetyl, propiol, butyryl, isoptyryl, pentanoyl, pivaloyl, norelinole, isonorelyl, octanoinole, nonanoyl, decanol, 3-methylnonanoyl, 3-methylnonanol, 3-methylnonanol, 3-methylnonanotyl, 3-methylnonanol 7-Dimethyloctanoyl, Pendecanoyl, Dodecanoyl, Tridecanoyl, Tetradecanoyl, Pentadecanoyl, Hexadecanyl, 1'-Methylpentadecanoyl, 14-Methylpentadecanoyl, 13,13-Dimethyltetradecanol, Heptadanol 1 5—Methylhexade Alkylcarbonyl groups such as canoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl and henicosanoyl, carboxylated alkylcarbinole groups such as succinoyl, glutaroyl, adipoinole, chloroacetinochlore, chloroacetylinocetyl , Halogeno lower alkylcarbonyl groups such as trifluoroacetyl, cyclopropylcarbonyl, cyclobutylcarboninole, cyclopentinolecanoleboninole, cyclohexinolecanoleboninole, cycloheptinolecanoleboninole, cyclo A saturated cyclic hydrocarbon-carbonyl group such as octylcarboel, a lower alkoxy-lower alkylcarbonyl group such as methoxyacetyl, (E) -2-methyl-12-butenoyl, etc. "Aliphatic acyl groups" such as unsaturated alkylcarboyl groups; benzoinole, α-naphthyl,] 3-naphthoinole, pyridoyl, chenoynole, arylcarbonyl groups such as froinore, 2-promobenzoyl, 4-chlorobenzoyl Halogenated arylcarbonyl groups such as benzoyl, lower alkylated arylcarbyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl, lower alkoxylated aryls such as 4-anisyl Carboxylated aryl carboxylic groups such as carbonyl group, 2-carboxybenzoyl, 3-carboxybenzoyl, 4-carboxybenzoyl, nitrated aryl groups such as 4-nitrobenzoyl, 2-nitrobenzoyl Carbonyl group, 2- (methoxycarbonyl) low-grade phenol such as benzoinole Power carbonyl reduction § reel carbonyl group, 4 one Hue - § Li Ichiru Kaa like Rupenzoiru "Aromatic acyl group" such as reelcarbonyl group; phenylacetyl, α-naphthyl-peptyl pionyl,] 3-naphthylbutyryl, diphenylisobutyryl, triphenylacetyl, ct-naphthyldiphenylisobutyryl, 9_anthrinolepentanoyl Lower alkylcarbonyl group substituted with 1 to 3 aryl groups such as 4-methylphenylacetyl, 2,4,6-trimethylphenylhonoleminole, 3,4,5-trimethylphenylenolebutyryl, 4- Methoxypheninolei-sobutyrinole, 4-Methoxyphenyludipheninolepinoyl, 2-tropheninoleacetinole, 4-nitropheninolepropionyl, 4-monophenyolenobutyrinole, 4-bromophenolenocelineole Lower alkyl, such as 4-cyanophenylpentanoyl, lower An "aralkylcarbonyl group" such as a lower alkylcarbonyl group substituted with one to three aryl groups in which the aryl ring is substituted with an alkoxy, nitro, nitrogen, or cyano group; tetrahydropyran Such as 1-yl, 3-bromotetrahydridopyran-1-2-yl, 4-methoxytetrahydrodropyrane 4-yl, tetrahydroxythiopyran-1_yl, 4_methoxytetrahydrodropyropyrane-1-4-yl A "tetrahydrofuranil or tetrahydrothiolananyl group"; a "tetrahydrofuranyl or tetrahydrothiofuranyl group" such as tetrahydrofuran-12-yl or tetrahydrofurofuran-12-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t —Butyldimethylsilyl, methyldiisopropylsilyl, One or two aryls, such as tri-lower alkylsilyl groups such as t-butylsilyl and triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl "Silyl group" such as tri-lower alkylsilyl group substituted with a group; such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl Lower alkoxymethyl group, lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, halogeno lower alkoxy such as bis (2-cycloethoxy) methyl "Alkoxymethyl group" such as methyl Lower alkoxylated tyl groups such as 1-ethoxyethoxyl, 1- (isopropoxy) ethyl, and halo such as 2,2,2-trichloromethylethyl "Substituted ethyl group" such as benzyl group; 1 to 1 such as benzyl, _α -naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 1-naphthyldiphenylmethyl, 91-anthrylmethyl Lower alkyl group substituted with three aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzinole, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methylbenzyl Lower alkyl, lower alkoxy, nitro, halogen, cyano, such as toxicphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzene, 4-bromobenzyl, 4-cyanobenzyl An “aralkyl group” such as a lower alkyl group substituted with one to three aryl groups, wherein the aryl ring is substituted with a group; methoxycarbonyl, ethoxy Lower anoreoxycarbonyl groups such as carboxy, tert-butoxycarbonyl, and isobutoxycarbonyl; halogen or tri-lower alkylsilyl groups such as 2,2,2-trichloromouth ethoxycarbonyl and 2 _trimethylsilyl ethoxycarbonyl An "alkoxycarbonyl group" such as a lower alkoxycarboxy group substituted with a; an "alkenyloxycarbonyl group" such as vinyloxycarbonyl or aryloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxy One or two lower alkoxys, such as carbole, 3,4-dimethoxybenzyloxycarbonyl / re, 2-2 trobenzodinoleoxy / reponyl, 4 _2-trobenzoyloxycarbonyl Even if the aryl group is substituted with a nitro group, Carboxyl group ",

On the other hand, as the “general protecting group” for the “ester of the carboxy group”, preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butynole, tert-butynole, n- Pentinole, Isopentinole, 2-Methynolebutinole, Neopentyl, 1-Ethylpropyl, n-Hexyl, Isohexyl, 4-methylpentyl, 3-Methylpentyl, 2-Methylpentyl, 1-Methylpentinole, 3, 3-Di “Lower alkyl groups” such as methylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl; 1-Propenyl, 2-Propenyl, 1-Methinole 2-Propenyl, 1-Methynole 1-Probene, 2-Methino One 1-professional Peninole, 2-methinole, 2-propeninole, 2-ethinole, 2-propionyl, 1-butenyl, 2-butul, 1-methyl-1-2-buteninole, 1-methyl-1-1-buteninole, 3-- Methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butul, 1-methyl-13-buteninole, 2-methinole-1 3-buteninole, 1-ethynole_3-buten-nore, 1-pentenyl, 2-pentenyl, 1-methyl-1-pentyl, 2-methinole 2-pentene-norre, 3-pentenore, 1-methinole 3-pentenore, 2-methinole_3-pentenore, 4- Penteninore, 1—Methinole 1—Pentennole, 2—Methinole 1—Pente-Norne 1—Hexeninole, 2—Hexinenole, 3—Hexen / le, 4—Hexeninole, 5—Hexen -Alkenyl groups, such as -le; ethynyl, 2-pro 1-methinole 2-piper mouth, 2-methyl-1 2-propiel, 2-ethinole 2-probyl, 2-butynyl, 1-methinole 2-butyninole, 2-methinole 1-2-petit-nore, 1- Echinore 1 2-Bucher, 3-butynyl, 1-Methinole 3-Petinole, 2-Methinole 3-butininole 1-Echinole 3-Boutinole, 2-pentininole, 1-Methinole 2-Pentinole, 2-Methinole 2 —Pentinole, 3—Pentinole, 1—Methinole 3—Pentinole, 2—Metinole 3 — ^ ^ tintinole, 4—Pentinole, 1—Metinole 4—Pentinole, 2— Methyl 4-pentynole, 2-hexynole, 3-hexynole, 4-hexynole, 5-hexyl-like "alkynyl group"; trifluoromethyl, trichloromethyl, difluoro Cyl, dichloromethyl, dibumomethinole, fluoromethyl, 2,2,2-trichloroenole / 2,2,2-trichloroethinole, 2-bromoethinole, 2-chloroethyl, 2-fluoroethyl, 2- “Halogeno lower alkyl groups” such as lodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-hexylhexole, 2,2-dibromoethyl; 2-hydroxyl, 2,3-dihydroxypropyl, “Hydroxy lower alkyl group” such as 3-hydroxypropyl Λ ^, 3,4-dihydroxybuty 4-hydroxybutynole; “Aliphatic acyl” such as acetylmethyl 1 “Lower alkyl group”; benzyl, phenethyl, 3— Phenylpropyl, α-naphthylmethyl,] 3-naphthylmethyl, dipheninolemethinole, trifeninolemethine Les, 6 - cyclohexyl-phenylene Le, alpha-naphthyl diphenyl methyl, 1 to 3 of the "lower alkyl group" substituted by Ariru groups such as 9 _ anthrylmethyl, 4-methylbenzyl, 2,4,6-Trimethylbenzyl, 3,4,5-Trimethylbenzyl, 4-Methoxybenzyl, 4-Methoxyphenyldiphenylmethyl, 2-Nitrobenzyl, 4-Nitrobenzylinole, 4-Black Lower alkyl, lower alkoxy, nitro, halogen, such as benzene, 4-bromobenzinole, 4-cyanobenzinole, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, pyrironyl, 4-methoxycarbonylbenzyl, "Aralkyl groups" such as lower alkyl groups substituted with one to three aryl groups in which the aryl ring is substituted with an alkoxycarbonyl group; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiiso Provirsilyl, methyldi-tert-butyl Le, Torii Sopurobirushiriru, methyl diphenyl silyl, isopropyl di Hue El silyl, blanking Chirujifue - Rushiriru, the "silyl group" such as phenylalanine diisopropenyl building silyl can ani gel.

"Protective group that can be cleaved in vivo by a biological method such as hydrolysis" means a protective group that is cleaved in the human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. The compound is administered by intravenous injection to a laboratory animal such as a rat or a mouse, and the body fluid of the subsequent animal is examined, and the original compound or a pharmacologically acceptable salt thereof is determined. Can be determined by being able to detect

Examples of the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a hydroxyl group” include, for example, formyloxymethyl, acetooxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, Butyryloxymethyl, pivaloyloxymethyl, valeryloxymethinole, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyxetil, 1-acetoxyl, 1-propionyloxyxetil , 1 butylyl / reoethyl, 1-pivaloylenoxetil, 1 valeryloxetil, 1 _ isovalerinoleoxyethyl, 1 hexanolyloxetil, 1-formyloxypropyl, 1-acetooxypropyl , 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-itubare Π Pill, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propiona-acetoxypentyl, 1-propio-noreoxypentinole, 1-butylinoleoxypentyl, 1-bivaloyloxypentyl, 1-("aliphatic acryl" oxy) "lower alkyl" such as 1-pivaloyloxyhexyl; formylthiomethyl, acetyl thiomethyl, dimethylaminoacetylthiomethyl, propionylthiomethyl, butyrylthiomethyl, Vivaloy Ruthiomethyl, valerylthiomethyl, isovalerylthiomethyl, hexanoylthiomethinole, 1-forminorethiochinole, 1_acetinolethioethyl, 1-propionylthioethyl, 1-butyrylthioethyl, 1-pivaloylthioethyl, 1-pivalylthioethyl Valery Grechoe 1—Isovalerino Lechoe Nole, 1-hexanoylthioethyl, 1-formylthiopropyl, 1-acetylthiopropyl, 1-port pionylthiopropyl, 1-butyrylthiopropyl, 1-bivaloylthiopropyl, 1-valerylthiopropyl, 1-f Sovalerylthiopropyl, 1 Hexanolylthiopropyl, 1-Acetylthiobutyl, 1-Propionylthiobutyl, 1-Butyrylthiobutyl, 1-Pivaloylthiobutyl, 1-Acetinorethiopentinole , 1-propionylthiopentyl, 1-butyrylthiopentyl, 1-pivaloylthiopentyl, 1-bivaloylthiohexyl, etc. 1-("aliphatic acyl" thio) "lower anoalkyl group"; cyclopentylcarbonyl Xymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxy 1-cyclohexylcarbonyloxyl-propyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarboninoleoxypropyl, 1-cyclopentylcarbonylcarbonyloxybutyl, 1-cyclohexylcanolevo 1-(“cycloalkyl” carbonyloxy) such as niloxybutyl “lower alkyl”, 1-(“aromatic acyl” oxy) such as benzoyloxymethyl “lower alkyl” — (Asiloxy) “Lower alkyl group”: methoxycarbonyloxymethyl, ethoxycanoleponinoleoxymethinole, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarboxyloxymethyl, isobutoxycarboninoleoxymethyl , Pentyloxycarbonyloxy Methyl, hexyloxycarbonyloxymethyl, cyclo Hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarboxy) ethyl, 1- (propoxy) Carbonyloxyethyl, 1- (isopropoxycarbonyloxy) ethyl, 1— (butoxycarbonyloxy) ethyl, 1— (isobutoxycarboxy-loxy) ethyl, 1— (tert-butoxycarbonyloxy) Ethyl, 1- (Pentyloxycarboxy-loxy) Ethyl, 1— (Hexyloxycarboxy-loxy) Ethyl, 1— (Cyclopentynoleoxycarboxyloxy) Ethyl, 1- (Cyclopentyloxycarboxy-loxy) Propyl, 1 — (cyclohexyloxycarbonyloxy) propyl, 1 (cyclopentyl) 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonylinoleoxy) ethynole, 1— (ethoxycarbonyl / reoxy) propynole, 2— ( 2- (ethoxypropanol / reoxy) ethyl, 2- (isopropoxycarbonyloxy) ethyl, 2- (butoxycarbonyloxy) ethyl, 2 — (Isobutoxycarbonyloxy) ethyl, 2— (Pentyloxycanoleponyloxy) ethylinole, 2— (Hexinoleoxycarboninoleoxy) ethyl, 1— (Methoxycarboninoleoxy) propy ^ 1- (ethoxycanoleboninoleoxy) propyl, 1- (propoxycarbonyloxy) propyl Pill, 1 — (isopropoxycarbonyloxy) propyl, 1 — (butoxycarbonyloxy) propyl, 1 (isobutoxycarboninoleoxy) propyl, 1 _ (pentyloxycarbonyloxy) propyl, 1 ( Hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonylcarbonyl) Butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycanoleponyloxy) pentinole, 1- (ethoxycarbonyloxy) pentyl, 1- ( Methoxycarboxy-hexyl, 1- (ethoxycarboninoleoxy) hexyl Le like (alkoxycarbonyl two Ruokishi) alkyl: phthalidyl, dimethyl-phthalidyl, dimethyl Tokishifutarijiru A "phthalidyl group" such as: (5-phenyl-1-oxo-1,1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) 1-2-oxo-1,3-dioxolen-14 —Yl] methyl, [5- (4-methoxyphenyl) -12-oxo-1,3, -dioxolene 4-yl] methyl, [5- (4-fluorophenyl) 1-2-oxo-1 1 , 3-Dioxolen-1-41] methyl, [5- (4-chlorophenyl) -2-oxo-1,3_dioxolen-4-yl] methyl, (2-oxo-1, · 3— Dioxolene 4-methyl), (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-1-2-oxo-1,3,3-dioxolen-4-yl) ) Methyl, (5-propyl-2-oxo-1, 3-dioxolen-4-yl) methyl, (5-iso Oxodioxorenylmethyl groups such as ropir-2-oxo-11,3-dioxolen-4-yl) methyl, (5-butyl_2-oxo-11,3-dioxolen-14f) methyl "Carbooxyalkyl group": the above "aliphatic acyl group": the above "aromatic acyl group": "half ester salt residue of succinic acid": "phosphate residue": "amino acid etc. Ester-forming residue ": carbamoyl group: carbamoyl group substituted by one or two lower alkyl groups: 2-carboxyethyldithioethyl, 3-carboxypropyldithiochinole, 4-carboxybutyldithio Ethyl, 5-force / Repoxypentyldithiochi / re, 6_Carboxy such as carboxyhexyldithioethyl "Lower alkyl" dithioethyl group: methyldithioethyl, ethyldithiethyl Echiru, propyl di Chio E chill, butyl Roh registration Chio E chill can Rukoto mentioned "lower alkyl" Jichioechiru groups such as Penchirujichi Oechiru, hexyl di Chio E chill,

On the other hand, as the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of carboxy group”, specifically, methoxymethyl, 1-ethoxyxyl, 1-methyl-1 -Methoxyxetil, 1- (isopropoxy) ethyl,

Lower alkoxy lower alkyl such as 2-methoxyethoxy, 2-ethoxyhexyl, 1,1 dimethy ^ / 1-1-methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, tert-butoxymethyl Groups, lower alkoxylated lower alkoxy lower alkyl groups such as 2-methoxyethoxymethyl, “Alkyl lower alkyl” such as “aryl” oxy “lower alkyl” such as phenoxymethyl, and halogenated lower alkoxy lower alkyl such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl "Group": "lower alkoxy" such as methoxycarbonyl, carbonyl "lower alkyl group"; cyano such as cyanomethyl and 2-cyanoethyl "lower alkyl group";"loweralkynole" thiomethyl group such as methylthiomethyl and ethylthiomethyl An "aryl" thiomethyl group such as phenylthiomethyl and naphthylthiomethyl; a "lower alkyl" sulfonyl "which may be substituted with a halogen such as 2-methanesulfonylethyl and 2-trifluoromethanesulfo-norethyl; Lower alkyl group "Aryl" such as 2-benzenesulfonylethyl, 2-toluenesulfo-ruethyl, snolephonyl "Lower alkyl group"; formyloxymethyl, acetomethyl, propionyloxymethyl, butyryloxymethyl, pivaloynoreoxy Methyl, valeryloxymethinole, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxetil, 1-acetoxicetyl, 1-propioninoleoxyethyl Λ ^, 1-butylinoleoxy Methyl, 1-pivaloyloxetil, 1_valerilloxetil, 1-isovaleryloxetil, 1-hexanoyloxetil, 2-formyloxetil, 2-acetoxetil, 2 —Propionyloxyxetil, 2-butyryloxetil, 2-Vivaloyloxixil, 2-ba Linoleoxyethyl, 2-Isono-l-relinoxyl, 2-Hexanoloxyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propioeroxypropyl, 1-butyryloxyp Pill, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxoxybutyl, 1-propionyloxybutyl, 1-butylicyl 1-pivalonyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxypentyl Such as “aliphatic acyl” oxy “lower alkyl group”, cyclopentylcarbonyloxymethyl, Rukarubo - Ruokishimechiru, 1 Shiku port pen chill carbonitrile Nino les oxy E chill, hexyl carbonyl O key Chez chill to 1-cyclopropyl, 1 one "Cycloalkyl" such as pentyl canoleboninoleoxypropyl, 1-neck hexyl carboxy-l-oxypropynole, 1-neck pentyl canolebonoleoxy-butynole, 1-neck hexyl canolebonyloxybutyl Carbonyloxy “lower alkyl group”, “aromatic acyl” such as benzoyloxymethyl “oxy” “lower alkyl group”, etc. “lower alkyl group”; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl , Propoxycarbonyl / reoxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethinole, cyclohexanol Cyclohexyloxy, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl 1- (isopropoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1- (tert-butoxycarboeroxy) ethyl, 1- (pentyl) 1 / (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1 — (cyclo Hexyloxycarboxy-propyl, 1 — (cyclopentylo) (Cyclocarbonyloxy) butynole, 1— (cyclohexyloxycarbonyloxy) butyl, 1_ (cyclohexyloxycarbonyloxy) ethyl, 1_ (ethoxycarbonyloxy) propyl, 2-(methoxy Carboxyoxy) ethyl, 2- (ethoxycarboxy / reoxy) ethyl, 2- (butoxycarbonyloxy) ethyl, 2- (isopropoxycarbonyloxy) ethyl, 2- (butoxycarboxy) ' Ethyl, 2- (isobutoxycarbonyloxy) ethylinole, 2- (pentinoleoxycarboninoleoxy) ethylinole, 2- (hexyloxycarbonyloxy) ethyl, 1- (methoxycarbonyloxy) propyl, 1- ( Ethoxycarboxy-propyl, 11- (propoxycarbonyloxy) propyl, 11-isopropo Shi force Lupo - Ruokishi) propyl, 1 i (Butokishika Ruboniruokishi) propyl, 1 - (isobutoxy Cal Poeru O carboxymethyl) propyl, 1 ― (Pentyloxycarbonyloxy) propyl, 1- (hexyloxycarboxy-propyl) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyl) Butoxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarboxy) butyl, 1- (methoxycarbonyloxy) pentinole, 1- (ethoxycaboninoleoxy) pentinole, 1- (methoxycarbonyl / reoxy) hexyl, 1- (ethoxycanoleboenoleoxy) hexinole

(Alkoxycarboxy) alkyl group; (5-phenyl-2-oxo1-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) 1-2-oxo1-1,3 —Dioxolen-1-yl] methyl, [5- (4-Methoxyphenyl) —2-oxo_1,3-Dioxolen-1-ynole] methyl, [5- (4-Funoleophenyl) 1-2—oxo-1 1,3-dioxolen-1 4-yl] methyl, [5- (4-chlorophenyl) 1-2-oxo-1,3,3-dioxolen-1 4-yl] methyl, (2-oxo1, 3-dioxolen) Methyl, (5-Methyl-12-oxo-1, 3-dioxolen-4-yl) Methyl, (5-Ethyl-1-oxo-1, 3-Dioxolen-4-yl) Methyl, (5-propyl-1 2 _oxo1, 3, -dioxolen-1 4-yl) methyl Oxodi such as (5-Isopropyl_2-oxo-1, 3-dioxolen-1-yl) methyl, (5-butyl-12-oxo-1-1,3-dioxolen-14-yl) methyl "Carboxyalkyl groups" such as oxolenylmethyl groups: such as phthalidyl, dimethylphthalidyl, and dimethoxyphthalidyl

“Phthalidyl group”: phenyl, indaryl, etc. “aryl group”: above “lower alkyl group”: “carboxyalkyl group”, such as carboxymethyl: and “amino acid amide-forming residue, such as phenylalanine” ].

The “pharmacologically acceptable ester” refers to an ester having the above “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as an ester residue. The compound (1) of the present invention may have an asymmetric carbon in the molecule, and there are stereoisomers each having an R configuration or an S configuration. Mixed All of the compounds are included in the present invention. Among the compounds (1) of the present invention, preferred compounds include

<1> R ¹ force; hydrogen atom, alkyl group having 1 to 6 carbon atoms, aralkyl group having 7 to 18 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms, or 1 to 3 halogen A compound, a pharmacologically acceptable salt or an ester thereof, which is an alkylsulfonyl group having 1 to 6 carbon atoms substituted with

<2> R ^{1 A} compound, a pharmacologically acceptable salt or an ester thereof, which is a hydrogen atom, a methyl group, a benzyl group or a chloromethanesulfonyl group;

3> R ¹ force A compound which is a hydrogen atom, a pharmacologically acceptable salt thereof, or an ester thereof;

<4> a compound, a pharmaceutically acceptable salt or an ester thereof, wherein R ² is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;

<5> the compound, the pharmaceutically acceptable salt or the ester thereof, wherein R ² is a hydrogen atom or a methyl group;

<6> R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms A substituted or unsubstituted alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a hydroxyl group, an aliphatic alkoxy group having 1 to 6 carbon atoms, a heteroarylcarbonyloxy group or an amino group A compound, a pharmaceutically acceptable salt or an ester thereof;

<7> R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a methyl group, a methoxy group, a methoxy methoxy group, a nitro group, a hydroxyl group, an aceethoxy group, an amino group or A compound, a pharmacologically acceptable salt or an ester thereof, which is a pyridylcarbonylamino group;

<8> A compound, wherein R ³ , R ⁴ , R ^5, and R ⁶ are the same or different and are a hydrogen atom, a methyl group, a methoxymethoxy group, a nitro group, a hydroxyl group, an acetoxy group, or an amino group. A pharmaceutically acceptable salt or an ester thereof;

9> X is a group of the formula (C = 0) — group, a group of the formula (C = NOR ⁷ ) — group or the formula — CH ₂ _ group A compound of the formula X—U, wherein the formula CH = CH is a compound, a pharmaceutically acceptable salt or an ester thereof;

X is a compound, a pharmaceutically acceptable salt or an ester thereof, wherein X is a group of the formula — (C = 0) —, a group of the formula — (C = NOR ⁷ ) — or a group of the formula —CH ₂ —;

<11> R ⁷ is the same or different and is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, a compound thereof, a pharmaceutically acceptable salt thereof or ester;

A compound, a pharmacologically acceptable salt or an ester thereof, wherein at least 12> R ⁷ are the same or different and are a hydrogen atom, a methyl group or a benzyl group;

<1 3> A has the formula - (C = 0) - group, or the formula one S 0 ₂ - is a radical compound, a salt or an ester thereof acceptable on the medicine management;

<14> The compound, wherein A is a group of the formula — (C = 0) —, a pharmacologically acceptable salt thereof, or an esterizole thereof;

Is a force that is a CH ₂ — group, a formula C (R ² ) —U, a force that is a formula C = CH group, a formula X—U is a force that is a CH 2 CH group, A compound, a pharmacologically acceptable salt or an ester thereof;

<16> a compound, a pharmacologically acceptable salt or an ester thereof, wherein Y is a group of the formula I O- or a group of the formula S-;

<17> a compound, a pharmaceutically acceptable salt or an ester thereof, wherein Y is an O- group of the formula:

<18> Q is the same or different and is a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with halogen, An alkoxycarbonyl group having 2 to 7 carbon atoms, a cycloalkyloxy group having 4 to 9 carbon atoms, an oxygen atom (provided that Ar ¹ is a pyridine ring, and nitrogen on the ring is an oxide; An amino group or a mono- or di-substituted amino group. (The substituent is an aliphatic acyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a carbamoyl group, a substituted thiol group.) A carbamoyl group or a heterocarbonyl group), a pharmacologically acceptable salt thereof or a salt thereof. Tenore;

<19> Q is the same or different and represents a hydrogen atom, a hydroxyl group, a chlorine atom, a tert-butyl group, a trifluoromethyl group, a carboxynole group, a methoxycarbonyl group, a cyclopentyloxy group, an oxygen atom (however, A r ¹ force A pyridine ring in which the nitrogen on the ring is an oxide), an amino group, an acetylamino group, a methanesulfonylamino group, a methylaminothiocarbonylamino group, or 3-pyridylcarbonyl A compound which is an amino group, a pharmaceutically acceptable salt or an ester thereof;

<20> Q is the same or different and is a hydrogen atom, a compound, a pharmaceutically acceptable salt or an ester thereof;

Wherein 2 1> k is an integer of 1 to 6, a compound, a pharmaceutically acceptable salt or an ester thereof;

A compound, a pharmacologically acceptable salt or an ester thereof, having a <2 2> k power of 1;

<23> m is 0 to 3, a compound, a pharmaceutically acceptable salt thereof, or estenole thereof;

24> m is 0 to 2, a compound, a pharmacologically acceptable salt thereof, or a salt thereof, or a salt thereof;

<25> m is 0 or 1, a compound, a pharmaceutically acceptable salt thereof, or estenole thereof;

<26> n is 0 to 4, a compound, a pharmaceutically acceptable salt thereof, or estenole thereof;

<27> a compound, a pharmacologically acceptable salt thereof, or a salt thereof, wherein n is 0 to 2;

A compound, a pharmacologically acceptable salt thereof, or an estenole thereof;

<29> A compound, wherein A r ¹ is a benzene ring, a pyridine ring, or a biphenylene group, a pharmacologically acceptable salt thereof, or an ester thereof;

<30> a compound wherein A is a benzene ring, a pharmacologically acceptable salt thereof, or an estozore thereof: <31> Ar ² compound, a pharmaceutically acceptable salt or ester thereof, which is a aryl ring, a heteroaryl ring or a nitrogen-containing heterocyclic ring;

<32> the compound, the pharmaceutically acceptable salt or the ester thereof, wherein Ar ² is an aryl ring or a heteroaryl ring;

<33> The compound, the pharmaceutically acceptable salt or the ester thereof, wherein Ar ² is a benzene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a quinoline ring or an indole ring;

<34> A compound, a pharmacologically acceptable salt or an ester thereof, wherein Ar ² is a benzene ring or a pyridine ring. Also, R ¹ is selected from the above <1> to <3>, R ² is selected from the above <4> to <5>, and R ³ , RR ⁵ and R ⁶ are each independently the above <6> to Select <8>, select X from 9> to 10>, select R ⁷ from 11> to 1 2>, and select A from 13> to 1 4>, select U from above 15>, select Y from above 16> to 17> force, and select Q from above 18> to 19>. , K from above 2 1> to 2 2> force, m from above 2 3> to 2 5>, n from above 2 6> to 2 8>, A r ¹ is selected from the above 2 9> to 3 0>, and Ar ² is selected from the above 3 1> to 3 4>, and any combination is also preferable. Especially, 3 5〉! ^ Force; substituted with a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 18 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, or 1 to 3 halogen atoms An alkyl sulfo group having 1 to 6 carbon atoms,

R ² is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms A substituted or unsubstituted alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a hydroxyl group, an aliphatic acyloxy group having 1 to 6 carbon atoms, a heteroarylcarbonyloxy group or an amino group; X is a formula— (C = 0) —group, a formula— (C = NOR ⁷ ) —group or a formula _CH ₂ —group, a force that is a formula X—U, a formula CH = CH group,

R ⁷ is the same or different and is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aralkyl group having 7 to 18 carbon atoms,

A is a formula— (C = 0) —group or a formula S〇 ₂ —group;

U is a force that is a CH ₂ — group, a formula C (R ² ) — U, a force that is a formula C = CH group, a formula X — U, a formula that is a CH = CH group,

Y is a group of formula —O— or a group of formula S—

Q is the same or different and represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with halogen, a carboxy group, a carbon atom having 2 to 7 carbon atoms. Alkoxycarbonyl group, cycloalkyloxy group having 4 to 9 carbon atoms, oxygen atom (however, in the case of Ar ¹ force pyridine ring, only when nitrogen on the ring is oxidized), amino group Or a mono- or di-substituted amino group (the substituent is an aliphatic acyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a carbamoyl group, a substituted thiocarbamoyl group or a heteroalkenyl group). A rubonyl group)

k force is an integer from 1 to 6,

m is 0 to 3,

n force 0 to 4,

Ar ¹ is a benzene ring, a pyridine ring or a biphenylene group,

A compound, a pharmacologically acceptable salt or an ester thereof, wherein Ar ² is an aryl ring, a heteroaryl ring, or a nitrogen-containing heterocyclic ring; 36> 1 ^ force, a hydrogen atom, a methyl group, a benzyl group, or chloromethanesulfonyl , And

R ² is a hydrogen atom or a methyl group,

R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a methyl group, a methoxy group, a methoxy methoxy group, a nitro group, a hydroxyl group, an acetyl group, an amino group or a 3-pyridyl group; A lucarbo-amino group,

X is a group of the formula (C = 〇), a group of the formula — (C = NOR ⁷ ) — or a group of the formula — CH ₂ —, and R ⁷ is the same or different and is a hydrogen atom, a methyl group or a benzyl group Group,

A is a formula (C = 0) —group or a formula—S 0 ₂ _ group,

U is a force that is a CH ₂ — group, a formula C (R ² ) — U, a force that is a formula C = CH, a formula X — U, a formula that is CH = CH,

Y is an O— group of the formula

Q is the same or different and represents a hydrogen atom, a hydroxyl group, a chlorine atom, a tert-butyl group, a trifluoromethyl group, a carboxyl group, a methoxycarbonyl group, a cyclopentyl / reoxy group, an oxygen atom (however, when A is a pyridine ring, And only when the nitrogen on the ring is an oxide), an amino group, an acetylamino group, a methanesulfonylamino group, a methylaminothiocarbonylamino group or a 3-pyridylcarbonylamino group;

k, 1

m is 0 to 3,

n force 0 to 4,

A r ¹ is a benzene ring, a pyridine ring or a biphenylene group,

A compound wherein A r ² is aryl or heteroaryl, a pharmaceutically acceptable salt or an ester thereof; ^ Is a hydrogen atom, a methyl group, a benzyl group or a chloromethanesulfonyl group;

R ² is a hydrogen atom or a methyl group,

R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a methyl group, a methoxy group, a methoxy methoxy group, a nitro group, a hydroxyl group, an acetyl group, an amino group or a 3-pyridylcarbonyl group; A amino group,

X is a CH ₁ _ group of the formula (C = 0) — group, formula (C = NOR ⁷ ) — or a CH ₂ _ group, and R ⁷ is the same or different and is a hydrogen atom, a methyl group or a benzyl group Group, A is a group of the formula— (C = 0) —

Where U is a _CH ₂ — group, a formula C (R ² ) — U, a formula C = CH group, a formula X—U, a formula CH = CH group,

Y is a group of formula —O—,

Q is the same or different and is a hydrogen atom, a hydroxyl group, a chlorine atom, a tert-butyl group, a trifluoromethyl group, a carboxyl group, a methoxycarbonyl group, a cyclopentyloxy group, an oxygen atom (however, in the case of a pyridine ring, And the nitrogen on the ring is an oxide), an amino group, an acetylamino group, a methanesulfonylamino group, a methylaminothiocarbonylamino group or a 3-pyridylcarboamino group;

k force 1 and

m is 0 to 2,

n force 0 to 2;

A r ¹ is a benzene ring, a pyridine ring or a biphenylene group,

A compound or a pharmacologically acceptable salt thereof, wherein Ar ² is a benzene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a quinoline ring or an indole ring;

<38> R ¹ is a hydrogen atom,

R2 is a hydrogen atom or a methyl group,

R ³ , R ⁴ , R ^5, and R ^{6 are the} same or different and are a hydrogen atom, a methyl group, a methoxymethoxy group, a nitro group, a hydroxyl group, an acetyloxy group, or an amino group;

X is a formula— (C = 0) —group, a formula— (C = NOR ⁷ ) —group or a formula CH ₂ —group, and R ⁷ is the same or different and is a hydrogen atom, a methyl group or a benzyl group Group,

A is a group of the formula— (C = 0) —

U is a force that is a CH ₂ — group, a formula C (R ² ) —U, a formula C = a force that is a CH group, a formula X—U, a formula CH = CH group,

Y is a group of the formula —o—,

Q is the same or different and is a hydrogen atom, k force 1 and

m is 0 or 1,

n force 0 or 1;

A r ¹ is a benzene ring,

Compound A or a pharmaceutically acceptable salt thereof, which is a benzene ring or a pyridine ring, is preferred. Hereinafter, the compounds of the present invention will be specifically exemplified.

The compounds of the present invention are not limited to these exemplified compounds.

In each of the exemplified compounds, R ^{1 to} R ⁶ are the same as in Table 1, Ar ¹ Ar ² , Υ, Α and Q are the same as Table 2 and Z, k, m, n, X and U are the same as Table 3 Select the one with the number and specify it _(in Tables 1-3,

Me is a methyl group,

A c is an acetyl group,

A 11 is an aryl group,

MOMO has a methoxy methoxy group,

N ct represents a nicotinyl group,

Boc is a tert-butoxycarbonyl group

B oz represents a benzoyl group,

Et represents an ethyl group, '

丄 Pr is an isopropyl group,

丄 Bu is a tert-butyl group,

丄 Bu is an iso-butyl group,

B u is a butyl group,

Pr is a propyl group,

P n represents a pentyl group,

B z represents a benzyl group,

i P n represents an isopentyl group, Hx represents a hexyl group,

Ph represents a phenyl group or a phenylene group,

c Hx is a cyclohexynole group,

Pyr represents a pyridyl group or a pyridinediyl group,

Pym represents a pyrimidinyl group or a pyrimidinediyl group,

P h P h is a biphenyl-ene group,

P i p represents a piperidinyl group,

P yz represents a birazinyl group,

Q u i n represents a quinolyl group,

Ind is an indolyl group.

Above Bu is a sec-butyl group,

P rn represents a propionyl group,

B y r represents a butyryl group,

P n represents a cyclopentinole group,

丄 Nct is an isonicotinoyl group,

F ur represents a floyl group,

Th n o is a 2-tenol group,

Th i z is a thiazolyl group,

O X a represents an oxazolyl group,

Hp is a cycloheptyl group,

Is shown.

In Table 3, Z represents a substituent in A r ^2.

Further, in Compound Nos. 17 to 33, 322, 323 and 379, R ² and U are taken together to have the formula C (R ² ) —U and the formula C = CH.

Furthermore, (1,4) etc. in A indicate that it is bonded to Y at position 1 and (CH ₂ ) m at position 4, and (3) etc. at Ar ² is position 3 Indicates that it is bonded to (CH ₂ ) n. (table 1 )

Example

No.R R R R

1 Η Me Me AcO Me Me

2 Η Me Me HO Me Me

3 Η Me Me AcO Me Me

4 Η Me Me AcO Me Me

χ1 Me Me AC ri Me Μβ

7 Η Me Me AcO Me Me

8 Η Me Me MOMO Me Me

9 Η Me Me AcO Me Me

10 Η Me Me HO Me Me

11 Η Me Me AcO Me Me

12 Η Me Me HO Me Me

13 Η Me Me AcO Me Me

14 Η Me Me HO Me Me

15 Η Me Me AcO Me Me

16 Η Me Me HO Me Me

17 Η Me NH ₂ Me Me

18 Η Me NH ₂ Me Me

19 Η Me NH ₂ Me Me

20 Η Me NH Me Me t

D CD D <O O (¾ (t ft) (T 0 fD ft> <t> D t> t> CD Φ <Χ> CO <Χ> CD Φ Co Φ

¾e MNI H Me Me AcO Me Me

H H Η H

H Me ArO Me Me

H Me AcO Me Me

H Me Me MeO Me Me

H Me Me AcO Me Me

H Me Me thigh. Me Me

Me Me Me AcO Me Me

Bz Me Me AcO Me Me S0 ₂ CH ₂ C1 Me Me AcO Me Me S0 ₂ CH ₂ C1 Me Me AcO Me Me

H Me Me Me Me OH

H Me Me AcO Me Me

H Me Me ^IJ "2 Me Me

H Me Me NH Me Me

H Me Me NH ₂ Me Me

H Me Me Me Me

H Me Me τττ

Thigh 2 Me Me

H Me Me ΝΗ ₂ 'Me Me

H Me Me ΝΗ ₂ Me Me

H Me Me ΝΗ ₂ Me Me CD C £) () D £ D Cr> CD 0O 0O O0 0O O0 00 00 00

O O o o o o o o o cr> oo σ ^ ^ c tc o ςο oo o σ¾ n ^

O D x ^ CO o

e Mel NH A 7: $ 00K> :: d OAV

¾N

0) <ϋ Φ Φ Φ 1 <1) (1) <1> Φ Φ Φ <1> Φ 1) ① ^

¾N

N ¾

¾N

¾N 11 丄 vie AJTJ

丄 vie 丄 V c ^ D η IVlti Ivlc 丄 ΜΓ1 ₂ ec

XX 丄 vie 丄 vie 丄, n ₂ Iv c

η M IVloti MP IN o V c η 丄 vie IN 丄¹ Jl MP MP 4 11 丄 vie 丄 vie 丄 N 2 c

XI T 丄 V v / iToe Ma JTJ

丄 \ ji ₂

C 1

01 η lvlt? IVlti 丄, njD vit; MP η a IVlPti 丄 \ in ₂ M v P t;

S3 η IVlti Ivlc 丄 MX ₂ vie

O vie v c Me J 11 vit; j M c

1 ovt; c Mp Me

Ό vit: MP M

T ηJ

00 ivlti ΚΓΤ M IVlPc V c

1 X 1T1 on vie M v P t; N T

ΌΌ 11 IVlti v t; I v e v t;

I

οη η η ivlc M viPt; NT MP V c ΌΟ 11 IVlti vit; TSJTJ

丄 M 1 2 ivxt; V c

169 Η Me Me NH ₂ Me Me

170 Η Me Me NH ₂ Me Me

171 Η Me Me NH ₂ Me Me

172 Η Me Me NH ₂ Me Me

173 Η Me Me NH ₂ Me Me

174 Η Me Me NH ₂ Me Me 17C

丄 XI M MP "vi ν

ί ο vit; Me

1 Q n IN 2 M VIPC V c on XI vie vie TV / To NTT vt; MP

丄 v ti MP

1 QO

丄 lv ti T 丄 S NJHX1 ₂ MVP ti IVXC 丄 0 n lvloti lvlti IN JT 2 vit; V

o M ViPtJ Me Me 7 MVP c NH Me Me

1 Q VIC Me Me

Η c Me Me

1 a

丄 J Η M v P ti H H

Η VI Et NH Me H

1 QQ MP t 1 ΜΠ ₂

00 Me H ΝΗ ₂ tBu H

202 H NH ₂ H Η Η H

203 HH NH ₂ Η Η H

204 HHH 腿 Thigh ₂ H

205 HHH Η Η NH ₂ 9H O ³ V ⁹ Η 9 £ Ζ

OH ^Θ ΙΛΙ Η 9 £ Ζ

⁹ H 9M O ° V Η £ Z

O ³ V Η ££ Ζ

O ³ V Η Ζ2Ζ

O ³ V Η ΙξΖ

O ³ V 0 £ Ζ

O. V Η 6ΖΖ

O ³ V Η 2ΖΖ

⁹ MO ³ V Η LZZ

O ³ V ^Θ Η Η 9ΖΖ

¾N ^Θ Η Η ΖΖ aH ¾N ⁹ W Η 2ΖΖ

¾N ^Θ Η Η ΖΖΖ

¾N aw 9Η Η ιζζ

⁹ H ¾N 3 Η οζζ

¾N 9] A [Η 61Ζ

¾N 9Η Η 21Ζ

¾N Η LIZ

¾N θΗ Η 91Ζ

¾N Η 1Ζ

¾N Η ηζ

9H ¾N Η

3 ¾NOOHN Η Η ιιζ

9H ⁿ 9HNO0HN Η Η οιζ

9H ¾N Η Η 60S

H H H H Η Η 80S

^S 0N 9] A [HO H Η LZ

H HO ⁹ Η Η 90S

9f

Z £ Lt0 / 00d £ / ∑Jd 08.S0 / T0 OAV 3] Α [OH 9H 9] Ι H L9Z

OH H 99Z

^Θ Μ OH 9Κ H 99Z

OH 9H H Ψ9Ζ

3PM OH 9H H £ 9Z

9H OH 9M H Z9Z

9] A [OH 9H H 19Z

9] A [OH H 09Z

9H OH H 6 Z

ΘΗ OH ^Θ Η H 2 Z

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280 4-NHBoz 1 0 0 CHo CH ₂

281 3-NHCSNH ₂ 100 2 CH ₉

282 4-NHCONHMe 1 0 0 2 CH ₂

283 4-N (Ac) S0 ₂ CH ₂ Cl 1 0 0 CH 2 CH ₂

284 3-NHCONEt ₂ 1 0 0 2 CH

285 2-NHCO (CH ₂ ) ₃ Ph 1 0 JT CH 2

286 4-OH-3,5-di-Me 1 0 _n ₂ CH 2

287 2,4,6-tri-OH 1 n V 2 CH ₉

288 4-OH-3,5-di-MeO 100 PH. C_Ho 2

289 4-OH-3 _; 5-di-MeO 10 V 2 2

291 6-NH ₂ 1 0 0 C = NOMe CH

293 6-NH ₂ 1 0 0 C = NOMe CH

294 6-NH ₂ 1 0 0 C = N0Me CH

295 6-NH ₂ 1 0 0 C = N0Me CH

300 6-NH ₂ 1 0 0 C = N0Me CH

301 6-NH ₂ 1 0 0 C = N0Me CH

302 6-NH ₂ 1 0 0 C = NOMe CH

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I 2 丄 U n υ n ₂

A

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374 6-NH 1 o o C = N0Me CH

375 6-OMe 1 oo C = N0Me CH ₂

376 6- 1 o 0 CH, CH ₂

377 6-NH ₂ 1 oo CO CH ₂

378 6- 丽₂ 1 oo C = N0Me CH ₉

379 6-NH ₂ 1 oo CO

0 A fi-tri -iPr 1 ni ₂ 2

Ο QΟfiOώ vt; J n xa ₂ 2 o QofiQ UJ Π n ₂ 2

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389 2,6-di-NH ₂ 100 CO H ₂

390 2,6-di-NH ₂ 100 CO CH ₂

391 2,6-di-NH ₂ 100 CO CH ₂

392 2-NH ₂ 100 CO CH ₂

393 2-belly ₂ 1 0 0 CO CH ₂

394 2-NH ₂ 100 CO CH ₂ 24-di-NH „1 o 0 CO 2

4- Η 1 n π CH

QQvoQ 1 π

Two

1 π o CHo

4.01 one 2

403 2- 丽₂ 1 0 0 C = NOMe CH ₂

404 2-NH ₂ 1 0 0 C = NOMe CH ₂

405 2,6-di-NH ₂ 100 C = NOMe CH ₂

406 4- 丽₂ 1 0 0 CO CH ₂

407 4-NH ₂ 1 0 0 C = NOMe CH ₂

408 4-NH ₂ 100 C = NOMe CH ₂ Of the above-exemplified compounds, preferred ones are 1 to 7 9 10 1 2 1 5 1 6 34 to 43 45 to 48 50 51 58 59 6 1 to 64 69 to 71 149 1 50 21 2 21 3 23 1 to 23 7 323 3 25, 3

48 to 352 3 54 to 357 363 to 365 367 369 374 3 79 381 382 384 to 408,

More preferred are 1 to 35 1 2 1 5 16 34 to 37 39 41 43 45 48 50 59 63 69 to 71 149, 1 50 2 1 2 21 3 23 1 to 237 323 325 348 348 to 3 50 352 355 to 357, 363 to 365 367 369 374 379 381 382 384 to 408,

Even more preferred are 1 to 35 1 2 1 6 34 35 3 7, 43,

59, 69 to 71 149 1 50 21 2 21 3 323 325 348 to 350 357 364 365 367 369 374 and 379, the most preferred being N— [4 _ (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —pyridine-13 f fluoracetamide (5),

N- [4-(6-hydroxy2,5,7,8-tetramethyl [1H] chromene-2-ylmethoxy) benzyl] -nicotinamide (12),

N- [4- (6-Methoxymethoxy-1,2,5,7,8-tetramethyl [1H] chromen-2-ylmethoxy) benzyl] -nicotinamide (34),

N— [4 -— (6-hydroxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl] -nicotinamide (35),

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —6-aminoaminotinamide (37),

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman_2-ylmethoxy) phenyl] —2-aminoaminotinamide (43),

N— [4- (6-Amino-4-oxo-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] nicotinamide (59),

N— [4 -— (6-amino-1-oxo-2,5,7,8-tetramethylchroman—2-ylmethoxy) phenyl] —6-aminoaminotinamide (69),

N— [4— (6-amino-4- 4-hydroxyimino_2,5,7,8-tetramethylchroman-2f-methoxy) phenyl] —6-aminoaminotinamide (70), N— [4— (6-Amino-4-methoximino 2,5,7,8-tetramethylchroman-1 f-methoxy) phenyl) —6-aminoaminotinamide (71),

N— [4— (6-—Toro 4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -1-6-aminonicotinamide (149),

N— [4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) benzyl] -1-6-aminonicotinamide (150),

N- [4 -— (6-Amino-4-Methoxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl] — 6-aminonicotinamide (21 2), N- [ 4- (6-amino-1-4-benzyloxyimino-1,2,5,7,8-tetraroman-1-2-ylmethoxy) benzyl] —6-aminoaminotinamide (2 13),

N— [4— (6-Amino-4—Methoxymino 5,7,8—Trimethyloctene-2-ylmethoxy) phenyl] 16-Aminiconicotinamide (323),

N- [4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) -12-trifluoromethylphenyl] 1,3,5-di-t-butynole 4 -Droxybenzamide (325),

N— [4 -— (6-acetoxy-1 4-methoxyethoxymino 2,5,7,8-tetramethizolechroman-1-2-inolemethoxy) phen-nore]-2,6—t-butynole-1 4-hydrodroxybenz Amid (348),

N— [4 -— (6-acetoxy-1-4-benzyloxyiminor 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] _2,6-ge t—buty 4-h Droxybenzamide (349),

Ν— [4 -— (6-acetoxy-14-hydroxyoximino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -2,6-di-t-butyl-14-hydroxybenz Amido (350),

N— [4 -— (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —3,5-di-t-butyl-4-hydroxybenzamide (357) ,

N- [4- (6-amino-4-oxo- 1,2,5,7,8-tetramethylchroman- 2-ylmethoxy) phenyl] -1-aminonicotinamide (364),

N- [4- (6-Amino-4-Methoxyimino-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] -12-Amino-cotinamide (365),

N— [4 -— (6-amino-4-methoxyethoxymino 2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] —6-aminoaminotinamide dihydrochloride (369),

N— [4— (6-Amino-4-methoximinol 2-methylchroman-2-ylmethoxy) phenyl] —6-aminonicotinamide dihydrochloride (374) or N— [3— ( 6-amino-4, oxo-1,5,7,8-trimethyl-2,3_ It is 6-aminonicotinamide (37-9).

The compound having the general formula (1) of the present invention can be produced according to the following method.

(First step)

In the above formula, A, U, X, Y , Q, k, m, n, A r A r 2 and R ¹ to R ⁶ have the same meanings as those described above.

The first step is a step for producing a compound having the general formula (1) of the present invention, and comprises a reactive derivative (acid halide, active ester) of the compound having the general formula (3) in an inert solvent. Or mixed acid anhydrides) with a compound having the general formula (2).

(Method A) In the acid halide method, compound (3) is reacted with a halogenating agent (for example, thiol chloride, thionyl bromide, oxalic acid chloride, oxalic acid dichloride, oxychloride) in an inert solvent. Reaction with phosphorus, phosphorus trichloride, phosphorus pentachloride, etc. to produce an acid halide, and then reacting the acid halide with the compound (2) in an inert solvent in the presence or absence of a base (preferably). In the presence of a). The base used in the present method includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; and alkali metal carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and lithium hydrogen carbonate. Carbonates; lithium hydride, sodium hydride Alkali metal hydrides such as aluminum and hydrogenating power; Lithium hydroxide, sodium hydroxide, and alkali metal hydroxides such as watering lithium; lithium methoxide, sodium methoxide, sodium methoxide Metal alkoxides, such as 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-5-ene, 1,4-Diazabicyclo [2.2.2] octane (DAB CO), 1, 8 —Diazabicyclo [5.4.0] —7— Organic amines such as pendene (DBU), preferably organic amines (particularly preferably triethyla It is down). The inert solvent used in the present method is not particularly limited as long as it does not inhibit the reaction. Examples of the inert solvent 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; Jethyl ether, diisopropyl ether, tetrahydrofuran Ethers such as dioxane, dimethoxetane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphate triamide; dimethylsulfoxide Such sulfoxides; sulfolane; , Preferably, hydrogenated hydrocarbons, ethers or amides (particularly preferably, dichloromethane, chloroform, tetrahydrofuran or dimethylformamide). The reaction temperature varies depending on the starting compounds, reagents, and the like. However, the reaction temperature of the reaction between the halogenating agent and the compound (3) and the reaction between the acid halides and the compound (2) is usually from 20 ° C to 150 ° C. ° C, and preferably between 110 ° C and 100 ° C in the reaction between the halogenating agent and the compound (3), and the reaction between the acid halide and the compound (2). In this case, the temperature is between 20 ° C and 100 ° C. The reaction time varies depending on the starting compounds, reagents, reaction temperature, and the like. However, in the reaction between the halogenating agent and the compound (3) or between the acid halides and the compound (2), the reaction time is usually 3 hours. It is 0 minute to 80 hours (preferably 1 hour to 48 hours).

(Method B) In the active ester method, the compound (3) is reacted with an active esterifying agent in an inert solvent to produce active esters, and then, in an inert solvent, in the presence or absence of a base ( (Preferably in the presence of) compound (2). The active esterifying agent used in the present method is, for example, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-15-norbornene-1,2,3-dicarboximid. N-hydroxy compounds such as; disulfide compounds such as dipyridyl disulfide; carbodiimides such as dicyclohexylcarbodiimide; carboerdiimidazole; 1-ethyl-3- (3-dimethylaminoprodide) It is suitably carried out in the presence of a condensing agent such as pill) carbodiimide hydrochloride; The inert solvent used in the present method is not particularly limited as long as it does not inhibit the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; benzene , Toluene, xylene; aromatic hydrocarbons; dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons, such as carbon tetrachloride; getyl ether, diisopropyl ether, tetrahydrofuran, dioxan, dimethoxetane, Ethers such as diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphate triamide; dimethylsulfoxide Sulfoxides; sulfolane; Are ethers or amides (particularly preferably, dioxane, tetrahydrofuran or dimethylformamide). Bases used in the present method include, for example, those used in the acid halide method. And the same bases as described above. The reaction temperature varies depending on the starting compounds, reagents, and the like, but is generally from −70 ° C. to 150 for active esterification. C (preferably −10 ° C. to 100 ° C.), and —20 ° C. to 100 ° C. for the reaction of the active ester with the compound (2). C (preferably 0 ° C. to 50 ° C.). The reaction time varies depending on the starting compounds, reagents, reaction temperature, and the like. However, in the case of the active esterification reaction or the reaction of the active ester with the compound (2), the reaction time is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours).

(Method C) In the mixed acid anhydride method, the compound (3) is reacted with a mixed anhydride agent in an inert solvent, in the presence or absence (preferably, in the presence of a base) of the mixed acid anhydride, After the production of the compounds, the reaction is carried out by reacting the mixed acid anhydrides with the compound (2) in an inert solvent.

The base used in the present method includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; and alkali metal carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and lithium hydrogen carbonate. Carbonates; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, Alkyli metal alkoxides such as sodium methoxide, sodium methoxide, potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N- Dimethylamino) pyridine, N, N-dimethyla-line, N, N_ ethylenaniline 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_ pendene (DBU), preferably organic amines (particularly preferably triethylamine). Mixed acid anhydride agent used in the method, for example, chlorocarbonate Echiru, carbonate such as chlorosulfonic carbonated isobutyl C i-C alkyl pay de; Pibaroirukurori c such as de, - c ₅ Arca Noi Le pay de ; Shianohosuhon acid Jechiru, current events one c ₄ alkyl, such as Shianohosuhon acid diphenyl, di c ₆ - c ₁₄ § Li one Rushianorin acid Wakashi Ku is N, N-bis (2-Okiso _ 3 Okisazorijiniru) phosphinic acid Kurori de And preferably di-C ₄ alkyl or di-C ₆ -C ₁₄ arylcyanophosphoric acid (particularly preferably 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.For example, hexane, heptane, rig Aliphatic hydrocarbons such as ketones or petroleum ethers; Aromatic hydrocarbons such as benzene, toluene, xylene; Halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, carbon tetrachloride; Ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide Amides such as hexamethyl phosphate triamide; and 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 for producing the 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 producing mixed acid anhydrides varies depending on the starting compounds, reagents, reaction temperature, etc., but is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours). is there.

The reaction between the mixed acid anhydrides and the compound (2) is carried out in an inert solvent in the presence or absence (preferably, in the presence) of a base. It is the same as that used in the reaction for producing the mixed anhydrides described above.

The reaction temperature in the reaction between the mixed acid anhydrides and the compound (2) is as follows. Usually, it is −30 ° C. to 100 ° C. (preferably 0 ° C. to 80 ° C.).

The reaction time in the reaction of the mixed acid anhydrides with the compound (2,) varies depending on the starting compound, the reagent, the reaction temperature, etc., but is usually 5 minutes to 24 hours (preferably 30 minutes to 16 hours). When di ^ -C ₄ alkyl cyanophosphoric acid or di C ₆ -C ₁₄ aryl cyanophosphoric acid is used in this reaction, compound (2) and compound (3) are directly reacted in the presence of a base. You can also.

Compound (2) used in Method A to Method C is produced by the method described in the following fourth step.

After completion of the reaction by any one of the methods A to C, the target compound (1) of this step 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 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 obtained by a conventional method, for example, a method commonly used for separation and purification of organic compounds, such as recrystallization and reprecipitation, appropriately combined, in some cases, and further by a chromatography method. Can be separated and purified by elution with an appropriate eluent. (2nd step)

In the above formula, A, U, Y, Q , k, m, n, A r A r 2 and R ¹ to R ⁷ have the same meanings as those described above.

The second step is a step for producing an oxime compound having the general formula (1b), and in an inert solvent, a compound having the general formula (la) and a hydroxylamine derivative (and an acid addition salt of the hydroxy'xylamine derivative). ) In the presence of a base.

The inert solvent used in this step is not particularly limited as long as it does not inhibit this reaction. Examples of the inert solvent include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether. Aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol, ethanol, and isopropanoyl; Ethers such as diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide; sulfoxides such as dimethylsulfoxide; sulfolane; pyridine Or a mixed solvent of the above solvents; It is down.

The base used in this step is, for example, lithium carbonate, sodium carbonate, potassium carbonate. Alkali metal carbonates, such as aluminum; alkali metal bicarbonates, such as lithium hydrogen carbonate, sodium hydrogen carbonate, and hydrogen hydride; alkali metals, such as lithium hydride, sodium hydride, and potassium hydride Hydride; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxide hydroxide; Alkali metals such as lithium methoxide, sodium methoxide, sodium methoxide, potassium t-butoxide Metal alkoxides: triethylamine, tributylamine, diisopropylpropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-getylaniline, 1,5-Diazabicyclo [4.3.0] Nona 5-ene, 1,4-Diazabicyclo [2.2.2] ] Organic amines such as octane (DAB CO) and 1,8-diazabicyclo [5.4.0] -7-decene (DBU), preferably organic amines (particularly preferably pyridine ). '

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C to 200 ° C, preferably 20 ° C to 100 ° C.

The reaction time varies depending on the starting compound, the reagent, the reaction temperature, etc., but the reaction of the hydroxylamine with the compound (1a) is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours). .

(3rd step)

In the above formula, A, U, X, Y, Q, k, m, n, A r \ A r ² and R ^{1 to} R ⁶ are The meaning is as described above.

The third step is a step of producing a compound having the general formula (I d) of the present invention, which is performed in an inert solvent in the presence or absence of a base with respect to the general formula (1 c). This is carried out by substituting a kill, sulfonic acid ester, carboxylic acid chloride or sulfonic acid chloride.

This reaction is generally performed by a well-known method (Angewandte Chemie International Edition, 1968, 7, 919, Journal of American Chemical Society, 1972, 94, 679, Organic Synthesis 11,60, The Chemistory of Amides, 759-773 _; 1970, John Wiley & Sons].

(4th step)

In the above formula, U, Y, Q, k, m, Ar ¹ and R ^{1 to} R ⁷ have the same meanings as described above.

The fourth step is a step of producing an oxime compound having the general formula (2a), and the compound having the general formula (4) and the hydroxylamine derivative (and the acid addition salt of the hydroxylamine derivative) in an inert solvent. The reaction is carried out in the presence of a base in the same manner as in the second step.

(Fifth step)

In the above formulas, Y, Q, k, A r R 2 to R ⁶ have the same meanings as described above, H a 1 o represents a fluorine atom, a chlorine atom, a bromine atom, a halogen atom such as iodine atom , PG represents a protecting group for a hydroxyl group or a mercapto group, and X .. 'represents one group of the formula — (C = 〇), one group of the formula (C = NOR ⁷ ) — group, the formula — (CHOH) — group, the formula — CH (oR ⁸⁾ - group, wherein - CH ₂ - group, or the formula ^{^{- (C = NNR 9 R 1}} ()) - group, or the formula - CH ₂ - represents a group, U 'is - CH ₂ - or a group, In the formula X'-U ', the formula CH = CH represents a group. R ^{7 to} R ^1Q have the same meanings as described above. The protecting group for a hydroxyl group or a mercapto group is not particularly limited as long as it is used as a protecting group, but is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, or t-butyl. , Lower alkyl groups such as pentyl and hexyl or benzyl, phenetinole, 3-pheninolepropyl, -naphthyl / remethinole, β-naphthinolemethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Lower alkyl substituted with one to three aryl groups such as Group, 4-methylinobenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldimethyl, 2-nitrobenzyl, 4-nitrobenzyl 1 to 3 aryl groups in which the aryl ring is substituted with lower alkyl, lower alkoxy, halogen, and cyano groups such as benzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, and pyranyl. An aralkyl group such as a substituted lower alkyl group can be mentioned. Step 5-1 is a step for producing a compound having the general formula (7). In the inert solvent, the compound having the general formula (5) and the compound having the general formula (6) are combined with a secondary compound. The reaction is carried out in the presence of an amine.

The secondary amine used in this step is, for example, organic amines such as getylamine, dibutylamine, diisopropylamine, morpholine, piperidine, and pyrrolidine, and preferably, morpholine, piperidine, and pyrrolidine. Such a cyclic amine.

The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, hexane, heptane, lignin, aliphatic hydrocarbons such as petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; dimethyl formamide, dimethyl acetate Amides such as amides and hexamethylphosphoric acid triamide; alcohols such as methanol, ethanol, isopropanol and ethylene glycol, or mixed solvents of the above solvents, and preferably alcohols (particularly preferably Methanol).

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 100 ° 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 1 week (preferably 12 hours to 5 days). Step 5-2 is a step of producing a compound having the general formula (8), The ability to oxime, hydrazine, or reduce a carbonyl group of a compound having the formula: to a methylene group or an alcohol, and to alkylate, acylate, Performing a sulfonylation, a carbamoylation reaction, etc., and further dehydrating the alcohol by a dehydration reaction to form a X′—u ′ moiety as a double bond, and a hydroxyl group or a mercapto group before and after the reaction. This is done by deprotecting the protecting group.

The method for oximation of a carboxyl group is carried out according to the second step.

The method of hydrazine-forming a carbonyl group is a generally known method [Organic

Synthesis VI, 10 mag. ].

A method for reducing a carboxyl group to an alcohol is a generally well-known method, for example, a catalytic hydrogenation reaction; a reduction reaction with a metal hydride such as sodium borohydride or lithium aluminum hydride is performed. [Reagents for Organic Synthesis, Fieser & Fieser, John Wiley & Sons].

Alcohols can be further alkylated, acylated, sulfolated, and catabolized by methods known in general [The Chemistry of the Amino Group, chapter 6, 1968, John Wiley & Sons, The Chemistry of the Amino Group, chapter2, 1970, John Wiley & Sons, etc. ].

The alcohol dehydration reaction is carried out in the presence of an acid catalyst according to a generally well-known method [SURVEY of ORGANIC SYNTHESES, C.A. Buehler and D.E. Pearson, Wiley-Interscience].

The deprotection reaction of a protecting group for a hydroxyl group or a mercapto group can be performed by a generally well-known method [Protective Groups in Organic Synthesis, 1981, John Wiley & Sons et al. ] And Φ.

In addition, by proceeding to the next step without passing through this step, compound (2c) in which X ′ is the same as in formula (c = o) can be produced. Step 5-3 is a step for producing a compound having the general formula (10), in which the compound having the general formula (8) and the compound having the general formula (9) are reacted in the presence of a base. This is done by letting

The base used in this step includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Alkali metal hydrides such as lithium hydride, sodium hydride and hydrogenation power; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and water oxidation power; lithium methoxide; Alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium t-butoxide; triethylamine, tributylamine, disopropylethylamine, 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] —7— Organic amines such as pendene (DBU), preferably alkali metal hydrides (particularly preferably sodium hydride). The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, hexane, heptane, lignin, aliphatic hydrocarbons such as petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; dimethylformamide, dimethylacetamide; Amides such as hexamethylphosphoric triamide; or a mixed solvent of the above solvents; and preferably amides (particularly preferably 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 0.1C to 120 ° C).

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

After completion of the reaction, the target compound (10) 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 desired compound obtained can be combined with a conventional method, for example, recrystallization, reprecipitation, or the like, which is usually used for the separation and purification of organic compounds. It can be separated and purified by elution. Prior to this step, when an amino group or a hydroxy group is present in the compound having the general formula (10), a protecting group or a deprotection may be applied to the amino group or the hydroxy group. it can. These reactions can be performed by a well-known method [for example, the method described in TWGreen, (Protective Groups in Organic Synthesis), John Wiley &Sons; JFWMcomie, (Protective Groups in Organic Synthesis), Plenum Press].

Step 5-4 is a step for producing a compound having the general formula (2b), and is performed by reducing a nitro group of the compound having the general formula (10) in an inert solvent. In this reaction, catalytic reduction method, zinc monoacetic acid method, tin-alcohol method, tin-hydrochloric acid method, which is a general method for reducing nitro groups, and sodium dithionite or triphenylphosphine as a reducing agent are used. Done by the method.

After completion of the reaction, the target compound (2b) of this reaction is collected from the reaction mixture according to a conventional method.

For example, in the case of the catalytic reduction method, the catalyst can be obtained by filtering off the catalyst from the reaction mixture and then distilling off the solvent. In the case of other methods, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to contain the target compound. The organic layer is separated, washed with water or the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, or the like, and then the solvent is distilled off.

If necessary, the obtained target compound can be used in a usual manner, for example, recrystallization, reprecipitation, etc. Separation and purification can be performed by appropriately combining conventional methods for separation and purification of organic compounds, applying chromatography, and eluting with an appropriate eluent.

(Step 6)

Q O

6-1 Q 6-2

_{_{1- (CH 2) m -i- WR}} , 2 2 persons _{_{^ (CH 2) k -Y-}} Ar 1 -. (CH 2) m l -W

Q

6-4 (CH ₂ ) _k — Y-Ar ¹ — (CH ₂ ) _m-1 — C0 ₂ H

(16)

Q

6-5 (CH ₂ ) _k — Y-Ar ¹ — (CH ₂ ) _m .i— CONHR ¹

(17)

Q

6-6 (CH ₂ ) _k -Y-Ar ^1- (CH ₂ ) _m -NHR ¹ (2c) In the above formula, U ', X', Y , Q, A r \ m, k, R 2 to R ⁶ are indicates above as defined above, W is in C0 ₂ R ^a group (wherein, R ^a is Represents an alkyl group having 1 to 6 carbon atoms (preferably a methyl group); or a CH ₂ OH group, and Ha 1 o represents a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Show. Step 6-1 is a step for producing a compound having the general formula (13), and in an inert solvent, a compound having the general formula (11) and a compound having the general formula (12) are The reaction is carried out in the presence of a base.

The base used in this step includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; and alkali metal heavy metals such as lithium hydrogen carbonate, sodium hydrogen carbonate, and hydrogen carbonate. Carbonates; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, hydroxylating power; lithium methoxide Alkali metal alkoxides such as sodium methoxide, sodium methoxide, sodium methoxide, potassium butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N Detjyla dilin, 1,5-diazabicyclo [4.3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (D ABC 0), 1,8-diazabicyclo [5 4.0] — organic amines such as 7-indene (DBU); preferably alkali metal carbonates and alkali metal hydrides (particularly preferred are potassium carbonate and cesium carbonate). , Sodium hydride).

The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; benzene Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; acetone, methylethyl ketone, and cyclohexanone Ketones such as dimethyl honole Amides such as muamide, dimethylacetamide, and hexamethylphosphate triamide; or a mixed solvent of the above solvents; preferably, ketones and amides (particularly preferably, acetone and dimethyl amide). Formamide).

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually from −50 ° C. to 200 ° C. (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). Step 6-2 is a step for producing a compound having the general formula (14). In an inert solvent, the compound having the general formula (13) and the compound having the general formula (5) are converted to a secondary compound. The reaction is carried out in the presence of an amine, and is carried out in the same manner as in Step 5-1. Step 6-3 is a process for producing a compound having the general formula (15). The compound having the general formula (14) is capable of oxidizing a carbonyl group, hydrazine-forming or reducing the compound. To give a methylene group or an alcohol, and after a reduction reaction to the alcohol, an alkylation, an acylation, a sulfuration, a carbamoylation reaction, etc. are performed, and the alcohol is dehydrated by a dehydration reaction to obtain X′—U ′ This is accomplished by making the moiety a double bond and deprotecting the hydroxyl or mercapto group before and after the reaction.

Step 6-3 is performed according to Step 5-2.

In addition, by proceeding to the next step without passing through this step, compound (2c) in which X ′ is of the formula (c = o) 1 can be produced. Step 6-4 is a process for producing a compound having the general formula (16). The reaction for converting a carboxylate group of the compound having the general formula (15) into a carboxyl group in an inert solvent is carried out. It is performed by performing.

This step is carried out by generally well-known methods, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal heavy metals such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. Carbonates; hydroxylation Alkali metal hydroxides, such as lithium, sodium hydroxide, and hydroxide power; the power of the reaction with an alkali, such as water. Hydrolysis in the presence of a base catalyst or an acid catalyst in the presence of water. It is performed by. Step 6-5 is a process for producing a compound having the general formula (17). The reaction for converting a carboxyl group of the compound having the general formula (16) into an amide group in an inert solvent is performed. It is performed by performing.

This step is carried out by subjecting a compound having the general formula (16) and an amine compound having the general formula {Ι} ₂ to dehydration condensation, and is carried out in the same manner as the first step.

Further, by subjecting the compound having the general formula (16) to a Curtius reaction, that is, a general reaction for converting a carboxy group to an amino group, the compound (2c.) Can be obtained without passing through the compound (17). However, R ¹ is a hydrogen atom.) Step 6-6 is a process for producing a compound having the general formula (2c), and the reaction for converting an amide group of the compound having the general formula (17) into an amino group in an inert solvent. It is performed by performing.

This step is carried out using a generally well-known method, for example, lithium aluminum hydride, diisobutylaluminum hydride, or the like.

(Step 7)

In the above formula, U ′, Χ ′, Υ, Q, Ar ¹ , k, m, ^Ra, and R ^{1 to} R ⁶ have the same meanings as described above.

Step 7-1 is a step of producing a compound having the general formula (18), and converting an ester group of the compound having the general formula (15) into a hydroxy group in an organic solvent. Done.

This step is carried out using a generally well-known method, for example, lithium aluminum hydride ′, diisobutylaluminum hydride, lithium borohydride, or the like. The seventh-second step is a step for producing a compound having the general formula (19). In the inert solvent, a reaction for converting a hydroxyl group of the compound having the general formula (18) into an azide group is performed. It is performed by performing.

In this step, a well-known method, for example, a method of converting a hydroxyl group to an alkylsulfonyl group, an arylsulfonyl group or a halogen atom, and then reacting with sodium azide or potassium azide, or Mitsunobu reaction of compound having the general formula (18) with hydrogen azide (phosphine and azodicarbonate in an inert solvent) The condensation reaction is carried out using acid compounds [O. Mitsunobu, Synthesis, 1, 1981]). Is performed. Step 7.3 is a step for producing a compound having the general formula (2d), in which an azide group of the compound having the general formula (19) is converted to an amino group in an inert solvent. This is done by:

This step includes a well-known method, for example, a catalytic hydrogenation reaction; a reduction reaction with a metal hydride such as lithium aluminum hydride or diisobutylaluminum hydride; a reduction reaction with triphenylphosphine. It is performed using.

(8th process)

(2e) In the above formula, Y, Q, νν k and R ^{3 to} R ⁶ have the same meaning as described above.

The eighth step is a step for producing a compound having the general formula (20), and the eighth step is a step for producing a compound having the general formula (21).

Steps 8-1 and 8-2 are based on the previously disclosed methods [J. Med. Chem.,, 934 (1975)]. Further, among the compounds represented by the general formula (21), those in which any one of R ^{3 to} R ⁶ is a hydrogen atom can be obtained by halogenation, nitration, or the like by a generally known method. Can be performed.

Step 8-3 is a step for producing a compound having the general formula (23).

Step 8-3 is a step for producing a compound having the general formula (23), and reacting the compound having the general formula (21) with the compound having the general formula (22) in an inert solvent. This is done by letting This step is performed according to the first step. Steps 8-4 and 8-7 are steps for producing a compound having the general formula (24) and the general formula (2d). It is carried out by subjecting the compound having the formula (25) to a reduction reaction to convert the amino group into an amino group. .

Steps 8_4 and 8-7 are performed according to step 5-4. Steps 8-5 and 8-6 include subjecting the compound having the general formula (25) or (2e) to a cyclization reaction in an inert solvent in the presence of a base, This is performed by performing a dehydration reaction in the presence of an acid.

The inert solvent used in Steps 8-5 and 8-6 is not particularly limited as long as it does not inhibit the reaction. For example, hexane, heptane, rigoin, petroleum oil Aliphatic hydrocarbons such as ter; aromatic hydrocarbons such as benzene, toluene, and xylene; such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethinolene Ethers such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; sulfolane; or a mixed solvent of the above solvents; Preferably, they are aromatic hydrocarbons (particularly preferably toluene).

The base used in the steps 8-5 and 8-6 is, for example, lithium metal carbonates such as lithium carbonate, sodium carbonate and carbon dioxide; lithium hydrogen carbonate, sodium hydrogen carbonate and hydrogen carbonate. Alkali metal bicarbonates such as iron lime; hydrogenation Alkali metal hydrides such as lithium, sodium hydride, hydrogen hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, hydroxide lime; lithium methoxide, sodium methoxide, sodium Alkali metal alkoxides such as ethoxide, 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] non-5-ene, 1,4-Diazabicyclo [2.2.2] octane (DABCO), 1,8- Organic amines such as diazabicyclo [5.4.0] -7-indene (DBU), preferably organic amines (particularly preferred It is 1, 8-Jiazabishikuro [5. 4.0] - 7- Undesen (DBU)).

The acid used is then acetic acid, hydrochloric acid, sulfuric acid, bromic acid or mixtures thereof. The cyclization reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C to 200 ° C, preferably 10 ° C to 100 ° C, and the same applies to the dehydration reaction.

The cyclization reaction time varies depending on the starting compound, the base, the reaction temperature and the like, but is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours), and the same applies to the dehydration reaction.

(9th step)

(Five)

In the above formula, showing Y, Q, A r \ m , k, W, R 3 to R ⁶ are the same meaning as above. The ninth step is a step for producing a compound having the general formula (27), and reacting the compound having the general formula (26) with the compound having the general formula (5) in an inert solvent. This is done by letting

This step is performed according to the first step.

The ninth step is a step for producing a compound having the general formula (28). The compound having the general formula (27) is subjected to a cyclization reaction in the presence of a base, followed by a dehydration reaction. It is performed by performing.

This step is performed according to the above-mentioned step 8-5 or step 8-6. The ninth step is a step for producing a compound having the general formula (2f) ₍ this step is performed according to the sixth to sixth steps described above).

(Step 10)

In the above formula, k, R ^{3 to} R ⁶ have the same meanings as described above, and J represents a hydroxyl group, a mercapto group or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Step 10-1 is a step for producing a compound having the general formula (30), and the compound having the general formula (29) and getyl bromomalonate in an inert solvent in the presence of a base. The reaction is carried out.

The base used in this step includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, hydrogen hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, hydration power; lithium methoxide, sodium hydride Alkali metal alkoxides such as toxide, sodium methoxide and potassium butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine , N, N-dimethyla-line, N, N-getylanili , 1,5-diazabicyclo [4.3.0] nonane 5-ene, 1,4-diazabicyclo [2.2.2] octane (DAB CO), 1,8-diazabicyclo [5.4.0] — 7—Organic amines such as pendecene (DBU), preferably potassium carbonate. The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, hexane, heptane, lignin, aliphatic hydrocarbons such as petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; dimethylformamide, dimethylacetamide And amides such as hexamethylphosphoric triamide; or a mixed solvent of the above-mentioned solvents; and preferably amides (particularly preferably dimethylformamide).

The reaction time varies depending on the starting material, the base used, the solvent, the reaction temperature or the like, usually for 30 minutes to 2 4 hours (preferably 1 hour to 1 0 ^hours): There. Step 10-2 is a step for producing a compound having the general formula (31a), wherein the ester group of the compound having the general formula (30) is reduced in an inert solvent to give an aldehyde group. Is converted to alcohol, and the aldehyde group is subjected to a Wittig reaction or a Homon-Emmons reaction, and then the unsaturated bond is reduced to reduce the ester group as necessary. The conversion is performed by converting the obtained hydroxyl group to a mercapto group or a halogen group. '

The method of converting an ester group into an aldehyde group or an alcohol is a generally well-known method [Chemistory Lettters, 1974, 1447, Comprehensive Organic Transformations, 1989, 549, VCH: New York, etc.]. ].

ゥ The Ittsch reaction or the Horner-Emmons reaction can be performed by a generally well-known method [Chemistory Review, 1989, 89, 863, etc.]. ].

A method for converting a hydroxyl group to a mercapto group or a halogen group is a generally well-known method [The Chemistory of the Thiol Chemistory, 1974, 179, Wiley: New York, Comprehensive Organic Transformations, 1989, 549, VCH: New York, etc. . ]. (Step 1)

In the above formula, k, R ^{2 to} R ⁶ have the same meanings as described above, and J represents a hydroxyl group, a mercapto group or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The eleventh step is a step for producing a compound having the general formula (34), wherein the compound having the general formula (32) and the compound having the general formula (33) are prepared in an inert solvent. Is carried out in the presence of a base.

The base used in this step includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal phosphates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, Alkali metal alkoxides such as sodium methoxide, potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N—Dimethylaniline, N, N—Jetylanili 1,5-Diazabicyclo [4.3.0] Nona-5-ene, 1,4-Diazabicyclo [2. 2. 2] Organic amines such as octane (DAB CO) and 1,8-diazabicyclo [5.4.0] — 7- pendene (DBU), and preferably potassium carbonate.

The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, hexane, heptane, lignin, aliphatic hydrocarbons such as petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; dimethylformamide, dimethylacetamide And amides such as hexamethylphosphoric acid triamide; or a mixed solvent of the above solvents; and preferably amides (particularly preferably 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). -Further, a transfer reaction in a base solvent can be carried out if necessary.

The base solvent used at that time is, for example, triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4_ (N, N-dimethylamino) pyridine, .N, N-dimethylaniline. , N, N—Jetjylaniline, 1,5-Diazabicyclo [4.3.0] Nona-5-ene, 1,4_Diazabicyclo [2.2.2] octane (D ABC 0), 1, Organic amines such as 8-diazabicyclo [5.4.0] -7-indene (DBU), and preferably N, N-getylaerin.

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually 0 ° C to 300 ° C (preferably 100 ° C to 200 ° 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). The first 1-2 step is a step of producing a compound having the general formula (35), and a step of preparing the compound having the general formula (34) in an inert solvent in the presence of an oxidizing agent and a base. It is performed by reacting. '

The oxidizing agent used in this step includes, for example, manganese oxides such as potassium permanganate and manganese dioxide; ruthenium oxides such as ruthenium tetroxide; selenium compounds such as selenium dioxide; Iron compounds; osmium tetroxide, potassium osmate. Osmium compounds such as dihydrate (K ₂ OsO ₄ ′ 2H ₂₀ ); silver compounds such as silver oxide; mercury compounds such as mercury acetate; lead oxide And lead oxide compounds such as lead tetraacetate; chromate compounds such as potassium chromate, chromate-sulfuric acid complex, chromate-pyridine complex, and cellulite compounds such as ammonium cellium nitrate (CAN) Inorganic metal oxidizing agents such as compounds; halogen molecules such as chlorine molecules, bromine molecules and iodine molecules; periodic acids such as sodium periodate; ozone; Such as nitrous acid compounds; chlorite compounds such as potassium chlorite and sodium chlorite; inorganic oxidants such as persulfate compounds such as potassium persulfate and sodium persulfate; used for DMSO oxidation Reagents (dimethylsulfoxide and dicyclohexylcarpomide, oxalyl chloride, complexes with acetic anhydride or phosphorus pentoxide, or pyridine-anhydrous sulfuric acid complexes); peroxides such as tert-butynolehydropropoxide and vanadium or Combination with molybdenum complex; Stable cations such as triphenylmethyl cation; Combinations of succinic imids such as N-bromosuccinic imid and alkali; Oxysilanes such as dimethyldioxysilane; Hypochlorous compounds such as tert-butyl chlorite; azo compounds such as azodicarboxylic acid esters Carboxylic acid compounds; peracids such as m-chloroperbenzoic acid and perphthalic acid; disulfides such as dimethyl disulfide, diphenyl disulfide and dipyridyl disulphide and triphenylphosphine; Nitrite esters such as methyl nitrite; tetrahalogenated carbon such as methane tetrabromide; organic oxidation of quinone compounds such as 2,3-dichloro-5,6-dicyano-p.benzoquinone (DDQ) And m-chloroperbenzoic acid. The base used in this step includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, hydrogen hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, Alkali metal alkoxides such as sodium methoxide, potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N—dimethylaniline, N, N—Jetylanili , 1,5-Diazabicyclo [4.3.0] Nona-5-ene, 1,4-Diazabicyclo [2.2.2] octane (DAB CO), 1,8-Diazabicyclo [5.4.0] — 7—Organic amines such as pendene (DBU), preferably sodium bicarbonate.

The inert solvent used in this step is not particularly limited as long as it does not inhibit the 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, 1,2-dichloroethane, and carbon tetrachloride; getyl ether, diisopropyl ether, Ethers such as tetrahydrofuran, dioxane, dimethoxetane, and diethyleneglycol dimethyate; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide Amides; sulfoxides such as dimethyl sulfoxide; sulfolane; Preferably, Nono b Gen hydrocarbons, ethers or § Mi earth (particularly preferably are dichloromethane) is.

The reaction time varies depending on the starting compound, base used, solvent, reaction temperature and the like, but is usually 30 minutes to 24 hours (preferably 1 hour to 10 hours). Step 1-1-3 is a step of producing a compound having the general formula (31a), and oxidizing a hydroxyl group of the compound having the general formula (35) in an inert solvent to form an aldehyde group. And then subjecting the aldehyde group to a Wittig reaction or a Homon-Emmons reaction, followed by a reduction reaction of the unsaturated bond to reduce the ester group as necessary, or to convert the hydroxyl group to a mercapto group. Alternatively, it is carried out by converting into a halogen group. The method of oxidizing a hydroxyl group to an aldehyde group is a generally well-known method [Oxidations in Organic Chemistry, 1990, American Chemical Society, etc.]. ]. '

Methods for converting an ester group into an aldehyde group or an alcohol are generally well-known methods [Chemistory hettters, 1974, 1447, Comprehensive Organic Transformations, 1989, 549, VCH: New York, etc.]. ].

A method for converting a hydroxyl group to a mercapto group or a halogen group is a generally well-known method [The Chemistory of the Thiol Chemistory, 1974, 179, Wiley: New York, Comprehensive Organic Transformations, 1989, 549, VCH: New York, etc. . ].

(Step 12)

In the above formula, Y, Q, Ar \ m, k, J, W, R ^{1 to} R ⁶ have the same meanings as described above, and U "represents a —CH ₂ — group or a formula C (R ² ) —U represents the formula C = CH group.

Step 12-1 is a step for producing a compound having the general formula (36), and is carried out by reacting a compound having the general formula (31) in an inert solvent. This step is performed according to the above-mentioned Step 6-1.

The 12-2 step is a step for producing a compound having the general formula (37), and is carried out by reacting a compound having the general formula (31) in an inert solvent. This step is performed according to the above-mentioned fifth to third steps. The first 2-3 step is a step for producing a compound having the general formula (2 g), and is carried out by reacting a compound having the general formula (36) in an inert solvent. This step is performed according to the above-mentioned steps 6-4 to 6-6.

Step 1.2-4 is a step for producing a compound having the general formula (2 g), and is carried out by reacting a compound having the general formula (37) in an inert solvent. This step is performed according to the third and fifth-fourth steps. This step can also be applied to compound (8) (including those in which X ′ is the formula (C = 0) —), and compound (2b) (where X ′ is the formula (1)). (Including C = 0).) Can be manufactured. Examples of the dosage form of the compound (1) of the present invention include oral administration such as tablets, capsules, granules, powders or syrups, and parenteral administration such as injections or suppositories. Preparations of excipients (eg, lactose, sucrose, dextrose, saccharides such as glucose, mannitol, sorbitol; corn starch, valley starch, starch derivatives such as _α- starch, dextrin; cellulose such as crystalline cellulose) Derivatives: arabia gum; dextran; organic excipients such as pullulan: and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate and magnesium phosphate; phosphoric acid such as calcium hydrogen phosphate Salt; carbonate such as calcium carbonate; sulfuric acid such as calcium sulfate Inorganic excipients such as salts can be mentioned.) Lubricants (for example, metal stearates such as stearic acid, calcium stearate, and magnesium stearate; talc; colloidal syrup; Waxes such as 蠟; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salts; sodium lauryl sulfate; lauryl sulfate such as magnesium lauryl sulfate Salts; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives.) Binders (eg, hydroxypropylcellulose, hydroxy.propinolemethinoresenole hydrate) Polyvinylinolepyrrolidone, Macrogonore, and compounds similar to the above-mentioned excipients Disintegrants (eg, low substitution degree Cellulose derivatives such as droxypropinoresenololose, canoleboximethizoresenololose, canolepoximethynoresulose calcium, internally cross-linked carboxymethylcellulose-snatridium; carboxymethyl starch, carboxymethyl starch sodium, Mention may be made of chemically modified starch'celluloses, such as crosslinked polyvinylinolepyrrolidone. ), Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanoyl alcohol, benzinole alcohol, phenylenoethyl alcohol; benzalcoium chloride; phenols such as phenol and cresol; thimerosal Dehydroacetic acid; and sorbic acid), flavoring agents (for example, commonly used sweeteners, acidulants, flavors, etc.), diluents and the like. It is manufactured by a well-known method using additives. The amount used depends on the symptoms, age, administration method, etc. For example, in the case of oral administration, the lower limit is 0.01 mg / kg body weight (preferably 0.1 mg / kg body weight) and the upper limit is 1000 mg / kg body weight (preferably 100 mg / kg body weight), for intravenous administration, 0.001 mg / kg body weight (preferably 0.01 mg / kg body weight) per dose, It is desirable to administer 100 mg / kg body weight (preferably 10 mg / kg body weight) once to several times per dose depending on the symptoms.

Hereinafter, the present invention will be described in detail with reference to Examples. BEST MODE FOR CARRYING OUT THE INVENTION (Example 1)

N— [4 -— (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —nicotinamide (Exemplified Compound No. 1)

4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) 1.0 g of aniline is dissolved in 2 ml of tetrahydrofuran 2 Om 1, and triethylamine 0.99 under ice cooling. m 1 and then 0.58 g of nicotinic acid chloride hydrochloride were added, followed by stirring at room temperature for 2 hours. The reaction mixture is poured into water, extracted with ethyl acetate, and the extract is saturated. After washing with a saline solution, the extract was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was crystallized from a mixed solvent of ethyl acetate and hexane to obtain 1.20 g of the desired compound having a melting point of 185-186 ° C.

(Example 2)

N- [4- (6-hydroxy-1,2,5,7,8-tetramethinolechroman-1-ylmethoxy) phenyl] nicotinamide (Exemplified Compound No. 2)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] -nicotinamide 0.80 g is dissolved in methanol 20 ml, and sodium methoxide is dissolved. After dropwise addition of 0.33 ml of a 28% methanol solution, the mixture was stirred at room temperature for 2 hours and then at 60 ° C for 2 hours. After methanol was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 0.59 g of the desired compound having a melting point of 159 ° -161 ° C.

(Example 3)

N— [4- (6-acetoxy-1,2,5, '7,8-tetramethylchroman-1-ylmethoxy) phenyl] —benzamide (Exemplified Compound No. 3)

4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) aniline 3.71 g, tetrahydrofuran 100m1, triethylamine 3g and benzoyl chloride 1.48g, Example The reaction was performed according to 1, and 3.9 g of the desired compound having a melting point of 185-18.5.5 ° C. was obtained.

(Example 4)

N- [4 -— (6-acetoxy 2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] —pyridine-12-ylacetoamide (Exemplary Compound No. 4)

Dissolve 1.63 g of 1,1'-carbonyldimidazole and 1.74 g of 2-pyridylacetic acid in 3 Om1 of N, N-dimethylformamide, and stir at room temperature for 30 minutes. Then, 3.69 g of 4- (6-acetoxy-1,2,5,7,8-tetramethinolechroman-12-inolemethoxy) aniline was added, and reacted at room temperature for 2 days. A saturated saline solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The ethyl acetate was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to obtain 4.lg of the desired compound having a melting point of 166.degree.-169.degree.

(Example 5)

N- [4-(6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -pyridine-13-ylacetoamide (Exemplified Compound No. 5) 1, 1 ' 1.63 g of carbonyldimidazole, 1.74 g of 3-pyridylacetic acid, 30 ml of N, N-dimethylformamide and 4 ml of 4- (6-acetoxy 2,5,7,8-tetramethylchromane) The reaction was carried out according to Example 4 using 3.69 g of 2- (ylmethoxy) aniline to obtain 3.9 g of the desired compound having a melting point of 193-195 ° C.

Ή-NMR spectrum (δ p pm, DMS O-d ₆ ): 1.32 (3H, s), 1.8-2.1 (2H, m), 1.92 (6H, s), 1.99 (3H, s), 2.30 (3H, s), 2.62 (2H, t, J = 6.7Hz), 3.66 (2H, s), 3.94 & 3.98 (2H, AB type, J = 10Hz), 6.92 (2H, J = 8.9Hz), 7.35 (1H, dd, J = 4.8 and 7.8Hz), 7.48 (2H _; d, J = 8.9Hz), 7.73 (1H, d, J = 7.8Hz), 8.46 (1H, dd, J = 1.2 and 4.9Hz) , 8.51 (1H, d, J = 1.5Hz), 10.08 (1H, s, J = 7.8Hz, disappeared by adding heavy water)

(Example 6)

N— [4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —pyridine-14-ylacetamide (Exemplified Compound No. 6)

1,1'-Carboerdiimidazole 1.63 g, 4-pyridylacetic acid 1.74 g, N, N-dimethylformamide 30 ml and 4- (6-acetoxy-1,2,5,7,

The reaction was carried out according to Example 4 using 3.69 g of 8-tetramethylchroman-2-ylmethoxy) aniline to obtain 4.2 g of the desired compound having a melting point of 172-173 ° C.

(Example 7)

N- [4-(6-acetoxy 2, 5, 7, 8-tetramethylchroman-1-yl Methoxy) 1-3-trifluoromethylphenyl] -nicotinamide (Exemplified Compound No. 7)

4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) 1-3-trifluoromethylaline 0.50 g, tetrahydrofuran 10 ml, triethylamine 0.48 m 1 and nicotinic acid chloride hydrochloride (0.31 g) were reacted according to Example 1 to obtain 0.59 g of the desired compound having a melting point of 198-199 ° C.

(Example 8)

N- [3- (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —6-aminoaminotinamide (Exemplified Compound No. 321)

3- (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) aniline 3.0 g, 6-aminonicotinic acid 1.08 g, tetrahydrofuran 6 Om and N , N-Dimethylformamide 3 Om and 1.40 ml of getyl cyanophosphonate and 0.87 g of triethylamine were reacted according to Example 52, and the Rf value was 0.16 (silica gel thin-layer chromatography). 3.25 g of the desired compound having ethyl ethyl hexane: hexane = 4: 1) was obtained.

(Example 9)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-12 f-methoxy) phenyl] monoisonicotinamide (Exemplified Compound No. 9)

4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) aniline 7.43 g, tetrahydrofuran 150 ml, triethylamine 5.2 g and isonicotinic acid chloride Using 3.57 g of the hydrochloride, the reaction was carried out according to Example 1 to obtain 8.2 g of the desired compound having a melting point of 176 to 177 ° C.

(Example 10)

N— _ [2— (6—Hydroxy mouth 2, _5, 7, 8—Tetramethylchroman-1-yl Methoxy) pyridine-3-yl] nicotinamide (Exemplified Compound No. 10)

2- (6-Hydroxy_2,5 7 8-Tetramethylchroman-2-ylmethoxy) 1-3-aminoviridine 40 g, Tetrahydrofuran 10 mL, Triethylamine 0.34 ml and Nicotinic acid Using 0.22 g of chloride hydrochloride, the reaction was carried out in the same manner as in Example 1 to obtain 0.31 g of the desired compound having a melting point of 62 to 66 ° C.

(Example 11)

N- [2- (6-acetoxy2 57 8) -tetramethylchroman-2-inolemethoxy) pyridine-1-5-yl] —nicotinamide (Exemplified Compound No. 11)

2- (6-acetoxy-258-78-tetramethylchroman-2-ylmethoxy) -5-aminopyridine 0.40 g, tetrahydrofuran 10 ml, triethylamine 0.45 ml and nicotinic acid chloride Using 0.38 g of hydrochloride, the reaction was carried out in the same manner as in Example 1 to obtain 0.51 g of the desired compound having a melting point of 165-174 ° C.

(Example 12)

N-[. 4 -— (6-hydroxy-l 25,78-tetramethyl [lH] chromene-l-ylmethoxy) benzyl] mononicotinamide 'monohydrate (Exemplified Compound No. 12) 4- (6-Methoxymethyl-2,578-tetramethyl [1H] chromene-1 f-methoxy) 0.14 g of benzylamine, 5 ml of tetrahydrofuran, 0.12 g of triethylamine and 0.12 g of nicotinic acid chloride hydrochloride 0 After reacting according to Example 1 using 0.08 g, 6N hydrochloric acid was further added, and the mixture was stirred. Water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off, and the obtained residue was subjected to silica gel chromatography (ethyl acetate: hexane = 111), and R = 0.15 (silica gel thin layer chromatography; ethyl acetate: hexane = 0.1 g of the target compound having 3 1) was obtained.

— NMR spectrum (δ ppm, DMS O-d ₆ ) 1.42 (3Η, s 1.95 (3H, s), 2.03 (3H s), 2.10 (3H, s), 3.94 & 3.96 (2H, AB type, J = 10Hz), 4.41 (2H, d, J = 5.9Hz, 4.41 (2H, s) shift by adding heavy water), 5 ・ 74 (1Η, d J = 10Hz 6.68 (1H, d, J = 10Hz) ), 6.88 (2H, d, J = 8.7Hz), 7.22 (2H, d J = 8.6Hz), 7.50 (1H, dd, J = 5.1 & 8.0Hz), 7.59 (1H _; s, disappeared by adding heavy water), 8.20 (1H, d, J = 8.0), 8.70 (1H, dd, J = 1.7 & 4.7Hz), 9.03 (1H, d, J = 2.0Hz), 9.16 (1H, t, J = 5.9Hz, disappeared by adding heavy water).

Elemental analysis; C _3. H ₃₃ N ₃ O _{6. As} H ₂ O, calculated value (%), C: 70.11, H: 6.54, N: 6.06, analysis value (%), C: 70.10, H: 6.40, N: 5.82

(Example 13)

N— [2 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-6-cyclopentyloxypyridine-1-5yl] —nicotinamide (eg Compound No. 13)

2- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) 1-5-amino-6-cyclopentyloxypyridine 0.80 g, tetrahydrofuran 15 ml, triethylamine 0 Using 69 ml and 0.59 g of nicotinic acid chloride hydrochloride, the reaction was carried out in the same manner as in Example 1 to obtain 0.67 g of the desired compound having a melting point of 147 to 149 ° C.

(Example 14)

N- [2— (6-t-loki 2,5 丄 7,8-tetramethinolechroman-1-ylmethoxy) -1-6-cyclopentyloxypyridine-5-yl] —nicotinamide ( Example Compound No. 14)

N— [2 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-2-normethoxy) -1-6-cyclopentyloxypyridine-15-yl] —nicotinamide 0.40 g, The compound was dissolved in 8 ml of methanol, and reacted with 0.14 ml of a 28% methanol solution of sodium methoxide according to Example 2 to obtain 0.33 g of the desired compound having a melting point of 70 to 74 ° C.

(Example 15)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -13-chlorophenyl] —nicotinamide (Exemplified Compound No. 15)

4- (6-acetoxy-1,2,5,7,8-tetramethinolechroman-1—inoremet The reaction was carried out in the same manner as in Example 1 by using 0.80 g of 1-cyclooctane loaniline, 15 ml of tetrahydrofuran, 0.83 ml of triethylamine and 0.71 g of nicotinic acid chloride hydrochloride. 0.76 g of the title compound having a melting point of 185-188 ° C. were obtained.

(Example 16)

N- [4- (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-inolemethoxy) -13-chlorophenyl] -nicotinamide (Exemplified Compound No. 16)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -13-chlorophenyl] —nicotinamide 0.40 g dissolved in methanol 8 ml Then, 0.15 ml of a 28% methanol solution of sodium methoxide was reacted according to Example 2 to obtain 0.34 g of the desired compound having a melting point of 70 to 75 ° C.

(Example 17)

N- [4 -— (6-amino-14-oxo_5,7,8-trimethylchromene_2f-lumethoxy) phenyl] —6-amino-nicotinamide (Exemplary Compound No. 17)

4- (6-amino-4- 4-oxo-5, 7, 8-trimethylchromene-2-ylmethoxy) 0.18 g of aniline, 86 mg of 6-aminonicotinic acid, N, N-dimethylformamide 4 m and cyanophosphone Using 0.09 ml of getyl acid and 0.08 ml of triethylamine, react according to Example 52, and obtain a target compound having an Rf value of 0.12 (silica gel thin-layer chromatography; ethyl acetate). 20 g were obtained.

(Example 18)

N— [4 -— (6-Methoxymethoxy-1,2,5,7,8-tetramethyl [1H] chromen-2-ylmethoxy) benzyl] -nicotinamide. 1/4 hydrate (exemplified compound (Article number 34),

4- (6-Methoxymethoxy-1,2,5,7,8-tetramethyl [1H] chromene-2-ylmethoxy) benzylamine 2.3 g, pyridine 50 ml and nicotinic acid chloride hydrochloride 1.3 The reaction was carried out in the same manner as in Example 1 to obtain 1.9 g of the desired compound having R = 0.47 (silica gel thin-layer chromatographic chromatography; ethyl acetate). Was.

^J H- NMR spectrum (δ p pm, DMS O- d e) 1.43 (3H, s), 1.96 (3H, s), 2.07 (3H, s), 2.16 (3H, s), 3.48 (3H , s), 3.98 (2H, s), 4.41 (2H, d, J = 5.9Hz), 4.80 (2H, s), 5.79 (1H, d, J = 10Hz), 6.69 (1H, d, J = 10Hz) ), 6.88 (2H, d, J = 8.7Hz), 7.22 (2H, d, J = 8.5Hz), 7.50 (1H, dd, J = 5.3 & 8.lHz), 8.21 (1H, d, J = 8.0Hz) Hz),, 8.70 (1H, dd, J = 1.5 & 5.0Hz), 9.03 (1H, d, J = 2.0Hz), 9.16 (1H, t, J = 5.9Hz).

Elemental _{_{_{analysis; C 29 H 32 N 2 0}}} 5 .1 / 4H 2 0 Calculated (%), C: 70.64, H: 6.64, N: 5.68, analysis (%), C: 70.33, H: 6.69, N: 5.48.

(Example 19)

N— [4 -— (6-hydroxy-1,2,5,7,8-tetramethinolechroman-12-inolemethoxy) benzyl] —ecotinamide. 1/4 hydrate (Exemplified Compound No. 35)

4- (6-Hydroxy 2,5,7,8-tetramethyl [1H] chromene-1-ylmethoxy) Benzamine 0.2 1 g, a mixture of methanol 20 ml and 5% palladium carbon 20 Omg was hydrogenated. The mixture was stirred at room temperature for 10 hours under an atmosphere. The insolubles are discriminated, the oral solution is concentrated under reduced pressure, the residue is subjected to silica gel column chromatography (ethyl acetate), and R = 0.36 (silica gel thin-layer chromatography; ethyl acetate) is obtained. 0.19 g of the desired compound was obtained.

iH-NMR spectrum (δ ppm, DMS O-d ₆ ): 1.29 (3H, s), 1.7-2.1 (2H, m), 1.94 (3H, s), 2.01 (3H, s), 2.03 ( 3H, s), 2.56 (2H, t, J = 6.8Hz), 3.92 & 3.95 (2H, AB type, J = 10Hz), 4.42 (2H, d, J = 5.9Hz), 6.92 (2H, d, J = 8.6Hz) _; 7.24 (2H, d, J = 8.6Hz), 7.42 (1H _; s, disappeared by adding heavy water), 7.50 (lH, dd, J = 5.0 & 8.lHz), 8.21 (1H, d , J = 8.0Hz), 8.70 (1H, dd, J = 1.6 & 4.9Hz), 9.03 (1H, d, J = 2.0Hz), 9.16 (1H, t, J = 5.9Hz) ₀

Elemental _{_{_{analysis; C 2V H 30 N 2 O}}} 4 .l / 4H 2 O Calculated (%), C: 71.90, H: 6.82, N: 6.21, Analysis C: 71.26, H: 6.68, N: 5.98.

(Example 20)

N— {3-[4— _ (6-acetoxy-1,2, —5, —7, —8—tetramethylchroman-1 —Irmethoxy) phenyl) propyl) nicotinamide (Exemplified Compound No. 36) 3— [4- (6-Acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) obtained in Reference Example 28 The reaction was carried out according to Example 1, using 1.16 g of phenyl] propylamine, 0.52 g of pyridin 3 Om1 and nicotinic acid hydrochloride, and the Rf value was 0.3. 0.45 g of the desired compound having 1 (silica gel thin layer chromatography; ethyl acetate) was obtained.

(Example 21)

N— [4- (6-acetoxy-1,2, _5,7.8-tetramethylchroman-2-ylmethoxy) phenyl] —6-aminoaminotinamide (Exemplified Compound No. 37)

4- (6-Acetoxy-2,5,7,8-tetramethylchroman-l-^-methoxy) aniline 3.69 g and 6-aminonicotinic acid 1.38 g to N, N-dimethylformamide 15 ml Then, 1.91 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was allowed to stand at room temperature for 1 S, and then stirred at 110 ° C. for 5 hours. A saturated saline solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate. The oral liquid was subjected to silica gel column chromatography (ethyl acetate) to obtain 0.5 g of the desired compound having a melting point of 195-199 ° C. Was obtained.

iH—NMR spectrum (Sp pm, DMS 0-d ₆ ), 1.34 (3H, s), 1.8-2.1 (2H, m), 1.92 (3H, s), 1.93 (3H, s), 2.01 (3H , s), 2.31 (3H, s), 2.63 (2H, t, J = 6.7Hz), 3.97 & 4.00 (2H, AB type, J = 9.9Hz), 6.47 (1H, d, J = 8.8Hz), 6.56 (2H, s, disappeared by adding heavy water), 6.95 (2H, d, J = 9.1Hz), 7.61 (2H, d, J = 8.9Hz), 7.91 (1H, dd, J = 2.4 & 8 7Ηζ), 8.57 (1H, d, J = 2.4Hz), 9.78 (1H, s, disappeared by adding heavy water).

. Elemental _{_{_{analysis; C 28 H 31 N 3 0}}} 5 l / 2CH 3 COOC 2 H 5 Calculated (%), C: 67.52, H: 6.61, N: 7.87, analytical values (;%), C: 67.25 , H: 6.72, N: 7.67.

(Example 22)

N— [4— (6-acetoxy-1,2,5,7, _8—tetramethylchroman-1-yl [Methoxy) phenyl] -1-5-carboxycarbiridine-12-carboxamide (Example Compound No. 38)

'5-Methoxycarbonylpyridine-12-hydrorubonic acid salt 2.17 g were suspended in 40 ml of tetrahydrofuran, and a solution of 1,10 g of chlorocarbonate in 10 ml of tetrahydrofuran was added under ice cooling. It was dropped. After stirring at room temperature for 2 hours and sonication for further 3 hours, 3.69 g of 4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) aniline was added, and 30 Sonicated for 1 minute and left at room temperature for 1 day. The solvent was distilled off under reduced pressure, saturated saline 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. The ethyl acetate was distilled off under reduced pressure, and the residue was crystallized from tetrahydrofuran to obtain 5.4 g of the desired compound having a melting point of 175-177 ° C.

(Example 23)

N— [4- (6-hydroxy-1,2,5,7,8-tetramethylechroman-1-inolemethoxy) phenyl] —N-methyl-nicotinamide (Exemplary Compound No. 39) In Reference Example 29 The obtained 4- (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) 1-38 g of 1-N-methylaniline, 50 ml of pyridine and 0.1 ml of nicotinic acid chloride hydrochloride. Using 64 g, react according to Example 1, and react with N- [4- (6-methoxymethoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] -1-N— 1.5 g of a crude product of methyl mononicotinamide was obtained.

N— [4 -— (6-Methoxymethoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -N-methyl-nicotinamide 1.4 g, acetic acid 50 ml, concentrated A mixture of 2 ml of hydrochloric acid and 10 ml of water was left at room temperature for 2 days. The solvent was distilled off under reduced pressure, an aqueous solution of potassium carbonate 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. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 5: 1) to obtain 0.8 g of the desired compound having a melting point of 173-178 ° C. I got (Example 24)

— 丄 4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-yl methoxy) phase] —pyridinesulfonamide (Exemplified Compound No. 40)

8.2 g of pyridine-1-sulfonic acid, 8 Om1 of 1,2-dichloroethane and 9.9 g of phosphorus pentachloride were heated under reflux for 20 hours. Dichloroethane was distilled off under reduced pressure, and the residue was heated at 120 for 5 hours. To the mixture were added 150 ml of tetrahydrofuran and 20 g of 4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline, and the mixture was heated under reflux for 20 hours. The solvent was distilled off under reduced pressure, an aqueous solution of carbon dioxide was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1 _: 3 → 1 _: 1) to give 5.8 g of the desired compound having a melting point of 75-80 ° C. I got

(Example 25)

N— [4 -— (6-acetoxy 2,5,7,8-tetramethinolechroman-1-ylmethoxy) phenyl] —6-clotic nicotinamide (Exemplified Compound No. 41)

1,1'-carbodiimidazole 3.14 g, 6-chloronicotinic acid 3.15 g, N, N-dimethylformamide 5 Om 1 and 4- (6-acetoxy-1,2,5 7,8-Tetramethylchroman-1-ylmethoxy) ferrin 7.39 g, the desired compound having a melting point of 216-221 ° C., 6.04 g Was obtained.

(Example 26)

N- [4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-inolemethoxy) phenyl] —6-hydroxynicotinamide (Exemplified Compound No. 42)

1,1'-Carboerdiimidazolone 3.33 g, 6-hydroxynicotinic acid 2.79 g, N, N-dimethylformamide 4 Om 1 and 4- (6-acetoxoxy 2,5 , 7,8-tetramethylchroman-2-ylmethoxy) aniline 7.39 g The reaction was carried out in the same manner as in Example 4 to obtain 7.92 g of the desired compound having a melting point of 2448-251 ° C.

(Example 27)

N— [4 -— (6-acetoxy 2,5.7,8-tetramethylchroman-2-inolemethoxy) phenyl] —2-aminonicotinamide (Exemplified Compound No. 43)

1,1'-carboeldimidazole 3.50 g, 2-aminonicotinic acid 2.76 g, N, N-dimethylformamide 50 m 1 and 4- (6-acetoxy 1,2,5,

7,8-Tetramethylchroman-2-ylmethoxy) aniline 7.39 g was used. The target compound having a melting point of 186-19-1 ° C was reacted according to Example 4, and had a melting point of 186-19-1 ° C. g.

! "! NMR spectra (δ ppm, DMS O-d ₆ ): 1.34 (3H, s), 1.8-2.1 (2H, m), 1.93 (3H, s), 2.01 (3H, s), 2.3l (3H, s), 2.63 (2H, t, J = 6.7Hz), 3.97 & 4.01 (2H, AB type, J = 9.9Hz), 6.64 (1H, dd, J = 4.8 & 7 ·), 6.97 (2H, d, J = 8.9Hz), 6.97 (2H, s, disappeared by adding heavy water), 7.58 (2Η, d, J = 8.9Hz), 8.02 (1Η, dd, J = 1.8 & 7.7Hz) , 8.11 (1H, dd, J = 1.4 & 4.9Ηζ), 10.0 (1H, s, disappeared by adding heavy water).

(Example 28)

N- {4- [4-(6-acetoxy-4-oxo_2,5,7.8-tetramethylchroman-1-ylmethoxy) phenyl] phenyl) nicotinamide (Ex. Compound No. 4 4)

4— [4— (6-Acetoxy-1-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] aniline. 1/4 hydrate 60.6 mg, N, Using 1 ml of N-dimethylformamide, 56 mg of triethylamine and 24 mg of nicotinic acid chloride hydrochloride, the reaction was carried out according to Example 1, and RH = 0.47 ( Silica gel thin-layer chromatography; 50 mg of the desired compound having ethyl acetate: ethanol = 15: 1) was obtained.

(Example 29) N- [4-^-Acetoxy-2,5.7,8-tetramethylchroman-2-ylmethoxy) phenyl] -2-cyclonicotinamide (Exemplified Compound No. 45)

1,1'-Carboerdiimidazole 3.50 g, 2-chloronicotinic acid 3.15 g, N, N-dimethylformamide 5 Om 1 and 4- (6-acetoxoxy 2,5 , 7,8-Tetramethylchroman-2-ylmethoxy) aniline 7.39 g, 0.88 g of the desired compound having a melting point of 197-199 ° C. was obtained by reacting according to Example 4. Obtained.

(Example 30)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —picolinic acid amide (Exemplified Compound No. 46)

4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-2- ^ f-l-methoxy) aniline 3.69 g, N, N-dimethylformamide 3 Om 1 and picolinol chloride hydrochloride Using 2.01 g, the reaction was carried out according to Example 1 to obtain 2.32 g of the desired compound having a melting point of 170-172 ° C.

(Example 31)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -nicotinamide-1-oxide (Exemplified Compound No. 47)

1,1'-carboerdiimidazole 3.50 g, nicotinic acid N-oxide 2.78 g, N, N-dimethylformamide 5 Om 1 and 4- (6-acetoxy-1,2,5,7,8 —Tetramethylchroman-2-ylmethoxy) aniline 7.39 g was used and reacted according to Example 4 to obtain 8.28 g of the desired compound having a melting point of 215-2218 ° C.

(Example 32)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-inolemethoxy) phenyl] —2-piperazinecarboxamide (Exemplified Compound No. 48) 1, 1'- Carbonyl diimidazole 3.50 g, 2-piperazinecarboxylic acid 2. 48 g, N, N-dimethylformamide 50 ml and 4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-2-f-l-methoxy) aniline 7.39 g The reaction was carried out according to Example 4, and 4.7 g of the desired compound having a melting point of 186-187 ° C was obtained.

(Example 33)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -3-carboxyisonicotinamide (Exemplified Compound No. 49) 3, 4 To a solution of 2.98 g of tetrahydrofuran in 50 ml of tetrapyridinefuran anhydride was added 7.5 g of 4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) aniline. Then, 50 ml of N, N-dimethylformamide was added, and the mixture was sonicated for 3 hours. The solvent was distilled off under reduced pressure, and the residue was crystallized from a mixed solvent of methanol and ethyl acetate to obtain 6.8 g of the desired compound having a melting point of 171-174 ° C.

(Example 34)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] monoquinoline-13-carboxamide (Exemplary Compound No. 50)

1,1'-carbodiimidazole 3.3 g, 3-quinolinecarboxylic acid 3.46 g, N, N-dimethylformamide 7 Om 1 and 4- (6-acetoxy-1,2,5,7 The reaction was carried out according to Example 4 using 7.40 g of 8,8-tetramethylchroman-2-ylmethoxy) aniline to obtain 8.83 g of the desired compound having a melting point of 236 to 237 ° C.

(Example 35)

N- [4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —6-methanesulfonylaminonicotinamide (Exemplified Compound No. 51)

N— [4— (6-acetoxy-1,2,5,7,8-tetramethylchroman-2-y Noremethoxy) phenyl] — 979 mg of 6-aminonicotinamide is dissolved in 1 Om 1 of N, N-dimethylformamide, 47 Omg of methanesulfonyl chloride and 500 mg of triethylamine are added, and the mixture is stirred at room temperature for 5 hours, and then stirred for 30 hours. Sonicated for minutes. The solvent was distilled off under reduced pressure, an aqueous solution of potassium carbonate 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. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: ethanol = 1: 0 → 10: 1) to give the target compound having a melting point of 216-225 ° C. 21 mg were obtained.

(Example 36)

N— [4 -— (2-Methyl [1H] chromen-1-ylmethoxy) benzyl] —nicotinamide (Exemplified Compound No. 52)

4 -— (2-Methyl [1H] chromene-one 2- ^ f-methoxy) Use 0.25 g of benzylamine, 5 ml of tetrahydrofuran, 0.37 ml of triethylamine and 0.20 g of nicotinic acid chloride hydrochloride. The reaction was carried out in the same manner as in Example 1 to obtain 0.26 g of the desired compound having an Rf value of 0.54 (silica gel thin-layer chromatography; ethyl acetate: ethanol = 10: 1).

(Example 37)

N- {2- [4 -— (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] —nicotinamide (Exemplary Compound No. 53)

2— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] ethylamine 1.45 g, N, N-dimethylformamide 70 ml, triethylamine 0. Using 98 ml and 0.63 g of nicotinic acid chloride hydrochloride, the reaction was carried out according to Example 1 to obtain 100 mg of the desired compound having a melting point of 137-139 ° C.

(Example 38) _N- [4- (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -nicotinamide (Exemplified Compound No. 54)

4-1- (6-acetoxy-1-4-oxo-1,2,5,7,8-tetramethylchroman-2-1-^-flumethoxy) aniline 1.0 g, N, N-dimethylformamide 3 Om 1, triethylamine 0 Using 72 ml and 0.46 g of nicotinic acid chloride hydrochloride, the reaction was carried out according to Example 1, and the Rf value was 0.25 (silica gel thin layer mouth chromatography; ethyl acetate: hexane = 4: 1.10 g of the target compound having 1) was obtained.

(Example 39)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) fuel] —6-methylthiopotambylaminoaminotinamide (Exemplified Compound No. 55)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman_2-ylmethoxy) phenyl] —6-aminoaminotinamide 0.45 ^^, N-dimethylformamide It was dissolved in 5 ml, 1.5 g of methyl isothiocyanate was stirred, stirred at room temperature for 3 hours, and then heated and stirred at 100 ° C for 20 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The precipitated crystals were collected to obtain 127 mg of the desired compound having a melting point of 219-230 ° C.

(Example 40)

N— [4— (6-Methoxy-14-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] —nicotinamide (Exemplified Compound No. 56)

4- (6-Methoxy 4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) ayurin 1.88 g, N, N-dimethylformamide 16m1, triethylamine 2.5m Using 1.5 g of 1 and nicotinic acid chloride hydrochloride, the reaction was carried out according to Example 1 to obtain 237 mg of the desired compound having a melting point of 75-90 ° C.

(Example 41)

N— [4— (6-acetoxy 2,5,7,8-tetramethylchroman-1-yl Methoxy) phenyl] -1-6-cotinoylaminonicotinamide 'tetrahydrate (Example Compound No. 57)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethinolechroman-1-ylmethoxy) phenyl] —1.23 g of 6-aminonicotinamide dissolved in 10 ml of pyridine Then, 0.5 g of nicotinic acid chloride hydrochloride was added, and the mixture was stirred at room temperature for 30 minutes, and then heated and stirred at 70 ° C. for 10 hours. An aqueous solution of sodium carbonate was added to the reaction mixture, and the mixture was stirred at room temperature for 1 day, ethyl acetate was added, and the precipitated crystals were taken out to obtain 1.13 g of the desired compound having a melting point of 243 to 246 ° C.

Elemental _{_{_{analysis; C 34 H 34 N 4 0}}} 6 .1 / 4H 2 0 Calculated (%), C: 68.16, H: 5.80, N: 9.35, analysis (%), C: 68.22, H: 5.84, N: 9.36

(Example 42)

N- [4- (6-Acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenol] — 6-acetylaminonicotinamide. 1/4 hydrate (Exemplified Compound No. 58)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-2 -— ^ f-methoxy) phenyl] —6-aminoaminotinamide 0.52 g, pyridine 5 ml and anhydrous rooster The reaction was carried out in the same manner as in Example 41 using 0.2 g of anhydrous acid to obtain 0.12 g of the desired compound having a melting point of 247-251 ° C.

Elemental analysis; C _3. _{_{_{H 33 N 3 0 6 .1 /}}} 4H 2 0 Calculated (%), C: 67.21, H: 6.30, N: 7.84, analysis (%), C: 67.14, H: 6.45, N: 7.46

(Example 43)

N— [4 -— (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —nicotinamide (Exemplified Compound No. 59)

4- (6-amino-4-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline 1.8 g, N, N-dimethylformamide 15 m1, triethylamine 0 Using 53 g and 0.94 g of nicotinic acid chloride hydrochloride, the reaction was carried out according to Example 1, and R

27 (silica gel thin layer chromatography; acetic acid 0.76 g of the desired compound having the formula:

iH-NMR spectrum (δ ppm, DMS O-d ₆ ): 1.40 (3H, s), 2.07 (3H, s), 209 (3Η, s), 2.41 (3H, s), 2.67 ( 1H, d, J = 16Hz), 2.99 (1H, d, J = 16Hz), 4.08 & 4.11 (2H, AB type, J = 10Hz), 5.0 (2H, broad, disappeared by adding heavy water), 6.96 (2H , d, J = 9.1Hz), 7.56 (1H, dd, J = 4.9 & 7.9Hz), 7.66 (2H, d, J = 9.0Hz), 8.28 (1H, dd, J = 1.9 & 8.0Hz), 8.75 (1H, dd, J = 1.5 & 4.7Hz), 9.09 (1H, d, J = 2.0Hz), 10.3 (1H, s, disappeared by adding heavy water)

Elemental _{_{_{analysis; C 26 H 2V N 3 0}}} 4 .1 / 2H 2 0 Calculated (%), C: 68.71, H: 6.21, N: 9.24, analysis (%), C: 69.03, H: 6.36, N: 9.16

(Example 44)

N— [4 -— (6-amino-1-4-benzyloxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —6-aminoaminotinamide (Exemplified Compound No. 60)

N— [4 -— (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman—2-ylmethoxy) phenyl] —6-aminoecotinamide 130 mg, O-benzylhydroxylamine Using 23 mg of hydrochloride, 0.1 ml of pyridine and 5 ml of methanol, react according to Example 54 to obtain 0.08 g of the target compound having a softening point of 50 to 52 ° C. Obtained.

(Example 4 5)

N- [4 -— (6-acetoxy 2,5,7,8-tetramethylchroman-2-inoleme-toki) —3-to-V-fluoromethylphenol 1-N-methyl-nicotinamide (Example Compound No. 6 1)

5 5 wt. /. 8.0 mg of sodium hydride was washed with hexane, 2 ml of N, N-dimethylformamide was added, and then N- [4- (6-acetoxy-2,5,7,8-tetrafluoroethylene) was added under ice cooling. 0.1 g of methylchroman-1-ylmethoxy-1-3-trifluoromethylphenyl] -nicotinamide was added. After stirring at room temperature for 1 hour, 11 μl of methyl iodide was added, and the mixture was further stirred for 2 hours. The solvent was distilled off under reduced pressure, and water was added to the residue. Then, 2N hydrochloric acid and then an aqueous solution of sodium bicarbonate were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate) to obtain 9 Omg of the desired compound having a melting point of 68-71 ° C.

(Example 46)

N- [4-(6-acetoxy-1,2,5,7,8-tetramethylchroman-12-yl_methoxy) -13-trifluoromethylphenyl] —N-benzyl-nicotinamide ( (Exemplary Compound No. 62)

55 wt% sodium hydride 8. Omg, N, N-dimethylformamide 2m1, N— [4- (6-acetoxity 2,5,7,8-tetramethylchroman-1-ylmethoxy) 1 3-Trifluoromethylphenyl] mononicotinamide 0.1 g and benzyl bromide 22a1 were reacted according to Example 45, and the target compound 70 having a melting point of 68-71 ° C. 70 mg was obtained.

(Example 47)

N- [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) —3-trifluoromethylinophenyl] —N-chloromethanesulfoninole Nsamide (Exemplary Compound No. 63)

N— [4 _ (6-acetoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) -1-3-trifluoromethylphenyl] methanesulfonamide 0.1 0 g, tetrahydrofuran 2 m, and triethylamine 76 // 1 and benzoyl chloride 32 μl were reacted according to Example 1 to obtain 0.10 g of a target compound having a melting point of 79-84 ° C. .

(Example 48)

N- [4- (6-acetoxy 2,5.7.8-tetramethylchroman-2-niinolemethoxy) — 3-trifluo-methyl-phenyl] -N-chloromethanesulfonyl-nicotinamide (Exemplary compound number 64) N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethinolechroman-12-ylmethoxy) -13-trifluoromethylphenyl] —chloromethanesulfonamide 70 mg, tetrahydrofuran The reaction was carried out in the same manner as in Example 1 using 2 ml, 53 μl of triethylamine and 34 mg of nicotinic acid oxalate hydrochloride to obtain 79 mg of the desired compound having a melting point of 75 to 80 ° C.

(Example 49)

N— [4 -— (8-hydroxy-1-4-oxo-1,2,5,6.7-tetramethylchroman-1-ylmethoxy) phenyl] —nicotinamide (Exemplified Compound No. 65)

4- (8-hydroxy-1,4-oxo-1,2,5,6,7-tetramethylchroman-1-ylmethoxy) aniline 344mg, N, N-dimethylformamide 12m1, triethylamine 0.28m l and 179 mg of nicotinic acid chloride hydrochloride were reacted according to Example 1 to obtain 368 mg of the desired compound having a melting point of 222.8 to 224.6 ° C.

(Example 50)

N— [4- (4,8-dihydroxy-1,2,5, _6,7-tetramethylchroman-12-ylmethoxy) funyl] —nicotinamide (Exemplified Compound No. 66)

N— [4— (8-hydroxy-4-oxo-1,2,5,6,7-tetramethylchroman-2-ylmethoxy) phenyl] -nicotinamide 8 Omg, methanol 10 ml and tetrahydro 70 mg of sodium borohydride was added to a mixture of 5 ml of drofuran, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, saturated saline 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. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 3: 1 → 1: 0) and further recrystallized from methanol to give a melting point of 200-203. 19.4 mg of the target compound having a temperature of ° C was obtained.

(Example 51)

N— _ [4— (8—hydroxy 2, _5, 6, 7—tetramethyl “1 H” chromene 2-ylmethoxy) phenyl] -nicotinamide (Exemplified Compound No. 67)

N- [4- (4,8-dihydroxy-1,2,5,6,7-tetramethylchroman-2-ylmethoxy) phenyl] -nicotinamide 19.5 mg, p-tonolenesulfonic acid. A mixture of 50.5 mg of the product and 20 ml of tetrahydrofuran was stirred at 50 ° C for 4 hours. The solvent was concentrated under reduced pressure, sodium carbonate and saturated saline were 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. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate) to obtain 93 mg of the desired compound having a melting point of 148-152 ° C.

(Example 52)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —6-aminoaminotinamide hydrochloride (Exemplary Compound No. 68) 4— ( Dissolve 7.39 g of 6-acetoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline and 2.77 g of 6-aminonicotinic acid in 200 ml of N, N-dimethylformamide. Then, 2.3 g of getyl cyanophosphonate and 2.1 g of triethylamine were added, and the mixture was stirred at room temperature for 5 hours and allowed to stand for another day. The solvent was distilled off from the reaction mixture under reduced pressure. An aqueous solution of sodium carbonate and ethyl acetate were added to the residue, and the precipitated crystals were taken out. The crystals were added to a 4N hydrogen chloride-dioxane solution (7 Om1) and left at room temperature for 1 day. did. The crystals were taken out to give 5.5 g of the desired compound (hydrochloride) having a melting point of 233-240 ° C.

Elemental _{_{_{analysis; C 28 H 32 N 3 0}}} 5 Calculated C 1 (%), C: 63.93, H: 6.13, N: 7.99,

C1: 6.74, analysis value (%), C: 63.70, H: 6.13, N: 7.93, C1: 6.80.

(Example 53)

N- [4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -1-6-aminonicotinamide (Exemplified Compound No. 69) 4— (6 —Amino-41-oxo-1,2,5,7,8-Tetramethinorechroman-1-ylmethoxy) aniline 0.65 g, 6-aminonicotinic acid 0.264 g, tetra Using 10 ml of hydrofuran, 0.32 g of getyl cyanophosphonate and 0.20 g of triethylamine, the reaction was carried out according to Example 52, and the target compound having a melting point of 90 to 120 ° C. 0 5.5 g were obtained.

1 H-NMR spectrum (δ ppm, DMS O-d ₆ ) 1.39 (3H, s), 2.06 (3H, s), 2.08 (3H, s), 2.39 (3H, s), 2.65 (1H, d, J = 16Hz), 3.99 (1H, d, J = 16Hz),

4.05 & 4.08 (2H, AB type, J = 10Hz), 4.7 (2H, broad, disappeared by adding heavy water), 6.50 (1H, d,

J = 8.8Hz) _; 6.68 (2H, broad, disappeared by adding heavy water), 6.92 (2H, d, J = 9.1Hz)

, 7.61 (2H, d, J = 8.9Hz), 7.94 (1H, dd, J = 1.6 & 8.8Hz), 8.57 (1H _; d, J = 2.3Hz),

9.82 (1H, s, disappeared by addition of heavy water).

(Example 54)

N- [4- (6-amino-4- 4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl]-6-aminonicotinamide (Exemplified Compound No. 70)

N— [4 -— (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman—2-ylmethoxy) phenyl] —6-aminoecotinamide 112 mg, hydroxylamine A mixture of 1.09 g of hydrochloride and 2 ml of pyridine was heated at 80 ° C. for 1 hour, and then left at room temperature for 2 days. The solvent was concentrated under reduced pressure, an aqueous solution of potassium carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 65 mg of the desired compound having a melting point of 215-222 ° C. IH- NMR spectrum _{(δ ppm, DMS O- d 6} ) 1.31 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.33 (3H, s), 2.89 (1H, d, J = 16Hz), 2.96 (1H, d, J = 17Hz),

3.96 (2H, s), 4.25 (2H, broad s, disappeared by adding heavy water), 6.47 (1H, d, J = 8.7 Hz), 6.57 (1H, s, disappeared by adding heavy water), 6.91 (2H, s) d, J = 8.9Hz), 7.61 (2H, d, J = 9.lHz), 7.91 (1H, dd, J = 2.3 & 8.8Hz), 8.57 (1H, d, J = 2.4Hz), 9.79 (2H , s, disappeared by adding heavy water), 11 · 1 (1Η, s, disappeared by adding heavy water).

(Example 55) N_ [4 -— (6-amino-1-4-methoximino-1,2,5,7,8-telomun-2-ylmethoxy) phenyl] — 6-aminonicotinamide (Exemplified Compound No. 71)

N— [4 -— (6-Amino-4-oxo) 2,5,7,8-tetramethylchroman—2-ylmethoxy) phenyl] —6-Aminiconicotinamide 120 mg, 0-methylhydroxylamine Using 1.09 g of the hydrochloride and 2 ml of pyridine, the reaction was carried out according to Example 54 to obtain 0.13 g of the desired compound having a melting point of 90-105 ° C.

Pt 11 NMR spectrum (δ ppm, DMS O-d ₆ ) 1.30 (3H, s), 2.02 (3Η, s), 2.03 (3H, s), 2.34 (3H, s), 2.92 (2H , s), 3.90 (3H, s), 3.96 (2H, s), 4.27 (2H, broad s, disappeared by addition of heavy water), 6.47 (1H, d, J = 8.7 Hz), 6.57 (1H, s, 6.90 (2H, d, J = 9.0Hz), 7.60 (2H, d, J = 9.lHz), 7.91 (1H, dd, J = 2.6 & 8.8Hz), 8.57 (1H, d, J = 2.3Hz), 9.79 (2H, s).

(Example 56)

N— [4— (6-nicotinylamino-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —nicotinamide (Exemplified Compound No. 1-48)

4- (6-amino-4-oxo-2,5,7,8-tetramethylchroman-12-ylmethoxy) aniline 0.17 g, pyridine 3 ml and nicotinic acid chloride hydrochloride 0.2 g The reaction was carried out according to Example 1 to obtain 0.06 g of the desired compound having a melting point of 140 ° C. to 190 ° C.

(Example 5 7)

1 [4-1 (6-Nitro-4-oxo-2,5,7,8-tetramethylchroman- 1 ^^ T-methoxy) benzyl]-6-aminonicotinamide (Exemplified Compound No. 14 9 )

4- (6-nitro-4, oxo-1,2,5,7,8-tetramethinolechroman-1-ylmethoxy) benzylamine 0.25 g, 6-aminonicotinic acid 0.10 g, N, N —Dimethylformamide 10 ml, 0.1 ml of getyl cyanophosphonate and The reaction was carried out according to Example 52 using 0.10 ml of triethylamine to obtain 0.25 g of the desired compound having a melting point of 82 to 87 ° C.

IH- NMR spectrum (S p pm, DMS 0- d β), 1 · 45 (3Η, s), 2 · 07 (3Η, s), 2 · 11 (3Η, s), 2.40 (3H, s) , 2.86 (1H, d, J = 16Hz), 3.11 (1H, d, J = 16Hz),

4.13 (1H, d, J = llHz) _; 4.21 (1H, d, J = llHz), 4.34 (2H, d, J = 5.8Hz s by adding heavy water),

6.42 (1H, d, J = 8.8Hz), 6.48 (2H, s, disappeared by adding heavy water), 6.86 (2H, d,

J = 8.5Hz), 7.20 (2H, d, J = 8.6Hz), 7.82 (1H, dd, J = 2.6 & 8.7Hz), 8.46 (1H, d, J = 2.3Hz), 8.63 (1H, t, J = 6.0Hz, disappeared by addition of heavy water).

(Example 58)

N— [4 -— (6-amino-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl] —6-aminoaminotinamide (Exemplary Compound No. 150)

N— [4- (6-nitro-4-oxo-1,2,5,7,8-tetramethylchroman—2-ylmethoxy) benzyl] —6-aminoaminotinamide 0.12 g, zinc 0. A mixture of 25 g, 4 ml of methanol and 0.1 ml of acetic acid was heated under reflux for 2 hours. The insolubles were separated and washed with ethyl acetate. The oral solution was washed with an aqueous sodium bicarbonate solution and then with a saturated saline solution, and then dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: ethanol = 1: 0: 1) to obtain 90 mg of the desired compound having a melting point of 58-65 ° C.

1H-NMR spectrum _{(δ ppm, DMS O- d 6} ) 1.37 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.38 (3H, s), 2.64 (1H, d, J = 16Hz), 2.96 (1H, d, J = 16Hz), 4.0-4.1 (2H, m), 4.35 (2H, d, J = 4.6Hz s by adding heavy water), 6.47 (1H, d, J = 8.8 Hz), 6.67 (2H, broads, disappeared by adding heavy water), 6.89 (2H, d, J = 8.6Hz), 7.20 (2H, d, J = 8.5Hz), 7.87 (1H, d, J = 8.7Hz) ), 8.46 (1H, d, J = 2.2Hz), 8.67 (1H, t, J = 5.3Hz, disappeared by adding heavy water).

(Example 59)

N— [4 -— (6-amino-4-methoxyethoxymino 2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl Ί—6-aminoaminotinamide (Example compound (Number 21 2)

N— [4- (6-amino-4-oxo-2,5,7,8-tetramethinolechroman-12-ylmethoxy) benzyl] -6-aminonicotinamide 1 50 mg The reaction was carried out according to Example 54 using 8 Omg of droxylamine hydrochloride, 0.08 ml of pyridine and 3 ml of methanol to obtain 106 mg of the desired compound having a softening point of 76 to 78 ° C.

¹ H—NMR spectrum (δ ppm, DMS O-d ₆ ) 1.29 (3H, s), 2.00 (6H, s), 2.33 (3H, s), 2.90 (2H, s), 3.88 (3H, s) , 3.94 (2H, s), 4.19 (2H, br s, disappeared by adding heavy water), 4.34 (2H, d, / = 5.9 Hz, s by adding heavy water), 6.41 (1H, d, zo = 8.7 Hz) ), 6.46 (2H, s, disappeared by adding heavy water), 6.88 (2H, d, zo = 8.6 Hz), 7.19 (2H, d, zo = 8.6 Hz), 7.82 (1H, dd, / = 2.3 and 8.7 Hz), 8.46 (1H, d, zo = 2.3 Hz), 8.61 (1H, t, = 5.9 Hz, disappeared by adding heavy water).

(Example 60)

N— [4- (6-amino-4-41-benzyloxyimino_2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -6-aminonicotinamide (Exemplified Compound No. 213) )

N- [4- (6-amino-4-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -6-aminonicotinamide 1 50mg, O-benzylhydroxylamine hydrochloride The reaction was carried out according to Example 54 using 255 mg, 0.113 ml of pyridine and 4 ml of methanol to obtain 0.14 g of a target compound having a softening point of 64-67 ° C.

IH- NMR spectrum _{(δ ppm, DMS O- d 6} ) 1.29 (3H, s), 1.99 (3H, s), 2.00 (3H, s), 2.23 (3H, s), 2.96 (2H, d, J = 9.6 Hz), 3.93 (2H, d, J = 2.8 Hz), 4.34 (2H, d, J: 5.9 Hz, s with addition of heavy water), 5.15 (2H, s), 6.42 (1H, d, J = 8.7 Hz), 6.48 (1H, s, disappeared by adding heavy water), 6.87 (2H, d, J: 8.6 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.3-7.4 (5H, m), 7.83 (1H, dd, J = 2.3 and 8.7 Hz), 8.47 (1H, d, J = 2.3 Hz), 8.62 (1H, t, J = 5.9 Hz, disappeared by adding heavy water). (Example 61)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-inolemethoxy) phenyl] -3-phenylpropionate amide (Exemplary Compound No. 231) 4 _ (6 —Acetoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline 10.6 g, tetrahydrofuran 280 ml, triethylamine 3.3 g and 3-phenylpropionyl chloride 4.88 The reaction was carried out according to Example 1 to obtain 12.03 g of the desired compound having a melting point of 150 ° -151 ° C.

(Example 62)

N— [4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-methoxy) phenyl] —4-phenylbutyric acid amide (Exemplified Compound No. 232)

4- (6-acetoxy 2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline 3.69 g, tetrahydrofuran 50 ml, triethylamine 1.2 g, ethyl ethyl carbonate 1.09 g and 4-phenylbutyric acid (1.64 g) were reacted according to Example 22 to obtain 2.5 g of the desired compound having a melting point of 96-97 ° C.

(Example 63)

N- [4- (6-acetoxy 2,5,7 · —8-te] ^ methylc-man-1-yl 'methoxy) phenyl] —5-fuylvaleric acid amide (Exemplified Compound No. 233) )

4- (6-acetoxy 2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline 3.69 g, tetrahydrofuran 50 ml, triethylamine 1.2 g, black ethyl carbonate 1.09 g and The reaction was carried out according to Example 22 using 1.78 g of 5-phenylvaleric acid to obtain 4.05 g of the desired compound having a melting point of 130 to 131 ° C.

(Example 64)

N— [4 -— (6-acetoxy 2,5-7,8-tetramethylchroman_2-ylmethoxy) phenyl] —pipecotate amide (Exemplified Compound No. 234)

N— [4— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1 A mixture of 3.1 g of lumetoxy) phenyl] _1-t_butoxycarbonilbipecotate amide and 60 ml of a 4N hydrogen chloride nodoxane solution was left at room temperature for one day. The solvent was concentrated under reduced pressure, an aqueous solution of potassium carbonate 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. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethanol: ethyl acetate: triethylamine = 10: 5: 1), and then recrystallized from a mixed solvent of ethyl acetate and hexane. 1.64 g of the desired compound having a melting point of 163.degree.-171.degree. C. was obtained.

(Example 65)

N— [4 -— (6-acetoxy 2,5,7,8-tetramethylchroman-1-yl methoxy) phenyl] monophenylacetamide (Exemplary Compound No. 235)

4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) aniline 1.00 g, tetrahydrofuran 20m, triethylamine 0.42ml and phenylacetyl chloride 0.40m Using l, 1.08 g of the desired compound having a melting point of 187-189 ° C was obtained by reacting according to Example 1.

(Example 66)

N2 [4-1 (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -N-methyl-1-phenylacetamide (Exemplary Compound No. 236)

55 wt% sodium hydride 31 mg, N, N-dimethylformamide 6 ml 1, N— [4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-yl methoxy) ) Phenyl] -reacted according to Example 45 using 30 Omg of phenylacetamide and 0.07 ml of yodani methinole, R f value = 0.26 (silica gel thin layer chromatography; ethyl acetate) : Hexane = 2: 3) to obtain 78 mg of the desired compound.

(Example 67) N- [4 -— (6-acetoxy-1,2,5,7_, 8-tetramethylchroman-1-ylmethoxy) phenyl] —indole-3-acetoamide (Exemplified Compound No. 237) 1, 1'— Carbonyl diimidazole 1.63 g, indole-3-acetic acid 1.75 g, N, N-dimethylformamide 3 Om 1 and 4- (6-acetoxy 2,5,7,8-tetramethyl The reaction was carried out in the same manner as in Example 4 using 3.69 g of chroman-2-ylmethoxy) phenyl to obtain 4.4 g of the desired compound having a melting point of 15-197 ° C.

(Example 6 8)

N- [3- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -6-aminonicotinamide (Exemplified Compound No. 238)

3- (6-amino-1-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline 5.74 g, 6-aminonicotinic acid 2.12 g, N, N-dimethylform The desired compound having a melting point of 77-80 ° C was reacted using amide 10 Om 1, 2.5 ml of getyl cyanophosphonate and 2.1 g of triethylamine, according to Example 52. 79 g were obtained.

(Example 6 9)

N— [3- (6-Amino-4-methoximinol 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] — 6-aminonicotinamide (Exemplified Compound No. 239)

N— [3— (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] —6-aminoecotinamide 0.19 g, The target compound having a melting point of 57-62 ° C was reacted using thiohydroxylamine hydrochloride (17 1 mg), methanol (10 ml) and pyridine (0.16 ml) according to Example 54, and having a melting point of 57-62 ° C. 0.13 g was obtained.

(Example 70) N- [4-(6-Acetoxy-1-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenino] —3,5-di-tert-butyl-4-hydroxybenzamide (example (Compound No. 24.0)

4- (6-acetoxy 4-oxo-1,2,5,7,8-tetramethylchromane-2- ^ f-l-methoxy) aniline 3.06 g, 3,5-di-t-butynole 4-hydroxy Using 2.00 g of benzoic acid, 50 ml of tetrahydrofuran, 1.3 ml of getyl cyanophosphonate and 1.2 ml of triethylamine, reacted according to Example 52, and had a melting point of 95-115 ° C. 4.92 g of the desired compound was obtained.

(Example 71)

N— [4— (6-hydroxy-1-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) fuel] —3,5-di-t-butynole-1-hydroxy Benzamide (Exemplary Compound No. 247)

N— [4 -— (6-acetoxy-1-oxo-2,5,7,8-tetramethinolechroman-1-ylmethoxy) phenyl] —3,5-di-t-butynole-1—hydroxy Benzamide; 1.00 g, 20 ml of methanol, 0.28 ml of a 28% solution of sodium methoxide in methanol, reacted according to Example 2, melting point 192-194 ° C 0.85 g of the desired compound having the formula was obtained.

(Example 72)

N— [4 -— (6-acetoxy-4-methoxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —3,5-di-t-butyl-4-hydroxybenzamide (Exemplified Compound No. 236)

N— [4— (6-acetoxy-4-oxo- 2,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -13,5-di-t-butylbenz-14-hide Using 0.40 g of roxyamide, 0.16 g of O-methylhydroxylamine hydrochloride, 1 Om1 of methanol and 0.15 ml of pyridine, the reaction was carried out according to Example 54, and the softening point was 107_1. 0.38 g of the desired compound having 30 ° C. and R f value = 0.42 (silica gel thin layer chromatography—ethyl acetate: hexane = 1: 3) was obtained. (Example Ί 3)

N— \ Λ-(6-acetoxy-4-benzyloxyminnow 2,5,7,8-tetramethylcun-2-ylmethoxy) phenyl] -3,5-di-t-butyl-4-h Droxybenzamide (Exemplary Compound No. 237)

N— [4 -— (6-acetoxy-1-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —3,5-di-t-butyl —4-h Using 0.40 g of droxybenzamide, 0.31 g of O-benzylhydroxylamine hydrochloride, 10 ml of methanol and 0.15 ml of pyridine, the reaction was carried out according to Example 54, and R—i = 0. 0.44 g of the desired compound having the following formula: 60 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 2) was obtained.

(Example 74)

N- [4--(6-Acetoxy-l 4-hydroxy xyminino_2,5,7,8-tetramethylchroman-l-inolemethoxy) phenyl]-3,5-Di-t-butyl- 4-hydroxybenzamide ( (Exemplary compound number 238)

N— [4 -— (6-acetoxy-4-oxo- 1,2,5,7,8-tetramethylchromane-2 -— ^ f-methoxy) phenyl] —3,5-di-t-butyl-1-hydroxy Using 0.40 g of benzamide, 0.13 g of hydroxylamine hydrochloride, 10 ml of methanol and 0.15 ml of pyridine, the reaction was carried out according to Example 54, and the softening point was 141 to 149 ° C and R 0.23 g of the desired compound having an f-value = 0.37 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 2) was obtained.

(Example Ί 5)

N- [4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl]-3,5,2-di-t-butyl-14-hydroxybenzamide (Example Compound No. 239)

4- (6-acetoxy-1,2,5,7,8-tetramethinolechroman_2-inolemethoxy) anilin 2.95 g, 3,5-di-t-butyl-4-hydroxybenzoic acid 2. The target compound having a melting point of 136 to 139 ° C by reacting according to Example 52, using 00 g, 50 ml of tetrahydrofuran, 1.3 ml of getyl cyanophosphonate and 1.2 ml of triethylamine. 4. 68 g were obtained.

(Example 76)

N— [4 — ^ — Hydroxy_ 2,5,7,8-Tetramethylchroman 1- ^ L-tol) phenyl] -3,5: Di-t-butyl-14-Hydroxybenzamide (Example Compound No. 240)

4-1 g of (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) aniline, 1.00 g of methanol, 20 ml of methanol and 0.29 ml of a 28% methanol solution of sodium methoxide. The reaction was carried out according to Example 2 to obtain 0.84 g of the target compound having an Rf value of 0.44 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 2).

(Example 77)

N— [2— (6-hydroxy-1,2,5—7,8—tetramethylchroman-2 -— ^ fnormethoxy) pyridine-5-yl] —3,5-zy t-butyl-1- Hydroxybenzamide (Exemplified Compound No. 24 1)

2- (6-hydroxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-5-aminopyridine 2.62 g, 3,5-di-t-butyl-1-4-hydroxy Using 2.00 g of benzoic acid, 50 ml of tetrahydrofuran, 1.3 ml of getyl cyanophosphonate and 1.2 ml of triethylamine, and reacted according to Example 52, having a melting point of 190 to 194 ° C 2.57 g of the compound were obtained.

(Example 78)

N- [2 -— (6-hydroxy 2,5,7,8-tetramethylchroman-1-inolemethoxy) pyridine-3-yl] -13,5_-di-1_butyl _1-4-h , Xybenzamide (Exemplified Compound No. 242)

2- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy B) 1.05 g of 1,3-aminoviridine, 0.80 g of 3,5-di-t-butyl-4-hydroxybenzoic acid, 20 ml of tetrahydrofuran, 20 ml of getyl cyanophosphonate.

The reaction was carried out according to Example 52 using 5 ml and 0.5 ml of triethylamine.

1.00 g of the title compound having a temperature of 179-181 ° C. were obtained.

(Example 79)

N— [4— (6-Amino-4-methoxyethoxymino 5,7,8-trimethylchromene-2-ylmethoxy) phenyl] —6-aminoaminotinamide (Exemplified Compound No. 323)

N— [4- (6-amino-4-oxo-1,5,7,8-trimethylchromene-2-ylmethoxy) phenyl] —6-aminonicotinamide 120 mg, O-methylhydroxylamine hydrochloride 120 mg, Using pyridine 0.1 11 ^ 1 and 1 ^, N-dimethylformamide 3 ml, reacting according to Example 54, R = 0.53 (silica gel thin layer chromatography; ethyl acetate: ethanol = 81 mg of the target compound having the following formula: 10: 1) was obtained.

1 ^ —? 1 \ [1 ^ spectrum (δ ppm, DMS O-d ₆ ) 2.18 (3H, s), 2.30 (3H, s), 2.61 (3H, s), 3.34 (3H, s), 4.77 (1H, d, J: 7.3 Hz, disappeared by adding heavy water), 5.09 (2H, s), 6.22 (1H, s), 6.47 (1H, d, J = 8.7 Hz), 6.57 (1H, d, J = 3.2 Hz, disappeared by adding heavy water), 7.05 (2H, d, J = 9.2 Hz), 7.66 (2H, d, J = 9.2 Hz), 7.91 (1H, dd, J = 2.3 and 8.7 Hz), 8.57 (1H, d, J = 2.3 Hz), 9.82 (1H, s, disappeared by adding heavy water).

(Example 80)

N- [4- (6-acetoxy 2,5, _7,8-tetramethylchroman-1-ylmethoxy) -12-trifluoromethylphenyl] -nicotinamide (Exemplified Compound No. 324)

4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) 1-2-trifluoromethylalanine 0.4 g, tetrahydrofuran 10 ml, triethylamine 0.38 m 1 And 0.33 g of nicotinic acid chloride hydrochloride were reacted according to Example 1 to obtain 0.46 g of the desired compound having a melting point of 80-90 ° C. (Example 81)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-2-trifluoromethylphenyl] —3,5-di-t-butyl-4 — Hydroxybenzamide (Exemplary Compound No. 325)

4- (6-acetoxy 2,5,7,8-tetramethylchroman_2-ylmethoxy) 1-2-trifluoromethylalanine 0.40 g, 3,5-di-t-butyl 4- 0.23 g of hydroxybenzoic acid, 1 Om 1 of tetrahydrofuran, 0.15 ml of getyl cyanophosphonate and 0.14 ml of triethylamine were used, and reacted according to Example 52, melting point 75-85 °. 0.38 g of the target compound having C was obtained.

IH- NMR spectrum _{(δ ppm, DMS O- d 6} ) 1.35 (3H, s), 1.42 (18H, s), 1.93 (6H, s), 1.98 (3H, s), 2.31 (3H, s), 1.8-1.9 (IH, m), 2.0-2.1 (IH, m), 2.6-2.7 (IH, m), 4.16 (2H, d, J = 6.4 Hz), 7.3-7.4 (2H, m), 7.38 ( IH, d, J = 8.8 Hz), 7.70 (2H, s), 7.51 (IH, s, disappeared by adding heavy water), 9.75 (1H, s, disappeared by adding heavy water).

(Example 82)

N— [3— (6-Acetoxy-1-4-methoxyoximino_2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —6-aminoaminotinamide (Ex. Compound No. 326)

N— [3- (6-Acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) phenol] —6-aminoaminotinamide 0.20 g, O Using 0.17 g of 1-methylhydroxylamine hydrochloride, 5 ml of methanol and 0.16 ml of pyridine, reacting according to Example 54, R f value = 0.52 (silica gel thin-layer chromatography; ethyl acetate) There was obtained 112 mg of the target compound having the following formula:

(Example 83)

N— [3— (6-Acetoxy-1.4-oxo-2,5,7,8-tetramethylchroman-2f-l-methoxy) phenyl 16-Aminonicotinamide (Exemplary Compound No. 347) 3- (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) 3.0 g of phosphorus, 1.08 g of 6-aminonicotinic acid, anhydrous N, N— The reaction was carried out according to Example 52 using 30 ml of dimethylformamide, 6 Om1 of anhydrous tetrahydrofuran, 1.20 ml of triethylamine and 1.3 ml of getyl cyanophosphonate. 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 successively with saturated sodium bicarbonate and 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 = 8: 1) to obtain a pale yellow amorphous target compound having a melting point of 78-88 ° C (softening). 3.25 g were obtained.

(Example 84)

N_ “4 -— (6-acetoxy-1- 4-methoxyimino _ 2,5,7,8-tetramethylchroman-2-inolemethoxy) phen-nore] 2,6-di-t-butisolate 4-hydroxybenzami (Exemplary Compound No. 348)

N— [4 -— (6-acetoxy-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -1,2,6-di-t-butyl-1 4- The reaction was carried out according to Example 54 using 0.40 g of hydroxybenzamide, 0.16 g of O-methylhydroxylamine hydrochloride, 0.16 ml of pyridine and 1 Om1 of anhydrous methanol. 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. The extract from the distilling off acetic Echiru, the residue was purified by silica gel column chromatography one: after subjecting the (acetic E Chi le. Hexane = iota 4 to _n _), acetic acid Echiru and the n- was recrystallized from a mixed solvent of hexane This gave 0.27 g of the target compound as a white powder having a melting point of 107-130 ° C (softening).

iH-NMR spectrum (δ ppm, DMS O-d ₆ ): 1.35 (3H, s), 1.43 (18H, s), 1.99 (3H, s), 2.06 (3H, s), 2.28 (3H, s) , 2.34 (3H, s), 2.9-3.1 (2H, m), 3.32 (3H, s), 4.06 (2H, d, J = 4.4 Hz), 6.94 (2H, d, J = 8.9 Hz), 7.47 ( 1H, s, disappear by adding heavy water Loss), 7.59 (2H, d, J = 8.9 Hz), 7.65 (2H, s), 9.90 (1H, s, disappeared by adding heavy ice). (Example 85)

N_-shi 4-1- (6-acetoxy-1-4-benzyloxyimino-1,2,5,7,8-tetramethylchroman-1-2-ylmethoxy) phenol 1-3-3,5-di-t-butyl _ 4-Hydroxybenzamide (Exemplary Compound No. 349)

N— [4 -— (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —3,5-di-t_butyl_4-h The reaction was carried out according to Example 54 using 0.40 g of droxybenzamide, 0.31 g of O-benzylhydroxylamine hydrochloride, 16 ml of pyridine and 1 Om1 of anhydrous methanol. 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 = 2: 5), and then recrystallized from a mixed solvent of ethyl acetate and n-hexane. Te, mp ₉ 9 - to obtain a 1 14 ° C objective compound as a white powder with a (softening) 0. 30 g.

iH—NMR spectrum (δ ppm, DMS O-d ₆ ): 1.35 (3H, s), 1.43 (18H, s), 1.98 (3H, s), 2.05 (3H, s), 2.17 (3H, s) , 2.32 (3H, s), 3.0-3.1 (2H, m), 4.05 (2H, d, J = 6.6 Hz), 5.19 (2H, s), 6.93 (2H, d, J = 8.8 Hz), 7.3- 7.4 (5H, m), 7.47 (1H, s, disappeared by adding heavy water), 7.59 (2H, d, J = 8.8 Hz), 7.66 (2H, s), 9.90 (1H, s, disappeared by adding heavy water) ).

(Example 86)

N— [4— (6-acetoxy 4-hydroxyhydroxymino 2,5,7,8-tetramethylinolechroman 2-inolemethoxy) phenyl 1_—3,5-di-t-butyl-1 4-hydroxybenzami (Exemplary Compound No. 350)

N— [4— (6-Acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —3,5-Di-t-butyl 4-Hydroxy Benzamide 0.40 g, hydroxylamine hydrochloride 0.13 _§ , pyridine 0.1 The reaction was carried out according to Example 54 using 6 ml and 1 Om1 of anhydrous methanol. 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), and then recrystallized from a mixed solvent of ethyl acetate and n-hexane. 0.23 g of the target compound as a white powder having a melting point of 141-149 ° C (softening) was obtained.

! One NMR spectrum (δ ppm, DMS O-d ₆ ): 1.35 (3H, s) _; 1.43 (18H, s), 1.98 (3H, s), 2.06 (3H, s), 2.27 (3H, s) ), 2.33 (3H, s), 2.8-3.0 (1H, m), 3.0-3.2 (1H, m), 4.06 (2H, d, J = 5.0 Hz), 6.95 (2H, d, J: 8.9 Hz) , 7.47 (1H, s, disappeared by adding heavy water), 7.59 (2H, d, J = 8.9 Hz), 7.66 (2H, s), 9.90 (1H, s, disappeared by adding heavy water), 11.34 (1H, s) , s, disappeared by addition of heavy water).

(Example 87).

N- [4- (6-hydroxy-1-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -p-toluenesulfonamide (Exemplary Compound No. 351)

4- (6-hydroxy-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) a-1.00 g, pyridine 20 ml and p-toluenesulfonyl chloride 0.6 Using 1 g, the reaction was carried out according to Example 1 to obtain 1.46 g of the desired compound having a melting point of 74 to 76 ° C (softening point).

(Example 88)

N— [2 -— (6-hydroxy 2,5,7,8-tetramethylchroman-1-yl methoxy) —5-pyridyl] —p—toluenesulfonamide (Exemplary Compound No. 352)

5-Amino-2- (6-hydroxy2,5,7,8-tetramethylchroman-12-ylmethoxy) pyridine 0.50 g, pyridine 1 Om 1 and p-toluenesulfuric chloride 0.3 Reaction was carried out according to Example 1 using 2 g, and the melting point was 68-70 ° C. 0.63 g of the desired compound was obtained. (Example 8 9)

N— [4 -— (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) —3-trifluoromethylphenyl] —nicotinamide (Exemplified compound number No. 3 5 3)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) _3-trifluoromethylphenyl] —nicotinamide 0.40 g, methanol 1 0 m 1 and 28% methanol solution of sodium methoxide 0.1 3 m

Using Example 1 and reacting according to Example 2, the desired compound having a melting point of 20.7 to 20.9 ° C.

15 g were obtained.

(Example 90)

N— [4 -— (6-nicotinyloxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) -1-3-trifluoromethylphenyl] N-nicotinylinoletin Cotinamide (Example compound (Number 3 5 4)

6-Hydroxy-1- (4-amino-1-2-trifluoromethylphenoxymethyl) 1,2,5,7,8-tetramethylchroman 100.0 g, pyridine 200 ml and nicotine Using 45.0 g of acid chloride hydrochloride, the reaction was carried out according to Example 41 to obtain 15.3 g of the desired compound having a melting point of 99-103 ° C.

(Example 91)

N— [4- (6-nicotinyloxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —N-nicotinyl nicotinamide (Exemplified Compound No. 35 5)

4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-inolemethoxy) aniline 1.0 g, pyridine 20 m1, and nicotinic acid mouth hydrochloride 5.44 Using g, the reaction was carried out according to Example 41 to obtain 1.96 g of the desired compound having a melting point of 90-93 ° C. (Example 9 2)

N- [4- (6-hydroxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -N-nicotinyl nicotinamide (Exemplified Compound No. 35 6)

4- (6-hydroxy-1,2,5,7,8-tetramethinolechroman-12-ylmethoxy) aniline 12.Og, tetrahydrofuran 500ml, triethylamine 56m1 and nicotinic acid chloride hydrochloride 65.2 g of the salt was used and reacted according to Example 1 to obtain 12.2 g of the desired compound having a melting point of 159-160 ° C.

(Example 93)

N- [4 -— (6-acetoxy-2,5,7,8-tetramethylchroman-l- ^ f-l-methoxy) phenyl] —3,5-di-t-butyl-l-hydroxybenzamide ( Example Compound No. 3 5 7)

4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline 2.95 g, 3,5-di-t-butyl-1-hydroxybenzoic acid Using 2.00 g, 50 ml of tetrahydrofuran, 1.3 m1 of cyanophosphonate and 1.3 ml of triethylamine, and reacting according to Example 52, the target compound having a melting point of 13 36 -13 ° C. 4. 68 g were obtained.

¹ H—NMR spectrum (δ ppm, DMS O-d ₆ ): 1.35 (3H, s), 1.43 (18H, s), 1.93 (6H, s), 2.01 (3H, s), 2,31 (3H , s), 1.8-1.9 (1H, m), 2.0-2.1 (1H, m), 2.64 (2H, t, J = 6.7 Hz), 4.00 (2H, d, J = 7.1 Hz), 6.96 (2H, d, J: 9.2 Hz), 7.47 (1H, s, disappeared by adding heavy water), 7.59 (2H, d, J = 9.2 Hz), 7.65 (2H, s), 9.90 (1H, s, adding heavy water) Disappeared).

(Example 94) ''

N— [4 -— (6-acetoxy-4-oxo-1,2,5,7,8-tetramethylchromane-1-ylmethoxy) phenyl] —3,5-di-1-tert-butyl-4-hydroxybenzylamine (Exemplary Compound No. 358) 4- (6-Acetoxy-1-4-oxo-1,2,5,7,8-Tetramethylchroman-2-ylmethoxy) aniline 3.06 g, 3,5-Di-t-butyl-1 4-Hydroxybenzo Using 2.00 g of the acid, 50 ml of tetrahydrofuran, 1.3 ml of getyl cyanophosphonate and 1.2 ml of triethylamine, the reaction was carried out according to Example 52, and the melting point was 95-115 ° C (softening point). 4.92 g of the target compound having the following point:

(Example 95)

N- [2- (6-hydroxy-1,2,5,7.8-tetramethylchroman_2-normethoxy) -1-5-pyridyl] -1,3,5-di-tert-butyl 4-hydroxybenzamide (example (Compound No. 359)

5-Amino-2- (6-hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) pyridine 2.62 g, 3,5-di-tert-butyl 4-hydroxybenzoic acid 2 .00 g, 50 ml of tetrahydrofuran, 1.3 ml of getyl cyanophosphonate and 1.2 ml of triethylamine, were reacted according to Example 52, and the target compound having a melting point of 190 ° -194 ° C. 2. 57 g were obtained.

(Example 96)

N- [2- (6-Hydroxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) -1-pyridyl] —3,5-Di-t-butyl-1-4-Hydroxybenza Mid (Exemplary Compound No. 360)

3-Amino-2- (6-hydroxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) pyridine 1.05 g, 3,5-di-t-butyl-4-hydroxybenzoic acid 0.80 g, 20 ml of tetrahydrofuran, 0.5 ml of getyl cyanophosphonate and 0.5 ml of triethylamine, and reacted according to Example 52 to give the desired compound 1 having a melting point of 179-181 ° C. .00 g were obtained.

(Example 97)

N- [4- (6-hydroxy-4-oxo-1,2,5 on 7.8-tetramethylchroman-2-ylmethoxy) _phenyl] -3,5-di-t-butyl-1-4- Droxybe Nsamide (Exemplary Compound No. 361)

N— [4 -— (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] — 3,5-di-t-butyl-4-hydroxy Using 1.00 g of benzamide, 20 ml of methanol and 0.28 ml of a 28% methanol solution of sodium methoxide, the reaction was carried out in accordance with Example 2, and the melting point was 192-194 ° C. 0.85 g of the desired compound was obtained.

(Example 98)

N- [4 -— (6-hydroxy-1-_2,5.7,8-tetramethylchroman-2-inolemethoxy) phenyl] —3,5-di-t-butyl-4-hydroxybenzamide (Example compound number 362)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenol] —3,5-di-t-butyl-1-4-hydroxybenzami 0.30 g of the target compound having a melting point of 84-104 ° C using 1.00 g of methanol, 20 ml of methanol and 0.29 ml of a 28% methanol solution of sodium methoxide according to Example 2. I got

(Example 99)

N— [4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] monophenylmethanesulfonamide (Exemplified Compound No. 363) 4 -— (6-acetoxy 1,2,5,7,8-Tetramethylchroman-2-ylmethoxy) aniline (7.4 g), tetrahydrofuran (15 Om1, triethylamine (3 g), and dimethyl sulfonyl chloride (3.82 g)) The reaction and post-treatment were carried out in the same manner as in Example 1 to obtain 5.71 g of the desired compound having a melting point of 163-164 ° C.

(Example 100)

N- [4- (6-amino-4-oxo-2,5 丄 7,8-tetramethylchroman-2-permethoxy) phenyl] -12-aminonicotinamide (Exemplified Compound No. 364) 4- (6-amino-4-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline 0.37 g, dimethylformamide 5m1, getyl cyanophosphonate 0.18 g, Using 0.2 g of triethylamine and 0.15 g of 2-aminonicotinic acid, the reaction and post-treatment were carried out according to Example 52, and the mixture was subjected to silica gel column chromatography (ethyl acetate). 0.24 g of the desired compound having the formula was obtained.

H—NMR spectrum (δ p pm, DMS O- d ₆ ) 1.39 (3H, s), 2.06 (3H, s), 2.08 (3H, s), 2.40 (3H, s), 2.66 (IH, d, J = 16.2 Hz), 2.98 (1H, d, J = 16.2 Hz), 4.08 (2H, d, J = 6.1 Hz), 6.68 (IH, dd, J = 4.9 and 7.4 Hz), 6.94 (2H, d, J = 8.9 Hz), 7.06 (IH, br s, disappeared by adding heavy water), 7.5-7.6 (2H, m), 8.06 (IH, d, J = 7.4 Hz), 8.12 (IH, dd, J = 1.8 and 4.9 Hz), 10.1 (IH, s, disappeared with the addition of heavy water).

(Example 10 1)

N- [4- (6- (amino-4-methoxymethoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -12-aminonicotinamide (Exemplified Compound No. 365)

N- [4- (6-amino-1-4-oxo-1,2,5,7,8-tetramethylchroman —2-ylmethoxy) phenyl] -1-2-aminonicotinamide 0.26 g, dimethyl hydrhydroxylamine Using 0.30 g of hydrochloride and 2.5 ml of pyridine, carry out the reaction and post-treatment according to Example 54, and subject to silica gel column chromatography (ethyl acetate) to have a softening point of 80-83 ° C. 0.2 g of compound was obtained.

¹ H-NMR spectrum (S ppm, DMS O-d ₆ ): 1.31 (3Η, s), 2.02 (3H, s), 2.04 (3H, s), 2.34 (3H, s), 2.92 (2H , s), 3.90 (3H, s), 3.97 (2H, s), 4.20-4.21 (2H, broad s, disappeared by adding heavy water), 6.64 (1H, dd, J = 4.8 & 7.7Hz), 6.93 ( 2H, d, J = 8.9Hz), 6.96 (2H, s), 7.57 (2H, d, J = 8.9Hz), 8.01 (1H, dd, J = 1.7% 7.7Hz), 8.11 (1H, dd, J = 1.7 & 4.8Hz), 10.03 (1H, s, disappeared by adding heavy water)

(Example 102) N- [4- (6-amino-4-oxo-2,5._7.8-tetramethylchroman-2-ylmethoxy) phenyl] -13-aminovirazine-12-carboxylic acid amide (Example compound number 3 6 6)

4- (6-Amino-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy)) 0.43 g of aniline, 5 ml of dimethylformamide, and getyl cyanophosphonate 0. Using 24 g, 0.15 g of triethylamine and 0.20 g of 3-aminobirazin-2-carboxylic acid, the reaction and post-treatment were carried out according to Example 52, and silica gel column chromatography (ethyl acetate: hexane) = 20: 1) to give 0.46 g of the desired compound having a melting point of 153-156 ° C.

(Example 10 3)

N- [4-(6-acetoxy 2,5,7,8-tetramethylchroman-1-yl methoxy) phenyl] -3-3-rubbermoylpyrazine-2-carburamide (Example compound (Number 3 6 7)

4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy)) 1.02 g of aniline, 10m1 of dimethylformamide, 1.04 g of getyl cyanophosphonate, triethylamine The reaction and post-treatment were carried out according to Example 52 using 0.50 g and 1.44 g of 3-hydroxyruburylpyrazine-2-birubonic acid, and the mixture was subjected to silica gel column chromatography (ethyl acetate). , Softening point 1 4 0— 1 4

0.176 g of the desired compound having a temperature of 3 ° C. was obtained.

(Example 104)

N- [4- (6-amino-4-methoxyximino-1,2,5,7,8-tetramethylchroma ^: ^ 2-ylmethoxyphenyl) —3-aminopyrazine-12-carboxylic acid amide (Example compound (Number 3 68)

N— [4 _ (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] -13-aminovirazine-12-hydroxyrubonamide 0.

Using 4 g, 1.0 g of O-methylhydroxylamine hydrochloride and 5 ml of pyridine, The reaction and work-up were carried out according to Example 54, and the mixture was subjected to silica gel column chromatography (ethyl acetate: hexane = 2: 1) to give the desired compound having a melting point of 183-185 ° C. 33 g were obtained.

(Example 105)

N- _ “4- (6-amino-4- methoxyimino_2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] —6-aminoaminotinamide dihydrochloride (example (Compound No. 369)

N— [4 -— (6-amino-1-oxo-2,5,7,8-tetramethylchroman—2-ylmethoxy) phenyl] —6-aminoaminotinamide 5.17 g, 0-methyl The reaction was carried out according to Example 54 using 4.79 g of tylhydroxylamine hydrochloride, 4.5 ml of pyridine and 10 Om1 of anhydrous methanol. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was recrystallized from methanol to obtain 5.27 g of the target compound as a white powder having a decomposition point of 150 ° C.

(Example 106)

N— [3 -— (6-acetoxy-1-4-methoxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —6-aminoaminotinamide (exemplified compound number 370)

N— [3- (6-Acetoxy-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —6-aminonicotinamide 200 mg, O—Methylhydroxylamine hydrochloride 1 The reaction was carried out according to Example 54 using 71 mg, 0.16 ml of pyridine and 5 ml of anhydrous methanol. The solvent was distilled off from the reaction mixture under reduced pressure, aqueous sodium hydrogen carbonate solution 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 = 4: 1 → 1: 0). The product was subjected to reversed phase preparative high performance liquid chromatography 1 (acetonitrile: water = 3: 2 → 13: 7). Solvent under 减 pressure from eluent Was concentrated to obtain 112 mg of a white amorphous target compound having R f = 0.52 (silica gel thin-layer chromatography; ethyl acetate).

(Example 107)

N— [4 -— (6-Acetoxy-1-4-oxo-1,2,5,7,8-tetramethinolechroman-2-ylmethoxy) phenyl] —6-Methoxynicotinamide (Exemplary Compound No. 371)

4- (6-acetoxy-1 4-oxo-1 2,5,7,8-tetramethylchroman-1

Use 460 mg of 2- (ylmethoxy) farin, 20 mg of 6-methoxynicotinic acid, 9 ml of anhydrous N, N-dimethylformamide, 0.18 ml of triethylamine and 0.20 ml of getyl cyanophosphonate. The reaction was carried out according to Example 52. 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: ethanol = i _: 0 → 20 _: 1 → 10: 1). The product was further subjected to reversed-phase preparative high-performance liquid chromatography (acetonitrile: water = 2: 3 → 9:11). Concentration of the solvent under reduced pressure from the eluent gave 389 mg of the target compound as a white powder with a melting point of 192-194 ° C.ヽ

(Example 108).

N— [4 -— (6-t-butoxycarbonylamino-4-oxo-1-21-methylchroman-2-ylmethoxy) phenyl] —6-aminoaminotinamide (Exemplary compound number

3—72)

4- (6-t-butoxycarbonylamino- 4-oxo-l-methylchroman-l- ^ f-l-methoxy) a-lin 5.13 g, 6-aminonicotinic acid 1.93 g, anhydrous N, N- The reaction was carried out according to Example 52 using 10 Om 1 of dimethylformamide, 1.9 ml of triethylamine and 2.1 ml of getyl cyanophosphonate. 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. Extraction The liquid 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 = 3: 1 → 1: 0 → ethyl acetate: ethanol = 20: 1). Further, 400 mg of the obtained 4.23 g was subjected to reversed-phase preparative high-performance liquid chromatography (acetonitrile: water = 2: 3 → 1: 1 → 3: 2). The solvent was concentrated under reduced pressure from the eluate, and the precipitate was collected by filtration to obtain 323 mg of the target compound as a pale yellow powder having a melting point of 132-135 ° C.

(Example 109)

N— [4- (6-amino-4-oxo-1-2-methylchroman-1-ylmethoxy) phenyl] —6-aminoaminotinamide dihydrochloride (Exemplary Compound No. 373)

N- [4- (6-t-butoxycarbo-l-amino-1-4-oxo-1-2-methylc-man-1-2-ylmethoxy) phenyl] —6-aminonicotinamide 2.12 g of ethyl acetate acetate 30 m To one solution, 3 ml of 4N-ethyl acetate hydrochloride was added. After stirring at room temperature for 1 hour and 30 minutes, 7 ml of 4N-ethyl acetate hydrochloride was added to the reaction solution, and the mixture was further stirred for 1 hour and left at room temperature overnight. The precipitate was collected by filtration from the reaction solution to give 1.88 g of a brown powder of the target compound having a decomposition point of 210 ° C.

(Example 110)

N- [4- (6-amino-4-methoxime—2-methylchroman-2-ylmethoxy) phenyl] -16-aminoucotinamide dihydrochloride (Exemplary Compound No. 374)

N— [4- (6-Amino-4-oxo1-2-methylchroman-2-ylmethoxy) phenyl] —6-aminonicotinamide dihydrochloride 500 mg, O-methylhydroxyxylamine hydrochloride 418 mg, pyridine The reaction was carried out according to Example 54 using 0.57 ml and anhydrous methanol 10 ml. Filtration of the precipitate from the reaction solution yielded 261 mg of the target compound as a white powder with a decomposition point of 180 ° C.

— NMR spectrum (S ppm, DMS O-d ₆ ) 1.36 (3H, s), 3.00 (2H, d, J = 10.8 Hz), 3.95 (3H, s), 4.09 (2H, d, J = 2.4 Hz) ), 6.95 (2H, d, J = 9.0 Hz), 6.9-7.1 (2H, m), 7.29 (1H, dd, J = 2.5 and 8.9 Hz), 7.65 (2H, d, J = 9.0Hz), 7.75 (1H, d, J2 2.5 Hz), 8.2-8.4 (1H, br s, disappeared by addition of heavy water), 8.34 (1H, d, J = 8.9 Hz), 8.68 (1H, s).

(Example 1 1 1)

— 丄 4-(6-Acetoxy-4-methoxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl, 16-methoxynicotinamide (Ex. Compound No. 375)

N— [4 -— (6-acetoxy-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -6-methoxynicotinamide 15 Omg, dimethylhydroxide The reaction was carried out according to Example 54 using 125 mg of xylamine hydrochloride, 0.12 ml of pyridine and 5 ml of anhydrous methanol. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was neutralized to pH = 9-10 with a saturated aqueous sodium hydrogen carbonate solution, and 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 reversed phase preparative high performance liquid chromatography (aceto-tolyl: water = 3: 2 → 13: 7) to give a melting point of 99-102 ° C (softening). 15 mg of a white amorphous target compound having the following formula: was obtained.

(Example 1 12)

N- [4- (6-acetoxy-2-isobutyl-l, 7,8-trimethylchroman-l-ylmethoxy) fuel] -16-aminonicotinamide (Exemplified Compound No. 376)

N— [4 -— (6-acetoxy-1-isobutyl-5,7,8-trimethinolechromane-2-—T-methoxy) aerin 20 Omg, 6-aminoaminotinic acid 75 mg, water-free N, N-dimethylform The reaction was carried out according to Example 52 using 5 ml of amide, 0.07 ml of triethylamine and 0.08 ml of getyl cyanophosphonate. 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. Acetic acid from the extract The residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 3: 1 → 1: 0) to give a white powder having a melting point of 96-100 ° C (softening). 26 mg of the desired compound of morphus was obtained.

(Example 1 1 3)

N- [4- (4-oxo-1,2,5,7,8-tetramethinolechroman_2_inolemethoxy) phenyl] -16-aminonicotinamide (Exemplified Compound No. 37 7)

N— [4 -— (4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline 0.34 g, 6-aminonicotinic acid 166 mg, anhydrous N, N-dimethyl The reaction was carried out according to Example 52 using 8 ml of formamide, 0.17 ml of triethylamine and 0.18 ml of getyl cyanophosphonate. 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 = 3: 1 → 1: 0 → ethyl acetate: ethanol = 20: 1). 274 mg of a pale orange amorphous target compound having a melting point of 73-77 ° C (softening) was obtained.

(Example 1 1 4)

N— [4— (4-Methoxyimino 2,5,7,8-tetramethyltylman-2-ylmethoxy) phenyl] -16-aminonicotinamide (Exemplified Compound No. 3778) N— [4— (4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] — 6-aminonicotinamide 149 mg, O-methylhydroxylamine hydrochloride 125 mg, pyridine The reaction was carried out according to Example 54 using 0.12 ml and methanol 5 ml. The crystals precipitated from the reaction mixture were collected by filtration to obtain 94 mg of the target compound as a white powder having a decomposition point of 194 ° C.

(Example 1 1 5)

N- [4- (6-Acetoxy 4-oxo_5,7,8-trimethylchroman-121-ylmethoxy) phenyl] -2-6-aminoaminotinamide (Exemplified Compound No. 32 7) 4- (6-Acetoxy-14-oxo-5,7,8-trimethylchroman-2-ylmethoxy) aniline (366 mg) and 6-aminonicotinic acid (273 mg) were dissolved in anhydrous N, N-dimethylformamide (26 ml). Then, 0.32 ml of triethylamine and 0.36 ml of getyl cyanophosphonate were added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off from the reaction mixture under reduced pressure, water was added, 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: ethanol = 1: 0 → 10 _: 1) to obtain 39 mg of the desired compound having a melting point of 241-243 ° C.

(Example 1 1 6)

N- [4- (6-A-4-1SO-5,7,8-Trimethylchroman-1-ylmethoxy) phenyl] -6-aminoaminotinamide (Exemplified Compound No. 328)

3- (6-amino-4-oxo-5,7,8-trimethylchroman-2-ylmethoxy) 64 mg of aniline and 33 mg of 6-aminoecotic acid are dissolved in 15 ml of anhydrous N, N-dimethylformamide, 0.03 ml of triethylamine and 0.04 ml of getyl cyanophosphonate were added, and the mixture was stirred at room temperature for 17 hours. The solvent was distilled off from the reaction mixture under reduced pressure, water was added, 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 gel chromatography (ethyl acetate → ethyl acetate: ethanol = 10: 1) to give the target compound having a melting point of 231 to 233 ° C. mg was obtained.

(Example 1 1 7)

N- [3- (6-Amino-1-4-oxo-1,5,7,8-trimethyl_2,3-chromen-2-ylmethoxy) phenyl] -6-aminonicotinamide (Exemplified Compound No. 379 )

N— [3— (6-Amino-1-oxo-5,7,8-trimethyl-1,2,3-chromene-1-ylmethoxy) aniline 0.18 g, 6-aminonicotinic acid 86 mg, anhydrous N, N-dimethylformamide 4 ml 1, triethylamine 0.08 ml and The reaction was carried out in the same manner as in Example 52, using 0.09 ml of getyl anophosphonate. The solvent was distilled off from the reaction mixture under reduced pressure, water and ethyl acetate were added to the residue, and the insoluble matter was collected by filtration to obtain a yellow powder having R f = 0.12 (silica gel thin-layer chromatography; ethyl acetate). 0.198 g of the desired compound was obtained.

¹ H—NMR spectrum (δ ppm, DMS O-d ₆ ) 2.18 (3H, s), 2.30 (3H, s), 2.61 (3H, s), 5.09 (2H, s), 6.22 (IH, s) , 6.48 (IH, d, J = 8.8 Hz), 6.62 (IH, br s, disappeared by adding heavy water), 7.05 (2H, d, J = 9.0 Hz), 7.65 (2H, d, J = 9.0 Hz) ), 7.92 (IH, dd, J = 2.3 and 8.8 Hz), 8.57 (IH, d, J = 2.3 Hz), 9.83 (1H, s, disappeared by adding heavy water).

(Example 1 1 8)

N- [4-(6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -2,4,6-triisopropylbenzenesulfonamide

(Exemplified Compound No. 380)

4- (6-acetoxy-1,2,5,7,8-tetramethinolechroman_2-inolemethoxy) aniline 3..72 g, triethylamine 6m1, tetrahydrofuran 50ml and 2,4,6-triisopropylbenzene Using 3.03 g of sulfochloride, reacting according to Example 1, and having R f = 0.76 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 2). I got lg.

(Example 1.19) "

N— [4 -— (6-acetoxy-1,2,5,7.8-tetramethylchroman-1-ylmethoxy) phenyl] -p-toluenesulfonamide (Exemplified Compound No. 38 1) 4- (6- Acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) aniline (1.00 g), pyridine (20 ml) and p-toluenesulfonyl chloride (0.57 g) were used. 1.42 g of the desired compound having a melting point of 79-84 ° C (softening point) was obtained.

(Example 1 20)

N— [4— _ (6—hydroxy-2._5, 7.8—tetramethinolechroman-1—2-inole [Methoxy) phenyl] — p-Toluenesulfonamide (Exemplary Compound No. 382) N— [4- (6-Acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] — P-Toluenesulfonamide 1.04 g, reacted with 20 ml of methanol and 0.38 ml of a 28% methanol solution of sodium methoxide according to Example 2, having a melting point of 63-65 ° C (softening) 0.88 g of the desired compound was obtained.

(Example 1 21)

N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethyl-2-ylmethylthio) funil] — 6-aminonicotinamide (Exemplified Compound No. 383)

6-acetoxy-1- (4-aminophenylthio) methyl-1,2,5,7,8-tetramethylchroman 0 · 50 g, 6-aminonicotinic acid 0.21 g, N, N-bis (2- Oxo-13-oxazolidinyl) phosphinic acid chloride 0.38 g, triethylamine 0.15 g, 4-dimethylaminopyridine 0.18 g, anhydrous tetrahydrofuran 20 m1 and anhydrous N, N-dimethyl A mixture of 20 ml of formamide was stirred at room temperature for 24 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate) to give the target compound having a melting point of 98-101 ° C. 9 g were obtained.

(Example 122)

N- [4- (6-amino-4-methoximino-5,7,8-trimethylchroman—2-T-methoxy) phenyl] -6-aminouccotinamide (Exemplified Compound No. 384)

N- [4- (6-amino-4-oxo-1,5,7,8-trimethylchroman-2-inolemethoxy) phenyl] -1-aminonicotinamide 11 Omg, 0-methylhydroxylamine hydrochloride 102.7 mg And 0.1 ml of pyridine were dissolved in methanol and heated under reflux for 4 hours. The solvent was distilled off from the reaction mixture, and the residue was washed with water and ether. 58.6 mg of the target compound having a melting point of 106-108 ° C. were obtained. (Example 1 2 3)

N— [4- (6-amino-4-methyloxymin-5,7,8-trimethylchroman—2-ylmethoxy) phenyl] —2-aminonicotinamide (Exemplified Compound No. 385)

4- (6-amino-4-1-oxo-5,7,8-trimethylchroman-1-inolemethoxy) Use of aniline, dimethylformamide, getyl cyanophosphonate, triethylamine and 2-aminonicotinic acid, Examples Perform the reaction and post-treatment according to 52 to obtain the desired compound.

(Example 1 2 4)

N- [4- (6-amino-4-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -16-benzyloxyaminonicotinamide (Exemplified Compound No. 38 6)

4- (6-amino-4-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) aniline, dimethylformamide, getyl cyanophosphonate, triethylamine and 6-benzyloxyamino nicotine Using the amide, the reaction and post-treatment are carried out according to Example 52 to obtain 0.24 g of the desired compound.

(Example 1 2 5)

N- [4-1 (6-amino-4-methoxyoximino-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -6-benzyloxyaminonicotinamide (Exemplary Compound No. 3 8 7)

N- [4- (6-amino-4_oxo- 1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] _6-benzyloxyaminonicotinamide, O-methylhydroxylamine hydrochloride The reaction and post-treatment are carried out according to Example 54 using a salt and pyridine to obtain the desired compound. (Example 26)

N- [4-(^-Amino-4-Methoxyimino-1,2,5,7,8-tetramethylchroman-12- _ylmethoxy) phenyl] -1 6-Hydroxyaminoaminonicotinamide (Example compound (Number 388)

N- [4_ (6-amino-4-methoxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -1-6-benzyloxyaminonicotinamide, 10% Pd— Using carbon and methanol, the catalytic hydrogenolysis reaction and post-treatment are carried out according to Example 4 to obtain the desired compound.

(Example 127)

N- [4- (6-amino-4-oxo-1,5,7,8-trimethylchroman-1-ylmethoxy) phenyl] _2,6-diaminonicotinamide (Exemplified Compound No. 389)

4- (6-Amino-1-oxo-5,7,8-trimethylchroman-1-ylmethoxy) Example using aniline, dimethylformamide, getyl cyanophosphonate, triethylamine and 2,6-diaminonicotinic acid The reaction and post-treatment are carried out according to 52 to obtain the desired compound.

(Example 1 28)

N- [4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] _2,6-diaminonicotinamide (Exemplified Compound No. 390)

4- (6-Amino-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) a-line, dimethylformamide, getyl cyanophosphonate, triethylamine and 2,6-diaminonicotinic acid The reaction and post-treatment were carried out according to Example 52 to obtain the desired compound.

(Example 1 29)

N- [4-1 (6-acetoxy 1-4-oxo 1, 5, 7._ 8 -trimethylchroman _ 2 —Ilmethoxy) phenyl] —2,6-Diaminonicotinamide (Exemplified Compound No. 391)

4- (6-acetoxy-1-oxo-5,7,8-trimethylchroman_2-ylmethoxy) a-, dimethylformamide, cyanophosphonate getyl, triethylamine and 2,6-diaminonicotinic acid The reaction and post-treatment are carried out according to Example 52 to obtain the desired compound.

(Example 1 30)

N- [4- (6-acetoxy-4-oxo-1,2,5.7,8-tetramethylchroman-1-ylmethoxy) pheninohi] —2-aminovirimidine-15-carboxylic acid amide (Example compound number 392)

4- (6-Acetoxy-1-4-oxo-1,2,5,7,8-Tetramethylchroman-1-ylmethoxy) aniline, dimethylformamide, getyl cyanophosphonate, triethylamine and 2-aminobirimidine-1-5-carboxylic acid The reaction and post-treatment are carried out according to Example 52 to obtain the desired compound.

(Example 13 1)

N- [4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] -1-aminopyrimidine-1-carboxylic acid amide (Example Compound No. 393)

4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) a-line, dimethylformamide, getyl cyanophosphonate, triethylamine and 2-aminopyrimidine The reaction and post-treatment are carried out in the same manner as in Example 52 using 5-hydroxycarboxylic acid to obtain the desired compound.

(Example 1 32)

N— [4- (6-Amino-4-oxo-1,5,7,8-trimethinolechroman-1-ylmethoxy) phenyl] -12-Aminobirimidine-1-5-carboxylic acid amide (Example compound (Article number 394) 4- (6-amino-4-oxo-5,7,8-trimethylchroman-2-inolemethoxy) aniline, dimethylformamide, getyl cyanophosphonate, triethylamine and 2-aminopyrimidine-15-carboxylic acid The reaction and post-treatment were carried out according to Example 52 to obtain the desired compound.

(Example 133)

N- [4- (6-amino-1 4-oxo-1,5,7,8-trimethylchroman-2-^-methoxy) phenyl] -1,2,4-diaminopyrimidine-1-5-carboxylic acid amide (Example Compound No. 395)

4- (6-amino-14-oxo-1,5,7,8-trimethylchroman-2-inolemethoxy) aniline, dimethylformamide, getyl cyanophosphonate, triethylamine and 2,4-diaminopyrimidine-15-carboxylic acid The reaction and post-treatment are carried out according to Example 52 using to obtain the desired compound.

(Example 134)

N— [4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl, -2,4-diaminopyrimidine-15-carboxylic acid amide (Example compound (Number 396)

4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline, dimethylformamide, getyl cyanophosphonate, triethylamine and 2,4-diaminopyrimidine-5- The reaction and post-treatment are carried out according to Example 52 using a carboxylic acid to obtain the desired compound.

(Example 1 3 5)

N- [4_j (6-Tamino-4-oxo-5,7,8-trimethylchroman-1-ylmethoxy) phenyl] _4-aminobirimidine-1-5-carboxylic acid amide (exemplified compound number 397 )

4- (6-amino-4-oxo-5,7,8-trimethylchroman-1-ylmethoxy) aniline, dimethylformamide, getyl cyanophosphonate, trieti The reaction and post-treatment are carried out in the same manner as in Example 52 using luminamine and 4-aminobirimidine-1-5-rubric acid to obtain the desired compound.

(Example 1 36)

N- [4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -14-aminobirimidine-15-carboxylic acid amide (Example compound number) 398)

4- (6-amino-4-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) aniline, dimethylformamide, getyl cyanophosphonate, triethylamine and 4-aminobirimidine-1-5-force The reaction and post-treatment are carried out according to Example 52 using rubonic acid to obtain the desired compound.

(Example 1 37)

N— [4-(6-amino-1—4-met ^: simino-5,7,8_trimethinolechroman _2_ilmethoxy) phenyl] 1,2,6-diaminonicotinamide (Exemplary Compound No. 399)

N- [4- (6-amino-4-oxo-1,5,7,8-trimethylchroman-2-ylmethoxy) phenyl] -1,6-diaminoecotinamide, O-methylhydroxyxylamine hydrochloride and Using pyridine, the reaction and post-treatment are carried out according to Example 54 to obtain the desired compound.

(Example 1 38)

N- [4- (6-amino-1-4-methoximino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -1,2,6-diaminonicotinamide (Exemplified Compound No. 400)

N- [4- (6-amino-4-oxo- 1,2,5,7,8-tetramethylchroman-2-1 ^ flumethoxy) phenyl] 1,2,6-diaminonicotinamide, O-methyl Using droxylamine hydrochloride and pyridine, the reaction and post-treatment are carried out according to Example 54 to obtain the desired compound. (Example 1 39)

N- [4- (6-acetoxy-1-4-methoximino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -1 2,6-diaminonicotinamide (Example compound number) 401)

N- [4- (6-Acetoxy-1.4-oxo-1,2,5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -12,6-Diaminonicotinamide, O-Metylch Using droxylamine hydrochloride and pyridine, the reaction and post-treatment are carried out according to Example 54 to obtain the desired compound.

(Example 140)

N- [4-1 (6-amino-4- methoxyimino-5,7,8-trimethylchroman-12 flumethoxy) phenyl] -12-aminovirimidine-15-carboxylic acid amide (Exemplary Compound No. 402 )

N- [4- (6-amino-4-oxo-1,5,7,8-trimethylchroman_2-ylmethoxy) phenyl] -12-aminovirimidine-15-carboxylic acid amide, O-methylhydroxylamine hydrochloride The reaction and post-treatment are carried out according to Example 54 using a salt and pyridine to obtain the desired compound.

(Example 14 1)

N- [4- (6-amino-41-methimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) enyl] -2-aminopyrimidine-15-potassium amide (Example compound (Number 403)

N- [4- (6-amino-4-oxo- 1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] -12-aminovirimidine-15-carboxylic acid amide, 1-methylhydroxylamine The target compound is obtained by performing the reaction and post-treatment according to Example 54 using hydrochloride and pyridine.

(Example 142) N _- [4- (6-acetoxy-1-4-methoximinol 2,5,7,8-tetramethylchroman "^-ylmethoxy) phenyl] —2-aminobilimidine-15-carbonic acid amide (Exemplified Compound No. 4 04)

N— [4— (6-Acetoxy-1-4-oxo-1,2,5,7,8-Tetramethylchroman-1-ylmethoxy) phenyl] -12-Aminobilimidine-1 5-Carboxamide, O— Using methylhydroxylamine hydrochloride and pyridine, the reaction and post-treatment are carried out according to Example 54 to obtain the desired compound.

(Example 1 4 3)

N— [4— (6-Amino-4-Methoxyiminor 5,7,8-Trimethylchroman-2-ylmethoxy) phenyl] -1,2,4-Diaminopyrimidine-15-Carboxylic acid amide (Exemplified Compound No. 40 5 )

N— [4- (6-amino-4-oxo-5,7,8-trimethylchroman-1-ylmethoxy) phenyl] -1,2,4-diaminopyrimidine-15-carboxylic acid amide, O-methylhydr The reaction and post-treatment are carried out according to Example 54 using droxylamine hydrochloride and pyridine to obtain the desired compound.

(Example 144)

N— [4- (6-Amino-4-methoxyimino 2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -1,2-diaminopyrimidine-15-carbonamide (exemplified compound (Number 40 6)

N— [4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -1,2,4-diaminopyrimidine-15-butyronic acid amide, O —The reaction and post-treatment are carried out according to Example 54 using methylhydroxylamine hydrochloride and pyridine to obtain the desired compound.

(Example 1 4 5)

N— [4- (6-amino-4-methoxyminino-5,7,8-trimethinolechroman-l-ylmethoxy) phenyl]-4-aminobirimidine-1-5-carboxylic acid amide (Exemplary Compound No. 407)

N- [4- (6-amino-4-oxo-1,5,7,8-trimethylchroman-2-ylmethoxy) phenyl] -14-aminovirimidine-15-carboxylic acid amide, O-methyl Using droxylamine hydrochloride and pyridine, the reaction and post-treatment are carried out according to Example 54 to obtain the desired compound.

(Example 146)

N- [4- (6-amino-4- methoxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -14-aminopyrimido_midine-15-carboxylic acid amide (example (Compound No. 408)

N- [4- (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -14-aminovirimidine-5-carboxylic acid amide, O-methylhydroxylamine The reaction and post-treatment are carried out according to Example 54 using hydrochloride and pyridine to obtain the desired compound.

(Reference example 1)

6-Methoxymethoxy-2- (4-nitro-12-trifluoromethylphenoxymethyl) 1,2,5,7,8-tetramethylchroman

Dissolve 5.00 g of 2-hydroxymethyl-1,6-methoxymethoxy 2,5,7,8-tetramethylchroman in 10 Om1 of N, N-dimethylformamide, and add 2.72 ml of trifluoromethylnitrobenzene and then 0.78 g of sodium hydride (55 wt%) were added, and the mixture was stirred at room temperature for 3 hours and left overnight. After completion of the reaction, N, N-dimethylformamide was distilled off under reduced pressure, water was added, the mixture was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane == 1: 3) to obtain an R f value = 0.46 (silica gel thin-layer chromatography; ethyl acetate: 7.9 g of the target compound was obtained as a yellow oil having hexane = 1: 3).

(Reference Example 2) 6—Hydro 1 2— (4 12 1—2—Trifluoromethylphenoxymethinole) —2,5,7,8—Tetramethylchroman

6-methoxime small oxime 2- (4-nitro-2-trifluoromethylphenoxymethyl) 1,2,5,7,8-tetramethylchromane 4.50 g, methanol 50m

1 and 4N—HC 1 dioxane solution 5 Om 1 was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.05 g of a yellow oily target compound having an Rf value of 0.42 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 3). .

(Reference example 3)

6-acetoxy-1- (4--2-trou-2-trifluoromethylphenoxymethyl) -2,5,7,8-tetramethylchroman

6-Hydroxy 2- (4-nitro-12-trifluoromethylphenoxymethyl) 1,2,5,7,8-Tetramethylchroman 4. Dissolve 60 g in 100 ml of pyridine and cool on ice Under acetic anhydride (3.1 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed with 0.5N hydrochloric acid, water, saturated sodium bicarbonate, and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and recrystallized from ethanol to obtain 4.66 g of the desired compound having a melting point of 149 to 50 ° C.

(Reference Example 4)

6-Acetoxy-1- (4-amino-1-trifluoromethylphenoxymethyl) -2,5,7,8-Tetramethylchroman

6-acetoxy 2-((412-nitro-2-trifluoromethylphenoxymethyl) 1,2,5,7,8-tetramethylchroman 3.00 g, methanol 6 Oml and 10% palladium A mixture of 0.60 g of carbon was stirred under a hydrogen atmosphere for 4 hours. After the completion of the reaction, the insolubles were filtered off, and the solvent was distilled off from the mouth liquid under reduced pressure to obtain 2.77 g of the desired compound having a melting point of 117-119 ° C. (Reference example 5)

3-(6-Acetoxy-1,4-oxo-1,2,5,7,8-Tetramethylchroman-1-ylmethoxy) nitrobenzene

Using 5.75 g of 5-acetoxy-1-hydroxy-3,4,6-trimethylacetophenone, 5.75 g of 3- (2-oxopropoxy) nitrobenzene, 1.73 g of pyrrolidine and 100 ml of methanol, The reaction was carried out according to Reference Example 38, and the compound having an R f value of 0 · 51 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 2) 7.34 g (3- (6-acetoxoxy-one) 4- Okiso one 2, 5, 7, 8-1-tetramethyl-chroman one 2- Irume butoxy) _c which was obtained containing a small amount of nitrobenzene)

(Reference example 6)

3- (6-Acetoxy-1-4-oxo-1,2,5,7,8-Tetramethylchroman 1-2-Ilmethoxy) Ayurin

3- (6-acetoxy 4-oxo-1,2,5,7,8-tetramethylchroman-1-inolemethoxy) 7.55 g of ditrobenzene, 140 ml of methanol / le and 0.76 g of 10% palladium on carbon The reaction was carried out according to Reference Example 4 to obtain 6.13 g of the desired compound having an Rf value of 0.19 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 2). Was.

(Reference example 7)

6-Hydroxy-1-2- (3-Ditropyridine-1-yloxymethyl) -1,2,5,7,8-Tetramethylchroman

1 sodium hydride ^{_{(55 wt 0/0) 3.}} 69 § [, N- dimethylformamidine de 1 0 Om 1 was added, under ice-cooling 6-arsenide Dorokishi one 2-arsenide Dorokishimechiru one 2, 5, 7, After 1-Og of 8-tetramethylchroman was added little by little, the mixture was stirred at room temperature for 2 hours, and 2.78 g of 2-cyclo-3--3-nitropyridine was added, followed by stirring at room temperature for 3 hours. After completion of the reaction, N, N-dimethylformamide was distilled off under reduced pressure, water was added, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. Solvent under reduced pressure The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 3), and R tt = 0.38 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3). ) Was obtained as a yellow oil.

(Reference Example 8)

6-Hydroxy-1- (3-aminopyridine-1-yloxymethyl) -1,2,5,7,8-Tetramethylchroman

6-Hydroxy-1- (3-dinitropyridine-1-yloxymethyl) -1,2,5,7,8-tetramethylchroman 4.80 g, methanol 60 m 1 and 10 <½palladium carbon 1.00 g The reaction was carried out according to Reference Example 4 to obtain 4.4 g of the desired compound having R f ¾ = 0.23 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3). Was.

(Reference Example 9)

6-Methoxyoxime 2- (5-dinitropyridine-1-yloxymethyl) 1,2,5,7,8-tetramethylchroman

1.37 g of sodium hydride (55 wt./o), 100 ml of N, N-dimethylformamide, 6-methoxymethoxy1-2-hydroxymethyl-1,2,5,7,8-tetramethylchroman 8.0 g, 5.48 g of 2-chloro-5-nitropyridine were reacted according to Reference Example 7, and the Rf value was 0.65 (silica gel thin layer chromatography; ethyl acetate: hexane = 1). : 3) The desired compound 12.Og having the following formula:

(Reference example 10)

6-Hydroxy-1- (5-dipyridine-1-yloxymethyl) _2,5,7,8-tetramethylchroman

6-Methoxymethoxy-2- (5-nitropyridine 1-2,2,5,7,8-tetramethylchroman 10 · 8 g, 100 ml methanol and 100 ml 4N-HC 1 Z dioxane solution Reaction was carried out according to Example 2, and R f value = 0.47 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3) 9.25 g of the target compound having the formula were obtained. (Reference Example 11)

6-acetoxy-2- (5-nitropyridine_2-yloxymethyl) -1,2,5,7,8-tetramethinolechromane

Using 6-hydroxy-1- (5-tropyridine-1-yloxymethyl) _2,5,7,8-tetramethylchroman 8.8 g, pyridine 20 Om1 and acetic anhydride 7.0 m1 The reaction was carried out according to Reference Example 3 to obtain 9.72 g of the desired compound having R tt = 0.49 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3).

(Reference Example 1 2)

6-acetoxy-1- (5-aminoviridine-1-yloxymethyl) -1,2,5,7,8-tetramethylchroman

6-acetoxy-1- (5-nitropyridine-2-yloxymethyl) -1,2,5

7,8-Tetramethylchroman 5.20 g, methanol 10 Om 1 and 100% palladium carbon 1.00 g were used. The reaction was carried out according to Reference Example 4, and the melting point was 1 15— 4.71 g of the target compound having a temperature of 116 ° C. was obtained.

(Reference Example 13)

4-Hydroxy 2- (4-methoxy ethoxypropyl) 1-6-methoxy 2,5,7,8-tetramethy ^^ mouth

3-acetoxy-6-hydroxy-1,4,5-trimethylacetophenone 25.2 g, 4- (2-oxopropoxy) benzoic acid methyl ester 21.5 g, pyrrolidine 15.5 g and A mixture of 500 ml of methanol was stirred at 45 ° C for 6 days. The solvent was distilled off under reduced pressure, diluted hydrochloric acid and ethyl acetate were added to the residue, and the mixture was stirred for 1 hour. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 2: 5) to give 6-hydroxy-2- (4-methoxycarbonylphenoxymethyl) -14. —O There was obtained 21.3 g of 2,5,7,8-tetramethylchroman.

Sodium hydride (55 wt%) 2.18 g was washed with hexane, N, N-dimethylformamide 300 ml was added, and the mixture was cooled with ice 6-hydroxy-1-2- (4- Methoxycarbolphenoxymethyl) 1,4-oxo_2,5,7,8-tetramethylchromane 18.9 g was added little by little, and the mixture was stirred at room temperature for 1 hour, and chloromethyl methyl ether 5 m 1 Was added dropwise under ice cooling, and the mixture was stirred for 8 hours. After leaving overnight at room temperature, N, N-dimethylformamide was distilled off under reduced pressure, water was added, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 22.5 g of 2_ (4-methoxycarbonylphenoxymethyl) -16-methoxymethoxy-4-oxo-1,2,5,7,8-tetramethylchroman was obtained. Obtained.

Dissolve 21.3 g of 2- (4-methoxycarbonylphenoxymethyl) -1-6-methoxy-4-ethoxy-2,5,7,8-tetramethylchroman in 200 ml of methanol, and add hydrogen 3.5 g of sodium borohydride were added in small portions. The mixture was stirred at room temperature for 3 hours, methanol was distilled off under reduced pressure, and the residue was crystallized from a mixed solvent of ethyl acetate and hexane to obtain the target compound having a melting point of 1 1 1 1 1 1 1 4 ° C. 5 g were obtained. On the other hand, the recrystallization mouth liquid was concentrated to obtain 12.7 g of the target product containing impurities.

(Reference example 14)

2-(4-Methoxycarboephenoxymethyl) -6-Methoxymethoxy 2,5,7,8-Tetramethyl- 1H-chromene

4-Hydroxy-l 2- (4-Methoxycarbylphenoxymethyl) -l-6-Methoxymethoxy 2,5,7,8-tetramethylchroman (containing the impurities obtained in Reference Example 13 above) 12.7 g, 100 ml of tetrahydrofuran and 1.3 g of p-toluenesulfonic acid monohydrate were stirred at room temperature for 4 hours and then at 50 ° C for 5 hours. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 5) to obtain a value of! ¾ = 0.52 (silica gel thin-layer chromatography; ethyl acetate: Hexane = 5.4 g of the target compound having the ratio of 1: 5) was obtained. (Reference example 15)

2- (4-azidomethinolephenoxymethyl) -1-6-methoxymethoxy 2,5,7 8-tetramethyl-2H-chromene

2- (4-Methoxycarboefuenoxymethyl) -16-methoxymethoxy-1,2,5,7,8-tetramethyl-2H-chromene 4.5 g was dissolved in 100 ml of tetrahydrofuran and hydrogenated under water cooling 1.24 g of aluminum lithium was added, and the mixture was stirred at room temperature for 2 hours. After standing at room temperature overnight, 1.3 ml of water and then 3.6 ml of 10% sodium hydroxide and 2.5 ml of water were added to the reaction mixture, followed by stirring at room temperature for 1 hour. The insoluble material is filtered off, and the solvent is distilled off from the oral solution under reduced pressure. 2- (4-Hydroxymethylphenoxymethyl) -16-methoxymethoxy-1,2,5,7,8-Tetramethyl-2H —Chromene 4.48 g was obtained.

2- (4-Hydroxymethylphenoxymethyl) 1-6-Methoxymethoxy 2,5,7,8-Tetramethyl_2H-chromene 4.12 g of N, N-dimethylformamide 1.29 g of methanesulfoyl chloride was added to the 85 ml solution under ice-cooling, and then N-ethyl-1-N, N-diisopropylamine 1.52 §? A 15 ml solution of ^, N-dimethylformamide was added dropwise, and the mixture was stirred for 1 hour under ice-cooling, and then stirred for 5.5 hours at room temperature. Then, 0.82 g of methanesulfonyl chloride and N-ethyl-N Then, 2.55 g of N-diisopropylamine was added, and the mixture was stirred at room temperature for 2 hours. After standing overnight, 2.5 g of sodium azide was added and the mixture was stirred at room temperature for 2 days. N, N-dimethylformamide was distilled off under reduced pressure, water was added, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 5), and R f value = 0.55 (silica gel thin layer chromatography; ethyl acetate: 3.5 g of the desired compound having hexane = 1: 5) was obtained.

(Reference Example 16)

2— _ (4-Aminomethylphenoxymethyl) _— 6-Methoxymethoxy 2,5_7_, 8-tetramethyl-2H-chromene

2-(4-Azidomethylphenoxymethyl) -1 6-methoxymethoxy-2,5,7,8-tetramethyl-1 2H-chromene 3.4 1 g of a 50 ml solution of tetrahydrofuran in ice The mixture was added dropwise to a mixture of 1.557 g of tetrahydrofuran and 10 Oml of lithium aluminum hydride under cooling, and the mixture was stirred at room temperature for 8 hours. The mixture was allowed to stand at room temperature for 3 S, and 1.6 ml of water, 1.6 ml of 10% sodium hydroxide, and 4.8 ml of water were added to the reaction mixture, followed by stirring at room temperature for 1 day. The insoluble material was separated by filtration, and the solvent was distilled off from the liquid under reduced pressure to obtain 2.8 g of the desired product.

(Reference Example 17)

6-Black mouth 2-Pin mouth pentinoleoxy-3-nitropyridine

Sodium hydride (55 wt./12.0 g) was washed with hexane, 100 ml of hexane was added, 25 ml of cyclopentanol was added dropwise under cooling with water, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled to 170 ° C, 2,6-dichloro-13-nitropyridine (116 g) was added in small portions, and the mixture was stirred at room temperature for 4 hours. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 20 → 1: 5) to give 54.8 g of the target compound as a yellow oil having an R f value of 0.70 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 5). Was.

(Reference Example 18)

6-Methoxymethoxy 2- (6-cyclopentyloxy-5-etropyridine-2-yloxymethyl) -1,5.7,8-tetramethylchroman

Sodium hydride (55 wt%) 3. llg, N, N-dimethylformamide 500 ml, 6-methoxymethoxy1-2-hydroxymethyl-1,2,5,7,8-tetramethinolechromane 20.0 g, 6-chloro-2-3-cyclopentynoleoxy-3-nitropyridine 19.0 Og was used, and the reaction was carried out according to Reference Example 7 to obtain R = 0.65 (silicone). Force gel thin-layer chromatography; Ethyl acetate: Hexane = 1: 3) 22.8 g of the compound were obtained. (Reference Example 19)

6-Hydroxy-1- (6-cyclopentyl-1-yl-5-etropyridine-12-yloxymethyl) 1,2,5,7,8-tetramethyl chroman

6-Methoxymethoxy-2- (6-cyclopentyloxy-5-tropyridine-12-loxymethyl) _2,5,7,8-tetramethylchroman 10.0 g, methanol 100 ml and 4N-HC 1 Z dioxane Using 100 ml of the solution, the reaction was carried out according to Reference Example 2, and the desired compound 9. Rg having an Rf value of 0.50 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3) was obtained. Obtained.

(Reference Example 20)

6-acetoxy-1 2- (6-cyclopentyloxy-5-nitropyridine 1-2-

-2, 5, 7, 8-tetramethylchroman

6-Hydroxy-2- (6-cyclopentinoleoxy-1-5-nitropyridine-12-yloxymethyl) 1,2,5,7,8-tetramethylchroman 9.0 g, pyridine 300 ml and acetic anhydride 5.8 Using m1, the reaction was carried out according to Reference Example 3 to obtain 8.85 g of the desired compound having a melting point of 98-99 ° C.

(Reference Example 21)

6-acetoxy-1- (5-amidoxy-6-octylpentoxyoxypyridine-2-yloxymethyl)-2,5,7,8-tetramethylchroman

6-acetoxy-1- (6-cyclopentyl-pentyloxy-5-nitropyridine-12-yloxymethyl) -2,5,7,8-tetramethylchroman 4.00 g, methanol 8 Om 1 and 10% palladium on carbon Using 0.70 g, react according to Reference Example 4 and obtain a target compound having a scale of 0.45 (silica gel thin-layer chromatography; ethyl ethyl sulphate: hexane = 1: 3). 3.73 g was obtained.

(Reference Example 22) 6-Methoxymethoxy 2- (2-chloro-4-ditrophenoxymethyl) 1,2,5,7,8-tetramethylchroman

2-Hydroxymethyl-1 6-Methoxymethoxy 2,5,7,8-Tetramethylchroman 10.0 g, N, N-Dimethinolehonolemamide 200 m 1, 4-Funoleo-1-chloro Nitrobenzene 7.25 g and sodium hydride (55 wt%) 1.7 lg were used for the reaction according to Reference Example 1, and the scale was 0.48 (silica gel thin layer chromatography; acetic acid). 15.2 g of the target compound was obtained as a yellow oil having ethyl: hexane = 1: 3).

(Reference Example 23)

6—Hydroxy-1 2 (2—Black 1 4 _Nitroph. 1 2, _5,

8-Tetramethinolechroman

6-Methoxymethoxy-2- (2-chloro-1-4-nitrophenoxymethyl) 1,2,5,7,8-tetramethylchroman 15.1 g, methanol 150 ml and 4 NH C 1 Z The target compound having a Rf value of 0.30 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3) was reacted with 50 ml of dioxane solution according to Reference Example 13. I got 6 R.

(Reference Example ₂₄ )

6-acetoxy-2— (2-chloro-4--4-diphenoxymethyl) 1,2,5,78-tetramethinolechromane

6-Hydroxy-1- (2-chloro-4-nitropheno-2,5,7,8-tetramethylchroman 13.3 g, 'pyridine 30 Om 1 and acetic anhydride 10.3 m 1 The reaction was carried out according to Reference Example 3 to obtain 14.8 g of the desired compound having a melting point of 121-124 ° C.

(Reference Example 25)

6-acetoxy-1 2 (4-amino-1 2-chloropheno 2, 5, --7

8—Tetramethy ^ / Chroman 6—a.Sethoxyxy 2— (2-chloro-1-4-ethrophenoxymethyl) -1,2,5,7,8-tetramethylchroman 4.00 g, methanol 160 m1, acetic acid 4 m1, and zinc 9. 64 g of the mixture was heated at reflux for 2 hours. The insoluble material was filtered, washed with ethyl acetate, and the oral solution was washed with saturated sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 2) ′ to give a value = 0.15 (silica gel thin-layer chromatography; ethyl acetate: Hexane = 1: 3) and 3.33 g of the desired compound having a melting point of 92-96 ° C were obtained.

(Reference Example 26)

3-[4-(6-Acetoxy- 1, 5,7,8-tetramethylchroman- 1 -ylmethyl) phenyl]-1 -Promopropionitrile

4-I (6-acetoxy-1,2,5,7,8-tetramethylchroman-2-inolemethoxy) aniline 18.6 g, acetone 105 ml 1, methanol 45 ml 1 into a mixture, ice-cooled Below 4 7. /. A solution of 36 ml of hydrobromic acid and then 4.7 ml of sodium nitrite in 12 ml of water was added dropwise. After stirring at the same temperature for 1.5 hours, 30 g of acrylonitrile was added, followed by cuprous bromide ', and the mixture was left overnight at room temperature. The solvent was distilled off 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. The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel gel chromatography (ethyl acetate: hexane).

There was obtained 16.58 g of the target compound as a yellow oil having 49 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 3).

(Reference Example 27)

4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-inolemethoxy) nitrile cinnamate

0.88 g of sodium hydride (55 wt ⁰ / o) was washed with hexane, N, N-dimethylformamide door Om 1 was added, and thiazolidine-1,2,4-dione 3.85 _§ was added to potassium hydroxide. Then, the mixture was stirred at room temperature for 20 minutes. Then, 3— [4— (6-acetoxy-1, 2, 5, 7, After adding 5.04 g of 8-tetramethylchroman-2-ylmethoxy) phenyl] -12-bromopropionitrile, the mixture was stirred at room temperature for 6 hours and left overnight. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain an R f value of 0.51 (silica gel thin-layer chromatography; ethyl acetate). : 1.5 g of a yellow oily target compound having hexane = 1: 3) and 1.2 g of the low-purity target compound were obtained.

(Reference Example 28)

3- [4— (6-acetoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] propylamine

Low-purity 4- (6-acetoxy-2,5,7,8-tetramethylchroman-1-ylmethoxy) obtained in (Reference Example 27) 1.2 g of nitrile cinnamate, 100 m of acetic acid

A mixture of 2.0 g of 1 and 10% palladium on carbon was stirred at room temperature for 2 [3] under a hydrogen atmosphere. The insolubles were separated and the oral liquid was concentrated to obtain 1.16 g of the target product containing the desired product.

(Reference Example 29)-

4— (6-Methoxymethoxy 2,2,5,7,8-tetramethylchroman-l-methoxy) 1-N-methyla-line

'4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) ferrin 3 7.37 g of tetrahydrofuran 300 ml solution under ice-cooling 11.3 g and then 15 ml of triethylamine were added dropwise. The reaction mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, the organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. After the treatment with activated carbon, the solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane to give a compound having a melting point of 143-145 ° C, N- [4- (6-methoxymethoxy-1-2). , 5,7,8-Tetramethinolechroman-1-2-isolemethoxy) feninole] acetinolecanomate, 38.2 g was obtained.

Sodium hydride (55./.) 2. After washing 18 g with hexane, N, N-dimethyl Add 250 ml of formamide, and cool 22.1 g of N- [4- (6-Methoxymethoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -ethylcabamate The mixture was added under reduced pressure and stirred at the same temperature for 1 hour. Then, 7.5 g of methyl iodide was added dropwise, and the mixture was stirred for 6 hours under ice cooling. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with ethyl acetate, the extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give R fi = 0.58 (silica gel thin layer chromatography; ethyl ethyl sulfate). Hexane = 1: 3), N- [4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) phenyl] -N-methylethylcarbamate 22 g was obtained.

A solution of 3.3 g of sodium hydride (55%) in a mixture of 40 ml of ethanol and 50 ml of tetrahydrofuran was added to a solution of N- [4- (6-acetoxy-2,5,7,8-tetramethynole). Chroman-1-dimethoxy) phenyl] —Ν-methinoletinol carbamate was added to a solution of 21.3 g of ethanol in 20 ml of ethanol, and the mixture was stirred at room temperature for 8.5 hours. The reaction mixture was concentrated, ice and ethyl acetate were added, and the mixture was adjusted to pH 5 with 1N hydrochloric acid. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give a compound having a melting point of 129-130 ° C, N- [4- (6-hydroxy1-2,5). , 7,8-tetramethylchroman-2-ylmethoxy) phenyl] —N-methylethylcarbamate — 14.15 g was obtained.

After washing 1.37 g of sodium hydride (55./o) with hexane, N, N-dimethylformamide 20 Om1 was added, and then N- [4- (6-hydroxy-1-2) was added under ice cooling. , 5,7,8-Tetramethylchroman_2-inolemethoxy) phenyl] -N-methylethylcarbamate 13.0 g was added, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 1 hour. Then, under ice-cooling, 3.17 g of chloromethyl methyl ether (15 ml) of N, N-dimethylformamide was added dropwise, and the mixture was stirred under ice-cooling for 5 hours and left overnight at room temperature. The solvent was distilled off under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent is distilled off and N— [4-(6 -Methoxymethoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -N-methylethylcarbamate 15.3 g was obtained.

To a solution of 20 g of hydroxide hydroxide in 500 ml of methanol, 80 ml of ethanol and 150 ml of water was added N- [4- (6-methoxymethoxy-1,2,5,7,8-tetramethylchromane). 2-Inolemethoxy) phenyl] —N-methinolecinolecarbamate 13.04 g was added, and the mixture was heated under reflux for 30 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 11.2 g of a desired crude product. (Reference Example 30)

4-1-toro 4 '-(2-oxopropoxy) biphenyl

4-Hydroxy_4'-ditrobiphenyl 3.00 g, cesium carbonate 9.12 g, 1.69 ml of acetone, and 80 ml of acetone 100 ml of a mixture of 16.5 hours at room temperature followed by 43 ° C. The mixture was stirred for 7 hours, and acetone (1.13 ml) was added thereto, followed by stirring overnight. The insolubles were separated and the oral solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 2: 5 → 1: 1) to give an R f value = 0. 3.07 g of the desired compound having 46 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 1) was obtained.

(Reference Example 3 1)

4- (6-acetoxy-1_4_oxo-1, 2,5,7,8-tetramethylchroman 2-1-normethoxy) 1-4'-Nitrobifu-norre

3-acetoxy-6-hydroxy-1,2,4,5-trimethylacetophenone 2.34 g, 4-toro-4 '-(2-oxopropoxy) biphenyl 2.68 g, mouth lysine 1. A mixture of 64 ml, 50 ml of methanol and 20 ml of tetrahydrofuran was stirred at 40 ° C for 1 day. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane == 1: 4 → 1: 2 → 1: 1) to obtain an R f value = 0.42 (silica gel thin film). Layer chromatography Chromatography: 3.08 g of the desired compound having ethyl acetate: hexane = 1: 2) was obtained.

(Reference Example 3 2)

—4-1-1 [4-1- (6-acetoxy-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] phenyl

4- (6-acetoxy-1 4-oxo-1 2,5,7,8-tetramethylchroman-12-ylmethoxy) 1-4'12-trobiphenyl 2.91 g, ethanol 6 Om l, tetrahydrofuran 30 ml Using 0.29 g of 10% palladium on carbon, the reaction was carried out according to Reference Example 4 to obtain 1.41 g of the desired compound having a melting point of 180 ° C. (decomposition).

(Reference Example 33)

2- (4-Methoxycarboylphenoxymethyl) -1-2-methyl-4-oxochroman

A mixture of 2-hydroxyacetophenone 9000 g, 4- (2-oxopropoxy) benzoic acid methyl ester 13.8 g, pyrrolidine 5.5 ml and methanol 20 Om 1 was reacted at room temperature for 2 days. . The reaction mixture was poured into water, and ethyl acetate was added. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 3), and the 1¾ £ value = 0.38 (silica gel thin-layer chromatography; ethyl acetate: hexane). 20. lg of the desired compound having the xane = 1: 3) was obtained.

(Reference Example 34)

4- (2-Methylchroman-4-oxo-1-2-methoxy) benzoic acid

Dissolve 9.00 g of 2- (4-methoxycarbonylphenoxymethyl) -2-methyl-4-oxochroman in 100 ml of methanol, add 100 ml of 1N sodium hydroxide, and add room temperature. The mixture was stirred for 5 hours. After standing overnight, 2N hydrochloric acid (5 Om 1) was added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was mixed with hexane-ethyl acetate. Recrystallization from the solvent gave 8.34 g of the desired compound having a melting point of 172-173 ° C. (Reference example 3 5)

4- (2-Methylchroman-1-oxo-2--2-methoxy) benzoic acid amide

4- (2-Methylchroman-1-oxo-2-ylmethoxy) benzoic acid To a solution of 5.00 g of tetrahydrofuran in 10 Om 1 under ice-cooling, 3.4 ml of triethylamine, then ethyl ethyl carbonate 1. 9 ml was added dropwise, and the mixture was stirred at room temperature for 2 hours. 11 ml of concentrated aqueous ammonia was added dropwise to the reaction mixture under ice cooling, followed by stirring at room temperature for 4 hours. After standing overnight, it was poured into water, extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate). ) Was obtained 2.60 g. -

(Reference Example 36)

4- (4-Hydroxy-1-methylchroman-2-ylmethoxy) benzylamine into a mixture of 0.59 g of lithium aluminum hydride and 50 ml of tetrahydrofuran 4- (2-methylchroman-4-oxo1-2) —Ilmethoxy) benzoic acid amide 2.20 g of a tetrahydrofuran 2 Om1 solution was added dropwise, and the mixture was heated under reflux for 1.5 hours. After standing overnight, 0.6 ml of water and then 0.61111 of 15% sodium hydroxide and 1.8 ml of water were added to the reaction mixture under ice cooling, followed by stirring at room temperature for 1 hour. The insoluble material is separated by filtration, and the solvent is distilled off from the liquid under reduced pressure. The target substance having an R f value of 0.10 (silica gel thin layer chromatography; ethyl acetate: ethanol = 1: 1) 1. 92 g were obtained.

(Reference Example 37)

4- (2-methyl-2H-chromene-2-ylmethoxy) benzylamine

4- (4-Hydroxy-2-methylchroman-1-ylmethoxy) benzylamine 1.50 g, benzene 50 ml, and p-toluenesulfonic acid monohydrate 1.14 g were used. React accordingly! Direct = 0.05 (Silica gel thin layer chromatography Chromatography: 1.20 g of the desired compound having ethyl acetate: ethanol = 1: 1) was obtained.

(Reference example 3 8)

2— [4— (6-Acetoxy-1-4-oxo-1,2,5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl]

3-acetoxy 6-hydroxy-1,2,4,5-trimethylacetophenone 2 2.

A mixture of 6 g, 2- [4- (2-oxopropoxy) phenyl] ethanol (20.4 g), pyridine (6.8 g) and methanol (547 ml) was reacted at room temperature for 1 day. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3 → 1: 2 → 2:

By applying 1), 9.77 g of the target compound having R fi = 0.18 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 2) was obtained.

(Reference example 3 9)

2— [4— (6-Acetoxy-1-4-oxo_2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] ethylazide

2— [4 -— (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] ethanol 9.3 8.g of N, N-dimethinoleformamide 1 To the solution of 00 ml, 3.25 g of methanesulfoyl chloride and then 3.3 ml of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 4 hours. 0.15 g of potassium iodide and 3.70 g of sodium azide were added, and the mixture was stirred at room temperature for 1 day. N, N-Dimethylformamide was distilled off under reduced pressure, water was added, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain an R f value of 0.44 ′ (silica gel thin-layer chromatography; ethyl acetate). : Hexane = 1: 4) to give 9.37 g of the desired compound. (Reference Example 40)

2_- [4-(6-Acehexi-1-oxo-1,2,5,7,8-Tetramethylchromane-l-ylmethoxy) phenyl] ethylamine

2- [4- (6-acetoxy-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] ethylazide 8.16 g, methanol 50 m and tetrahydrofuran 14m 1 and 1 A mixture of 4.86 g of 0% palladium on carbon was stirred for 1 day under a hydrogen atmosphere. The insoluble material is filtered off, the solvent is distilled off from the liquid under reduced pressure, and the residue is subjected to silica gel column chromatography (ethyl acetate → ethyl acetate: ethanol = 5: 1 → 7: 3). 1.81 g of the title compound having a melting point of 65-72 ° C. were obtained.

(Reference example 4 1)

4- (6-hydroxy-1-4-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) nitrobenzene

4- (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-12-ylmethoxy) 5.0 g of ditrobenzene, 100 ml of methanol, 50 ml of tetrahydrofuran and 50 ml of sodium methyl Using 20 g of a 28% methanol solution of toxide, react according to Example 2, and obtain an R f value of 0.31 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3). 4.5 g of the desired compound were obtained.

(Reference Example 42)

4- (6-Methoxy-1-4-oxo-1,2,5_7,8-Tetramethylchroman-2-ylmethoxy) nitrobenzene

4- (6-hydroxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) nitrobenzene 4.48 g, potassium carbonate 10.0 g, methyl iodide 7.2 g and A mixture of N, N-dimethylformamide 10 Om 1 was stirred at room temperature for 10 hours. N, N-dimethylformamide was distilled off under reduced pressure, water was added, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and R fi = 0.49 (silica gel thin layer chromatography; Hexane = 1: 3) to give 4.6 g of the desired compound. (Reference Example 43)

4- (6-Methoxy-1-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline

4- (6-Methoxy-1-4-oxo-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) nitrobenzene 4.6 g, methanol 250 ml, tetrahydrofuran 5 Om 1 and 10% palladium on carbon 2. Using 1 g, react according to Reference Example 4 and obtain the desired compound having an Rf value of 0.16 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3) 3.76 g I got

(Reference Example 44)

4- 丄 6-Etro-4-oxo: 2.5,7,8-tetramethylchroman-2-ylmethoxy) nitrobenzene

3-nitro-6-hydroxy-1,2,4,5-trimethylacetophenone 11.2 Og, 4- (2-oxopropoxy) nitrobenzene 9.80 g, pyrrolidine 4.0 m1 and methanol 200 ml of the mixture was stirred at room temperature for 3 days. The precipitated crystals were taken out to obtain 13.5 g of the desired compound having a melting point of 143-152 ° C.

(Reference Example 45)

4- (6-Amino-4-oxo-1,2,5,7,8-tetramethylchroman-2 f-Lumethoxy) anilin

4- (6-nitro-4-oxo-1,2,5,7,8-tetramethinolechroman-2-ylmethoxy) ditrobenzene 3.5 g, methanol 100 ml, tetrahydrofuran 5 Om 1 and Using 3 g of 10% palladium on carbon, the reaction was carried out according to Reference Example 4 to obtain 2.8 g of the desired compound having an Rf value of 0.43 (silica gel thin-layer chromatography; ethyl acetate).

(Reference Example 46) N- [4- (6-acetoxy-1,2,5.7,8-tetramethylchroman-1-yl ethoxy) phenyl] -methyl methanesulfonamide

4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline 120 g of tetrahydrofuran 1000 ml solution under ice-cooling 60 ml was dropped. The reaction mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and saline and ethyl acetate were added to the residue. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to 500 ml, hexane (500 ml) was added, and the precipitated crystals were taken out and recrystallized from methanol to obtain 92.5 g of the desired product having a melting point of 138 to 140 ° C.

(Reference Example 47)

4- (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy)

5-Acetoxy 2-hydroxy-1,3,4,6-trimethylacetophenone 25.1 g, 4- (2-oxopropoxy) methyl phenylacetate 26 g, Pyrrolidine 7.8 g and methanol 480 g. The reaction was carried out according to Reference Example 38 to obtain 17.5 g of the desired compound having R = 0.41 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3).

(Reference example 48)

4- (8-hydroxy-4,1-oxo-1,2,5,6,7-tetramethylchroman-12-ylmethoxy) aniline

4- (8-hydroxy-1,4-oxo-2,5,6,7-tetramethylchroman-2-inolemethoxy) 1.52 g of ditrobenzene, methanol 100 ml, tetrahydrofuran 3 Om 1 and 10% palladium on carbon Using 0.70 g, the reaction was carried out according to Reference Example 4 to obtain 1.14 g of the target compound having an Rf value of 0.56 (silica gel thin-layer chromatography; ethyl acetate: hexane = 2: 1). . (Reference example 49)

Acetic acid 2,3,5-trimethyl fuel ester

85 ml of acetyl chloride was added dropwise to a mixture of 136 g of 2,3,5-trimethylphenol, 167 ml of triethylamine and 1000 ml of tetrahydrofuran under ice cooling. After stirring at room temperature for 1 hour, the mixture was left overnight. The solvent was distilled off under reduced pressure, water was added, the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and R

185 g of the desired compound having 49 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 3) was obtained.

(Reference example 50)

2-hydroxy-1,3,4,6-trimethylacetophenone

257 ml of titanium tetrachloride was added dropwise to a solution of 185 g of 2,3,5-trimethyl acetic acid acetic acid in 1 000 ml of 1,2-dichloroethane under ice cooling. After heating and refluxing for 2 hours, it was left overnight. The reaction mixture was poured into water, extracted with 1,2-dichloroethane, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 20), and R¾ = 0.52 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1:10 g) was obtained.

(Reference Example 51)

2-hydroxy-1-4-nitro-1,4,6-trimethylacetofe

To a solution of 177 g of 2-hydroxy-1,3,4,6-trimethylacetophenone in 400 ml of acetic acid was added dropwise a solution of 200 ml of acetic acid in 63 ml of concentrated nitric acid under ice cooling. After stirring at room temperature for 3 hours, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, washed with an aqueous sodium carbonate solution, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1: 10) to obtain an R f value = 0.24 (silica gel thin-layer chromatography; ethyl acetate: 188 g of the desired compound having hexane = 1: io) were obtained. (Reference Example 5 2)

4- (2-oxopropoxy) benzylalkonyl

4-Hydroxybenzyl alcohol 30.0 g, bromoacetone 20.3 m and cesium carbonate 69.9 g and acetone 60 Om1 were reacted according to Reference Example 30 to obtain R Hfi = 36.0 g of the desired compound having 0.23 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 2) was obtained.

(Reference Example 53)

4- (4-oxo-6-nitro-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl alcohol

2-hydroxy-5-nitro-3,4,6-trimethylacetophenone 22.3 g, 4- (2-oxopropoxy) benzyl alcohol 18.0 g, pyrrolidine 8.4 g and methanol Using 500 ml, the reaction was carried out according to Reference Example 38, and the target compound having an Rf value of 0.23 (thin layer chromatography on silica gel; ethyl acetate: hexane = 1: 1) 1 5. 8 g were obtained.

(Reference example 54)

4- (4-oxo-6-nitro-1,2,5,7,8-tetramethylchroman_2-ylmethoxy) benzylazide

4- (4-oxo-6-nitro-1,2,5,7,8-tetramethinolechroman-1-ylmethoxy) benzyl alcohol 6.00 g, N, N-dimethylformamide 1

Using 20 ml, methanesulfonyl chloride 3.6 m 1, triethylamine 8.6 m 1 and sodium azide 5.05 g, the reaction was carried out according to Reference Example 39, and the Rf value was 0.

4.10 g of the desired compound having 39 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 3) was obtained.

(Reference Example 5 5)

4- (4-oxo-1-6-nitro-1,2,5,7,8-tetramethinolechroman-1-ylmethoxy) benzylamine 4- (1-oxo-6-nitro-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl azide 3.50 g, triphenylphosphine 3.36 g and tetrahydrofuran 50 ml Was stirred at room temperature for 1 hour and then at 60 ° C. for 1 hour. 5 ml of water was added to the reaction mixture, and the mixture was stirred at 60 ° C for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 10: 1), Rί value = 0.24 (silica gel thin-layer chromatography; ethyl acetate). : Hexane = 1: 10) 2.60 g was obtained.

(Reference Example 5 6)

N— [4 -— (6-acetoxy 2,5,7,8-tetramethylchroman-12 f-methoxy) phenyl]-1-t-butoxycarbonyl nipecotic acid amide

Dipecotic acid 1. 2 9 8? To a 20 ml solution of ^, N-dimethylformamide was added 2.18 g of di-t-butyldiphenyl-one-port and sonicated for 1 hour. 1.62 g of 1,1′-carbonyldiimidazole was added to the reaction mixture, and the mixture was subjected to ultrasonic treatment for 0.5 hour, and then treated with 4- (6-acetoxy-1,2,5,7,8-tetraethyl). Methylchroman — 2-ilmethoxy) aniline (3.71 g) was added and sonicated for 1 hour. N, N-Dimethylformamide was distilled off under reduced pressure, water was added to the residue, extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 2), and R = 0.75 (silica gel thin-layer chromatography; ethyl acetate: hexane). 3.2 g of the target compound having the following formula: xane = 2: 1) was obtained.

(Reference Example 5 7)

3- (2-oxopropoxy) -trobenzene

Using 10-Og 3-bromo-2-enol, 6.6 ml bromoacetone, 10.92 g potassium carbonate and 10 Om1 N, N-dimethylformamide, according to Reference Example 30 Reaction, Rf value = 0.55 (silica gel thin layer chromatography; ethyl acetate: Hexane = 1: 1.96 g of the target compound having 1) was obtained. (Reference Example 58)

—3-(4-oxo-6-nitro-2,5,7,8-tetramethylchroman-1-ylmethoxy) nitrobenzene

2-hydroxy-1-5-nitro-1,3,4,6-trimethylacetophenone 1.5.1 g, 3- (2-oxopropoxy) nitrobenzene 13.96 g, pyrrolidine 5.4 m1 and Reaction with 250 ml of methanol according to Reference Example 38 and the desired compound having an Rf value of 0.19 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 2) 15.16 g I got

(Reference example 59)

3- (6-amino-1-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) aniline

3- (4-oxo-1-6-nitro-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) ditrobenzene 1 5.16 g, ethanol 200 ml, tetrahydrofuran 20 m 1 And 1.52 g of 10% palladium on carbon, reacted according to Reference Example 4 to obtain R fi = 0.44 (silica gel thin-layer chromatography; ethyl acetate: hexane = 3: 1). 5.74 g of the compound were obtained.

(Reference Example 60)

4 12-Trophenoxyacetic acid t-butyl ester

To a solution of 50-mg of 4-ditrophenol in 1 Oml of N, N-dimethylformamide was added 1-75 mg of 55% sodium hydride [I, and stirred at room temperature for 1 hour to obtain bromoacetic acid t-butyl ester 0.59. m 1 was added and the mixture was stirred at room temperature for 2.5 hours. The solvent was concentrated 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. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 10 → 1: 5) to obtain R fg; = 0.32 (silica gel thin layer chromatography). ; Ethyl acetate: Hexa 0.73 g of the desired compound having the following formula: 1:10) was obtained.

(Reference example 6 1)

4-Nitrophenoxyacetic acid

4-N-mouth phenoxyacetic acid t-butylesterol 0.77 g of a dioxane 10 m 1 solution was added with 4 N—HC 1 _ / dioxane solution 10 m 1 and stirred at 70 ° C. for 3.5 hours. . The solvent was concentrated under reduced pressure to obtain 0.55 g of the desired compound having an Rf value of 0.01 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 2).

(Reference Example 62)

4 12-mouth phenoxyacetic acid 2-acetyl 4-nitro-1 3,5,6-trimethynolepheninoleestenole

To a solution of 50 Omg of 4-ditropoxyacetic acid and 0.39 ml of triethylamine in 15 ml of tetrahydrofuran was added dropwise 0.27 ml of ethyl chlorocarbonate, and the mixture was stirred at room temperature for 1 hour. —Nitro-1,4,6-trimethylacetophenone (625 mg) was added, and the mixture was stirred at room temperature for 1 hour and left overnight. The solvent was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 3 → 1: 2) to give R fi = 0.35 (silica gel thin layer chromatography; 0.32 g of the desired compound having ethyl acetate: hexane = 1: 2) was obtained.

(Reference Example 63)

2-Hydroxy-1-6-trow 2- (4-ditrophenoxymethyl) -4-oxo-1-5,7,8-trimethyl

4-Nitrophenoxyacetic acid 2-acetyl-1-4-nitro-1,3,5,6-trimethinolephenyl ester 0.34 g of 1,8-diazabicyclo [5,4,0] -17 in a 10 ml suspension of toluene —Dendene 0.12 _§ was stirred at room temperature for 1 hour and then left overnight. Concentrate the solvent under reduced pressure, add water to the residue, extract with ethyl acetate, extract The solution was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 3 → 1: 2 → 1: 1) to obtain RHi: = 0.50 (silica gel thin layer). Chromatography I: Ethyl acetate: Hexane = 1: 1 1) yielded 0.18 g of the desired compound.

(Reference Example ₆₄ )

6-Amino-2- (4-aminophenoxymethyl) 1-2-Hydroxy-1-oxo-5,7,8-Trimethinolechromane

2-hydroxy-6- -toro-2- (4-ditrophenoxymethyl) -14-oxo-5,7,8-trimethinolechroman 400 mg, 10% palladium on carbon 40 mg and ethanol 1 The mixture of Om 1 was stirred under a hydrogen atmosphere at 50 ° C. for 11 hours. 10% Pd—Carbon is separated off, the solvent is distilled off under reduced pressure, and the target compound having a value of 0.59 (silica gel thin layer gel chromatography; ethyl acetate) 0.35 g was obtained.

(Reference example 65)

4- (6-amino-4-oxo-5,7,8-trimethylchromene-2-ylmethoxy) anilin

6-Amino 2- (4-aminophenoxymethyl) 1-2-Hydroxy-1-oxo-5,7,8-Trimethylchroman 0.35 g, acetic acid 6 ml and 30% HBr vinegar A mixture of 1 ml of the acid was stirred at room temperature for 0.5 hour. The reaction mixture was poured into ice water, and the precipitate was taken out to obtain 0.19 g of the desired compound having an Rf value of 0.57 (silica gel thin-layer chromatography; ethyl acetate).

(Reference Example 6 6)

6-Methoxymethoxy-2- (4-nitro-3--3-trifluoromethylphenoxymethyl) -1,2,5,7,8-tetramethylchroman

2-Hydroxymethyl-1 6-Methoxymethoxy 2,5,7,8-Tetramethylchromane 6.26 g, N, N-Dimethinolehonolemamide 120 ml, 4-Chloro-3 The reaction was carried out in the same manner as in Reference Example 1 using 3.3 m 1 of monotrifluoronitrobenzene and 0.97 g of sodium hydride (55 wt%), and R g = 0.43 (silica gel thin layer chromatography; ethyl acetate). : Hexane = 1: 3) to give 6.95 g of the target compound as a yellow oil.

(Reference example 67)

6-hydroxy-1- (4-nitro-3-trifluoromethylphenoxymethyl)-2,5,7,8-tetramethylchroman

6-Methoxymethoxy-2- (4_nitro-13-trifluoromethylphenoxymethyl)-2,5,7,8-tetramethylchroman 6.86 g, methanol 70 m1 and 4 NHC1 dioxane solution The reaction was carried out in the same manner as in Reference Example 2 using 7 Om 1, and the R f value was 0.40 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 3). I got

(Reference Example 68)

6-acetoxy-l 2_ (4-l- 3-l-trifluoromethylphenoxymethyl)-2,5,7.8-tetramethinolechroman

6-Hydroxy-l 2- (4-L-tallow 3-trifluoromethylphenoxymethyl) 1,2,5,7,8-tetramethylchroman 5.77 g, pyridine 12 Om 1 and acetic anhydride The reaction was carried out according to Reference Example 3 using 3.9 ml to give 5.93 g of the desired compound having a melting point of 1 1 1 to 1 1 14 ° C.

(Reference example 69)

6-acetoxy—2— (4-amino3—trifluoromethylphenoxymethyl) —2,5,7,8—tetramethinolechromane

6-acetoxy-1 2— (4-nitro_3 _ triphenylenomethyl phenoxymethyl) _2,5,7,8-tetramethynolechromane 2.20 g, methanol 4 Oml and 10% palladium on carbon 0 The reaction was carried out according to Reference Example 4 using 40 g, and R = 0.55 (silica gel thin-layer chromatography; ethyl acetate: hexane = 1: 2). 2.06 g of the desired compound was obtained. (Reference example 70)

3- (2-oxopropoxy) benzene

After dissolving 4.0 g of m-ditrophenol in 8 Om 1 of acetone and adding 9.37 g of cesium carbonate, 2.42 ml of bromoacetone was added dropwise at room temperature, stirred for 1 hour at room temperature and left overnight. did. 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 is distilled off from the extract, and the residue is subjected to silica gel column chromatography (ethyl acetate: _n- hexane).

5.28 g of the target compound having 37 (silica gel thin-layer chromatography; ethyl acetate: _n- hexane = 1: 2) was obtained.

(Reference example 71)

3- (6-acetoxy-1-oxo-1,2,5,7,8-tetramethylchroman-1-2-inolemethoxy) nitrobenzene

3-acetoxy-6-hydroxy-2,4,5-trimethy ^^ acetophenone 5.75 g 3- (2-oxopropoxy) ditrobenzene 4.75 g, anhydrous methanol 100 ml and The reaction was carried out according to Reference Example 44 using 2.03 ml of pyrrolidine. 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: 3), and R = 0.48 (silica gel thin layer chromatography; ethyl acetate: _n— The target compound having hexane = 1: 2) and 3 _ (6-hydroxy-1-4-oxo-1) having R f value = 0.43 (silica gel thin-layer chromatography; ethyl acetate: _n- hexane = 1: 2) 7.34 g of a mixture of 2,5,7,8-tetramethylchroman_2-ylmethoxy) nitrobenzene was obtained.

Subsequently, the resulting 3- (6-acetoxy-4-oxo-1, 2,5,7,8-tetra Mixture of methinolechroman-2-ylmethoxy) nitrobenzene and 3- (6-hydroxy-14-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) nitrobenzene 7.34 g of pyridine The residue was dissolved in 14 Om1, and 1.81 g of acetic anhydride was added. The mixture was stirred at room temperature for 2 hours and left overnight. The solvent was distilled off from the reaction mixture under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed sequentially with a 2N aqueous hydrochloric acid solution, water and saturated saline, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off to obtain 7.67 g of the target compound having an Rf value of 0.34 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 3).

(Reference example 72)

3- (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) arin.

3- (6-acetoxy-4-oxo-1,2,5,7,8-tetramethylchroman-12 f-methoxy) 7.55 g of nitrobenzene, 0.76 g of 10% palladium on carbon and 14 Om 1 of methanol The reaction was carried out according to Reference Example 4. After completion of the reaction, 10% palladium carbon was removed by filtration, and methanol was distilled off from the filtrate. The residue was subjected to silica gel column chromatography (ethyl acetate: _n- hexane = 1: 2), and the Rf value was 0.19 (silica gel thin-layer chromatography; ethyl acetate: n-hexane = 1: 2). 6.13 g of the desired compound having

(Reference example 73)

(6-hydroxy-1-41,2,5,7,8-tetramethinolechroman _2 -ilmethoxy) anilin

4- (6-hydroxy-4-oxo-1,2,5,7,8-tetramethinolechroman—2-ylmethoxy) nittobenzene 20. Og, methanol 300 ml and 10% palladium on carbon 2.0 Using g, the reaction was carried out according to Reference Example 4 to obtain 14.4 g of the desired compound having a melting point of 133-135 ° C. (Reference example 74)

6-Hydroxy-1- (5-aminoviridine-1-yloxymethyl) -1,2,5,7,8-tetramethinolechroman

6-Hydroxy-2- (5-nitropyridine-1-yloxymethyl) -1,2,5,7,8-tetramethinolechroman 3.50 g, methanol 5 Om 1 and 10 ^ο / ο ヽ. The target compound 3 was reacted with 0.70 g of radium carbon according to Reference Example 4 and having R fi = 0.05 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 2). 20 g were obtained.

(Reference example 7 5)

6-Hydroxy-1- (4-amino-1-2-trifluoromethylphenoxymethyl) -1,2,5,7,8-Tetramethylchroman

6-Hydroxy-1-2- (4--Tro-2--2-trifluoromethylphenoxymethyl) 1,2,5,7,8-Tetramethylchroman 1 1.O g, 200 ml of methanol and 10% palladium on carbon 1 The reaction was carried out according to Reference Example 4 using 1 g, and R

10.1 g of the desired compound having 19 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 2) was obtained.

(Reference Example 76)

4- (6-hydroxy-1,2,5,7.8-tetramethylchroman-2-ylmethoxy) aniline

4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) 100 g of phosphorus, 1000 ml of methanol, 500 ml of tetrahydrofuran and 28% methanol solution of sodium methoxide The reaction was carried out according to Example 2 using 9.6 ml to obtain 88.6 g of the desired compound having a melting point of 121-122 ° C.

(Reference Example 7 7). 4- (6-Acetoxy-1-oxo-5,2,5,7,8-Tetramethylchroman-1-ylmethoxy) aniline

4- (6-acetoxy-1-oxo-2,5,7,8-tetramethylchroman-2-ylmethoxy) ditrobenzene 10.0 g, methanol 200 ml and 10% palladium carbon 1.0 g for reference The reaction was conducted according to Example 4, and 7.25 g of the desired compound having a melting point of 166 ° -167 ° C. was obtained.

(Reference Example ₇ 8)

4-Nitrophenoxyacetic acid 4-Acetoxy-l-Acetyl-l, 3,5,6-Trimethynolefene / Lestenole

5. Oml of thionyl chloride was added to 30 Omg of 4-nitrophenoxyacetic acid, and the mixture was heated under reflux for 30 minutes. Then, excess of thionyl chloride was distilled off under reduced pressure, and 5.Oml of anhydrous methylene chloride was added to the residue. This solution is added to a mixture of 4-acetoxy-2-acetyl-1,3,5,6-trimethylphenol 36 Omg, trimethylamine 0.2 ml and anhydrous methyl chloride 5.Oml, and the mixture is added at room temperature for 3 hours. Stirred. The solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: _n- hexane = 1: 2) to obtain 431 mg of the desired compound having a melting point of 177-179 ° C. .

(Reference example 79)

4- (6-acetoxy 2-hydroxy-1 4-oxo-1,5,8-trimethinole romone 2-inolemethoxy) Nitrobenzene

4-Nitrophenoxyacetic acid 4-acetoxy-2-acetyl-1,3,5,6-trimethylphenyl ester 4.0 g is dissolved in anhydrous tetrahydrofuran 150 ml, and potassium t-butoxide 1.08 g is added thereto, and ice is added. After stirring for 1 hour under cooling, the mixture was allowed to stand at room temperature. The solvent was distilled off from the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Acetic acid from the extract The ethyl was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane-2-1: 2) to obtain 1.25 g of the desired compound having a melting point of 193-196 ° C.

(Reference example 80)

4- (6-acetoxy-1-4-oxo-5,7,8-trimethylchromene-2-ylmethoxy) ditrobenzene

4 _ (6-Acetoxy-1 2-Hydroxy-1 4-Oxo-1 5,7,8_Trimethinole chroman-2-Inolemethoxy) Nitrobenzene 1.25 g of acetic acid 27 m and 30% hydrogen bromide / acetic acid 2 .0 ml was added, and the mixture was stirred at room temperature for 1.5 hours. The precipitated crystals were collected by filtration and washed with water and ether to obtain 0.98 g of the desired compound having a melting point of 203-207 ° C.

(Reference example 81)

4- (6-acetoxy-1 4-oxo-5,7,8-trimethylchroman-2-ylmethoxy) anilin

3 _ (6-acetoxy-1-oxo-5,7,8-trimethylchromene_2-ylmethoxy) A mixed solvent of 702 mg of ditrobenzene in 1,20 ml of 1,4-dioxane and 20 ml of ethanol And 0.74 ml of triethylamine and 340 mg of 10% palladium on carbon were added, followed by stirring under a hydrogen atmosphere for 24 hours. After filtering off the palladium carbon from the reaction mixture, the solvent was distilled off under reduced pressure, water was added, 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: 1 → 3: 2 → 2: 1) to obtain an R f value of 0.15. There was obtained 27 mg of the target compound having the following properties (silica gel thin-layer chromatography; ethyl ethyl sulphate: n-hexane = 1: 1).

(Reference Example 82)

4-nitrophenoxyacetic acid 2-acetyl 4-t-butoxycarboeramino — 3, 5, §— trimethinolephenyl ester

1.95 g of 2-acetyl-1-t-butoxycarbonylamino-3,5,6-trimethylphenol and 1.3 lg of 4-nitrophenoxyacetic acid were combined with anhydrous tetrahydrofuran 4 Om 1, anhydrous N, Dissolved in a mixed solvent of N-dimethylformamide 4 Om 1 and mixed with N-hydroxybenzotriazo mono hydrate 1.53 g, 1- [3- (dimethyl / reamino) propyl] ― 3— 3.4 g of ethyl carbodiimide hydrochloride and 826 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: _n- hexane = 1: 3 → 1: 2) to have a melting point of 151-153 ° C. 1.3 g of compound were obtained.

(Reference Example 8 3)

4- (6-t-butoxycarbonylamino_2-hydroxy-4-oxo-5,7,8-trimethylchroman-21-ylmethoxy) nitrobenzene

4-Nitrophenoxyacetic acid 2-acetyl-41-butoxycarbonylamino-1,3,5,6-trimethylphenyl ester 944 m, g was dissolved in anhydrous tetrahydrofuran 45 ml, and t-butoxy potassium 2 24 mg And stirred under ice cooling for 4.5 hours. The solvent was distilled off from the reaction mixture under reduced pressure, water was added, and the extract extracted with ethyl acetate was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: _n- hexane = 1: 2 → 1: 1), R f value = 0.55 (silica gel thin layer chromatography). There was obtained 36 1 mg of the target compound having the following characteristics: n-hexane: ethyl acetate = 1: 1).

(Reference example 84)

4- (6-amino-4-oxo-1,5,7,8-trimethylchromene-1-ylmethoxy) ditrobenzene 4-(6-t-butoxycarbonylamino-2-hydroxy-4, oxo-1,5,7,8-trimethylchroman-1-2- ^ flumethoxy) Ditrobenzene 416 mg is dissolved in acetic acid 1 Om 1 And 30% hydrogen bromide acetic acid 71 ^ 1, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture, the precipitated crystals were suspended in a filter and the precipitated crystals were collected by filtration and washed with ether to give 291 mg of the desired compound having a melting point of 238-240 ° C.

(Reference example 85)

3- (6-amino-4-oxo-5,7,8-trimethylchroman-2-ylmethoxy) aniline

3- (6-amino-4-oxo-5,7,8-trimethylchromene-2-ylmethoxy) 243 mg of ditrobenzene is dissolved in a mixed solvent of 70 ml of 1,4-dioxane and 25 ml of ethanol was added Toryechiruamin 0. 29m l and 10 ^_0/0 para Jiumu carbon 1 2 Omg, it was stirred under a hydrogen atmosphere for 29 hours. After palladium carbon was filtered off from the reaction mixture, the solvent was distilled off under reduced pressure, water was added, 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: 1 → 2 _: 1) to give the target compound having a melting point of 129-132 ° C. 79 mg were obtained.

(Reference Example 86)

N— (3-Acetyl-4-Hydroxyphenyl) 1-t-butyl carbamate

2-hydroxy-5-nitroacetophenone 2.50 g of ethanol 5 Om 1 solution, triethylamine 2.1 ml, di-t-butyl dicarbonate 3.4 ml and 10% palladium carbon 0.25 g was added, and the mixture was stirred for 1 hour under a stream of hydrogen gas. After standing at room temperature overnight, the reaction mixture was replaced with nitrogen gas, and 10% palladium carbon was removed by filtration. The solvent was distilled off from the mother liquor 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. When ethyl acetate was distilled off from the extract, R f = 0.38 (silica gel thin-layer chromatography; ethyl acetate: 3.48 g of the brown oily target compound having n-hexane = 1: 5) was obtained. (Reference Example 87)

4- (6-t-butoxycarbo-lu-no-)-4-oxo- 1 _methylchroman 1- 2-methyl- trobenzene

N- (3-Acetyl-1-hydroxypropyl) -t-butynolecarbamate 3.48 g, 4- (2-oxopropoxy) ditrobenzene 2.73 g, anhydrous methanol 6 Om 1 and pyrrolidine The reaction was carried out according to Reference Example 44 using 1.2 ml. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with 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: 4 → 1: 1) to obtain R f = 0.37 (silica gel thin-layer chromatography). 5.66 g of an orange amorphous target compound having ethyl acetate: n-hexane = 1: 1) were obtained.

(Reference example 88)

4- (6-t-butoxycarboeminamine 4-oxo-1-2-methylchroman-1—ilmethoxy) anilin '

4- (6-t-Butoxycarbonylamino-1-oxo-2-methylchroman-2-ylmethoxy) nitrobenzene 5.66 g, 0.57 g of 10% palladium on carbon and ethanol 1 O Oml, Reference Example The reaction was carried out according to 4. The reaction mixture was replaced with nitrogen gas, and 10% palladium carbon was removed by filtration. The solvent was distilled off from the mother liquor under reduced pressure to obtain 5.16 g of a yellow amorphous target compound having R f = 0.70 (silica gel thin-layer chromatography; ethyl acetate: n-hexane = 1: 1). Was done.

(Reference example 89)

4- (4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) Using 0.37 g of 2-hydroxy-1,3,4,6-trimethylacetophenone, 0.41 g of 4- (2-oxopropoxy) nitrobenzene, 8 ml of anhydrous methanol and 0.17 ml of pyrrolidine The reaction was carried out according to Reference Example 44. 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: 5—1: 3) to obtain R f = 0.30 (silica gel thin layer chromatography). 0.40 g of a brown oily target compound having ethyl acetate: _n- hexane = 1: 5) was obtained.

(Reference example 90)

4- (4-oxo-1,2,5,7,8-tetramethylchroman_2-ylmethoxy) anilin

4- (4-oxo-1,2,5,7,8-tetramethylchroman-l-methoxy) 0.40 g of nitrobenzene, 0.04 g of 10% palladium on carbon, and 10 ml of ethanol The reaction was performed. The reaction mixture was replaced with nitrogen gas, and 10% palladium carbon was removed by filtration. The solvent was distilled off under reduced pressure from the mother liquor. 0.35 g of brown oily target compound having R f = 0.42 (silica gel thin layer chromatography; ethinole diacid: _n- hexane = 1: 2) was gotten.

(Reference Example 9 1)

6-hydroxy-1,2,5,7,8-tetramethylchroman-2-thiocarboxylate S 2- (4-methoxybenzyl) ester

6-Hydroxy-1,2,5,7,8-Tetramethylchroman-12-Hydroxycarboxylic acid 26.5 g, 4-Methoxy-α-toluenethiol 16.3 g and Triethylamine 21.4 g After dissolving in 250 ml of anhydrous tetrahydrofuran, 150 ml of an anhydrous tetrahydrobran solution containing 36.6 g of getyl phosphonate chloride was added dropwise under ice cooling. After stirring the reaction mixture at room temperature for 30 minutes, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. Extraction After the solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate Zn-hexane = 13) to obtain R = 0.43 (thin layer chromatography; 25.4 g of the desired compound having ethyl acetate: _n- hexane = 1: 3) was obtained.

(Reference Example 92)

6-hydroxy-1- (4-methoxybenzylthio) methyl-2,5,7,8-tetramethinolechromane

To a mixture of 31.6 g of aluminum trichloride and 200 ml of anhydrous ether, 3.50 g of lithium aluminum hydride was added little by little, and the mixture was heated under reflux for 20 minutes, and then treated with 6-hydroxy-1,2,5,7,8-. A mixture of 25.4 g of tetramethylchroman-1-thiocarboxylate S- (4-methoxybenzyl) ester, 300 ml of anhydrous ether and 100 ml of anhydrous tetrahydrofuran was added dropwise with heating under reflux, followed by heating under reflux for 1.5 hours. did. After cooling, water was injected to consume excess lithium aluminum hydride, ethyl acetate was added, and the insoluble matter was removed by filtration. The filtrate was separated, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 5) to obtain an R f value of -0.42 (thin layer chromatography; ethyl acetate: 12.8 g of the desired compound having n-hexane-2-1: 3) was obtained.

(Reference example 93)

____________________________ 2-Mercaptomethyl-1, 2, 5, 7, 8-tetramethyl chroman

6-Hydroxy-1- (4-methoxybenzylthio) methyl_2,5,7,8-tetramethylchroman (11.6 g) was dissolved in 50 ml of anhydrous pyridine, and acetic anhydride was added.

55 g was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with 3N hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was dissolved in trifluoroacetic acid 5 Om 1,

The mixture was stirred at 50 ° C for 10.5 hours. The reaction mixture was concentrated, water was added, and neutralized with baking soda Thereafter, the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 5) to give an R f value = 0. 6.03 g of the desired compound having 43 (thin layer chromatography; ethyl acetate: n-hexane = 1: 4) was obtained.

(Reference example 94)

6-acetoxy-1,2,5,7,8-tetramethyl-1- 2- (4-ditrophenylthio) methinolechroman

6- Asetokishi one 2-mercaptomethyl-_ 2, 5, 7, 8-tetramethyl chroma down 6.03 Anhydrous g and 1 Furuoro 4-nitrobenzene 2.89 _8? ^, N-di-methyl was dissolved in formamidine de 5 Om 1, after the addition of sodium hydride (55 wt ./ ₀₎ 0. 89 g little by little, and stirred at room temperature for 21 hours. Water was added to the reaction solution, neutralized with 3N hydrochloric acid, 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 resulting residue was subjected to silica gel gel chromatography (ethyl acetate: _n- hexane = 1: 4). ) To give 5.03 g of the desired compound having a melting point of 129-131 ° C.

(Reference example 95)

6-acetoxy-1 2- (4-aminophenyl) methyl-2,5,7,8-tetramethinolechromane

6 Asetokishi 2, 5, 7, 8-tetramethyl-one 2- (4-Nitorofueniruchi O) methyl chroman 4. Hydrogen ⁹⁶ g, 10 ο / ο palladium carbon 5 g and 1, 4 mixture of Jiokisa down 100 m 1 Under an atmosphere, the mixture was vigorously stirred at 80 ° C for 2 hours. After filtering off the palladium carbon from the reaction mixture, the solvent was distilled off, and the target compound having an R f value of 0.32 (thin layer chromatography; ethyl acetate: _n- hexane = 1: 2) 4. 6

7 g were obtained.

(Formulation Example 1) (Hard capsule)

Each of the standard bisected hard gelatin capsules contains 100 me powder of Example 1 A unit capsule is prepared by filling the compound, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate, washing and drying.

(Formulation Example 2) (Soft capsule)

A mixture of the compound of Example 2 in a digestible oil, for example, soybean oil, cottonseed oil, or olive oil, is prepared and injected into gelatin with a positive displacement pump to contain 100 mg of active ingredient. Soft capsules are obtained, washed and dried.

(Formulation Example 3) (Tablets)

In a conventional manner, 100 mg of the compound of Example 3, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose It is manufactured using

In addition, if necessary, a coating is applied.

(Formulation Example 4) (Injection)

1.5% by weight of the compound of Example 4 are prepared by stirring in 10% by volume of propylene glycol, then making up to volume with water for injection and sterilizing.

(Formulation Example 5) (Suspension)

In 5 ml, contain 100 mg of the finely divided compound of Example 5, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (Japanese Pharmacopoeia) and 0.025 ml of vanillin Manufactured as follows.

(Formulation Example 6) (Cream)

100 mg micronized in a 5 g cream consisting of 40% white petrolatum, 3% microcrystalline wax, 10% lanolin, 5% span 20, 0.3% tween 20 and 41.7% water The compound is prepared by mixing the compound of Example 6 described above.

(Formulation Example 7) (Cream)

A mixture of 2 parts by weight of the compound of Example 7, 5 parts by weight of 1,2-propanediol, 5 parts by weight of glycerol stearate, 5 parts by weight of spermaceti, 10 parts by weight of isopropyl myristate, and 4 parts by weight of polysorbate was heated. Cool, then add 69 parts by weight of water with stirring to produce a cream.

(Formulation Example 8) (Solution for application) One part by weight of the compound of Example 8 is mixed with 99 parts by weight of polyethylene glycol 300 to prepare a coating solution.

(Formulation Example 9) (Ointment)

Ointment is prepared by mixing and dissolving 2 parts by weight of the compound of Example 9, 40 parts by weight of polyethylene glycol 400, and 58 parts by weight of polyethylene glycol 1500 while heating, followed by cooling.

(Test Example 1) Tumor growth inhibitory activity test

Cell>

The cancer cells used in this test are strains established as culture strains. The culture was carried out at 37 ° C., 5% CO ₂ , and 95% air.

Specimen preparation>

All samples were dissolved in DMSO (dimethyl sulfoxide, Dojin Chemical) and diluted with medium so that the concentration of DMSO at the highest drug concentration was 1% or less. All drugs were diluted in half log using the medium.

Tumor growth inhibition activity test (MTT assay or MTS assay)>

The cells were suspended and seeded at 100 μl on a 96-well flat-bottomed microtiterplate (NUNC), and cultured at 37 ° C under 5% CO ₂ for 24 hours. Then, add 培地 μΙ of medium prepared to twice the contact concentration, and add 37 ° C, 5 ° /. C0 ₂ 72 hours under, and in contact with the drug.

Then, apply 1 μg / ml MTT (3- (4,5-dimethylthiazole 2-yl) -2,5-diphenyltetrazoUum bromide, Dojin Chemical) test solution to 50 μL! ], And cultured at 37 ° C under 5% CO ₂ for 4 hours. Thereafter, the supernatant was removed, 150/1 DMSO was added, and the mixture was stirred with a plate shaker (IA-SCHUETTLER MTS 2, IKA-Labortechnik) for 5 minutes to dissolve formazan. OD ₅₄₀ was measured by ImmunoReader NJ 2000 (Nippon Intermed Co., Ltd.). In the case of the MTS assay, add 72 μl of MTS (“Cell titer-96 Aqueous cell proliferation test”, Cat.No. 4 hours at C0 ₂ under, then OD _49. Was measured. The concentration of the drug that inhibits the value in the absence of the drug by 50% is defined as _IC5Q, and this is used to evaluate the tumor growth inhibitory activity. Valued.

The results when using human tumor cell lines SK-N-MC and D283-Med are shown below. (Table 4) Compound (Example number) SK-N-MC D283-Med

IC ₅₀ (MM) IC ₅₀ (MM)

21 0.105 0.0735

53 0.0403 0.0144

54 0.0139 0.00456

55 0.00163 0.000916

59 0.00717 0.00166

60 0.0344 0.0131

79 0.011 0.00503

100 0.0000135 0.0175

101 0.000912 0.00172

105 0.00594 0.0012

110 0.0108 0.0219

117 0.0163 0.00754 As is clear from Table 4, the compounds of the present invention showed remarkable tumor growth inhibitory activity.

(Test Example 2) Lipid peroxide production inhibitory activity test

The activity of inhibiting lipid peroxide formation in rat liver microsomes was examined.

A buffer solution [aqueous solution adjusted to pH 7.4 by adding hydrochloric acid to 0.1 M tris (hydroxymethyl) aminomethane aqueous solution] and a 1: 2 mixed solution of 0.15 M aqueous chloridized solution to 400 μl Then, 5 μl of a dimethyl sulfoxide solution of a test compound at a constant concentration and 100 μl of liver microsomes prepared from a Wistar rat (10 weeks old) were added, and the mixture was stirred at 37 ° C for 5 minutes. To start the reaction, add 10 μl of a 0.5 mM ferrous sulfate heptahydrate aqueous solution and 5 OmM cysteine aqueous solution 1: 1 mixed solution. Stirred for 30 minutes. 1 ml of a 10% aqueous solution of trichloroacetic acid was added to the stirred solution to stop the reaction. The reaction solution was centrifuged at 300 ° C. for 10 minutes at 5 ° C., and the supernatant was collected. Supernatant to 1.0 ml, 0.67. /. 50 containing thiobarbituric acid. /. Aqueous acetic acid (1.0 mL) was added and the mixture was boiled at 100 ° C. for 15 minutes. After standing at room temperature for 15 minutes, the absorbance at a wavelength of 5355 nm was measured. The inhibition rate (%) was determined from the absorbance of the control obtained without using the test compound and the absorbance when the test compound was used at a certain concentration, and the concentration of the test compound that inhibited lipid peroxide by 50% was examined. Table 5 shows the results.

(Table 5) Example Compound No.Lipid peroxide production inhibitory activity

1 ₅₀ (βg / ml)

1 0.028

2 0.036

3 0.048

4 0.068

5 0.054

6 0.083

7 0.079

9 0.07

10 0.15

11 0.13

12 0.15

13 0.13

14 0.13

15 0.066

16 0.13

20 0.082

21 0.059

22 0.061 ^ ^ CO CO 00 CO CO CO

O t CO CO

ο 00 t to ts5 t

^ o D ^ CO

t

67 0.053

83 0.16

87 0.21

88 0.063

90 0.097

91 0.05

92 0.017

99 0.04

100 0.37

101 0.15

102 0.36

103 0.0088

104 0.14

118 0.8

119 0.032

120 0.047 From the above results, it was revealed that the compound of the present invention exhibited excellent lipid peroxide production inhibitory activity.

(Test Example 3) 5-lipoxygenase inhibitory activity test

To 5 μl of the test compound dissolved in dimethyl sulfoxide, add 115 μl phosphate buffer [1 powder of phosphate buffer (chatron) in 10 ml of water and adjust to pH 7.4. Aqueous solution] 75 0 μl, 30 mM aqueous calcium chloride solution 40 μl, 20 mM aqueous GSH (reduced glutathione) aqueous solution 50/1, 4 OmM ATP (adenosine 15-triphosphate) aqueous solution 50 μl and 100 μl of guinea pig polymorphonuclear leukocyte enzyme were added, and the mixture was stirred at 25 ° C for 5 minutes. To start the reaction, 5 μl of arachidonic acid (10 mg Zm 1 ethanol) was added, and the mixture was stirred at 25 ° C. for 5 minutes. 50 μl of 2N hydrochloric acid was added to the stirred solution to stop the reaction. After adding ethyl acetate containing internal standard substance 2.0m1 (internal standard substance: isoamylparaben 2 µg Zm1), use a mixer. And extracted for 1 minute, followed by centrifugation at 3000 rpm for 5 minutes. The ethyl acetate layer was separated, evaporated to dryness under reduced pressure, dissolved in acetonitrile 200 // 1, and the amount of 5-HETE produced was quantified by high performance liquid chromatography. Inhibition rate (° / o) was determined from the amount of 5-HETE in the control without the test compound and the amount of 5-HETE when the test compound was used to inhibit 5-lipoxygenase by 50%. The concentration of the test compound to be tested was determined. Table 6 shows the results.

(Table 6) Example compound No. 5-lipoxygenase inhibitory activity

I 50 (β g / m 1)

1 0.048

2 0.029

4 0.062

5 0.082

6 0.061

7 0.076

9 0.075

10 0.058

11 0.12

12 0.024

13 0.23

15 0.014

16 0.0086

20 0.037

21 0.097

22 0.089

23 0.05

24 0.23

25 0.055 26 0.65

27 0.18

29 0.26

30 0.15

32 0.21

34 0.02

35 0.48

38

39 0.1

41 0.35

42 0.07

45 0.69

46 1.4

48 0.85

61 0.038

62 0.029

63 0.03

64 0.42

65 0.039

66 0.29

67 0.034

83 0.41

87 0.076

88 0.035

99 0.16

103 0.78

118 0.94

119 0.087

120 0.036 From the above results, the compound of the present invention shows excellent 5-lipoxygenase inhibitory activity. It became clear that (Test Example 4) Hypoglycemic activity test

Blood was collected from the tail vein of KK mice (aged 4 to 5 months) who developed diabetes, and their blood glucose levels were measured. Next, the mice were divided into groups (4 mice per group) so that the average of the blood glucose levels of the mice in each group was the same, and the powdered mouse feed (F) adjusted to contain 0.01% of the test compound was prepared. (1, Funabashi Farm) for 3 days. The mouse group receiving the test compound was designated as the drug administration group. The group to which the powdered feed containing no test compound was given was set 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 (Gnoreco loader, A & T). The blood glucose lowering rate was calculated from the following equation.

Hypoglycemic rate (%) =

(Average blood glucose level of control group-average blood glucose level of drug-administered group) X 100 Blood glucose level of control group (Table 7) Hypoglycemic activity Example N o Hypoglycemic activity (° / o)

KK mouse, 0.01% diet,

3 days

86 14.5

85 22.2

81 26.9 From the above results, it was revealed that the compound of the present invention exhibits excellent hypoglycemic activity. INDUSTRIAL APPLICABILITY Since the compound of the present invention has excellent tumor growth inhibitory activity, 5-lipoxygenase inhibitory activity and / or lipid peroxide production inhibitory activity, it can be used as a preventive and / or therapeutic agent for cancer. Useful.

Further, the compound of the present invention has excellent 5-lipoxygenase inhibitory activity, lipid peroxide production inhibitory activity and / or hypoglycemic activity, and thus is useful as a preventive or therapeutic agent for diabetes.

Further, among the compounds of the present invention, insulin resistance improving action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, PPAR activating action, anti-osteoporosis action, leukotriene antagonistic action, adipocyte promoting action, calcium Those having an antagonistic effect include cancer, diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.) ), Arteriosclerosis, gestational diabetes, polycystic ovary syndrome, cardiovascular disease (for example, ischemic heart disease, etc.), cells induced by atherosclerosis or ischemic heart disease. Injury (eg, brain injury caused by a stroke), gout, inflammatory disease (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory Flame, Akune, sunburn, psoriasis, eczema, allergic diseases, asthma, G I ulcer, cachexia, autoimmune disease, a knee inflammation and the like.), Bone Sosusho, may also be used in diseases such as cataract.

Claims

The scope of the claims

1. The following general formula (1)

Wherein R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, an aralkyl group having 7 to 18 carbon atoms, 6 aliphatic acyl groups, 7 to 15 carbon atoms aromatic aryl group, 8 to 19 carbon atoms aralkyl carbonyl group, 4 to 9 carbon atoms cycloalkylcarboyl group, heteroaryl carbonyl Group, alkylsulfonyl group having 1 to 6 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms, arylsulfonyl having 6 to 14 carbon atoms A group, a rubamoyl group or a substituent rubamoyl group;

X is a single bond, formula (C = 0) —group, formula — (C = NOR ⁷ ) —group, formula — (CHO H) —group, formula 1 CH (OR ⁸ ) —group, formula _CH ₂ — Group or formula — (C = NNR ⁹ R ^1Q )-represents a group,

R ⁷ and R ⁸ are the same or different and each represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, Alkenyl group having 2 to 6 carbon atoms, aryl group having 6 to 14 carbon atoms, aralkyl group having 7 to 18 carbon atoms, aliphatic acryl group having 1 to 6 carbon atoms, carbon number 7 to 15 aromatic acyl groups, C8 to C19 aralkylcarbyl groups, C4 to C9 cycloalkylcarbonyl groups, heteroarylcarbonyl groups, C1 to C6 An alkylsulfonyl group, an arylsulfonyl group having 6 to 14 carbon atoms, a rubamoyl group or a substituent rubamoyl group,

R ⁹ and R ^1Q are the same or different and each represent a hydrogen atom and an optional substituent selected from <substituent group α>;

Α represents a formula— (C = 0> —group or a formula—S 0 ₂ —group;

U represents —CH ₂ _ group, or a formula C (R ² ) —U, formula C = CH group, or formula X—U, formula CH = CH group or a single bond;

Y represents a formula —O— group or a formula S— group,

Q represents a hydrogen atom, a nitro group, a hydroxyl group, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms, and a carbon atom having 6 to 1 carbon atoms. 4 aryl groups, 7 to 18 carbon atoms aralkyl group, 1 to 6 carbon atoms alkoxy group, 6 to 14 carbon atoms aryloxy group, 7 to 18 carbon atoms aralkyloxy group, carboxyl Group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a cycloalkyloxy group having 4 to 9 carbon atoms, an oxygen atom (provided that Ar ¹ or Ar ² is a pyridine ring, An amino group or an amino group substituted with an arbitrary substituent selected from <substituent group α>,

k represents an integer of 1 to 6,

m and n are the same or different and each represent an integer of 0 to 8,

A r ¹ represents a benzene ring, a pyridine ring or a biphenylene group,

However, in the above, the aryl ring, the heteroaryl ring or the nitrogen-containing heterocyclic moiety may have 1 to 6 substituents at any position. Same or different substituents more arbitrarily selected. ] The compound represented by A pharmacologically acceptable salt or an ester thereof.

Substituent group α>

Alkyl group having 1 to 6 carbon atoms, aryl group having 6 to 14 carbon atoms, aralkyl group having 7 to 18 carbon atoms, aliphatic acryl group having 1 to 6 carbon atoms, 7 to 1 carbon atoms 5 aromatic acyl groups, aralkylcarbonyl groups having 8 to 19 carbon atoms, cycloalkylcarbonyl groups having 4 to 9 carbon atoms, heteroarylcarbonyl groups, alkyl groups having 1 to 6 carbon atoms A sulfonyl group, an arylsulfonyl group having 6 to 14 carbon atoms, a sulfamoyl group, a substituted sulfamoyl group, a thiocarbamoyl group, a substituted thiocarbamoyl group, a substituted rubamoyl group, or a substituted rubamoyl group.

Substituent groups] 3>

Nitro group, hydroxyl group, halogen atom, alkyl group having 1 to 6 carbon atoms, alkyl group having 1 to 6 carbon atoms substituted with halogen, aryl group having 6 to 14 carbon atoms, carbon number of 7 to 18 Aralkyl groups, C1 to C6 alkoxy groups, C6 to C14 aryloxy groups, C7 to C18 aralkyloxy groups, carboxyl groups, C2 to C7 alkoxy groups Carboel group, cycloalkyloxy group having 4 to 9 carbon atoms, oxygen atom (however, in the case of Ar ¹ force pyridine ring, only when nitrogen on the ring becomes oxoxide), amino group Or an amino group substituted with any substituent selected from <substituent group α>.

2. In claim 1, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 1'8 carbon atoms, an alkylsulfoyl group having 1 to 6 carbon atoms or

An alkylsulfonyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogens,

R ^{2 is a} hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms Substituted with an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a hydroxyl group, an aliphatic acyloxy group having 1 to 6 carbon atoms, a heteroarylcarbonyloxy group or a Is an amino group,

X is a formula— (C = 0) —group, a formula— (C = NOR ⁷ ) —group or formula—CH ₂ —group, a force, a formula X—U, a formula CH 2 CH group,

A has the formula - (C = 〇) one group or the formula - S0 ₂ - group wherein

U is a force that is a CH ₂ — group, a formula C (R ² ) — U, a force that is a formula C = CH, a formula X — a force that is a CH = CH group,

Y is a group of formula —o_ or a group of formula S—

Q is the same or different and represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with halogen, a carboxy group, a carbon atom having 2 to 7 carbon atoms. Alkoxycarbonyl group, cycloalkyloxy group having 4 to 9 carbon atoms, oxygen atom (however, in the case of Ar ¹ force pyridine ring, and only when nitrogen on the ring is oxidized), amino group or A mono- or di-substituted amino group (the substituent is an aliphatic acyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a carbamoyl group, a substituted thiocarbamoyl group, or a heteroaryl group; )

k force is an integer from 1 to 6,

Is from 0 to 3,

n force 0 to 4,

A r ¹ is a benzene ring, a pyridine ring or a biphenylene group,

The compound, the pharmaceutically acceptable salt or an ester thereof, wherein Ar ² is an aryl ring, a heteroaryl ring or a nitrogen-containing heterocyclic ring.

3. The method according to claim 1, wherein R ^{1 is a} hydrogen atom, a methyl group, a benzyl group, or a chloromethanesulfonyl group;

R ^2; ¾ ^s, a hydrogen atom or a methyl group,

R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a methyl group, a methoxy group, A methoxy methoxy group, a nitro group, a hydroxyl group, an acetoxy group, an amino group, or a 3-pyridylcarporamino group;

X is a formula— (C = 0) —group, a formula— (C = NOR ⁷ ) —group or formula—CH ₂ — group, and R ⁷ is the same or different and is a hydrogen atom, a methyl group or a benzyl group Group,

A has the formula - (C = 〇) - a S0 ₂ _ group, - or the formula

Where U is a CH ₂ — group, the formula (R ² ) —U, a force of the formula C = CH group; formula X—U of a formula, CH = CH group;

Y is an O— group of the formula

Q are the same or different, a hydrogen atom, a hydroxyl group, a chlorine atom, tert- butyl group, triflate Ruoromechiru group, a carboxyl group, main butoxycarbonyl group, cyclopentyloxy Ruo alkoxy group, an oxygen atom (wherein, A r ¹ force pyridine ring And the nitrogen on the ring is an oxide), an amino group, an acetylamino group, a methanesulfolamino group, a methylaminothiocarbonylamino group or a 3-pyridylcarboamino group. ,

k force 1 and

m is 0 to 3,

n force 0 to 4,

A r ¹ is a benzene ring, a pyridine ring or a biphenylene group,

The compound, the pharmaceutically acceptable salt or the ester thereof, wherein Ar ² is aryl or heteroaryl.

4. The method according to claim 1, wherein R ^{1 is a} hydrogen atom, a methyl group, a benzyl group, or a chloromethanesulfonyl group;

R ² is a hydrogen atom or a methyl group,

X is a formula— (C = 0) —group, a formula— (C = NOR ⁷ ) —group or a formula CH ₂ —group, R ⁷ is the same or different and is a hydrogen atom, a methyl group or a benzyl group,

A is a group of the formula (C = 0) —

U is a force that is a CH ₂ — group, a formula C (R ² ) —U, and a formula C = CH group, a formula X—U, a formula CH = CH group,

Y is a group of the formula —o—,

Q are the same or different, a hydrogen atom, a hydroxyl group, a chlorine atom, tert- butyl group, triflate Noreoromechiru group, a carboxyl group, main butoxycarbonyl group, cyclopentyloxy Ruo alkoxy group, an oxygen atom (wherein, A r ¹ force pyridine ring And only when the nitrogen on the ring is an oxide), an amino group, an acetylamino group, a methanesulfonylamino group, a methylaminothiocarbonylamino group or a 3-pyridylcarbonylamino group. ,

k force 1 and

m is 0 to 2,

n force 0 to 2;

A r ¹ is a benzene ring, a pyridine ring or a biphenylene group,

A compound or a pharmacologically acceptable salt thereof, which is an Ar ² S, benzene ring, pyridine ring, pyrazine ring, pyrimidine ring, quinoline ring or indole ring.

5. The method of claim 1, wherein R ¹ is a hydrogen atom,

R ² is a hydrogen atom or a methyl group,

X is a formula— (C = 0) —group, a formula— (C = NOR ⁷ ) —group or a formula _CH ₂ —group, and R ⁷ is the same or different and is a hydrogen atom, a methyl group or a benzyl group And

A is a group of the formula— (C = 0) —

Y is a group of formula —O—, Q is the same or different and is a hydrogen atom,

k force 1 and

m is 0 or 1,

n is 0 or 1,

A r ¹ is a benzene ring,

A compound or a pharmacologically acceptable salt thereof, wherein Ar ² is a benzene ring or a pyridine ring.

6. N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-12 f-methoxy) phenyl] —pyridine-13-ylacetoamide.

7. N— [4 -— (6-hydroxy-1,2,5,7,8-tetramethyl [1H] chromen-2-ylmethoxy) benzyl] —nicotinamide. .

8. N— [4— (6-Methoxymethoxy-1,2,5,7,8-tetramethyl [1H] chromene-1— ^ lumethoxy) benzyl] —nicotinamide.

9. N— [4_ (6-hydroxy-1,2,5,7,8-tetramethylchroman-12T methoxy) benzyl] -nicotinamide.

10. N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —6-aminoaminotinamide.

1 1. N— [4 -— (6-acetoxy-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] —2-aminoaminotinamide.

1 2. N- [4 -— (6-amino-4-oxo-1,2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] —nicotinamide.

1 3. N— [4— (6-amino-4-oxo-2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] -1-6-aminoaminotinamide. '

1 4. N— [4— (6-amino-4-hydroxyimino 2,5,7,8—tetramethylchroman-2-ylmethoxy) phenyl] -6-aminonicotinamide.

1 5. N— [4— (6-Amino-4-Methoxyimino-1,2,5,7,8-Tetraroman-1-2-ylmenotoxy) phenyl] —6-Aminiconicotinamide.

1 6. N— [4- (6-Nitro-4-oxo- 1,2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl] -6-aminonicotinamide.

1 7. N— [4— (6-amino-4—oxo-2,5,7,8—te

Romone-2f-methoxy) benzyl] -6-amino-cotinamide.

1 8. N— [4 -— (6-Amino-4-Methoxyimino-1,2,5,7,8-tetramethylchroman_2- ^ f-l-methoxy) benzyl] —6-aminoaminotinamide.

1 9. N— [4 -— (6-amino-4-4-benzyloxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) benzyl] —6-aminonicotinamide

20. Ν— [4— (6-amino-4-methoximino-1,5,7,8-trimethizole chromene-2-ylmethoxy) phenyl] -1-6-aminoaminotinamide.

2 1. Ν- [4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) -12-trifluoromethylphenyl] 1,3,5-di-t-butyl Luh 4-Droxybenzamide.

22. N— [4 -— (6-acetoxy-1-4-methoxyimino-1,2,5,7,8-tetramethylchroman-1-ylmethoxy) phenyl] —2,6-di-t-butyl-4-hydr Roxibenzamide.

23. N— [4— (6-acetoxy-1-4-benzyloxyiminow 2, 5, 7,

8-tetramethylchroman-2-ylmethoxy) phenyl] —2,6-di-t-butyl-14-hydroxybenzamide.

24. N— [4 -— (6-acetoxy-4-hydroxyhydroxymino-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -2,6-di-t-butyl—4-hydrid Roxibenzamide.

25. N- [4- (6-acetoxy 2,5,7,8-tetramethylchroman-1-ylmethoxy) phenole] —3,5-di-t-butyl-1-4-hydroxybenzamide.

26. N— [4— (6-amino-4oxo-1,2,5,7,8—te

Romone 1-ylmethoxy) phenyl) 1-aminoaminotinamide

27. N— [4-1 (6-amino-4,5-methoxyminino-1,2,5,7,8-tetraroman-12-methyloxy) phenyl] -12-amino-cotinamide.

28. N— [4 -— (6-amino-4-methyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -1-6-aminonicotinamide dihydrochloride.

29. N— [4— (6-Amino-4-Methoxyimino-12-Methylchroman-21-ylmethoxy) phenyl] -6-aminoaminotinamide dihydrochloride.

3 0. N— [3- (6-amino-4-oxo-5,7,8-trimethyl-1,2,3-chromene-2-ylmethoxy) phenyl] —6-aminoaminotinamide.

31. A medicament comprising the compound according to claim 1 as an active ingredient.

32. A cancer preventive or therapeutic agent comprising the compound according to claim 1 as an active ingredient.

33. A cancer preventive or therapeutic agent comprising the compound according to claim 1 as an active ingredient.

34. A preventive or therapeutic agent for diabetes comprising the compound according to claim 1 as an active ingredient.

35. Use for producing a medicament comprising the compound according to any one of claims 1 to 30 as an active ingredient.

36. Use of the compound according to any one of claims 1 to 30 for producing a prophylactic or therapeutic agent for cancer.

37. Use of the compound according to any one of claims 1 to 30 for producing a prophylactic or therapeutic agent for diabetes.

38. A method for preventing or treating cancer, which comprises using an effective amount of the compound according to any one of claims 1 to 30 to a mammal.

39. A method for preventing or treating diabetes, comprising using an effective amount of the compound according to any one of claims 1 to 30 to a mammal.