JPH11106371A - Acylhydrazone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as a Maillard reaction inhibitor, an active oxygen-resistant medicine, a medicine for various kinds of diabetic complications, a medicine for senile diseases and the like. SOLUTION: A compound of the formula: X-W-Y X is a group of formula I [R<1> and R<2> are each a 1-4C alkyl; R<3> is H or a 1-4C alkyl; (n<1> ) is 0-2] or the like; Y is furyl, thienyl, pyrrolyl or the like; W is formula II (R<25> and R<26> are each H or a 1-4C alkyl; Z<1> is O or S) or the like}, e.g. benzaldehyde-3,5-di-t- butyl-4-hydroxybenzoyl hydrazone. The compound of the formula is obtained e.g. by reacting 3,5-ti-t-butyl-4-hydroxybenzhydrazide with benzaldehyde in ethanol at room temperature for 24 hr with agitation, distilling off the solvent, adding isopropyl ether, depositing the crystals, and subsequently filtering off the crystals, while using a column chromatography using silica gel or the like as a carrier, methanol and the like complication.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an acylhydrazone derivative and an analog thereof, and a pharmaceutical composition, particularly to a Maillard reaction inhibitor and an antireactive oxygen agent (lipid peroxide production inhibitor).

[0002]

2. Description of the Related Art In recent years, denaturation of proteins due to glucose has been greatly highlighted as one of the causes of diabetic complications. This is thought to be due to the Maillard reaction occurring in vivo. In the Maillard reaction, the amino acid of a protein is non-enzymatically saccharified (glycated) with glucose as an initial step, and Amadori (A
madori) The compound is formed. In addition, Amadori compounds react with other proteins to form crosslinks, and are late-stage products (AGE: Advanced Glycation End produc), which are insoluble, difficult to decompose by proteases, and are fluorescent browning substances.
ts) (Science, 232 , 1629 (1986)). The Maillard reaction is a phenomenon that is also observed in healthy subjects, but is a phenomenon that occurs particularly in diabetic patients, for example, hemoglobin, serum albumin, or a protein that is slow or not metabolized, collagen or elastin in connective tissue, It causes denaturation of proteins such as myelin and ocular lens crystallin. This protein alteration is thought to be one of the causes of diabetic complications such as retinopathy, nephropathy, cardiovascular disorders, neuropathy and cataracts, resulting in functional and abnormal organs. . Also,
The in vivo Maillard reaction is considered to be one of the mechanisms of aging, and is presumed to be closely related to aging-related diseases. Therefore, inhibiting the Maillard reaction is considered to be extremely useful for treating various complications of diabetes and senile diseases. Recent studies have also reported that free radicals may be involved in the Maillard reaction (J. Biol. Ch.
em., 262 (35), 16969-16972 (1987)).

[0003] Against this background, substances that inhibit the Maillard reaction have recently been searched for. Conventionally, various compounds have been reported as compounds having Maillard reaction inhibitory activity. For example, Japanese Unexamined Patent Publication No. 62-1421
Japanese Patent No. 14 suggests a composition for suppressing the production of a secondary glycosylation end product comprising a compound having an active nitrogen-containing group (hydrazine group) capable of reacting with an active carbonyl group in an Amadori rearrangement product. As such compounds, aminoguanidine, α-hydrazinohistidine and lysine are disclosed.

On the other hand, acyl hydrazone derivatives and their analogs are represented by the following formula (Ia):

[0005]

Embedded image Phe—CO—NH—N ＝ CH—Phe—OH-2 (Ia) (wherein Phe represents a phenyl group, and Phe—OH-2
Represents a 2-hydroxyphenyl group. Reeds shown with)
Luhydrazone derivative is an antituberculous agent hydrazi isonicotinic acid
Is described as a related compound of87
(1), 27-32 (1967)), and the following formula (Ib):

[0006]

Embedded image Ar ¹ —CO—NH—NH—CO—Ar ² (Ib) (wherein, Ar ¹ represents a 3,5-di-t-butyl-4-hydroxyphenyl group, and Ar ² represents a phenyl group Or a 2-hydroxyphenyl group) has been reported to be useful as a stabilizer for organic materials (U.S. Pat. No. 3,773,830; -35281, JP-A-51-1
No. 4885). However, there is no report that the compound has Maillard reaction inhibitory activity or anti-reactive oxygen activity.

[0007]

DISCLOSURE OF THE INVENTION The present invention relates to a novel acylhydrazone derivative and an analog thereof, and a pharmaceutical composition containing a known or novel acylhydrazone derivative or an analog thereof as an active ingredient, particularly a Maillard reaction inhibitor and It is intended to provide an antireactive oxygen drug.

[0008]

The present invention includes the following inventions. (1) The following formula (I): X-W-Y [where X is the following formula (A):

[0009]

Embedded image

(Wherein R ¹ and R ² are the same or different and each represents a C _1-4 -alkyl group, and R ³ is a hydrogen atom or a C
Represents an _1-4 -alkyl group, and n ¹ represents 0 to 2. )
A group represented by the following formula (B):

[0011]

Embedded image

(Wherein R ⁴ and R ⁵ are the same or different and each represents a C _1-4 -alkyl group, and R ⁶ is a hydrogen atom or C
_1-4 represents an alkyl group. A group represented by the following formula (C):

[0013]

Embedded image

(Wherein R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are
Identical or different, represents a C _1-4 -alkyl group, R ¹¹ represents a hydrogen atom or a C _1-4 -alkyl group, and n ² represents 0 to 3
Represents Or a group represented by the following formula (D):

[0015]

Embedded image

(Wherein R ²⁷ represents a C _1-4 -alkyl group, and R ²⁸ represents a hydrogen atom, a halogen atom, a hydroxyl group or a C _1-4
-Represents an alkoxy group. ) Represents a group represented by;
Furyl, thienyl, pyrrolyl, pyridyl, 2-
Hydroxy-6-methylpyridin-3-yl group, C _1-4
An alkyl group of the following formula (E):

[0017]

Embedded image

(Wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶
Are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-4 -alkoxy group, a C _1-4 -alkyl-carbonyloxy group, a nitro group, a cyano group, a phenyl group, a morpholino group, a pyrrolidino group, a piperidino group Group, piperazino group or amino group (the nitrogen atom in the piperazino group or amino group is selected from C _1-4 -alkyl, C _5-8 -cycloalkyl and C _1-4 -alkoxy-carbonylmethyl) or two groups may be substituted) or a nitrogen-containing heterocyclic ring-substituted -. represents a methyl group, also, R ¹² and R
¹³ or R ¹⁵ and R ¹⁶ may together form a fused 6-membered ring. A group represented by the following formula (F):

[0019]

Embedded image

(Wherein, R ¹⁷ , R ¹⁸ and R ¹⁹ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group)
A group represented by the following formula (G):

[0021]

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Wherein R ²⁰ and R ²¹ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group, or the following formula (H):

[0023]

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Wherein R ²² , R ²³ and R ²⁴ are the same or different and each represents a hydrogen atom or a C _1-4 -alkyl group.
W represents the following formula (J):

[0025]

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(Wherein R ²⁵ and R ²⁶ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group;
²⁶ may form a trimethylene group in cooperation with R ¹⁶ in the formula (E), and Z ¹ represents an oxygen atom or a sulfur atom. A group represented by the following formula (K):

[0027]

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(Wherein Z ² represents an oxygen atom or a sulfur atom), a group represented by the following formula (L):

[0029]

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Wherein Z ³ and Z ⁴ are the same or different and each represent an oxygen atom or a sulfur atom, and a group represented by the following formula (M):

[0031]

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(Wherein Z ⁵ represents an oxygen atom or a sulfur atom), a group represented by the following formula (N):

[0033]

Embedded image

Wherein Z ⁶ and Z ⁷ are the same or different and each represent an oxygen atom or a sulfur atom, and a group represented by the following formula (O):

[0035]

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Wherein Z ⁸ and Z ⁹ are the same or different and each represent an oxygen atom or a sulfur atom, and a group represented by the following formula (P): -CH = NN-CH = (P Or a group represented by the following formula (Q):

[0037]

Embedded image

(Wherein, Z ¹⁰ represents an oxygen atom or a sulfur atom). Or a pharmaceutically acceptable salt thereof as an active ingredient.

(2) The pharmaceutical composition according to the above (1), which is a Maillard reaction inhibitor. (3) The pharmaceutical composition according to the above (1), which is an antireactive oxygen drug. (4) The following formula (I ′): X—W—Y wherein X is the following formula (A):

[0040]

Embedded image

(Wherein R ¹ and R ² are the same or different and each represents a C _1-4 -alkyl group, and R ³ is a hydrogen atom or a C
Represents an _1-4 -alkyl group, and n ¹ represents 0 to 2. A group represented by the following formula (B):

[0042]

Embedded image

(Wherein R ⁴ and R ⁵ are the same or different and each represents a C _1-4 -alkyl group, and R ⁶ is a hydrogen atom or a C
_1-4 represents an alkyl group. A group represented by the following formula (C):

[0044]

Embedded image

(Wherein R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are
Identical or different, represents a C _1-4 -alkyl group, R ¹¹ represents a hydrogen atom or a C _1-4 -alkyl group, and n ² represents 0 to 3
Represents Or a group represented by the following formula (D):

[0046]

Embedded image

(Wherein R ²⁷ represents a C _1-4 -alkyl group, and R ²⁸ represents a hydrogen atom, a halogen atom, a hydroxyl group or a C _1-4
-Represents an alkoxy group. ) Represents a group represented by;
Furyl, thienyl, pyrrolyl, pyridyl, 2-
Hydroxy-6-methylpyridin-3-yl group, C _1-4
An alkyl group of the following formula (E):

[0048]

Embedded image

Wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶
Are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-4 -alkoxy group, a C _1-4 -alkyl-carbonyloxy group, a nitro group, a cyano group, a phenyl group, a morpholino group, a pyrrolidino group, a piperidino group Group, piperazino group or amino group (the nitrogen atom in the piperazino group or amino group is selected from C _1-4 -alkyl, C _5-8 -cycloalkyl and C _1-4 -alkoxy-carbonylmethyl) or two groups may be substituted) or a nitrogen-containing heterocyclic ring-substituted -. represents a methyl group, also, R ¹² and R
¹³ or R ¹⁵ and R ¹⁶ may together form a fused 6-membered ring. A group represented by the following formula (F):

[0050]

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(Wherein, R ¹⁷ , R ¹⁸ and R ¹⁹ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group)
A group represented by the following formula (G):

[0052]

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Wherein R ²⁰ and R ²¹ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group, or the following formula (H):

[0054]

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(Wherein, R ²² , R ²³ and R ²⁴ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group).
W represents the following formula (J):

[0056]

Embedded image

Wherein R ²⁵ and R ²⁶ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group, and Z ¹ represents an oxygen atom or a sulfur atom. Equation (K):

[0058]

Embedded image

(Wherein Z ² represents an oxygen atom or a sulfur atom), a group represented by the following formula (L):

[0060]

Embedded image

Wherein Z ³ and Z ⁴ are the same or different and each represent an oxygen atom or a sulfur atom, and a group represented by the following formula (M):

[0062]

Embedded image

(Wherein Z ⁵ represents an oxygen atom or a sulfur atom), a group represented by the following formula (N):

[0064]

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(Wherein Z ⁶ and Z ⁷ are the same or different and each represent an oxygen atom or a sulfur atom), a group represented by the following formula (O):

[0066]

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(Wherein Z ⁸ and Z ⁹ are the same or different and each represent an oxygen atom or a sulfur atom), a group represented by the following formula (P): -CH = NN-CH = (P Or a group represented by the following formula (Q):

[0068]

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(In the formula, Z ¹⁰ represents an oxygen atom or a sulfur atom.) Provided that X is 3,5-di-t
-Butyl-4-hydroxyphenyl group, Y is a phenyl group or a 2-hydroxyphenyl group, and W
Is -CONHNHCO-. Or a pharmaceutically acceptable salt thereof.

(5) The compound or a pharmaceutically acceptable salt thereof according to the above (4), wherein in the above formula (I '), W is a group represented by the above formula (J). (6) The compound according to (4) or a pharmaceutically acceptable salt thereof, wherein W in the formula (I ′) is a group represented by the formula (K). (7) The compound or a pharmaceutically acceptable salt thereof according to the above (4), wherein in the formula (I ′), X is a group represented by the above formula (A). (8) The compound according to (4) or a pharmaceutically acceptable salt thereof, wherein in the formula (I ′), X is a group represented by the formula (C).

In the present specification, a C _1-4 -alkyl group,
And "C _1-4 -alkyl" in each substituent includes, for example, methyl group, ethyl group, propyl group, isopropyl group,
Butyl group, isobutyl group, sec-butyl group and tert-butyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The C _1-4 alkoxy group and “C _1-4 alkoxy” in each substituent include, for example, methoxy group,
An ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group are exemplified. C _5-8 - cycloalkyl group such as cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group. In the present specification, a nitrogen-containing heterocyclic-substituted -methyl group refers to a piperidino group, a piperazino group, a morpholino group, a pyrrolidino group,
Means a methyl group substituted with a nitrogen-containing heterocyclic group such as a perhydro-1,4-diazepino group, an imidazolidino group, or a pyrazolidino group, and the nitrogen-containing heterocyclic group is a substituent such as a C _1-4 -alkyl group. May be substituted.

Examples of the fused 6-membered ring which R ¹² and R ¹³ or R ¹⁵ and R ¹⁶ can form together include a benzene ring and a nitrogen-containing heterocyclic ring (eg, a piperidine ring). In the formula (I), the spacer group represented by W is preferably a group represented by the formula (J) or (K), and a group represented by X is a group represented by the formula (A) or (C) Are preferred.

Among the compounds represented by the above formula (I), X
Is a 3,5-di-t-butyl-4-hydroxyphenyl group, Y is a phenyl group or a 2-hydroxyphenyl group, and W is -CONHNHCO-. The compound represented by the formula (I) can be used as a pharmaceutically acceptable salt depending on the type of the functional group, and examples of such a salt include hydrochloride, phosphate, and sulfate. Examples thereof include salts, acid addition salts such as fumarate and maleate, and alkali metal salts such as sodium salt.

[0075]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the above formula (I) can be produced, for example, according to the method represented by the following reaction formula.

[0076]

Embedded image

(Wherein X, Y, R ²⁵ and R ²⁶ are as defined above, Z represents an oxygen atom or a sulfur atom, V represents a methylene group, an oxygen atom, a sulfur atom or NH, and DCC represents Represents dicyclohexylcarbodiimide.)

To purify the product obtained in each reaction,
A commonly used method such as column chromatography using silica gel or the like as a carrier or a recrystallization method using methanol, ethanol, chloroform, dimethyl sulfoxide, water, or the like may be used. Examples of the elution solvent for column chromatography include methanol, ethanol, chloroform, acetone, hexane, dichloromethane, ethyl acetate, and a mixed solvent thereof.

The compound represented by the above formula (I) and a pharmaceutically acceptable salt thereof (hereinafter, referred to as “acylhydrazone derivative (I)”) are useful as a drug, particularly as a Maillard reaction inhibitor and an antireactive oxygen drug. In particular, coronary heart disease, peripheral circulatory disorders, cerebrovascular disorders, diabetic neuropathy, diabetic nephropathy, arteriosclerosis, arthrosclerosis, cataract,
Diabetic complications such as retinopathy, coagulopathy, and diabetic osteopenia; atherosclerosis, glomerulonephritis, cataract,
Senile diseases such as osteoarthritis, periarticular stiffness, arthrosclerosis, senile osteoporosis, Alzheimer's disease; arteriosclerosis, coronary heart disease, cerebrovascular disease, liver failure, renal failure, cataract, retinopathy, autoimmunity It is useful for treating various diseases caused by the production of active oxygen such as diseases (eg, Behcet's disease).

An acute toxicity test of the oral administration of the acylhydrazone derivative (I) was carried out using an SD type marat, and no death occurred at an oral administration of 2000 mg / kg.
Thus, the acylhydrazone derivative (I) has extremely low toxicity and high safety. Hereinafter, the dosage and formulation of the acylhydrazone derivative (I) will be described.

The acylhydrazone derivative (I) can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier. The administration form is not particularly limited and may be appropriately selected and used as needed. Examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, and parenteral preparations such as injections and suppositories. Can be In order to achieve the intended effect as an oral preparation, the dosage of the acylhydrazone derivative (I) is usually 1 mg to 2000 mg divided into several times a day for an adult, although it depends on the age, weight and degree of the disease of the patient. All doses are appropriate.

Oral preparations include, for example, starch, lactose, sucrose,
Manufactured according to a conventional method using mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like. In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavor, and the like can be used as appropriate in addition to the excipients. As a binder,
Examples include starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, and macrogol.

Examples of the disintegrant include starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose and low-substituted hydroxypropylcellulose. Examples of the surfactant include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, and polysorbate 80. Examples of the lubricant include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol.

Examples of the fluidity promoter include light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate and magnesium silicate. The acylhydrazone derivative (I) can also be administered as a suspension, emulsion, syrup, and elixir, and these various dosage forms may contain a flavoring agent and a coloring agent. . In order to achieve the desired effect as a parenteral drug, it depends on the age, weight and degree of the disease of the patient, but it is usually 0.1% to 600 mg per day as the weight of acylhydrazone derivative (I) for adults in adults. Intravenous, subcutaneous and intramuscular injections are suitable.

This parenteral preparation is produced according to a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, peanut oil, soybean oil,
Corn oil, propylene glycol, polyethylene glycol and the like can be used. Further, if necessary, a bactericide, a preservative and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation can be frozen after filling into a vial or the like, water can be removed by a usual freeze-drying technique, and a liquid preparation can be prepared from the freeze-dried product immediately before use. Further, if necessary, an isotonic agent, a stabilizer, a preservative, a soothing agent and the like may be added as appropriate. Other parenteral agents include
Examples thereof include liquid preparations for external use, ointments and other suppositories, suppositories for rectal administration, and the like.

[0086]

EXAMPLES Hereinafter, the present invention will be described in more detail by reference examples, examples, and test examples, but the scope of the present invention is not limited thereto. Reference Example 1 3,5-di-t-butyl-4-hydroxybenzohydrazide
ide) 25.04 g of methyl 3,5-di-t-butyl-4-hydroxybenzoate
(95 mmol) and hydrazine hydrate 4
5.95 ml (950 mmol) is suspended in 190 ml of 1-propanol,
The mixture was heated to reflux at a bath temperature of 140 ° C. The solvent was distilled off, 300 ml of ethyl acetate was added, and a saturated aqueous solution of ammonium chloride, water,
The extract was washed successively with saturated saline, dried over sodium sulfate, and the solvent was distilled off. The precipitated crystals are collected by filtration and dried under reduced pressure.
18.44 g (73% yield) of the title compound were obtained. (Physical properties) Colorless crystal (mp.190-193 ° C) PMR (CDCl ₃ , δ ppm): 7.57 (2H, s), 7.37 (1H, brs), 5.59 (1
H, s), 4.09 (2H, brs), 1.45 (18H, s)

Reference Example 2 6-hydroxy-2,5,7,
8-tetramethylchroman-2-acetohydrazide (6-h
ydroxy-2,5,7,8-tetramethylchroman-2-acetohydrazid
e) methyl 6-acetoxy-2,5,7,8-tetr
amethylchroman-2-acetate) 32.68 g (102 mmol) and hydrazine hydrate 49.48 ml (1020 mmol) in 1-propanol 2
It was dissolved in 04 ml and heated under reflux at a bath temperature of 110 ° C. for 4 hours. The solvent was distilled off to precipitate crystals, and the crystals were collected by filtration. The crystals collected by filtration were dried under reduced pressure to give 14.95 g of the title compound (yield
53%). The filtrate was subjected to silica gel column chromatography. The solvent eluted with methanol: chloroform = 1: 20 was evaporated, ethyl acetate was added for crystallization, and the crystal was dried under reduced pressure. 4.34 g (yield 15%) of the title compound was obtained. (Physical properties) Colorless crystal (mp.155-157 ° C) PMR (DMSO-d ₆ , δ ppm): 8.96 (1H, brs), 7.36 (1H, s), 4.18
(2H, brs), 2.62-2.44 (2H, m), 2.35 (1H, d, J = 13.2Hz), 2.24
(1H, d, J = 13.2Hz), 2.05 (3H, s), 2.02 (3H, s), 1.97-1.90 (4
(H, m), 1.80-1.72 (1H, m), 1.29 (3H, s) IR (KBr, cm- ¹ ): 3274,1650,1539,1458,1243,1101,1023,9
twenty three

Reference Example 3 6-hydroxy-2,5,7,
8-tetramethylchroman-2-carbohydrazide (6-h
ydroxy-2,5,7,8-tetramethylchroman-2-carbohydrazid
e) methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate (methyl 6-hydroxy-2,5,7,8-
tetramethylchroman-2-carboxylate) 3.06 g (11.6 mmol)
Then, 2.81 ml (57.9 mmol) of hydrazine hydrate were dissolved in 25 ml of 1-propanol, and the mixture was refluxed for 4 hours at a bath temperature of 110 ° C. The solvent was distilled off to precipitate crystals, and the crystals were collected by filtration. The crystals collected by filtration were dried under reduced pressure to give the title compound (2.63 g).
(86% yield). (Physical properties) Colorless crystal PMR (DMSO-d ₆ , δ ppm): 8.45 (1H, brs), 7.43 (1H, s), 4.22
(2H, brs), 2.56-2.38 (2H, m), 2.26-2.19 (1H, m), 2.09 (3H,
s), 2.07 (3H, s), 1.99 (3H, s), 1.74-1.66 (1H, m), 1.40 (3H,
s)

Reference Example 4 6-hydroxy-2,5,7,
8-tetramethylchroman-2-butyrohydrazide (6-h
ydroxy-2,5,7,8-tetramethylchroman-2-butyrohydrazid
e) methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-butyrate (methyl 6-hydroxy-2,5,7,8-tetram
3.06 g (10 mmol) of ethylchroman-2-butyrate) and 2.43 ml (50 mmol) of hydrazine hydrate were dissolved in 10 ml of 1-propanol, and the mixture was heated and refluxed at a bath temperature of 80 ° C. for 5 hours. The solvent was distilled off, and ethyl acetate was added.
Wash sequentially with saturated saline, dry over magnesium sulfate,
The solvent was distilled off. The residue was subjected to silica gel column chromatography. The solvent was distilled off from the eluted portion of methanol: chloroform = 1: 20, crystallized by adding ethyl acetate, and dried under reduced pressure. 2.83 g (yield 92%) of the title compound was obtained. (Physical properties) Colorless crystal (mp.112-113 ° C) PMR (DMSO-d ₆ , δ ppm): 8.90 (1H, brs), 7.31 (1H, s), 4.11
(2H, brs), 2.53-2.51 (2H, m), 2.05-1.98 (11H, m), 1.76-1.4
3 (6H, m), 1.16 (3H, s)

Reference Example 5 6-hydroxy-2,5,7,
8-tetramethylchroman-2-propionohydrazide
(6-hydroxy-2,5,7,8-tetramethylchroman-2-propionohy
drazide) The title compound was obtained in the same manner as in Reference Example 4 (yield: 10
0%). (Physical properties) Colorless crystal (mp. 89-91 ° C.) PMR (DMSO-d ₆ , δ ppm): 8.97 (1H, br)
s), 7.33 (1H, s), 4.08 (2H, br)
s), 2.54-2.51 (2H, m), 2.23-
1.98 (11H, m), 1.83-1.66 (4H,
m), 1.15 (3H, s)

Reference Example 6 Benzaldehyde methylhydrazone
razone) 1.02 ml (10 mmol) of benzaldehyde and 0.53 ml (10 mmol) of methylhydrazine are added to 20 ml of ethanol, and the mixture is added at room temperature.
Stir for 3 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. The solvent was distilled off from the eluted portion of ethyl acetate: n-hexane = 1: 3 to give the title compound (1.21 g)
(90% yield). (Physical properties) Colorless oil

Reference Example 7 Salicylaldehyde methylhydrazone 1.07 ml (10 mmol) of salicylaldehyde and 0.53 ml (10 mmol) of methylhydrazine were added to 20 ml of ethanol, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off to give the title compound (1.44 g).
(96% yield). (Physical properties) Yellow oil PMR (CDCl ₃ , δ ppm): 7.67 (1H, s), 7.17 (1H, td, J = 7.8,1.5
Hz), 7.12 (1H, dd, J = 7.8,1.5Hz), 6.93 (1H, d, J = 8.3Hz), 6.
86 (1H, td, J = 7.3,1.0Hz), 2.98 (3H, s)

Reference Example 8 2,4-dihydroxybenzaldehyde methylhydrazone (2,4-dihydroxybenzaldehyde
methylhydrazone) The title compound was obtained in the same manner as in Reference Example 7 (yield: 54
%). (Physical properties) Brown crystal PMR (DMSO-d ₆ , δ ppm): 11.58 (1H,
s), 9.47 (1H, brs), 7.63 (1H,
s), 7.02 (1H, d, J = 8.3 Hz), 6.9
9 (1H, q, J = 4.9 Hz), 6.25 (1H, d
d, J = 8.3, 2.4 Hz), 6.20 (1H, d,
J = 2.4 Hz), 2.76 (3H, d, J = 4.9 H)
z)

Reference Example 9 o-Vanillin methylhydrazo
ne) 1.52 g (10 mmol) of o-vanillin (2-hydroxy-3-methoxybenzaldehyde) and 0.53 ml of methylhydrazine
(10 mmol) was added to 20 ml of ethanol, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, and ethyl acetate: n-hexane = 1: 1.
The solvent was distilled off from the eluted portion to crystallize and was collected by filtration. Drying under reduced pressure gave 1.39 g (yield 77%) of the title compound. (Physical properties) Pale yellow crystal PMR (DMSO-d ₆ , δ ppm): 11.33 (1H, s), 7.64 (1H, s), 7.45 (1
H, brs), 6.87 (1H, dd, J = 7.8,1.0Hz), 6.82 (1H, dd, J = 6.4H
z), 6.75 (1H, t, J = 7.8Hz), 3.77 (3H, s), 2.81 (3H, s)

Reference Example 10 4- (Diethylamino) salicylaldehyde methylhydrazone (4- (diethylamino) sal
icylaldehyde methylhydrazone) 4- (diethylamino) salicylaldehyde 1.93g (10m
mol) and 0.53 ml (10 mmol) of methylhydrazine were added to a mixed solvent of 20 ml of ethanol and 10 ml of methanol, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off, the residue was subjected to silica gel column chromatography, and the eluted portion of ethyl acetate: n-hexane = 1: 2 was evaporated to remove the solvent.
(77% yield). (Physical properties) Brown oil PMR (CDCl ₃ , δ ppm): 11.40 (1H, brs), 7.67 (1H, s), 6.93 (1
H, d, J = 8.3Hz), 6.21 (1H, d, J = 2.4Hz), 6.19 (1H, dd, J = 8.3,
2.4Hz), 3.35 (4H, q, J = 7.2Hz), 2.92 (3H, s), 1.17 (6H, t, J =
(7.1Hz)

Reference Example 11 5-nitrosalicylaldehyde methyl hydrazone
(Drazone) 1.67 g (10 mmol) of 5-nitrosalicylaldehyde and 0.53 ml (10 mmol) of methylhydrazine were added to a mixed solvent of 20 ml of ethanol and 10 ml of methanol, and the mixture was stirred at room temperature for 24 hours. The resulting crystals were collected by filtration. Drying under reduced pressure gave 1.72 g (88% yield) of the title compound. (Physical properties) Yellow crystal PMR (DMSO-d ₆ , δ ppm): 12.42 (1H, brs), 8.30 (1H, d, J = 2.0
Hz), 7.97 (1H, dd, J = 8.8,2.0Hz), 7.86 (1H, brq, J = 3.9Hz),
7.73 (1H, s), 6.98 (1H, d, J = 8.8Hz), 2.86 (3H, d, J = 4.4Hz)

Reference Example 12 2,4-dihydroxybenzaldehyde oxime
e) 1,38 g of 2,4-dihydroxybenzaldehyde (10 mmo
l), 0.69 g (10 mmol) of hydroxylamine hydrochloride and 1.06 g (10 mmol) of sodium carbonate were added to 20 ml of methanol, followed by stirring at room temperature for 24 hours. The solvent was distilled off and ethyl acetate 100m
The organic layer was washed with water and saturated saline in this order, and the organic layer was dried over magnesium sulfate. The solvent was distilled off, and the resulting crystals were collected by filtration. Drying under reduced pressure gave 1.14 g (74% yield) of the title compound. (Physical properties) Light brown crystal PMR (DMSO-d ₆ , δ ppm): 10.92 (1H, s), 10.09 (1H, s), 9.67
(1H, s), 8.18 (1H, s), 7.20 (1H, d, J = 9.3Hz), 6.31-6.28 (2H,
m)

Reference Example 13 o-vanillin oxime (o-van
illin oxime) The title compound was obtained in the same manner as in Reference Example 12 (yield
77%). (Physical properties) Colorless crystal PMR (DMSO-d ₆ , δ ppm): 11.31 (1H, brs), 9.69 (1H, brs), 8.
32 (1H, s), 7.06 (1H, d, J = 7.8Hz), 6.95 (1H, d, J = 7.8Hz), 6.8
0 (1H, t, J = 7.8Hz), 3.80 (3H, s)

Reference Example 14 4- (diethylamino) salicylalde oxime
hyde oxime) 4- (diethylamino) salicylartifice 3.87 g (20 mmol), hydroxylamine hydrochloride 1.39 g (20 mmol) and sodium carbonate 2.12 g (20 m
mol) was added to 40 ml of methanol, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off, 100 ml of ethyl acetate was added, and the mixture was washed sequentially with water and saturated saline, and the ethyl acetate layer was dried over magnesium sulfate. The solvent was distilled off, the residue was subjected to silica gel column chromatography, and methanol: chloroform =
The solvent was distilled off from the 1:50 elution part, and the resulting crystals were collected by filtration. Drying under reduced pressure gave 1.34 g (yield 32%) of the title compound. (Physical properties) Colorless crystal PMR (DMSO-d ₆ , δ ppm): 10.74 (1H, s), 10.00 (1H, s), 8.13
(1H, s), 7.13 (1H, d, J = 8.8Hz), 6.20 (1H, dd, J = 8.8,2.4Hz),
6.09 (1H, d, J = 2.0Hz), 3.32 (4H, q, J = 6.8Hz), 1.09 (6H, t, J =
(7.1Hz)

Reference Example 15 5-nitrosalicylaldehyde oxime 3.34 g (20 mmol) of 5-nitrosalicylaldehyde, 1.39 g (20 mmol) of hydroxylamine hydrochloride and sodium carbonate
2.12 g (20 mmol) was added to 40 ml of methanol, and
Stirred for hours. The solvent was distilled off, 100 ml of ethyl acetate was added, the mixture was washed with water, and the insoluble matter was collected by filtration. Dissolve in methanol,
The solvent was distilled off, and the resulting crystals were collected by filtration. Dried under reduced pressure,
2.19 g (yield 60%) of the title compound were obtained. (Physical properties) Yellow crystal PMR (DMSO-d ₆ , δ ppm): 10.54 (1H, s), 8.22 (1H, d, J = 3.4H
z), 8.21 (1H, s), 7.73 (1H, dd, J = 9.3,3.5Hz), 6.06 (1H, d, J =
(9.3Hz)

Reference Example 16 3,5-diisopropyl-4
-Hydroxybenzohydrazide (3,5-diisopropyl-4-hyd
roxybenzohydrazide) methyl 3,5-diisopropyl-4-hydroxybenzoate 6.91 g
(29 mmol), a mixture of 10.0 ml of hydrazine hydrate and 100 ml of 1-propanol was heated under reflux for 10 hours. The solvent was distilled off, and the precipitated crystals were washed with ethyl acetate to give the title compound 6.
73 g (97% yield) was obtained. (Physical Properties) colorless crystals (mp.240-243 ℃) PMR (DMSO- d 6, δ ppm): 9.53 (1H, brs), 8.40 (1H, brs), 7.5
1 (2H, s), 4.35 (2H, brs), 3.30 (2H, sept, J = 7.0Hz), 1.16 (12
(H, d, J = 7.0Hz)

Reference Example 17 3- (3,5-di-t-butyl-4-hydroxyphenyl) propionohydrazide (3
-(3,5-di-t-butyl-4-hydroxyphenyl) propionohydrazid
e) methyl 3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate
A mixture of 10.46 g (36 mmol) of hydroxyphenyl) propionate, 10.0 ml of hydrazine hydrate and 100 ml of 1-propanol was heated under reflux for 10 hours. The solvent was distilled off, and the precipitated crystals were washed with isopropyl ether to give 9.66 g of the title compound (yield
92%). (Physical properties) Colorless crystal (mp.154-158 ° C) PMR (DMSO-d ₆ , δ ppm): 8.97 (1H, brs), 6.90 (2H, s), 6.69
(1H, s), 4.14 (2H, brs), 2.71-2.65 (2H, m), 2.28-2.23 (2H,
m), 1.36 (18H, s)

Reference Example 18 3- (3,5-diisopropyl-4-hydroxyphenyl) propionohydrazide (3
-(3,5-diisopropyl-4-hydroxyphenyl) propionohydrazid
e) The title compound was obtained by treating in the same manner as in Reference Example 17 (yield
100%). (Physical Properties) colorless crystals (mp.101-104 ℃) PMR (DMSO- d 6, δ ppm): 8.95 (1H, brs), 7.77 (1H, brs), 6.7
7 (2H, s), 4.13 (2H, brs), 3.25 (2H, sept, J = 7.0 Hz), 2.71-
2.65 (2H, m), 2.29-2.21 (2H, m), 1.13 (12H, d, J = 7.0Hz)

Example 1 Benzaldehyde 3,5-di-
t-butyl-4-hydroxybenzoylhydrazone (ben
zaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazon
e) Compound 3,5-di-t-butyl-4 synthesized in Reference Example 1
1.32 g (5 mmol) of -hydroxybenzohydrazide and 0.51 ml (5 mmol) of benzaldehyde were dissolved in 10 ml of ethanol, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off, isopropyl ether was added to precipitate crystals, and the crystals were collected by filtration. Drying under reduced pressure gave 1.09 g (yield 62%) of the title compound. (Physical properties) Colorless crystal (mp.223 ° C) PMR (CDCl ₃ , δ ppm): 9.09 (1H, brs), 8.36 (1H, brs), 7.74
(4H, m), 7.41-7.38 (3H, m), 5.63 (1H, s), 1.48 (18H, s) IR (KBr, cm- ¹ ): 3620,3412,3200,2958,1643,1555,1437 , 1
364,1308,1239,696

Example 2 4-Fluorobenzaldehyde 3,5-di-t-butyl-4-hydroxybenzoyl hydrazone
roxybenzoylhydrazone) Compound 3,5-di-t-butyl-4 synthesized in Reference Example 1.
-Hydroxybenzohydrazide 0.53 g (2 mmol) and 4-
0.22 ml (2 mmol) of fluorobenzaldehyde in ethanol
It was dissolved in 5 ml and stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration and washed with ethanol. Drying under reduced pressure gave 0.63 g (yield 85%) of the title compound. (Physical properties) Colorless crystals (mp. 220 ° C) PMR (DMSO-d ₆ , δ ppm): 11.60 (1H, brs), 8.46 (1H, brs), 7.
77 (2H, m), 7.65 (2H, s), 7.49 (1H, s), 7.26 (2H, t, J = 8.8Hz),
1.43 (18H, s) IR (KBr, cm ^-1 ): 3620,3510,3230,2956,1646,1606,1558,1
510,1306,1237,1156,1068,834

Examples 3-49 The following compounds were prepared by treating substantially the same as in Examples 1 or 2 except that benzaldehyde or 4-fluorobenzaldehyde was replaced with another aldehyde compound or ketone compound.

Example 3 4-chlorobenzaldehyde 3,5-di-t-butyl-4-hyd hydrazone
Roxybenzoylhydrazone) Yield: 72% (Physical Properties) colorless crystals (mp.260-261 ℃) PMR (DMSO- d 6, δ ppm): 11.65 (1H, brs), 8.45 (1H, brs), 7.
73 (2H, d, J = 7.3Hz), 7.65 (2H, s), 7.50-7.48 (3H, m), 1.43 (1
8H, s) IR (KBr, cm ^-1 ): 3618,3216,2958,1642,1539,1241

Example 4 4-bromobenzaldehyde 3,5-di-t-butyl-4-hydr
Oxybenzoylhydrazone) Yield: 75% (Physical Properties) colorless crystals (mp.264-265 ℃) PMR (DMSO- d 6, δ ppm): 11.66 (1H, s), 8.43 (1H, s), 7.65-
7.62 (6H, m), 7.50 (1H, s), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3612,3450,3216,2956,1642,1601,1544,1
303,1240,1071

Example 5 4-Hydroxybenzaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone
hydroxybenzoylhydrazone) Yield: 92% (physical properties) Colorless crystals (mp. 290-295 ° C (dec.)) PMR (DMSO-d ₆ , δ ppm): 11.39 (1H, brs), 9.85 (1H, brs), 8 .
34 (1H, brs), 7.62 (2H, s), 7.54 (2H, d, J = 7.8Hz), 7.46 (1H,
s), 6.83 (2H, d, J = 7.8Hz), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3620,3380,2960,1636,1604,1558,1518,1
436,1313,1275,1239,1170

Example 6 p-anisaldehyde 3,5-
Di-t-butyl-4-hydroxybenzoylhydrazone
(p-anisaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhyd
Razone) Yield: 81% (Physical Properties) colorless crystals (mp.244-246 ℃) PMR (DMSO- d 6, δ ppm): 11.46 (1H, brs), 8.40 (1H, s), 7.67
(2H, s), 7.64 (2H, d, J = 6.8Hz), 7.46 (1H, s), 7.00 (2H, d, J =
(8.3Hz), 3.81 (3H, s), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3590,3200,2958,1651,1514,1306,1248,1
180,1023,840

Example 7 4-dimethylaminobenzaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone
t-butyl-4-hydroxybenzoylhydrazone) Yield: 94% (physical properties) pale yellow crystal (mp.225-227 ° C) PMR (DMSO-d ₆ , δ ppm): 11.30 (1H, s), 8.30 (1H, s ), 7.61 (2
H, s), 7.53 (2H, d, J = 8.8Hz), 7.44 (1H, s), 6.75 (2H, d, J = 8.
8Hz), 2.98 (6H, s), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3598,3450,3230,2954,1647,1602,1525 ,,
1436,1364,1303,1237,1184

Example 8 4-nitrobenzaldehyde 3,5-di-t-butyl-4-hydr
(oxybenzoylhydrazone) Yield: 75% (physical properties) pale yellow crystal (mp. 284-287 ° C) PMR (DMSO-d ₆ , δ ppm): 11.91 (1H, brs), 8.56 (1H, brs), 8.
29 (2H, d, J = 8.3Hz), 7.98 (2H, brd, J = 7.3Hz), 7.68 (2H, s),
7.57 (1H, s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3618,3425,3214,2958,1645,1520,1344,1
239,1155

Example 9 4-cyanobenzaldehyde 3,5-di-t-butyl-4-hydr
(oxybenzoylhydrazone) Yield: 85% (physical properties) Colorless crystals (mp.274-275 ° C) PMR (CDCl ₃ , δ ppm): 9.30 (1H, brs), 8.45 (1H, brs), 7.82
(2H, d, J = 6.8Hz), 7.73 (2H, brs), 7.68 (2H, d, J = 8.3Hz), 5.
68 (1H, s), 1.48 (18H, s) IR (KBr, cm ^-1 ): 3450,3214,2956,1643,1540,1437,1361,1
303,1242

Example 10 4-phenylbenzaldehyde 3,5-di-t-butyl-4-h
ydroxybenzoylhydrazone) Yield: 82% (physical properties) Colorless crystal (mp.268 ° C) PMR (CDCl ₃ , δ ppm): 9.04 (1H, brs), 8.40 (1H, brs), 7.82
(2H, brs), 7.69 (2H, brs), 7.66-7.61 (4H, m), 7.46 (2H, t, J =
7.8Hz), 7.37 (1H, t, J = 7.3Hz), 5.64 (1H, s), 1.49 (18H, s) IR (KBr, cm ^-1 ): 3450,1649,1556,1308,1254,1238, 1073,7
70

Example 11 Acetophenone 3,5-di-
t-butyl-4-hydroxybenzoylhydrazone (a
cetophenone 3,5-di-t-butyl
l-4-hydroxybenzoylhydrazo
ne) Yield: 63% (Physical Properties) colorless crystals (mp.208 ℃) PMR (DMSO- d 6, δ ppm): 10.60 (1H, s), 7.81 (2H, brs), 7.62
(2H, s), 7.47 (1H, s), 7.40 (3H, brs), 2.34 (3H, s), 1.43 (18
H, s) IR (KBr, cm ^-1 ): 3616,3168,2960,1642,1373,1235,760

Example 12 Propiophenone 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (p
ropiophenone 3,5-di-t-butyl-4-hydroxybenzoylhydraz
one) Yield: 72% (Physical Properties) colorless crystals (mp.181-182 ℃) PMR (DMSO- d 6, δ ppm): 10.65 (1H, brs), 7.78 (2H, brs), 7.
59 (2H, s), 7.46 (1H, s), 7.39 (3H, brs), 2.90 (2H, q, J = 7.3H
z), 1.43 (18H, s), 1.10 (3H, t, J = 7.3Hz) IR (KBr, cm ^-1 ): 3616,2956,1642,1375,1233,768

Example 13 n-butyrophenone 3,5-
Di-t-butyl-4-hydroxybenzoylhydrazone
(n-butyrophenone 3,5-di-t-butyl-4-hydroxybenzoylhy
(drazone) Yield: 75% (physical properties) Colorless crystals (mp. 174-176 ° C) PMR (DMSO-d ₆ , δ ppm): 10.65 (1H, brs), 7.78 (2H, brs), 7.
58 (2H, s), 7.48 (1H, s), 7.39 (3H, brs), 2.89 (2H, brt, J = 7.8
Hz), 1.54 (2H, q, J = 7.5 Hz), 1.42 (18H, s), 0.98 (3H, t, J = 7.3
Hz) IR (KBr, cm ^-1 ): 3614,3450,3174,2962,1640,1448,1377,1
314,1234,1120,767,693

Example 14 Isobutyrophenone 3,5-
Di-t-butyl-4-hydroxybenzoylhydrazone
(isobutyrophenone 3,5-di-t-butyl-4-hydroxybenzoylh
ydrazone) Yield: 49% (Physical properties) Colorless crystals (mp. 124-125 ° C) PMR (DMSO-d ₆ , δ ppm): 9.06 (1H, brs), 7.55 (2H, t, J = 7.3H)
z), 7.51-7.48 (2H, m), 7.34 (2H, d, J = 7.3Hz), 7.22 (2H, br
s), 2.92-2.88 (1H, m), 1.31 (18H, s), 1.12 (6H, d, J = 6.8Hz) IR (KBr, cm ^-1 ): 3368,2958,1666,1506,1434,1238 , 773,70
8

Example 15 Salicylaldehyde 3,5-
Di-t-butyl-4-hydroxybenzoylhydrazone
(salicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhy
(drazone) Yield: 50% (physical properties) Colorless crystals (mp. 275-276 ° C) PMR (DMSO-d ₆ , δ ppm): 11.85 (1H, s), 11.46 (1H, s), 8.63
(1H, s), 7.69 (2H, s), 7.55 (1H, s), 7.49 (1H, d, J = 6.8Hz), 7.
28 (1H, d, J = 7.6Hz), 6.94-6.89 (2H, m), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3600,3222,2962,1645,1550,1361,1307, 1
275,1238,1152,753

Example 16 3-hydroxybenzaldehyde 3,5-di-t-butyl-hydroxybenzoyl hydrazone
4-hydroxybenzoylhydrazone) Yield: 100% (physical properties) of colorless crystals (mp.265-266 ℃) PMR (DMSO- d 6, δ ppm): 11.52 (1H, br
s), 9.56 (1H, brs), 8.36 (1H,
s), 7.64 (2H, s), 7.48 (1H, s),
7.25-7.19 (2H, m), 7.08 (1H,
d, J = 7.8 Hz), 6.81 (1H, d, J = 7.
3Hz), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3592, 3400, 3
230, 2968, 1646, 1557, 1242

Example 17 o-anisaldehyde 3,5
-Di-t-butyl-4-hydroxybenzoylhydrazone (o-anisaldehyde 3,5-di-t
-Butyl-4-hydroxybenzoylhy
Drazone) Yield: 35% (Physical Properties) colorless crystals (mp.250-251 ℃) PMR (DMSO- d 6, δ ppm): 11.59 (1H, brs), 8.80 (1H, brs), 7.
89 (1H, d, J = 7.3Hz), 7.66 (2H, s), 7.46 (1H, s), 7.40 (1H, t,
J = 7.6Hz), 7.09 (1H, d, J = 8.3Hz), 7.01 (1H, brt), 3.88 (3H,
s), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3594,3450,3246,2958,1656,1607,1553,1
436,1366,1304,1253,752

Example 18 o-acetylsalicylaldehyde 3,5-di-t-buty
l-4-hydroxybenzoylhydrazone) Yield: 79% (Physical properties) Colorless crystals (mp.246-248 ° C) PMR (DMSO-d ₆ , δ ppm): 11.61 (1H, brs), 8.43 (1H, brs), 7 .
83 (1H, d, J = 7.8Hz), 7.64 (2H, s), 7.52 (1H, s), 7.46 (1H, t,
J = 7.3Hz), 7.35 (1H, t, J = 6.8Hz), 7.18 (1H, d, J = 7.8Hz), 2.4
1 (3H, s), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3582,3192,2956,1754,1652,1553,1363,1
306,1243

Example 19 o-Tolualdehyde 3,5-
Di-t-butyl-4-hydroxybenzoylhydrazone
(o-tolualdehyde 3,5-di-t-butyl-4-hydroxybenzoylhyd
razone) Yield: 86% (physical properties) Colorless crystals (mp. 257-258 ° C) PMR (DMSO-d ₆ , δ ppm): 11.58 (1H, s), 8.72 (1H, s), 7.84 (1
H, brd), 7.65 (2H, s), 7.50 (1H, s), 7.30-7.23 (3H, m), 2.46
(3H, s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3620,3430,3224,2958,1647,1554,1437,1
366,1306,1241,758

Example 20 2-nitrobenzaldehyde 3,5-di-t-butyl-4-hydr-4-hydroxybenzoylhydrazone
(oxybenzoylhydrazone) Yield: 79% (physical properties) Colorless crystals (mp. 218-219 ° C) PMR (DMSO-d ₆ , δ ppm): 11.95 (1H, s), 8.86 (1H, s), 8.15 (1
H, brd), 8.06 (1H, d, J = 8.3Hz), 7.80 (1H, brt), 7.67-7.64
(3H, m), 7.54 (1H, s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3626,3250,2956,1651,1527,1346,1302,1
238,1160

Example 21 2-fluorobenzaldehyde 3,5-di-t-butyl-4-h
Ydroxybenzoylhydrazone) Yield: 22% (Physical Properties) colorless crystals (mp.192-193 ℃) PMR (DMSO- d 6, δ ppm): 11.71 (1H, s), 8.71 (1H, s), 7.96 (1
H, brs), 7.67 (2H, s), 7.51 (1H, s), 7.48-7.44 (1H, m), 7.30-
7.24 (2H, m), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3622,3228,2956,1646,1543,1438,1363,1
303,1238,759

Example 22 2-cyanobenzaldehyde 3,5-di-t-butyl-4-hydr
(oxybenzoylhydrazone) Yield: 42% (Physical properties) Pale yellow crystal (mp.200-201 ° C) PMR (DMSO-d ₆ , δ ppm): 11.98 (1H, s), 8.83 (1H, s), 8.14 (1
H, s), 7.88 (1H, d, J = 7.8Hz), 7.77 (1H, t, J = 7.6Hz), 7.68 (2
H, s), 7.59 (1H, t, J = 7.6Hz), 7.54 (1H, s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3624,3214,2958,2226,1653,1541 , 1437,1
364,1302,1239,1160,766

Example 23 α-tetralone 3,5-di-
t-butyl-4-hydroxybenzoylhydrazone (α
-tetralone 3,5-di-t-butyl-4-hydroxybenzoylhydrazon
e) Yield: 75% (Physical Properties) colorless crystals (mp.235-237 ℃) PMR (DMSO- d 6, δ ppm): 10.52 (1H, s), 8.06 (1H, brs), 7.62
(2H, s), 7.45 (1H, s), 7.29-7.18 (3H, m), 2.79-2.73 (4H, m),
1.89-1.85 (2H, m), 1.43 (18H, s) IR (KBr, cm- ¹ ): 3624,3170,2954,1641,1376,1314,1242,1
133,762

Example 24 o-Hydroxyacetophenone 3,5-di-t-butyl-4-o-hydroxyacetophenone 3,5-di-t-butyl-4-
hydroxybenzoylhydrazone) Yield: 80% (physical properties) Colorless crystals (mp. 218-219 ° C) PMR (DMSO-d ₆ , δ ppm): 13.42 (1H, brs), 11.14 (1H, brs),
7.65 (2H, s), 7.61 (1H, d, J = 7.3Hz), 7.56 (1H, s), 7.31-7.26
(2H, m), 2.46 (3H, s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3600,3250,2956,1640,1603,1522,1435,1
302,1154,755

Example 25 2,4-Dihydroxybenzaldehyde 3,5-d-tert-butyl-4-hydroxybenzoylhydrazone
it-butyl-4-hydroxybenzoylhydrazone) Yield: 87% (physical properties) Colorless crystal (mp. 261-264 ° C) PMR (DMSO-d ₆ , δ ppm): 11.64 (1H, s), 11.63 (1H, s) , 9.87
(1H, s), 8.48 (1H, s), 7.66 (2H, s), 7.49 (1H, s), 7.24 (1H, s
d, J = 8.3Hz), 6.35 (1H, d, J = 8.8Hz), 6.31 (1H, s), 1.43 (18H,
s) IR (KBr, cm ^-1 ): 3600,3214,2958,1634,1515,1436,1305,1
244

Example 26 2,3-dihydroxybenzaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone
it-butyl-4-hydroxybenzoylhydrazone) Yield: 61% (Physical Properties) colorless crystals (mp.273-275 ℃) PMR (DMSO- d 6, δ ppm): 11.83 (1H, s), 11.37 (1H, s) , 9.11
(1H, s), 8.58 (1H, s), 7.68 (2H, s), 7.54 (1H, s), 6.91 (1H,
d, J = 7.8Hz), 6.84 (1H, d, J = 7.8Hz), 6.73 (1H, t, J = 7.8Hz),
1.44 (18H, s) IR (KBr, cm ^-1 ): 3610,3222,2962,1643,1549,1361,1307,1
263,1239,732

Example 27 5-nitrosalicylaldehyde 3,5-di-t-butyl-4
-Hydroxybenzoylhydrazone) Yield: 74% (Physical properties) Colorless crystal (mp.265-267 ° C) PMR (DMSO-d ₆ , δ ppm): 12.47 (1H, brs), 12.04 (1H, s), 8.7
3 (1H, s), 8.56 (1H, s), 8.16 (1H, d, J = 8.8Hz), 7.70 (2H, s),
7.57 (1H, s), 7.11 (1H, d, J = 8.8Hz), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3598,2958,1646,1522,1481,1342,1307,1
241

Example 28 2-Hydroxy-5-methoxybenzaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone
aldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 84% (physical properties) colorless crystal (mp.283-284 ° C) PMR (DMSO-d ₆ , δ ppm): 11.83 (1H, s) , 10.83 (1H, s), 8.60
(1H, s), 7.68 (2H, s), 7.53 (1H, s), 7.07 (1H, d, J = 2.5Hz), 6.
91-6.83 (2H, m), 3.74 (3H, s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3614,3238,2962,1644,1551,1496,1268,1
240,1159,1039

Example 29 5-chlorosalicylaldehyde 3,5-di-t-butyl-
4-hydroxybenzoylhydrazone) Yield: 78% (Physical Properties) colorless crystals (mp.276-277 ℃) PMR (DMSO- d 6, δ ppm): 11.95 (1H, s), 11.43 (1H, s), 8.60
(1H, s), 7.68 (2H, s), 7.61 (1H, s), 7.56 (1H, s), 7.28 (1H, d,
J = 6.8Hz), 6.94 (1H, d, J = 8.8Hz), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3616,3210,2960,1642,1544,1481,1343,1
310,1273,1239

Example 30 5-bromosalicylaldehyde 3,5-di-t-butyl-4
-Hydroxybenzoylhydrazone) Yield: 72% (Physical Properties) colorless crystals (mp.279-280 ℃) PMR (DMSO- d 6, δ ppm): 11.94 (1H,
s), 11.43 (1H, s), 8.59 (1H,
s), 7.74 (1H, d, J = 1.5 Hz), 7.6
8 (2H, s), 7.57 (1H, s), 7.40 (1
H, d, J = 8.3 Hz), 6.89 (1H, d, J =
8.8 Hz), 1.44 (18 H, s) IR (KBr, cm ^-1 ): 3614, 3206,2
958, 1639, 1543, 1477, 1340, 1
300, 1237, 1241

Example 31 2-hydroxy-4-methoxybenzaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (2-hydroxy-4
-Methoxybenzaldehyde 3,5-
di-t-butyl-4-hydroxybenzo
ylhydrazine) Yield: 98% (physical properties) Colorless crystals (mp. 280-281 ° C) PMR (DMSO-d ₆ , δ ppm): 11.78 (1H, s), 11.73 (1H, s), 8.53
(1H, s), 7.67 (2H, s), 7.52 (1H, s), 7.37 (1H, d, J = 8.3Hz), 6.
52-6.49 (2H, m), 3.78 (3H, m), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3586,3230,2964,1649,1638,1609,1576,1
511,1436,1362,1292,1240,1164,1143,1029

Example 32 2,5-Dihydroxybenzaldehyde 3,5-d-t-butyl-4-hydroxybenzoylhydrazone
it-butyl-4-hydroxybenzoylhydrazone) Yield: 62% (physical properties) Colorless crystal (mp.229-232 ° C) PMR (DMSO-d ₆ , δ ppm): 11.74 (1H, s), 10.57 (1H, s) , 8.92
(1H, s), 8.54 (1H, s), 7.67 (2H, s), 7.52 (1H, s), 6.91 (1H,
s), 6.76-6.72 (2H, m), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3610,3222,2958,1644,1550,1492,1438,1
366,1309,1240,1156

Example 33: o-Vaniline 3,5-di-t
-Butyl-4-hydroxybenzoylhydrazone (o-van
illin 3,5-di-t-butyl -4-hydroxybenzoylhydrazone) Yield: 95% (Physical Properties) colorless crystals (mp.282-283 ℃) PMR (DMSO- d 6, δ ppm): 11.83 (1H, s) , 11.22 (1H, s), 8.63
(1H, s), 7.68 (2H, s), 7.54 (1H, s), 7.10 (1H, d, J = 7.8Hz), 7.
01 (1H, d, J = 7.8Hz), 6.86 (1H, t, J = 8.1Hz), 3.82 (3H, s), 1.4
4 (18H, s) IR (KBr, cm ^-1 ): 3578,3236,2964,1646,1540,1461,1246,7
35

Example 34 4- (Diethylamino) salicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (4- (diethylamino) salicylalde)
hyde3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 81% (Physical properties) Light brown crystal (mp.235-236 ° C) PMR (DMSO-d ₆ , δ ppm): 11.59 (1H, s) , 11.53 (1H, s), 8.41
(1H, s), 7.65 (2H, s), 7.48 (1H, s), 7.15 (1H, d, J = 8.8Hz), 6.
25 (1H, d, J = 8.3Hz), 6.12 (1H, s), 3.36 (4H, q, J = 6.4Hz), 1.4
4 (18H, s), 1.12 (6H, t, J = 6.8Hz) IR (KBr, cm ^-1 ): 3620,3228,1632,1599,1521,1355,1303,1
245,1135

Example 35 3,5-Dichlorosalicylaldehyde 3,5-dichlorosalicylaldehyde 3,5-d
it-butyl-4-hydroxybenzoylhydrazone) Yield: 62% (Physical properties) Colorless crystal (mp.298 ° C) PMR (DMSO-d ₆ , δ ppm): 12.66 (1H, s), 12.23 (1H, s), 8.56
(1H, s), 7.70 (2H, s), 7.62 (1H, s), 7.59 (1H, d, J = 2.0Hz), 7.
56 (1H, d, J = 2.0Hz), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3616,3418,3218,2960,1641,1539,1452,1
306,1239

Example 36 3,5-Dinitrosalicylaldehyde 3,5-di-nitrobutyl-4-hydroxybenzoylhydrazone
-t-butyl-4-hydroxybenzoylhydrazone) Yield: 88% (physical properties) Yellow crystal (mp.269-270 ° C) PMR (DMSO-d ₆ , δ ppm): 12.44 (1H, brs), 8.79 (2H, brs ), 8.
76 (1H, s), 7.72 (2H, s), 7.65 (1H, s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3565,2965,1680,1620,1535,1345,1225

Example 37 2-hydroxy-1-naphthaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone
di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 85% (Physical properties) Light brown crystal (mp.> 300 ℃) PMR (DMSO-d ₆ , δ ppm): 12.96 (1H, s), 11.94 (1H, s), 9.48
(1H, s), 8.22 (1H, d, J = 8.8Hz), 7.90 (1H, t, J = 9.0Hz), 7.74
(2H, s), 7.61-7.56 (2H, m), 7.40 (1H, t, J = 7.6Hz), 7.23 (1H,
d, J = 8.8Hz), 1.46 (18H, s) IR (KBr, cm ^-1 ): 3612,3188,2958,1640,1602,1329,1242

Example 38 2,4,6-Trihydroxybenzaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (2,4,6-trihydroxybenzaldeh)
yde3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 39% (physical properties) Light brown crystal (mp. 200 ° C (dec.)) PMR (DMSO-d ₆ , δ ppm): 11.60 (1H, s), 11.11 (2H, brs), 9.7
2 (1H, brs), 8.80 (1H, s), 7.67 (2H, s), 7.50 (1H, brs), 5.84
(2H, s), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3616,3225,2962,1640,1614,1525,1463,1
239,1156,1045,828

Example 39 4,6-Dimethoxysalicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (4,6-dimethyoxysa)
lycyldehyde 3,5-di-t-bu
tyl-4-hydroxybenzoylhydra
zone) Yield: 90% (physical properties) Light brown crystal (mp. 303 ° C.) PMR (DMSO-d ₆ , δ ppm): 12.55 (1H, s), 11.75 (1H, s), 8.83
(1H, s), 7.68 (2H, s), 7.53 (1H, s), 6.13 (2H, s), 3.84 (3H,
s), 3.79 (3H, s), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3600,2960,1634,1604,1437,1343,1241,1
213,1156

Example 40 2-Methylaminobenzaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone
butyl-4-hydroxybenzoylhydrazone) Yield: 28% (property) pale yellow crystals (mp.303 ℃) PMR (DMSO- d 6, δ ppm): 11.56 (1H, s), 8.51 (1H, s), 8.41 ( 1
H, brq, J = 4.4Hz), 7.68 (2H, s), 7.50 (1H, s), 7.26-7.20 (2H,
m), 6.69 (1H, d, J = 8.3Hz), 6.63 (1H, t, J = 7.8Hz), 2.93 (3H,
d, J = 4.4Hz), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3618,3425,3208,2964,1640,1599,1555,1
418,1370,1304,1241,1117,706

Example 41 8-Formyl-1,2,3
4-tetrahydroquinoline 3,5-di-t-butyl-4
-Hydroxybenzoylhydrazone (8-formyl-1,2,3,4-
tetrahydroquinoline 3,5-di-t-butyl-4-hydroxybenzoy
Lhydrazone) Yield: 69% (property) pale yellow crystals (mp.301-302 ℃) PMR (DMSO- d 6, δ ppm): 11.50 (1H, s), 8.47 (1H, s), 8.45 (1
H, brs), 7.67 (2H, s), 7.48 (1H, s), 7.00 (1H, d, J = 7.3Hz), 6.
90 (1H, d, J = 7.3Hz), 6.47 (1H, t, J = 7.6Hz), 3.45 (2H, m), 2.7
7 (2H, m), 1.87 (2H, m), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3612,3425,3222,2954,1637,1607,1556,1
518,1429,1366,1303,1240

Example 42 2,3-Dimethoxy-6-formyl-5-methylhydroquinone 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (2,3-dimetho
xy-6-formyl-5-methylhydroquinone 3,5-di-t-butyl-4-
hydroxybenzoylhydrazone) Yield: 71% (physical properties) pale yellow crystal (mp.272-275 ° C (dec.)) PMR (DMSO-d ₆ , δ ppm): 12.17 (1H, s), 11.80 (1H, s), 8.80
(1H, s), 8.21 (1H, s), 7.68 (2H, s), 7.54 (1H, s), 3.83 (3H,
s), 3.81 (3H, s), 2.23 (3H, s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3541,3221,2954,1639,1602,1552,1425,1
392,1285,1239,1197,1140,1108,1059,1024

Example 43 Pyridoxal 3,5-di-
t-butyl-4-hydroxybenzoylhydrazone (pyr
idoxal 3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 86% (physical properties) colorless crystal (mp.> 300 ℃) PMR (DMSO-d ₆ , δ ppm): 12.82 (1H, brs), 12.51 (1H, s), 8.9
5 (1H, s), 8.05 (1H, s), 7.75 (2H, s), 7.67 (1H, s), 5.57 (1H, b
(rs), 4.69 (2H, s), 2.51 (3H, s), 1.45 (18H, s) IR (KBr, cm ^-1 ): 3433,3211,2968,1645,1600,1539,1435,1
402,1361,1303,1260,1237,1218,1163,1121,1017,703

Example 44 2-Picolinaldehyde 3,
5-di-t-butyl-4-hydroxybenzoylhydrazone (2-picolinaldehyde 3,5-di-t-butyl-4-hydroxyben
Zoylhydrazone) Yield: 92% (property) pale brown crystals (mp.209-210 ℃) PMR (DMSO- d 6, δ ppm): 11.80 (1H, brs), 8.61 (1H, d, J = 4.9
Hz), 8.49 (1H, brs), 7.97 (1H, brs), 7.86 (1H, t, J = 7.1Hz),
7.67 (2H, s), 7.54 (1H, s), 7.39 (1H, t, J = 6.1Hz), 1.44 (18H,
s) IR (KBr, cm ^-1 ): 3620,3450,3220,2958,1651,1553,1437,1
307,1240,1164,1079,778

Example 45 Nicotinaldehyde 3,5-
Di-t-butyl-4-hydroxybenzoylhydrazone
(nicotinaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhy
Drazone) Yield: 96% (Physical Properties) colorless crystals (mp.224 ℃) PMR (DMSO- d 6, δ ppm): 11.76 (1H, brs), 8.84 (1H, brs), 8.
59 (1H, d, J = 3.9Hz), 8.52 (1H, brs), 8.12 (1H, brs), 7.66 (2
H, s), 7.53 (1H, s), 7.47 (1H, t, J = 6.1Hz), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3618,3425,3208,2964,1640,1599 , 1555,1
418,1370,1304,1241,1117,706

Example 46 Isonicotinaldehyde 3,
5-di-t-butyl-4-hydroxybenzoylhydrazone (isonicotinaldehyde 3,5-di-t-butyl-4-hydroxybe
Nzoylhydrazone) Yield: 96% (Physical Properties) colorless crystals (mp> 300 ℃) PMR ( DMSO-d 6, δ ppm):. 11.85 (1H, brs), 8.63 (2H, d, J = 5.4
Hz), 8.45 (1H, brs), 7.67 (2H, s), 7.64 (2H, brs), 7.54 (1H,
s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3622,3400,3194,2954,1640,1599,1550,1
361,1307,1244

Example 47 2-furaldehyde 3,5-
Di-t-butyl-4-hydroxybenzoylhydrazone
(2-furaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydr
Azone) Yield: 100% (physical properties) of colorless crystals (mp.233-235 ℃) PMR (DMSO- d 6, δ ppm): 11.52 (1H, brs), 8.36 (1H, brs), 7.
79 (1H, brs), 7.63 (2H, brs), 7.47 (1H, brs), 6.87 (1H, brs),
6.61 (1H, brs), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3607,3204,2958,1633,1549,1436,1335,1
304,1238,1162,1063,1015,941,743,700

Example 48 Pyrrole-2-carbaldehyde 3,5-di-t-butyl-4
-Hydroxybenzoylhydrazone) Yield: 37% (Physical Properties) colorless crystals (mp.275-280 ℃ (dec.)) PMR (DMSO-d 6, δ ppm): 11.48 (1H, brs), 11.25 (1H, brs),
8.27 (1H, d, J = 2.0Hz), 7.61 (2H, s), 7.42 (1H, s), 6.88 (1H,
s), 6.44 (1H, s), 6.12 (1H, d, J = 2.4Hz), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3631,3441,3212,2955,1634,1606,1551 , 1
437,1357,1307,1238,1141,1065,890,729

Example 49 2-thiophenaldehyde 3,5-di-t-butyl-4-hydro-4-hydroxybenzoylhydrazone
Xybenzoylhydrazone) Yield: 85% (Physical Properties) colorless crystals (mp.237-238 ℃) PMR (DMSO- d 6, δ ppm): 11.52 (1H, br
s), 8.70 (1H, brs), 7.63 (3H, b
rs), 7.47 (1H, brs), 7.40 (1H,
brs), 7.12 (1H, brs), 1.43 (18
H, s) IR (KBr, cm ^-1 ): 3610,3239,2
958, 1647, 1556, 1437, 1366, 1
325,1303,1234,700

Example 50 Benzaldehyde N-methyl-3,5-di-tert-butyl-4-hydroxybenzoylhydrazone
yl-3,5-di-t-butyl-4-hydro
Xybenzoylhydrazone) 1.21 g (9.0 mmol) of benzaldehyde methylhydrazone synthesized in Reference Example 6 and 3,5-di-t-butyl-
2.26 g (9.0 mmol) of 4-hydroxybenzoic acid was added to 20 ml of methylene chloride and stirred. 2.23 g (10.8 mmol) of dicyclohexylcarbodiimide (DCC) was added to this solution, and the mixture was stirred for 24 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, the solvent eluted from the chloroform-eluting portion, and the resulting crystals were collected by filtration. Dry under reduced pressure to give the title compound (2.02 g, 61% yield)
I got

(Physical properties) Colorless crystal (mp.245-246 ° C.) PMR (DMSO-d ₆ , δ ppm): 7.98 (1H, s), 7.61-7.57 (2H, m), 7.
51 (2H, s), 7.42 (1H, s), 7.37-7.34 (3H, m), 3.48 (3H, s), 1.4
1 (18H, s) IR (KBr, cm ^-1 ): 3585,2954,1643,1608,1471,1408,1345,1
314,1238,1069,958,883,756,685

Example 51 Salicylaldehyde N-methyl-3,5-di-t-but
yl-4-hydroxybenzoylhydrazone) 1.44 g (9.6 mmol) of the compound synthesized in Reference Example 7 and 2.40 g (9.6 mmol) of 3,5-di-t-butyl-4-hydroxybenzoic acid were added to 20 ml of methylene chloride. Addition and stirring. To this solution was added DCC 2.3
7 g (11.5 mmol) was added, and the mixture was stirred for 24 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the chloroform eluted portion was evaporated to remove the solvent.
Crystallization was performed by adding n-hexane, and the crystals were collected by filtration. Drying under reduced pressure gave 2.36 g (yield: 64%) of the title compound.

(Physical properties) Colorless crystal (mp. 242-243 ° C.) PMR (DMSO-d ₆ , δ ppm): 10.04 (1H, brs), 8.16 (1H, s), 7.47
(1H, d, J = 7.3Hz), 7.42 (3H, s), 7.20 (1H, t, J = 7.8Hz), 6.84-
6.79 (2H, m), 3.48 (3H, s), 1.40 (18H, s) IR (KBr, cm ^-1 ): 3585,2954,1645,1619,1600,1475,1409,1
343,1312,1229,1072,961,891,760,702,685

Example 52 2,4-Dihydroxybenzaldehyde N-methyl-3,5-di-tert-butyl-4-
Hydroxybenzoyl hydrazone (2,4-dihydroxybenzal
dehyde N-methyl-3,5-di-t-butyl-4-hydroxybenzoylhyd
razone) 0.83 g (5 mmol) of compound 2,4-dihydroxybenzaldehyde methylhydrazone synthesized in Reference Example 8 and 3,5
-Di-t-butyl-4-hydroxybenzoic acid 1.25 g (5 mm
ol) was added to a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride and stirred. To this solution, 1.24 g (6 mmol) of DCC was added.
Was added and stirred for 24 hours. The precipitate was suspended in methanol and collected by filtration. Drying under reduced pressure gave 1.14 g (57% yield) of the title compound.

(Physical properties) Light brown crystal (mp. 299-301 ° C. (dec.)) PMR (DMSO-d ₆ , δ ppm): 10.07 (1H, brs), 9.76 (1H, s), 8.06
(1H, s), 7.38 (3H, s), 7.26 (1H, d, J = 8.8Hz), 6.26 (1H, dd, J =
8.3,2.0Hz), 6.18 (1H, d, J = 2.0Hz), 3.44 (3H, s), 1.39 (18H,
s) IR (KBr, cm ^-1 ): 3579,3142,2967,1614,1587,1479,1411,1
399,1342,1311,1244,1174,1076,986,800

Example 53: o-Vaniline N-methyl-
3,5-di-t-butyl-4-hydroxybenzoylhydrazone (o-vanillin N-methyl-
3,5-di-t-butyl-4-hydroxyb
Enzyhydrazine 1.39 g (7.7 mmol) of compound o-vanillin methylhydrazone synthesized in Reference Example 9 and 3,5-di-t-
1.93 g (7.7 mmol) of butyl-4-hydroxybenzoic acid was added to 20 ml of methylene chloride and stirred. In this solution, DC
1.91 g (9.2 mmol) of C was added and stirred for 24 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the solvent eluted with chloroform was distilled off. The residue was crystallized with isopropyl ether and collected by filtration. Drying under reduced pressure gave 1.91 g (yield 60%) of the title compound.

(Physical properties) Colorless crystal (mp.154-155 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.66 (1H, brs), 8.14 (1H, s), 7.43
(2H, s), 7.42 (1H, s), 7.08 (1H, d, J = 7.8Hz), 6.93 (1H, dd, J =
8.3,1.0Hz), 6.74 (1H, t, J = 7.8Hz), 3.77 (3H, s), 3.48 (3H,
s), 1.40 (18H, s) IR (KBr, cm ^-1 ): 3543,2955,2911,1650,1574,1470,1406,1
332,1249,1115,1095,1069,974,727

Example 54 4- (Diethylamino) salicylaldehyde N-methyl-3,5-di-tert-butyl-
4-hydroxybenzoylhydrazone (4- (diethylamin
o) salicylaldehyde N-methyl-3,5-di-t-butyl-4-hydrox
ybenzoylhydrazone) 1.40 g (6.3 mmol) of compound 4- (diethylamino) salicylaldehyde methylhydrazone synthesized in Reference Example 10 and 3,5-di-t-butyl-4-hydroxybenzoic acid
1.58 g (6.3 mmol) was added to 20 ml of methylene chloride and stirred. 1.57 g (7.6 mmol) of DCC was added to this solution, and the mixture was stirred for 24 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, the chloroform eluted portion was evaporated, and ethyl acetate and n-hexane were added for crystallization, followed by filtration. Drying under reduced pressure gave 1.29 g (yield 45%) of the title compound.

(Physical properties) Light brown crystal (mp. 110 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.96 (1H, brs), 8.02 (1H, s), 7.36
(2H, s), 7.34 (1H, s), 7.20 (1H, d, J = 8.3Hz), 6.19 (1H, d, J =
(8.3Hz), 5.95 (1H, s), 3.44 (3H, s), 3.31 (4H, q, J = 6.8Hz), 1.
40 (18H, s), 1.08 (6H, t, J = 6.8Hz) IR (KBr, cm ^-1 ): 3553,2966,1624,1522,1474,1402,1338,1
239,1131,1072,667

Example 55 5-nitrosalicylaldehyde N-methyl-3,5-di-tert-butyl-4-hydroxybenzoylhydrazone
(Thyl-3,5-di-t-butyl-4-hydroxybenzone) 1.72 g (8.8 mmol) of the compound 5-nitrosalicylaldehyde methylhydrazone synthesized in Reference Example 11 and 3,5-di-
2.21 g (8.8 mmol) of t-butyl-4-hydroxybenzoic acid
Was added to a mixed solvent of 20 ml of methylene chloride, 10 ml of dioxane and 10 ml of dimethylformamide, followed by stirring. 2.18 g (10.6 mmol) of DCC was added to this solution, and the mixture was stirred for 24 hours.
The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the solvent eluted with chloroform was distilled off. The residue was crystallized with isopropyl ether and collected by filtration. Drying under reduced pressure gave 1.05 g (yield 28%) of the title compound.

(Physical properties) Light yellow crystal (mp. 257-259 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.50 (1H, brs), 8.38 (1H, d, J = 2.9)
Hz), 8.21 (1H, s), 8.10 (1H, dd, J = 9.3,2.9Hz), 7.48 (2H, s),
7.46 (1H, s), 7.04 (1H, d, J = 8.8Hz), 3.50 (3H, s), 1.40 (18H,
s) IR (KBr, cm ^-1 ): 3586,3090,2955,1662,1627,1524,1467,1
340,1309,1073,645

Example 56 N '-(2-hydroxybenzyl) -3,5-di-t-butyl-4-hydroxybenzohydrazide (N'-(2-hydroxybenzyl) -3,5-di-t-butyl) -Four
-hydroxybenzohydrazide) The compound synthesized in Example 15 salicylaldehyde 3,5
1.47 g (4 mmol) of di-t-butyl-4-hydroxybenzoylhydrazone and 0.15 g of 5% Pd / C in methanol 20m
and catalytic reduction for 18 hours. The catalyst was removed by filtration through Celite, and the solvent was distilled off. The residue was subjected to silica gel column chromatography. Methanol: chloroform = 1:
The solvent was distilled off from the 33 elution portion to precipitate crystals, and the crystals were collected by filtration. The crystals collected by filtration were dried under reduced pressure to give the title compound.
0.95 g (64% yield) was obtained.

(Physical properties) Colorless crystals (mp. 185-186 ° C.) PMR (DMSO-d ₆ , δ ppm): 10.00 (1H, d, J = 5.4 Hz), 9.73 (1H,
s), 7.58 (2H, s), 7.37 (1H, s), 7.18 (1H, d, J = 7.3Hz), 7.09 (1H
H, t, J = 7.3Hz), 6.79 (1H, d, J = 8.3Hz), 6.74 (1H, t, J = 7.6H)
z), 5.42 (1H, q, J = 6.2Hz), 3.93 (2H, d, J = 6.4Hz), 1.40 (18
H, s) IR (KBr, cm ^-1 ): 3633,3274,3206,2956,1635,1542,1485,1
433,1319,1262,1161,761,699

Example 57 N '-(2,4-dihydroxybenzyl) -3,5-di-t-butyl-4-hydroxybenzohydrazide (N'-(2,4-dihydroxybenzyl) -3,5-di
-t-butyl-4-hydroxybenzohydrazide) 1.54 g (4 mmol) of compound 2,4-dihydroxybenzaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone synthesized in Example 25 and 5% Pd / C 0.15
g was added to 20 ml of methanol and subjected to catalytic reduction for 24 hours. The catalyst was removed by filtration through Celite, the solvent was distilled off, and crystals were precipitated.
The crystals were collected by filtration. The filtered crystals are dried under reduced pressure,
0.44 g (yield 28%) of the title compound was obtained.

(Physical properties) Colorless crystal (mp.226-229 ° C. (dec.)) PMR (DMSO-d ₆ , δ ppm): 9.97 (1H, d, J)
= 3.9 Hz), 9.56 (1H, s), 9.09 (1
H, s), 7.58 (2H, s), 7.36 (1H,
s), 6.92 (1H, d, J = 8.3 Hz), 6.2
6 (1H, d, J = 2.5 Hz), 6.15 (1H, d
d, J = 8.3, 2.5 Hz), 5.25 (1H, b
rd), 3.80 (1H, d, J = 4.9 Hz), 1.
40 (18H, s) IR (KBr, cm- ¹ ): 3627, 3264, 3
066,2955,2345,1633,1612,1
551, 1430, 1320, 1238, 1180, 1
123,978,848

Example 58 N-phenethyl-3,5-di-tert-butyl-4-hydroxybenzamide (N-ph
ethyl-3,5-di-t-butyl-4-
hydroxybenzamide) 3,5-di-t-butyl-4-hydroxybenzoic acid 1.2
5 g (5 mmol) and 0.63 ml (5 mmol) of phenethylamine were added to 10 ml of methylene chloride and stirred. In this solution, DCC
1.24 g (6 mmol) was added and the mixture was stirred for 12 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the chloroform eluted portion was evaporated to remove the solvent.
The resulting crystals were collected by filtration. Dry under reduced pressure to give the title compound
0.30 g (17% yield) was obtained. (Physical Properties) colorless crystals (mp.198-202 ℃) PMR (DMSO- d 6, δ ppm): 8.31 (1H, brt, J = 5.4Hz), 7.56 (2H,
s), 7.32-7.17 (6H, m), 3.44 (2H, dt, J = 6.8,6.8Hz), 2.83 (2H
H, t, J = 7.3Hz), 1.40 (18H, s) IR (KBr, cm ^-1 ): 3616,3435,3250,2956,1629,1542,1434,1
329,1238,700

Example 59 N- (2-hydroxyphenethyl) -3,5-di-tert-butyl-4-hydroxybenzamide (N- (2-hydroxyphenethyl) -3,5-di-t-butyl-4-) h
ydroxybenzamide) 3,5-di-t-butyl-4-hydroxybenzoic acid 1.1
3 g (4.5 mmol) and 2-hydroxyphenethylamine 0.6
2 g (4.5 mmol) was added to 9 ml of dimethylformamide and stirred. To this solution, 0.93 g (4.5 mmol) of DCC was added, and 24
Stirred for hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the solvent eluted with chloroform was distilled off, followed by drying under reduced pressure to obtain 0.76 g (yield 46%) of the title compound.

(Physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.33 (1H, s), 8.30 (1H, brt, J = 4.9H)
z), 7.58 (2H, s), 7.28 (1H, s), 7.07 (1H, d, J = 7.3Hz), 7.01 (1
H, t, J = 7.6Hz), 6.80 (1H, d, J = 7.8Hz), 6.71 (1H, t, J = 7.3H)
z), 3.41 (2H, brq, J = 6.8Hz), 2.78 (2H, brt, J = 7.3Hz), 1.41
(18H, s) IR (KBr, cm ^-1 ): 3627,3381,2957,1634,1538,1456,1434,1
361,1316,1239,753

Example 60 Benzaldehyde O-3,
5-di-t-butyl-4-hydroxybenzoyloxime (benzaldehyde O-3,5-di-t-butyl-4-hydroxybenzoylo
xime) 3,5-di-t-butyl-4-hydroxybenzoyl chloride 0.54 g (2 mmol), α-benzaldoxime 0.24 g
(2 mmol) and 0.16 ml (2 mmol) of pyridine were added to 4 ml of ether and stirred for 3 hours. The solvent was distilled off. The residue was subjected to silica gel column chromatography, and ethyl acetate: n
The solvent was distilled off from the eluted portion of -hexane = 1: 3, and ethyl acetate and n-hexane were added for crystallization, followed by filtration. Drying under reduced pressure gave 0.04 g (yield 6%) of the title compound. (Physical properties) Colorless crystal (mp.159-161 ° C) PMR (DMSO-d ₆ , δ ppm): 8.86 (1H, s), 7.88 (1H, s), 7.86 (2
H, s), 7.82 (2H, d, J = 7.8Hz), 7.56-7.50 (3H, m), 1.44 (18H,
s) IR (KBr, cm ^-1 ): 3566,2959,1739,1598,1428,1308,1216,1
093,919,890,749,683

Examples 61 to 65 The following compounds were prepared in substantially the same manner as in Example 60 except that α-benzaldoxime was replaced with another aldoxime compound. Example 61 Salicylaldehyde O-3,5-di-t
-Butyl-4-hydroxybenzoyl oxime (salicyl
aldehyde O-3,5-di-t-butyl-4-hydroxybenzoyloxime) Yield: 46% (physical properties) colorless crystal (mp.167-168 ° C) PMR (DMSO-d ₆ , δ ppm): 10.30 (1H, s), 8.93 (1H, s), 7.88 (1
H, s), 7.86 (2H, s), 7.73 (1H, d, J = 7.8Hz), 7.37 (1H, t, J = 7.6
Hz), 6.98 (1H, d, J = 8.3Hz), 6.93 (1H, t, J = 7.3Hz), 1.44 (18
H, s) IR (KBr, cm ^-1 ): 3588,2960,1738,1611,1432,1301,1269,1
213,1109,1086,951,892,747,706

Example 62 2,4-Dihydroxybenzaldehyde O-3,5-di-t-butyl-4-hydroxybenzoyl oxime
-3,5-di-t-butyl- 4-hydroxybenzoyloxime) Yield: 45% (Physical Properties) colorless crystals (mp.167-170 ℃) PMR (DMSO- d 6, δ ppm): 10.16 (1H, s) , 10.05 (1H, s), 8.78
(1H, s), 7.83 (3H, s), 7.53 (1H, d, J = 8.3Hz), 6.38 (1H, s), 6.
37 (1H, d, J = 8.3Hz), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3579,3383,2955,1717,1630,1609,1519,1
428,1301,1207,1116,946,848,703

Example 63 o-Vaniline O-3,5-
Di-t-butyl-4-hydroxybenzoyl oxime (o
-vanillin O-3,5-di-t-butyl-4-hydroxybenzoyloxime) Yield: 19% (physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 11.44 (1H, s), 8.03 ( 1H, s), 7.94 (1
H, s), 7.93 (2H, s), 7.38 (1H, d, J = 7.8Hz), 7.27 (1H, t, J = 7.8
Hz), 7.15 (1H, d, J = 7.8Hz), 3.77 (3H, s), 1.44 (18H, s) IR (KBr, cm- ¹ ): 3610,3428,2959,1731,1713,1479,1438 , 1
303,1279,1228,1190,1169,1110,976,783

Example 64 4- (Diethylamino) salicylaldehyde O-3,5-di-tert-butyl-4-hydroxybenzoyloxime (4- (diethyla)
mino) salicylaldehyde O-3,
5-di-t-butyl-4-hydroxyben
zoloxime) Yield: 75% (physical properties) Yellow amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.90 (1H, s), 8.72 (1H, s), 7.83 (2
H, s), 7.80 (1H, s), 7.43 (1H, d, J = 9.3Hz), 6.29 (1H, dd, J = 9.
3,2.0Hz), 6.16 (1H, d, J = 2.0Hz), 3.37 (4H, q, J = 6.8Hz), 1.4
3 (18H, s), 1.14 (6H, t, J = 7.1Hz) IR (KBr, cm ^-1 ): 3619,3400,2970,1735,1634,1593,1518,1
297,1219,1133,1099,942

Example 65 5-Nitrosalicylaldehyde O-3,5-di-t-butyl-4-hydroxybenzoyl oxime
utyl-4-hydroxybenzoyloxime) Yield: 16% (physical properties) Colorless crystals (mp. 152-154 ° C) PMR (DMSO-d ₆ , δ ppm): 11.86 (1H, s), 8.60 (1H, d, J = 2.9H
z), 8.30 (1H, dd, J = 8.8,2.9Hz), 8.18 (1H, s), 8.05 (1H, s),
7.95 (2H, s), 7.62 (1H, d, J = 8.8Hz), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3577,3430,2966,1721,1533,1413,1352,1
305,1216,1095,979,839

Example 66 N-benzyloxy-3,5
-Di-t-butyl-4-hydroxybenzamide (N-ben
zyloxy-3,5-di-t-butyl-4-hydroxybenzamide) 3,5-di-t-butyl-4-hydroxybenzoic acid 2.5
0 g (10 mmol) and O-benzylhydroxylamine 1.23 g
(10 mmol) was added to 20 ml of methylene chloride and stirred. To this solution, 2.48 g (12 mmol) of DCC was added and stirred for 4 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the solvent was distilled off from the eluted portion of methanol: chloroform = 1: 50, and the resulting crystals were collected by filtration. Dry under reduced pressure to give the title compound (2.00 g, 56% yield)
I got (Physical properties) Colorless crystal (mp.158-159 ° C) PMR (DMSO-d ₆ , δ ppm): 11.54 (1H, brs), 7.53 (2H, s), 7.47
-7.33 (6H, m), 4.90 (2H, s), 1.39 (18H, s) IR (KBr, cm ^-1 ): 3619,3443,3146,2955,1635,1524,1434,1
332,1238,1163,1045,954,744,703

Example 67 3,5-Di-t-butyl-4
-Hydroxybenzaldehyde salicylidenehydrazone
(3,5-di-t-butyl-4-hydroxybenzaldehyde salicylidene
1.17 g (5 mmol) of 3,5-di-t-butyl-4-hydroxybenzaldehyde and salicylaldehyde hydrazone
0.68 g (5 mmol) was dissolved in 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off, ethyl acetate was added, the mixture was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography. Ethyl acetate: n-hexane =
The solvent eluted from the 1: 9 eluted portion was crystallized by adding ethyl acetate and n-hexane, and collected by filtration. Drying under reduced pressure gave 0.79 g (yield 45%) of the title compound. (Physical Properties) colorless crystals (mp.145-147 ℃) PMR (DMSO- d 6, δ ppm): 11.54 (1H, s), 8.92 (1H, s), 8.69 (1
H, s), 7.69 (2H, s), 7.62-7.58 (2H, m), 7.36 (1H, td, J = 7.8,
2.0Hz), 6.97-6.93 (2H, m), 1.43 (18H, s) IR (KBr, cm- ¹ ): 3620,2953,1625,1419,1369,1317,1271,1
234,1209,1152,754

Example 68 Propionaldehyde 3,5
-Di-t-butyl-4-hydroxybenzoylhydrazone (propionaldehyde 3,5-di-t-butyl-4-hydroxybenzoyl
hydrazone) Compound 3,5-di-t-butyl-4 synthesized in Reference Example 1.
0.53 g (2 mmol) of -hydroxybenzohydrazide and 0.15 ml (2 mmol) of propionaldehyde were dissolved in 10 ml of ethanol, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off, isopropyl ether was added, and the crystals were collected by filtration. Drying under reduced pressure gave 0.42 g (69% yield) of the title compound. (Physical Properties) colorless crystals (mp.190-192 ℃) PMR (DMSO- d 6, δ ppm): 11.17 (1H, brs), 7.73 (1H, brs), 7.
56 (2H, s), 7.42 (1H, s), 2.30-2.26 (2H, m), 1.41 (18H, s), 1.
06 (3H, t, J = 7.1Hz) IR (KBr, cm ^-1 ): 3630,3356,3212,3075,2964,1624,1555,1
435,1361,1313,1240,1159,1053,770,699

Examples 69 to 70 The following compounds were prepared in substantially the same manner as in Example 68 except that propionaldehyde was replaced with another aldehyde compound. Example 69 Glyceraldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone (glyceraldeh
yde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 82% (physical properties) colorless crystal (mp.227-229 ° C (dec.)) PMR (DMSO-d ₆ , δ ppm): 11.33 ( 1H, brs), 7.66 (1H, brd, J =
5.6Hz), 7.59 (2H, s), 7.47 (1H, s), 5.26 (1H, brd, J = 4.4Hz),
4.75 (1H, brt, J = 5.4Hz), 4.10 (1H, m), 3.51 (2H, brt, J = 5.6H
z), 1.41 (18H, s) IR (KBr, cm ^-1 ): 3402,3205,3066,2961,2360,2344,1616,1
546,1435,1340,1316,1252,1106

Example 70 2,2-Dimethyl-3-hydroxypropionaldehyde 3,5-di-tert-butyl-
4-hydroxybenzoylhydrazone (2,2-dimethyl-3-
hydroxypropionaldehyde 3,5-di-t-butyl-4-hydroxyben
Zoylhydrazone) Yield: 72% (Physical Properties) colorless crystals (mp.229-231 ℃) PMR (DMSO- d 6, δ ppm): 11.15 (1H, brs), 7.73 (1H, s), 7.56
(2H, s), 7.41 (1H, s), 4.77 (1H, brs), 3.30 (2H, s), 1.41 (18
H, s), 1.05 (6H, s) IR (KBr, cm ^-1 ): 3635,3422,3224,2950,1645,1550,1436,1
360,1311,1240,1047

Example 71 Benzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
tramethylchroman-2-acetylhydrazone) Compound 6-hydroxy-2,5,5 synthesized in Reference Example 2.
7,8-tetramethylchroman-2-acetohydrazide
(6-hydroxy-2,5,7,8-tetramethylchroman-2-acetohydra
zide) 0.56 g (2 mmol) and benzaldehyde 0.22 ml (2 mmo
l) was dissolved in ethanol (10 ml) and methanol (5 ml), and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. Ethyl acetate: n-
The solvent was distilled off from the eluted portion of hexane = 1: 1, chloroform was added for crystallization, and the crystal was collected by filtration. Drying under reduced pressure gave 0.71 g (yield .97%) of the title compound. (Physical Properties) colorless crystals (mp.121-123 ℃) PMR (DMSO- d 6, δ ppm): 11.33,11.29 (1H, each-s), 8.15,
7.94 (1H, each-s), 7.69,7.67 (1H, each-s), 7.45-7.32 (5H,
m), 3.01-2.46 (4H, m), 2.06-1.81 (11H, m), 1.39,1.35 (3H, e
ach-s) IR (KBr, cm ^-1 ): 3390,2930,1667,1558,1460,1373,1254,7
57,693

Examples 72 to 107 The following compounds were prepared in substantially the same manner as in Example 71 except that benzaldehyde was replaced with another aldehyde compound or ketone compound. Example 72 Salicylaldehyde 6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone (salicylaldehyde 6-hydroxy-2,5,7,8-tetrameth
ylchroman-2-acetylhydrazone) Yield: 100% (physical properties) pale yellow crystals (mp.116-118 ℃) PMR (DMSO- d 6, δ ppm): 11.58,11.28 (1H, each-s), 11.19,
10.05 (1H, each-s), 8.33,8.24 (1H, each-s), 7.47,7.40 (1
H, each-dd, J = 7.8,1.5Hz), 7.39,7.33 (1H, each-s), 7.27,
7.19 (1H, each-td, J = 7.8,1.5Hz), 6.92,6.77 (2H, m), 2.95-
2.45 (4H, m), 2.06-1.82 (11H, m), 1.36,1.25 (3H, each-s) IR (KBr, cm ^-1 ): 3160,3040,2928,1651,1614,1571,1460,1
358,1329,1250,1159,755

Example 73 3-Hydroxybenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
de 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhy
drazone) Yield: 55% (Physical properties) Colorless crystals (mp. 207-210 ° C) PMR (DMSO-d ₆ , δ ppm): 11.27, 11.24 (1H, each-s), 9.54,
9.51 (1H, each-s), 8.04,7.87 (1H, each-s), 7.39,7.33 (1H,
each-s), 7.23-7.14 (1H, m), 7.13,7.00 (1H, each-s), 7.04,
6.92 (1H, each-d, J = 7.8Hz), 6.81-6.76 (1H, m), 2.94-2.42
(4H, m), 2.05-1.81 (11H, m), 1.36,1.34 (3H, each-s) IR (KBr, cm ^-1 ): 3560,1674,1538,1462,1366,1260,1166,1
079

Example 74 4-Hydroxybenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
de 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhy
(drazone) Yield: 76% (physical properties) Colorless crystals (mp. 168-170 ° C) PMR (DMSO-d ₆ , δ ppm): 11.11, 11.08
(1H, etch-s), 9.82, 9.76 (1H,
each-s), 8.03, 7.85 (1H, each
-S), 7.49, 7.31 (2H, reach-d, J
= 8.3 Hz), 7.38, 7.34 (1H, each)
-S), 6.80, 6.75 (2H, reach-d, J
= 8.3 Hz), 2.91-2.39 (4H, m),
2.05-1.82 (11H, m), 1.38, 1.3
4 (3H, each-s) IR (KBr, cm- ¹ ): 3430,3396,1
675,1609,1515,1449,1371,1
238, 1170, 1089

Example 75 o-Anisaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2
-Acetylhydrazone (o-anisaldehyde
6-hydroxy-2,5,7,8-tetram
ethylchroman-2-acetylhyd
razone) Yield: 69% (physical properties) Colorless crystals (mp. 166-167 ° C) PMR (DMSO-d ₆ , δ ppm): 11.30, 11.25 (1H, each-s), 8.48,
8.29 (1H, each-s), 7.80,7.47 (1H, each-dd, J = 7.8,1.5Hz),
7.41-7.32 (2H, m), 7.07,7.03 (1H, each-d, J = 8.8Hz), 6.99,
6.90 (1H, each-t, J = 7.6Hz), 3.85,3.82 (3H, each-s), 2.99-
2.40 (4H, m), 2.06-1.78 (11H, m), 1.38,1.34 (3H, each-s) IR (KBr, cm ^-1 ): 3380,2936,1675,1604,1569,1467,1376,1
254,1161,1097,753

Example 76 o-acetylsalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
hyde6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylh
Ydrazone) Yield: 47% (Physical properties) Colorless crystals (mp. 170-171 ° C) PMR (DMSO-d ₆ , δ ppm): 11.34, 11.25 (1H, each-s), 8.15,
8.02 (1H, each-s), 7.80,7.50 (1H, each-d, J = 7.8Hz), 7.46,
7.41 (1H, each-d, J = 7.8Hz), 7.38,7.32 (1H, each-s), 7.32,
7.23 (1H, each-t, J = 7.6Hz), 7.16,7.12 (1H, each-d, J = 7.8H
z), 3.31-2.81 (2H, m), 2.62-2.42 (2H, m), 2.37,2.30 (3H, ea
ch-s), 2.09-1.80 (11H, m), 1.38,1.34 (3H, each-s) IR (KBr, cm ^-1 ): 3374,1773,1682,1557,1452,1366,1201,1
176,1091,1008,908,756

Example 77 o-Tolualdehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-
Acetylhydrazone (o-toludehyde)
6-hydroxy-2,5,7,8-tetrame
thylchroman-2-acetylhydra
zone) Yield: 91% (physical properties) Colorless crystals (mp. 150 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.31, 11.22 (1H, each-s), 8.42,
8.23 (1H, each-s), 7.78,7.47 (1H, each-d, J = 7.3Hz), 7.39,
7.33 (1H, each-s), 7.31-7.14 (3H, m), 3.00-2.43 (4H, m), 2.
41,2.36 (3H, each-s), 2.06-1.79 (11H, m), 1.38,1.35 (3H, e
ach-s) IR (KBr, cm ^-1 ): 3400,3200,2926,1662,1564,1458,1373,1
258,1087,757

Example 78 2-Nitrobenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
ydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazon
e) Yield: 36% (Physical Properties) colorless crystals (mp.160 ℃) PMR (DMSO- d 6, δ ppm): 11.67,11.56 (1H, each-s), 8.57,
8.31 (1H, each-s), 8.10-7.53 (4H, m), 7.38,7.30 (1H, each-s)
s), 3.29-2.46 (4H, m), 2.06-1.78 (11H, m), 1.40,1.35 (3H, e
ach-s) IR (KBr, cm ^-1 ): 3450,2932,1658,1526,1338,1259,1088

Example 79 2-fluorobenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydra
zone) Yield: 79% (physical properties) Colorless crystals (mp. 131-133 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.47, 11.41
(1H, each-s), 8.38,8.14 (1H,
each-s), 7.91-7.13 (5H, m),
3.08-2.4 3 (4H, m), 2.05-1.7
8 (11H, m), 1.39, 1.35 (3H, eac
h-s) IR (KBr, cm- ¹ ): 3420, 2930, ¹
666, 1559, 1460, 1370, 1256, 1
087,759

Example 80 2-cyanobenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (2-cyanobenz)
aldehyde 6-hydroxy-2,5,7,
8-tetramethylchroman-2-ac
Etylhydrazone) Yield: 27% (property) pale yellow crystals (mp.163-164 ℃) PMR (DMSO- d 6, δ ppm): 11.73,11.56 (1H, each-s), 8.52,
8.18 (1H, each-s), 8.08,7.87 (1H, each-d, J = 7.8Hz), 7.81-
7.49 (3H, m), 7.39,7.24 (1H, each-s), 3.25-2.46 (4H, m), 2.
06-1.78 (11H, m), 1.39,1.36 (3H, each-s) IR (KBr, cm ^-1 ): 3440,2934,2224,1657,1451,1378,1259,1
088,762

Example 81 α-tetralone 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone N-5398α-tetralone 6-hydroxy-2,5,7,8
-tetramethylchroman-2-acetylhydrazone) Yield: 54% (property) pale yellow crystals (mp.153-155 ℃) PMR (DMSO- d 6, δ ppm): 10.37,10.15 (1H, each-s), 8.03,
7.67 (1H, each-d, J = 7.8Hz), 7.40-7.09 (4H, m), 3.06-2.50
(8H, m), 2.06-1.81 (13H, m), 1.40,1.36 (3H, each-s) IR (KBr, cm ^-1 ): 3400,3222,2930,1662,1540,1454,1344,1
252,1087,762

Example 82: o-Hydroxyacetophenone 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (o-hydroxyacetophenone)
6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydr
Azone) Yield: 52% (Physical Properties) colorless crystals (mp.174-176 ℃) PMR (DMSO- d 6, δ ppm): 13.23 (1H, s), 10.85 (1H, s), 7.56
(1H, d, J = 6.8Hz), 7.41 (1H, s), 7.26 (1H, t, J = 7.1Hz), 6.89-
6.85 (2H, m), 2.67 (2H, s), 2.64-2.50 (2H, m), 2.33 (3H, s),
2.05-1.80 (11H, m), 1.37 (3H, s) IR (KBr, cm ^-1 ): 3350,3248,1663,1612,1525,1250,1231,1
173,1089,756

Example 83 2,4-Dihydroxybenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (2,4-dihydroxy
benzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-
2-acetylhydrazone) Yield: 90% (property) pale yellow crystals (mp.153 ℃) PMR (DMSO- d 6, δ ppm): 11.38 (1H, s), 11.36 (1H, s), 9.87
(1H, s), 8.19 (1H, s), 7.39 (1H, s), 7.23 (1H, d, J = 8.8Hz), 6.
34 (1H, d, J = 8.4Hz), 6.29 (1H, s), 2.70-2.40 (4H, m), 2.10-
1.70 (11H, m), 1.34 (3H, s) IR (KBr, cm ^-1 ): 3222,2932,1653,1633,1610,1521,1240,1
216,1177,1163,1083,759

Example 84 2,3-Dihydroxybenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (2,3-dihydroxy
benzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-
2-acetylhydrazone) Yield: 75% (property) pale yellow crystals (mp.184-186 ℃) PMR (DMSO- d 6, δ ppm): 11.58 (1H, brs), 11.05 (1H, brs),
9.12 (1H, brs), 8.28 (1H, s), 7.39 (1H, brs), 6.90 (1H, d, J =
7.8Hz), 6.83 (1H, d, J = 7.8Hz), 6.71 (1H, t, J = 7.8Hz), 2.70-
2.40 (4H, m), 2.10-1.80 (11H, m), 1.35 (3H, s) IR (KBr, cm ^-1 ): 3266,1663,1562,1370,1275,1162,1088

Example 85 5-Nitrosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (5-nitrosalal)
icylaldehyde 6-hydroxy-2,
5,7,8-tetramethylchroman-
2-acetylhydrazine) Yield: 75% (physical properties) Yellow crystal (mp. 230-231 ° C) PMR (DMSO-d ₆ , δ ppm): 12.27, 11.50 (1H, each-brs), 11.7
8,11.43 (1H, each-s), 8.55,8.23 (1H, each-d, J = 2.9Hz), 8.
45,8.20 (1H, each-s), 8.15,8.07 (1H, each-dd, J = 8.8,2.9H
z), 7.40,7.18 (1H, each-s), 7.09,7.02 (1H, each-d, J = 8.8H
z), 3.25-2.50 (4H, m), 2.10-1.75 (11H, m), 1.37,1.35 (3H, e
ach-s) IR (KBr, cm ^-1 ): 3600,3208,3062,2926,1667,1613,1528,1
482,1339,1284,1253,1197,1086

Example 86 2-hydroxy-5-methoxybenzaldehyde 6-hydroxy-2,5,7,8-
Tetramethylchroman-2-acetylhydrazone (2-hyd
roxy-5-methoxybenzaldehyde 6-hydroxy-2,5,7,8-tetra
methylchroman-2-acetylhydrazone) Yield: 90% (property) pale yellow crystals (mp.153-154 ℃) PMR (DMSO- d 6, δ ppm): 11.57,11.33 (1H, each-s), 10.60,
9.62 (1H, each-s), 8.32,8.22 (1H, each-s), 7.40,7.33 (1H, each-s)
each-s), 7.07,7.03 (1H, each-d, J = 2.9Hz), 6.89-6.77 (2H,
m), 3.72,3.64 (3H, s), 2.93-2.44 (4H, m), 2.06-1.80 (11H,
m), 1.35 (3H, s) IR (KBr, cm ^-1 ): 3384,3292,3210,3056,2934,1669,1628,1
493,1269,1164,1084,1038

Example 87 5-chlorosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
de 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhy
drazone) Yield: 85% (physical properties) Colorless crystals (mp. 159-160 ° C) PMR (DMSO-d ₆ , δ ppm): 11.67, 11.37 (1H, each-s), 11.19,
10.30 (1H, each-brs), 8.32,8.20 (1H, each-s), 7.61,7.45
(1H, each-d, J = 2.4Hz), 7.40,7.30 (1H, each-s), 7.26,7.19
(1H, each-dd, J = 8.8,2.9Hz), 6.89 (1H, d, J = 8.8Hz), 2.93-
2.44 (4H, m), 2.06-1.79 (11H, m), 1.35 (3H, s) IR (KBr, cm ^-1 ): 3238,3060,2926,1668,1549,1481,1346,1
271,1182,1088

Example 88 5-bromosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
e 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhyd
razone) Yield: 35% (physical properties) pale yellow crystal (mp.168-170 ° C) PMR (DMSO-d ₆ , δ ppm): 11.67, 11.37 (1H, each-s), 11.20,
10.32 (1H, each-brs), 7.74,7.60 (1H, each-d, J = 2.4Hz), 7.
41-7.31 (2H, m), 6.87,6.83 (1H, each-d, J = 8.8Hz), 2.93-2.
44 (4H, m), 2.09-1.79 (11H, m), 1.35 (3H, s) IR (KBr, cm ^-1 ): 3240,2926,1669,1547,1477,1344,1270,1
182,1085

Example 89 2-Hydroxy-4-methoxybenzaldehyde 6-hydroxy-2,5,7,8-
Tetramethylchroman-2-acetylhydrazone (2-hyd
roxy-4-methoxybenzaldehyde 6-hydroxy-2,5,7,8-tetra
methylchroman-2-acetylhydrazone) Yield: 85% (Physical Properties) colorless crystals (mp.140-142 ℃) PMR (DMSO- d 6, δ ppm): 11.51,11.18
(1H, each-s), 11.47, 10.25 (1
H, each-s), 8.24,8.14 (1H, ea
ch-s), 7.40-7.28 (2H, m), 6.5.
0-6.40 (2H, m), 3.77, 3.73 (3
H, each-s), 2.88-2.41 (4H,
m), 2.05-1.79 (11H, m), 1.35
(3H, s) IR (KBr, cm ^-1 ): 3350, 3042, 2
932, 1666, 1633, 1617, 1510, 1
456,1360,1245,1167

Example 90 2,5-Dihydroxybenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (2,5-di
hydroxybenzaldehyde 6-hyd
roxy-2,5,7,8-tetramethylc
roman-2-acetylhydrazine yield: 88% (physical properties) pale yellow crystal (mp. 229-232 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.47, 11.24 (1H, each-s), 10.31,
9.37 (1H, each-s), 8.90,8.84 (1H, each-s), 8.24,8.19 (1H, each-s)
each-s), 7.39,7.34 (1H, each-s), 6.95,6.89 (1H, each-d, J
= 2.0Hz), 6.73-6.62 (2H, m), 2.91-2.42 (4H, m), 2.05-1.79
(11H, m), 1.35,1.33 (3H, each-s) IR (KBr, cm ^-1 ): 3430,3248,1675,1549,1455,1375,1259,1
162,794

Example 91 o-vanillin 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
hylchroman-2-acetylhydrazone) Yield: 69% (physical properties) Light brown amorphous solid PMR (DMSO-d ₆ , δ ppm): 11.53, 11.27 (1H, each-s), 10.88,
9.41 (1H, each-s), 8.30,8.24 (1H, each-s), 7.36,7.30 (1H, each-s)
each-s), 7.04,7.00 (1H, each-d, J = 6.8Hz), 6.95,6.90 (1H,
each-d, J = 7.8Hz), 6.79,6.71 (1H, each-t, J = 8.1Hz), 3.77
(3H, s), 2.87-2.40 (4H, m), 2.02-1.76 (11H, m), 1.32 (3H, s) IR (KBr, cm ^-1 ): 3412,3222,2934,1667,1466,1366 , 1254,1
083,732

Example 92 4- (Diethylamino) salicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (4- (d
ielamino) salicylaldehy
de 6-hydroxy-2,5,7,8-tetra
amethylchroman-2-acetylhy
Drazone) Yield: 35% (Physical properties) Purple crystal (mp. 210-214 ° C) PMR (DMSO-d ₆ , δ ppm): 11.33 (1H, s), 11.26 (1H, s), 8.11
(1H, s), 7.39 (1H, s), 7.13 (1H, d, J = 8.8Hz), 6.23 (1H, dd, J =
8.3,2.0Hz), 6.09 (1H, d, J = 2.4Hz), 3.35 (4H, q, J = 6.8Hz),
2.83-2.39 (4H, m), 2.06-1.79 (11H, m), 1.35 (3H, s), 1.11 (6
(H, t, J = 6.8Hz) IR (KBr, cm ^-1 ): 3418,3266,2970,1669,1599,1554,1522,1
420,1356,1250,1135,1079,792

Example 93 3,5-Dichlorosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (3,5-dichlorosal
icylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-
2-acetylhydrazone) Yield: 55% (Physical Properties) colorless crystals (mp.210-212 ℃) PMR (DMSO- d 6, δ ppm): 12.38,11.56 (1H, each-s), 11.97,
10.51 (1H, each-s), 8.30,8.17 (1H, each-s), 7.62,7.48 (1
H, each-d, J = 2.4Hz), 7.55,7.42 (1H, each-d, J = 2.4Hz), 7.4
0,7.27 (1H, each-s), 3.00-2.48 (4H, m), 2.05-1.80 (11H,
m), 1.35 (3H, s) IR (KBr, cm ^-1 ): 3586,3206,3064,2928,1666,1555,1453,1
378,1253,1221,1184,1087

Example 94 3,5-Dinitrosalicylic aldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (3,5-dinitrosali
cylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2
-Acetylhydrazone) Yield: 86% (Physical Properties) colorless crystals (mp.270 ℃ (dec.)) PMR (DMSO-d 6, δ ppm): 12.13,11.55 (1H, each-s), 8.80,
8.65 (1H, each-d, J = 2.9Hz), 8.74,8.27 (1H, each-d, J = 2.9H
z), 8.55,8.21 (1H, each-s), 2.61-2.50 (4H, m), 2.05-1.77
(11H, m), 1.40,1.36 (3H, each-s) IR (KBr, cm ^-1 ): 3586,3202,3062,1691,1669,1618,1551,1
465,1339,1267,1085,741

Example 95 2-hydroxy-1-naphthaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (2-hydroxy-1-n
aphthaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman
-2-acetylhydrazone) Yield: 59% (property) pale brown crystals (mp.190 ℃) PMR (DMSO- d 6, δ ppm): 12.63,11.38 (1H, each-s), 11.69,
11.07 (1H, each-s), 9.17,8.93 (1H, each-s), 8.49,8.16 (1
H, each-d, J = 8.8Hz), 7.88 (2H, t, J = 9.0Hz), 7.58 (1H, t, J =
7.3Hz), 7.42-7.31 (2H, m), 7.20,7.17 (1H, each-d, J = 8.8H
z), 3.00-2.50 (4H, m), 2.09-1.83 (11H, m), 1.39,1.38 (3H, e
ach-s) IR (KBr, cm ^-1 ): 3372,3200,2932,1669,1626,1468,1245,1
177,1084,818,744

Example 96 2,4,6-Trihydroxybenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (2,4,6-t
rihydroxybenzaldehyde 6-hydroxy-2,5,7,8-tetramethy
lchroman-2-acetylhydrazone) Yield: 43% (Physical Properties) colorless crystals (mp.170 ℃ (dec.)) PMR (DMSO-d 6, δ ppm): 11.33 (1H, s), 10.93 (1H, s) , 9.73
(1H, s), 8.48 (1H, s), 7.40 (1H, s), 5.81 (2H, s), 2.58-2.38
(4H, m), 2.05-1.80 (11H, m), 1.34 (3H, s) IRIR (KBr, cm ^-1 ): 3234,2970,2930,1638,1616,1463,138
3,1332,1257,1161,1086,1051

Example 97 4,6-Dimethoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (4,6-dimethoxy
salicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchrom
an-2-acetylhydrazone) Yield: 75% (Physical Properties) colorless crystals (mp.115-117 ℃) PMR (DMSO- d 6, δ ppm): 12.23 (1H, s), 11.49 (1H, s), 8.52
(1H, s), 7.40 (1H, s), 6.11 (2H, s), 3.81 (3H, s), 3.77 (3H,
s), 2.58-2.39 (4H, m), 2.05-1.80 (11H, m), 1.34 (3H, s) IR (KBr, cm ^-1 ): 3400,2932,1636,1606,1460,1342,1218, 1
163,1095

Example 98 2-Methylaminobenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
aldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-ac
etylhydrazone) Yield: 19% (physical properties) Yellow crystals (mp. 209-210 ° C) PMR (DMSO-d ₆ , δ ppm): 11.28, 11.17 (1H, each-s), 8.19,
8.07 (1H, each-s), 8.18,7.43 (1H, each-m), 7.39,7.35 (1H, each-s)
each-s), 7.25-7.11 (2H, m), 6.68-6.59 (2H, m), 2.89,2.65
(3H, each-d, J = 4.9Hz), 2.88-2.42 (4H, m), 2.05-1.81 (11H,
m), 1.38,1.36 (3H, each-s) IR (KBr, cm ^-1 ): 3332,3210,3064,2934,1632,1613,1570,1
517,1379,1326,1236,1176,1157,1089,752

Example 99 8-Formyl-1,2,3
4-tetrahydroquinoline 6-hydroxy-2,5,
7,8-tetramethylchroman-2-acetylhydrazone (8-formyl-1,2,3,4-tetrahydroquinoline 6-hydroxy-
2,5,7,8-tetramethylchroman-2-acetylhydrazone) Yield: 21% (property) pale yellow crystals (mp.117-120 ℃) PMR (DMSO- d 6, δ ppm): 11.22,11.12 (1H, each-s), 8.22,
7.53 (1H, each-m), 8.15,8.03 (1H, each-s), 7.40,7.36 (1H, each-s)
each-s), 6.99-6.85 (2H, m), 6.45,6.44 (1H, each-t, J = 7.6H
z), 3.42,3.12 (2H, each-m), 2.87-2.40 (6H, m), 2.06-1.75
(13H, m), 1.36,1.35 (3H, each-s) IR (KBr, cm ^-1 ): 3358,2930,1657,1609,1579,1519,1463,1
426,1237,1085,741

Example 100 2,3-Dimethoxy-6
Formyl-5-methylhydroquinone 6-hydroxy-
2,5,7,8-tetramethylchroman-2-acetylhydrazone (2,3-dimethoxy-6-formyl-5-methylhydroqui
none 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetyl
Hydrazone) Yield: 59% (property) pale yellow crystals (mp.180-184 ℃) PMR (DMSO- d 6, δ ppm): 11.85 (1H, s), 11.55 (1H, s), 8.52
(1H, s), 8.22 (1H, s), 7.39 (1H, s), 3.82 (3H, s), 3.79 (3H,
s), 2.59-2.43 (3H, m), 2.17 (3H, s), 2.06-1.83 (12H, m), 1.3
3 (3H, s) IR (KBr, cm ^-1 ): 3455,3255,2924,1662,1455,1421,1390,1
290,1252,1193,1141,1114,1062,921

Example 101 Pyridoxal 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
methylchroman-2-acetylhydrazone) Yield: 26% (property) pale yellow crystals (mp.221-224 ℃) PMR (DMSO- d 6, δ ppm): 12.11 (1H,
s), 12.04 (1H, s), 8.66 (1H,
s), 7.92 (1H, s), 7.39 (1H, s),
5.35 (1H, t, J = 5.1 Hz), 4.58 (1
H, d, J = 5.4 Hz), 2.64-2.50 (3
H, m), 2.40 (3H, s), 2.05-1.81.
(12H, m), 1.36 (3H, s) IR (KBr, cm ^-1 ): 3345, 3095, 2
926, 1673, 1409, 1364, 1277, 1
248, 1166, 1132, 1090, 1029, 1
101

Example 102 2-picolinaldehyde 6
-Hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (2-picolinald
ehydro 6-hydroxy-2,5,7,8-t
Etramethylchroman-2-acety
Lhydrazone) Yield: 76% (Physical Properties) colorless crystals (mp.178-180 ℃) PMR (DMSO- d 6, δ ppm): 11.56,11.50 (1H, each-s), 8.58,
8.52 (1H, each-d, J = 4.9Hz), 8.17,7.96 (1H, each-s), 7.92,
7.41-7.30 (3H, m), 7.84,7.70 (1H, each-t, J = 7.6Hz), 3.15-
2.46 (4H, m), 2.05-1.76 (11H, m), 1.40,1.35 (3H, each-s) IR (KBr, cm ^-1 ): 3174,3060,2930,1669,1589,1381,1257,1
089,1002,943,781

Example 103 Nicotinaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2
-Acetylhydrazone (nicotinaldehyde 6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone) Yield: 95% (Physical Properties) colorless crystals (mp.186-188 ℃) PMR (DMSO- d 6, δ ppm): 11.51,11.45 (1H, each-s ), 8.81,
8.64 (1H, each-dd, J = 1.5Hz), 8.58,8.52 (1H, each-dd, J = 4.
9,1.5Hz), 8.21,7.95 (1H, each-s), 8.08,7.67 (1H, each-d
t, J = 8.3,1.5Hz), 7.45,7.33 (1H, each-dd, J = 7.8,4.9Hz),
7.40,7.31 (1H, each-s), 3.13-2.44 (4H, m), 2.06-1.76 (11
(H, m), 1.39,1.35 (3H, each-s) IR (KBr, cm ^-1 ): 3176,3068,2930,1667,1397,1374,1252,1
090,1033,921,806,703

Example 104 Isonicotinaldehyde 6
-Hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (isonicotinaldehyde 6-hydr
oxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone) Yield: 88% (Physical properties) Light yellow crystal (mp.224-225 ° C) PMR (DMSO-d ₆ , δ ppm): 11.62, 11.56 ( 1H, each-s), 8.62,
8.51 (2H, each-d, J = 5.9Hz), 8.15,7.88 (1H, each-s), 7.61,
7.27 (2H, each-d, J = 5.9Hz), 7.40,7.33 (1H, each-s), 3.17-
2.46 (4H, m), 2.05-1.77 (11H, m), 1.40,1.35 (3H, each-s) IR (KBr, cm ^-1 ): 3166,3082,2938,1679,1607,1452,1378,1
274,1185,1145,1092,924

Example 105 2-Furaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2
-Acetylhydrazone (2-furaldehyde 6-hydroxy-2,5,
7,8-tetramethylchroman-2-acetylhydrazone) Yield: 79% (physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 11.28,11,25 (1H, each-s), 8.05,
7.85 (1H, each-s), 7.78,7.72 (1H, each-s), 7.38,7.34 (1H, each-s)
each-s), 6.85,6.72 (1H, each-d, J = 3.0Hz), 6.59,6.55 (1H,
each-dd, J = 3.0,1.5Hz), 2.93-2.40 (3H, m), 2.05-1.77 (12
H, m), 1.36,1.33 (3H, each-s) IR (KBr, cm ^-1 ): 3425,3238,2926,1661,1456,1378,1346,1
158,1086,1006,931

Example 106 Pyrrole-2-carbaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
yde6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhy
Drazone) Yield: 49% (Physical Properties) colorless crystals (mp.200-201 ℃) PMR (DMSO- d 6, δ ppm): 11.41,11.08
(1H, each-brs), 10.98, 10.97
(1H, each-s), 7.99,7.81 (1H,
each-s), 7.38, 7.34 (1H, each
-S), 6.86 (1H, s), 6.41, 6.33
(1H, reach-d, J = 1.5 Hz), 6.10,
6.08 (1H, each-dd, J = 5.4,2.4
Hz), 2.93-2.38 (4H, m), 2.08-
1.79 (11H, m), 1.34 (3H, s) IR (KBr, cm ^-1 ): 3359, 3083,1
638, 1610, 1545, 1420, 1269, 1
238, 1166, 1128, 1090, 741

Example 107 2-thiophenaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (2-thiophena)
Idehyde 6-hydroxy-2,5,7,8
-Tetramethylchroman-2-ace
Tylhydrazine) Yield: 78% (physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 11.29 (1H, s), 8.38, 8.14 (1H, each
-s), 7.61,7.54 (1H, each-d, J = 4.9Hz), 7.41-7.31 (2H, m),
7.10,7.07 (1H, each-dd, J = 4.9,3.4Hz), 2.93-2.40 (3H, m),
2.09-1.77 (12H, m), 1.34 (3H, s) IR (KBr, cm ^-1 ): 3411,3214,2925,1659,1597,1564,1454,1
429,1372,1256,1160,1086,1003,921,707

Example 108 Benzaldehyde N-methyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
yl-6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhy
drazone) 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid (6-hydroxy-2,5,7,8-tetramethylchroman-
2-acetic acid) 0.79 g (3 mmol) and the compound synthesized in Reference Example 6 benzaldehyde methylhydrazone 0.40 g (3 mmo
l) was added to 6 ml of dioxane and stirred. In this solution, D
0.74 g (3.6 mmol) of CC was added, and the mixture was stirred for 24 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and ethyl acetate: n-hexane =
The solvent eluted from the 1: 2 eluted portion was crystallized by adding ethyl acetate and n-hexane, and collected by filtration. Drying under reduced pressure gave 0.80 g (yield 70%) of the title compound. (Physical Properties) colorless crystals (mp.140-145 ℃) PMR (DMSO- d 6, δ ppm): 7.88 (1H, s), 7.56-7.53 (2H, m), 7.
39-7.34 (4H, m), 3.33 (3H, s), 3.20 (1H, d, J = 13.2Hz), 3.13
(1H, d, J = 13.2Hz), 2.59-2.50 (1H, m), 2.04-1.90 (12H, m),
1.33 (3H, s) IR (KBr, cm ^-1 ): 3522,3289,2933,2851,1701,1635,1528,1
451,1237,1088,919

Examples 109 to 112 The following compounds were prepared in substantially the same manner as in Example 108 except that benzaldehyde methylhydrazone was replaced with another methylhydrazone compound. Example 109: Salicylaldehyde N-methyl-6-hydroxy-2,5,7,8-tetramethylchroman-2
-Acetylhydrazone (salicylaldehyde N-methyl-6-hy
droxy-2,5,7,8-tetramethylchroman-2-acetylhydrazon
e) Yield: 20% (Physical Properties) colorless crystals (mp.105-110 ℃) PMR (DMSO- d 6, δ ppm): 10.14 (1H, s), 8.07 (1H, s), 7.47 (1
H, dd, J = 7.8,1.0Hz), 7.34 (1H, s), 7.20 (1H, td, J = 7.6,1.5H
z), 6.87 (1H, d, J = 8.3Hz), 6.82 (1H, t, J = 7.3Hz), 3.34 (3H,
s), 3.13 (1H, d, J = 13.7Hz), 3.09 (1H, d, J = 13.7Hz), 2.59-2.
50 (1H, m), 2.00-1.82 (12H, m), 1.34 (3H, s) IR (KBr, cm ^-1 ): 3501,2925,1671,1480,1416,1347,1273,1
259,1166,1125,1069,764

Example 110 2,4-Dihydroxybenzaldehyde N-methyl-6-hydroxy-2,5
7,8-tetramethylchroman-2-acetylhydrazone (2,4-dihydroxybenzaldehyde N-methyl-6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone) Yield: 31% (physical properties) Colorless crystals (mp. 175-185 ° C (dec.)) PMR (DMSO-d ₆ , δ ppm): 10.21 (1H ,
s), 9.75 (1H, s), 7.99 (1H, s),
7.36 (1H, s), 7.30 (1H, d, J = 8.
8Hz), 6.29 (1H, s), 6.28 (1H, d
d, J = 7.3, 2.5 Hz), 3.30 (3H,
s), 3.05 (2H, s), 2.59-2.50 (1
H, m), 2.06-1.82 (12H, m), 1.3.
2 (3H, s) IR (KBr, cm ^-1 ): 3486, 3133, 2
924, 1626, 1600, 1484, 1423, 1
336,1257,1165,1118,1077

Example 111 o-Vaniline N-methyl-
6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (o-vanillin)
N-methyl-6-hydroxy-2,5,7,
8-tetramethylchroman-2-ac
Etohydorazone) Yield: 28% (Physical Properties) colorless crystals (mp.173-175 ℃) PMR (DMSO- d 6, δ ppm): 9.59 (1H, s), 8.08 (1H, s), 7.34 (1
H, s), 7.10 (1H, d, J = 7.8Hz), 6.95 (1H, d, J = 7.8Hz), 6.77 (1
(H, t, J = 8.1Hz), 3.81 (3H, s), 3.33 (3H, s), 3.11 (2H, brs), 2.
59-2.50 (2H, m), 2.00-1.80 (11H, m), 1.33 (3H, s) IR (KBr, cm ^-1 ): 3515,2929,2851,1669,1626,1572,1475,1
416,1349,1252,1128,1082,1070,784,731

Example 112 4- (Diethylamino) salicylaldehyde N-methyl-6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone (4- (diethylamino) salicylaldehyde N-methyl-6-
hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazo
ne) Yield: 38% (Physical Properties) colorless crystals (mp.177-179 ℃) PMR (DMSO- d 6, δ ppm): 10.22 (1H, s), 7.98 (1H, s), 7.35 (1
H, s), 7.26 (1H, d, J = 8.8Hz), 6.22 (1H, dd, J = 8.8,2.0Hz), 6.
09 (1H, d, J = 2.0Hz), 3.36-3.30 (7H, m), 3.04 (1H, d, J = 13.7H
z), 2.99 (1H, d, J = 13.7 Hz), 2.58-2.50 (2H, m), 2.02-1.84 (1
1H, m), 1.31 (3H, s), 1.11 (6H, t, J = 7.1Hz) IR (KBr, cm ^-1 ): 3433,2971,2927,1631,1526,1412,1354,1
256,1073,791

Example 113 N '-(2-hydroxybenzyl) -6-hydroxy-2,5,7,8-tetramethylchroman-2-acetohydrazide (N'-(2-h
hydroxybenzyl) -6-hydroxy-
2,5,7,8-tetramethylchroma
n-2-acetohydrazide) Compound synthesized in Example 72 Salicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2
1.53 g (4 mmol) of -acetylhydrazone and 0.15 g of 5% Pd / C were added to 20 ml of methanol, and the mixture was catalytically reduced for 18 hours. The catalyst was removed by filtration through Celite, and the solvent was distilled off.
The residue was subjected to silica gel column chromatography.
The solvent was distilled off from the eluted portion of methanol: chloroform = 1: 33 to precipitate crystals, and the crystals were collected by filtration. The crystals collected by filtration were dried under reduced pressure to obtain 1.31 g (yield: 85%) of the title compound.

(Physical properties) Colorless crystal (mp. 170-172 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.62 (1H, s), 9.43 (1H, d, J = 5.9H)
z), 7.37 (1H, s), 7.14 (1H, d, J = 6.4Hz), 7.07 (1H, t, J = 7.6H
z), 6.77 (1H, d, J = 8.3Hz), 6.72 (1H, t, J = 7.6Hz), 5.34 (1H,
td, J = 5.9,5.9Hz), 3.89-3.79 (2H, m), 2.59-2.41 (2H, m), 2.
33 (1H, d, J = 13.7Hz), 2.23 (1H, d, J = 13.7Hz), 2.08-1.67 (11
H, m), 1.27 (3H, s) IR (KBr, cm ^-1 ): 3477,3342,3294,2969,2923,2865,2353,1
647,1635,1488,1455,1264,1239,1168,1088,1033,757

Example 114 N '-(2,4-dihydroxybenzyl) -6-hydroxy-2,5,7,8-tetramethylchroman-2-acetohydrazide (N'-(2,4-d
ihydroxybenzyl) -6-hydroxy-2,5,7,8-tetramethylchrom
an-2-acetohydrazide) Compound synthesized in Example 83 2,4-dihydroxybenzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone 1.59 g (4 mmo
l) and 0.16 g of 5% Pd / C in 20 ml of methanol.
Catalytic reduction was carried out for an hour. The catalyst was removed by filtration through Celite, and the solvent was distilled off. The residue was subjected to silica gel column chromatography. The solvent eluted from methanol: chloroform = 2: 25 was evaporated and dried under reduced pressure to give the title compound (0.96 g, yield 60%).
I got

(Physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.44 (1H, s), 9.38
(1H, d, J = 5.4Hz), 9.05 (1H, s), 7.35 (1H, s), 6.87 (1H, d, J =
8.3Hz), 6.24 (1H, d, J = 2.4Hz), 6.13 (1H, dd, J = 8.3,2.4Hz),
5.15 (1H, m), 3.72 (2H, m), 2.58-2.40 (2H, m), 2.34 (1H, d, J
= 13.2Hz), 2.24 (1H, d, J = 13.2Hz), 2.05-1.69 (11H, m), 1.28
(3H, s) IR (KBr, cm ^-1 ): 3301,2978,2928,2353,1717,1651,1627,1
515,1463,1377,1298,1164,1110,1084,978,848

Example 115 N-benzoyl-N'-6
-Hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazine (N-benzoyl-N'-6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazine) benzoic acid 0.24 g (2 mmol) and triethylamine 0.33 ml
(2.4 mmol) was added to 10 ml of methylene chloride and cooled with ice, and ethyl chloroformate (ethyl chloroformate) 0.21 ml (2.2 mmol)
Was added dropwise. The mixture was stirred for 1 hour under ice cooling. 0.56 g (2 mmol) of the compound 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetohydrazide synthesized in Reference Example 2 was added, and the mixture was gradually heated and stirred at room temperature for 20 hours. 50 ml of chloroform was added to the reaction solution, and the mixture was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the solvent eluted with methanol: chloroform = 1: 50 was distilled off to give 0.36 g (yield 47%) of the title compound.

(Physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 10.31 (1H, s), 9.87 (1H, s), 7.88 (2
H, d, J = 7.8Hz), 7.56 (1H, t, J = 7.8Hz), 7.48 (2H, t, J = 7.8H
z), 7.38 (1H, s), 2.69-2.39 (4H, m), 2.10-1.79 (11H, m), 1.1
8 (3H, s) IR (KBr, cm ^-1 ): 3261,2940,1656,1461,1256,1087

Example 116 N-6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetyl-
N'-salicylhydrazine (N-6-hydroxy-2,5,7,8-tetra
methylchroman-2-acetyl-N'-salicylhydrazine) Compound 6-hydroxy-2,5 synthesized in Reference Example 2.
7,8-tetramethylchroman-2-acetohydrazide
0.56 g (2 mmol) and 0.28 g (2 mmol) of salicylic acid were added to 10 ml of dimethylformamide and stirred. In this solution,
0.41 g (2 mmol) of DCC was added, and the mixture was stirred for 24 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and ethyl acetate: chloroform =
The solvent was distilled off from the 1: 1 eluted part to give 0.21 g of the title compound (yield 26
%). (Physical properties) Pale yellow amorphous solid PMR (DMSO-d ₆ , δ ppm): 11.91 (1H, s), 10.58 (1H, brs), 10.
19 (1H, s), 7.89 (1H, d, J = 7.8Hz), 7.42 (1H, t, J = 7.8Hz), 7.3
8 (1H, s), 6.96-6.89 (2H, m), 2.68-2.43 (4H, m), 2.07-1.79
(11H, m), 1.39 (3H, s) IR (KBr, cm ^-1 ): 3303,2938,1648,1607,1472,1372,1313,1
259,1162,1086,755

Example 117 N-phenethyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-
Acetamide (N-phenethyl-6-hydroxy-2,5,7,8-tetrame
thylchroman-2-acetamide) 0.53 g (2 mmol) of 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid and phenethylamine 0.2
5 ml (2 mmol) was added to 4 ml of dimethylformamide and stirred. 0.41 g (2 mmol) of DCC was added to this solution, and the mixture was stirred for 12 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the solvent was distilled off from the eluted portion of methanol: chloroform = 1: 50, and the resulting crystals were collected by filtration. Dry under reduced pressure to give the title compound 0.30 g
(17% yield).

(Physical properties) Colorless crystal (mp.122-123 ° C.) PMR (DMSO-d ₆ , δ ppm): 7.85 (1H, brt, J = 5.1 Hz), 7.36 (1H,
s), 7.28-7.15 (5H, m), 3.31-3.27 (2H, mn), 2.71 (2H, t, J = 7.
1Hz), 2.56-2.43 (2H, m), 2.36 (1H, d, J = 13.7Hz), 2.27 (1H,
d, J = 13.7Hz), 2.05 (3H, s), 2.02 (3H, s), 1.96 (3H, s), 1.92-
1.85 (1H, m), 1.74-1.67 (1H, m), 1.26 (3H, s) IR (KBr, cm ^-1 ): 3377,2931,1654,1533,1454,1417,1236,1
176,1089,755,706

Example 118 N- (2-hydroxyphenethyl) -6-hydroxy-2,5,7,8-tetramethylchroman-2-acetamide (N- (2-hydroxypheneth)
yl) -6-hydroxy-2,5,7,8-tetramethylchroman-2-acetami
de) 0.53 g (2 mmol) of 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid and 0.25 ml (2 mmol) of 2-hydroxyphenethylamine were added to 4 ml of dimethylformamide.
And stirred. 0.41 g (2 mmol) of DCC was added to this solution.
Was added and stirred for 12 hours. The precipitate was removed by filtration, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, the solvent eluted with methanol: chloroform = 1: 50 was evaporated, and the residue was dried under reduced pressure to obtain 0.68 g (yield 89%) of the title compound. (Physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.27 (1H, s), 7.81 (1H, brt, J = 5.1H
z), 7.35 (1H, s), 7.03-6.97 (2H, m), 6.77 (1H, d, J = 7.8Hz),
6.68 (1H, t, J = 7.3Hz), 3.26 (1H, q, J = 6.7Hz), 2.66 (2H, t, J =
7.3Hz), 2.60-2.43 (1H, m), 2.37 (1H, d, J = 13.2Hz), 2.28 (1
(H, d, J = 13.2Hz), 2.05-1.88 (11H, m), 1.78-1.70 (1H, m), 1.2
8 (3H, s) IR (KBr, cm ^-1 ): 3388,2928,1645,1539,1456,1379,1252,1
085,754

Example 119 Propionaldehyde 6-
Hydroxy-2,5,7,8-tetramethylchroman-
2-acetylhydrazone (propionaldehyde 6-hydroxy-
(2,5,7,8-tetramethylchroman-2-acetylhydrazone) Compound 6-hydroxy-2,5 synthesized in Reference Example 2.
7,8-tetramethylchroman-2-acetohydrazide
0.56 g (2 mmol) and propionaldehyde 0.15 ml (2 mmo
l) was dissolved in methanol (10 ml) and stirred at room temperature for 24 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. Ethyl acetate: n-hexane = 2: 1
The solvent was distilled off from the eluted portion, and crystallized by adding ethyl acetate and n-hexane, and collected by filtration. Drying under reduced pressure gave 0.27 g (42% yield) of the title compound.

(Physical properties) Colorless crystals (mp. 85-89 ° C.) PMR (DMSO-d ₆ , δ ppm): 10.89, 10.84 (1H, each-s), 7.44,
7.28 (1H, each-t, J = 4.9Hz), 7.38,7.35 (1H, each-s), 2.83-
1.76 (17H, m), 1.33,1.31 (3H, each-s), 1.02,0.96 (3H, each
-t, J = 7.6Hz) IR (KBr, cm ^-1 ): 3393,3214,3057,2972,2933,1660,1560,1
457,1379,1254,1158,1087,1017,922,856

Examples 120 to 121 The following compounds were prepared in substantially the same manner as in Example 119 except that propionaldehyde was replaced with another aldehyde compound. Example 120 Glyceraldehyde 6-hydroxy-
2,5,7,8-tetramethylchroman-2-acetylhydrazone (glyceraldehyde 6-hydroxy-2,5,7,8-tetram
ethylchroman-2-acetylhydrazone) Yield: 40% (Physical Properties) colorless crystals (mp.110-112 ℃) PMR (DMSO- d 6, δ ppm): 11.04,11.00 (1H, each-s), 7.40,
7.37 (1H, each-s), 7.33,7.20 (1H, each-d, J = 6.4Hz), 5.22,
5.14 (1H, d, J = 4.9Hz, t, J = 5.6Hz), 4.71,4.66 (1H, each-t, J
= 5.9Hz), 2.85-2.33 (4H, m), 2.09-1.77 (11H, m), 1.33,1.31
(3H, each-s) IR (KBr, cm ^-1 ): 3393,3248,3063,2931,2363,2344,1663,1
570,1456,1379,1350,1256,1164,1086

Example 121 2,2-Dimethyl-3-hydroxypropionaldehyde 6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone (2,2-dimethyl-3-hydroxypropionaldehyde 6-hyd
roxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone) Yield: 74% (physical properties) Colorless crystals (mp. 209-211 ° C) PMR (DMSO-d ₆ , δ ppm): 10.84, 10.83 (1H , each-s), 7.40,
7.39 (1H, each-s), 7.35,7.23 (1H, each-s), 4.73,4.69 (1H, each-s)
each-t, J = 5.4Hz), 3.29,3.24 (2H, each-d, J = 5.4Hz), 2.85-
2.32 (4H, m), 2.05-1.76 (11H, m), 1.33,1.31 (3H, each-s),
1.00,0.93 (6H, each-s) IR (KBr, cm ^-1 ): 3407,3258,2928,1649,1569,1457,1347,1
237,1170,1063

Example 122 Benzaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-
Carbohydrazone (benzaldehyde 6-hydroxy-2,5,7,8-te
(tramethylchroman-2-carbohydrazone) Compound 6-hydroxy-2,5,5 synthesized in Reference Example 3.
7,8-tetramethylchroman-2-carbohydrazide
0.53 g (2 mmol) and 0.21 ml (2 mmol) of benzaldehyde were dissolved in 10 ml of methanol and stirred at 70 ° C. for 5 hours. The resulting crystals were collected by filtration. Dry under reduced pressure to give the title compound 0.5
8 g (82% yield) was obtained.

(Physical properties) Colorless crystal (mp. 192-194 ° C.) PMR (DMSO-d ₆ , δ ppm): 10.72 (1H, s), 8.35 (1H, s), 7.67-
7.64 (2H, m), 7.48 (1H, s), 7.45-7.40 (3H, m), 2.58-2.54 (2
H, m), 2.34-2.27 (1H, m), 2.18 (3H, s), 2.09 (3H, s), 2.01 (3
(H, s), 1.83-1.76 (1H, m), 1.50 (3H, s) IR (KBr, cm ^-1 ): 3336,3289,2931,1677,1521,1449,1374,1
255,1193,1134,1113,1086,1058,964,942,755,692,577

Examples 123 to 125 The following compounds were prepared in substantially the same manner as in Example 122 except that benzaldehyde was replaced with another aldehyde compound. Example 123 Salicylaldehyde 6-hydroxy-
2,5,7,8-tetramethylchroman-2-carbohydrazone (salicylaldehyde 6-hydroxy-2,5,7,8-tetrame
thylchroman-2-carbohydrazone) Yield: 92% (property) pale yellow crystals (mp.184-186 ℃) PMR (DMSO- d 6, δ ppm): 11.20 (1H, s), 11.1 (1H, s), 8.57 (1
H, s), 7.48 (1H, s), 7.43 (1H, d, J = 6.8Hz), 7.26 (1H, t, J = 7.1
Hz), 6.90-6.85 (2H, m), 2.57 (2H, m), 2.34-2.26 (1H, m), 2.1
7 (3H, s), 2.09 (3H, s), 2.02 (3H, s), 1.85-1.77 (1H, m), 1.50
(3H, s) IR (KBr, cm ^-1 ): 3416,3332,2938,1675,1618,1520,1488,1
456,1373,1272,1256,1237,1201,1140,1114,1086,751

Example 124 4,6-Dimethoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-carbohydrazone (4,6-dimethoxy
salicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchrom
an-2-carbohydrazone) Yield: 90% (Physical Properties) colorless crystals (mp.103-104 ℃) PMR (DMSO- d 6, δ ppm): 12.33 (1H, s), 11.15 (1H, s), 8.79
(1H, s), 7.46 (1H, s), 6.09 (2H, s), 3.81 (3H, s), 3.77 (3H,
s), 2.56-2.51 (2H, m), 2.32-2.25 (1H, m), 2.16 (3H, s), 2.09
(3H, s), 2.02 (3H, s), 1.82-1.74 (1H, m), 1.48 (3H, s) IR (KBr, cm ^-1 ): 3465,3282,2937,1673,1631,1604,1539 , 1
346,1261,1213,1154,1120,816

Example 125 4- (Diethylamino) salicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-carbohydrazone (4- (diethy
lamino) salicylaldehyde 6-hydroxy-2,5,7,8-tetrameth
ylchroman-2-carbohydrazone) Yield: 27% (Physical Properties) colorless crystals (mp.228-230 ℃) PMR (DMSO- d 6, δ ppm): 11.31 (1H, s), 10.71 (1H, s), 8.33
(1H, s), 7.48 (1H, s), 7.09 (1H, d, J = 8.3Hz), 6.22 (1H, d, J =
8.8Hz), 6.08 (1H, s), 3.34 (1H, q, J = 6.8Hz), 2.60-2.47 (2H,
m), 2.32-2.25 (1H, m), 2.17 (3H, s), 2.09 (3H, s), 2.01 (3H,
s), 1.82-1.75 (1H, m), 1.48 (3H, s), 1.11 (6H, t, J = 6.8Hz) IR (KBr, cm ^-1 ): 3426,3347,2971,2929,1674,1636 , 1598,1
514,1354,1244,1135

Example 126: o-vanillin 6-hydroxy-2,5,7,8-tetramethylchroman-2-butyrylhydrazone (o-vanillin 6-hydroxy-2,5,7,8-tetram
ethylchroman-2-butyrylhydrazone) Compound 6-hydroxy-2,5,5 synthesized in Reference Example 4.
7,8-tetramethylchroman-2-butyrohydrazide
0.61 g (2 mmol) and 0.30 g (2 mmol) of o-vanillin were dissolved in 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off, ethyl acetate was added, and the mixture was washed sequentially with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The resulting crystals were collected by filtration. Drying under reduced pressure gave 0.85 g (96% yield) of the title compound.

(Physical properties) Colorless crystals (mp. 197 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.52, 11.19 (1H, each-s), 10.96,
9.52 (1H, each-s), 8.33,8.25 (1H, each-s), 7.31,7.30 (1H, each-s)
each-s), 7.17,7.05 (1H, each-d, J = 7.8Hz), 6.98,6.94 (1H,
each-d, J = 7.3Hz), 6.82,6.78 (1H, each-t, J = 8.0Hz), 3.82,
3.81 (3H, each-s), 2.59-2.45 (3H, m), 2.26-2.17 (1H, m), 2.
05-1.97 (9H, m), 1.81-1.51 (6H, m), 1.19 (3H, s) IR (KBr, cm ^-1 ): 3548,2924,1666,1471,1429,1400,1255,1
088,724

Example 127 4- (Diethylamino) salicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-butyrylhydrazone (4-
(Diethylamino) salicylalde
hydraulic 6-hydroxy-2,5,7,8-te
tramethylchroman-2-butyry
lhydrozone) Compound 6-hydroxy-2,5 synthesized in Reference Example 4.
0.61 g (2 mmol) of 7,8-tetramethylchroman-2-butyrohydrazide and 4- (diethylamino)
0.39 g (2 mmol) of salicylaldehyde was dissolved in 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off, ethyl acetate was added, and the mixture was washed sequentially with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The resulting crystals were collected by filtration. Dry under reduced pressure, 0.50 g of the title compound
(Yield 52%).

(Physical properties) Light brown crystal (mp. 180 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.33, 10.92 (1H, each-s), 11.21,
10.17 (1H, each-s), 8.10,8.01 (1H, each-s), 7.31,7.30 (1
H, each-s), 7.19,7.11 (1H, each-d, J = 8.8Hz), 6.22,6.20 (1
H, each-dd, J = 8.8,2.4Hz), 6.08 (1H, d, J = 2.4Hz), 3.34 (4H,
q, J = 6.8Hz), 2.54-2.45 (3H, m), 2.21-2.12 (1H, m), 2.05-1.
97 (9H, m), 1.79-1.49 (6H, m), 1.18 (3H, s), 1.11 (6H, t, J = 6.
8Hz) IR (KBr, cm ^-1 ): 3507,2969,1658,1632,1528,1398,1352,1
244,1201,1127,781

Examples 128 to 129 Compounds obtained by synthesizing hydrazide compounds in Reference Example 5 6-hydroxy-2,5,7,8-tetramethylchroman-2-
Propionohydrazide (6-hydroxy-2,5,7,8-tetramethyl
Example 1 except for replacing with chroman-2-propionohydrazide)
Substantially the same as 26 or 127, the following compounds were prepared: Example 128 o-Vaniline 6-hydroxy-2,5,
7,8-tetramethylchroman-2-propionylhydrazone (o-vanillin 6-hydroxy-2,5,7,8-tetramethylchr
oman-2-propionylhydrazone) Yield: 82% (Physical Properties) colorless crystals (mp.191-195 ℃) PMR (DMSO- d 6, δ ppm): 11.58,11.20 (1H, each-s), 10.97,
9.47 (1H, each-s), 8.33,8.27 (1H, each-s), 7.34,7.33 (1H, each-s)
each-s), 7.18,7.06 (1H, each-d, J = 7.8Hz), 6.98,6.96 (1H,
each-d, J = 7.8Hz), 6.82,6.79 (1H, each-t, J = 8.1Hz), 3.82,
3.81 (3H, each-s), 2.80-2.28 (4H, m), 2.12-1.98 (9H, m), 1.
95-1.74 (4H, m), 1.23,1.19 (3H, s) IR (KBr, cm ^-1 ): 3357,2968,2930,1654,1465,1419,1253,1
089,735

Example 129 4- (Diethylamino) salicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-propionylhydrazone (4-
(diethylamino) salicylaldehyde 6-hydroxy-2,5,7,8-te
tramethylchroman-2-propionylhydrazone) 64% yield (Physical Properties) pale yellow crystals (mp.202-203 ℃) PMR (DMSO- d 6, δ ppm): 11.34,10.95 (1H, each-s), 11.27,
10.16 (1H, each-s), 8.11,8.02 (1H, each-s), 7.34 (1H, s),
7.19,7.11 (1H, each-d, J = 8.8Hz), 6.23,6.21 (1H, each-dd,
J = 8.8,2.4Hz), 6.10,6.08 (1H, each-d, J = 2.4Hz), 3.35 (4H,
q, J = 7.1Hz), 2.69-2.23 (4H, m), 2.06-1.98 (9H, m), 1.93-1.
71 (4H, m), 1.18 (3H, s), 1.11 (6H, t, J = 7.1Hz) IR (KBr, cm ^-1 ): 3421,2968,2929,1655,1630,1525,1449,1
405,1354,1245,1129,1101,783

Example 130 4-Isopropoxysalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone
3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Compound synthesized in Reference Example 1, 3,5-di-t-butyl-4
-Hydroxybenzohydrazide 1.06 g (4 mmol) and 4-
0.72 g (4 mmol) of isopropoxysalicylaldehyde was dissolved in 20 ml of ethanol, and the mixture was stirred at room temperature for 18 hours. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound 1.1
5 g (67% yield) was obtained.

(Physical properties) Light yellow crystal (mp. 243-248 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.73 (1H, brs), 11.71 (1H, brs),
8.53 (1H, s), 7.67 (2H, s), 7.56 (1H, s), 7.36 (1H, d, J = 8.3H
z), 6.51-6.44 (2H, m), 4.65 (1H, sept, J = 5.9Hz), 1.43 (18H,
s), 1.28 (6H, d, J = 5.9Hz)

Examples 131 to 145 The following compounds were prepared in substantially the same manner as in Example 130 except that 4-isopropoxysalicylaldehyde was replaced with another aldehyde compound. Example 131 3-isopropoxysalicylaldehyde 3,5-di-t-buty
l-4-hydroxybenzoylhydrazone) Yield 47% (Physical properties) Colorless crystal (mp.285-289 ° C) PMR (DMSO-d ₆ , δ ppm): 11.85 (1H, s), 11.21 (1H, s), 8.62
(1H, s), 7.68 (2H, s), 7.58 (1H, s), 7.11 (1H, dd, J = 1.5 and
7.8Hz), 7.01 (1H, d, J = 7.8Hz), 6.83 (1H, t, J = 7.8Hz), 4.56
(1H, sept, J = 5.9Hz), 1.44 (18H, s), 1.28 (6H, d, J = 5.9Hz)

Example 132 2-Hydroxy-3-methoxycinnamaldehyde 3,5-di-tert-butyl-4-
Hydroxybenzoyl hydrazone (2-hydroxy-3-methoxy
cinnamaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydr
azone) Yield: 69% (physical properties) pale yellow crystal (mp. 152-156 ° C) PMR (DMSO-d ₆ , δ ppm): 11.43 (1H, brs), 9.11 (1H, s), 8.62
(1H, s), 8.20 (1H, br-d, J = 8.8Hz), 7.61 (2H, s), 7.50 (1H,
s), 7.22-7.12 (2H, m), 7.10-6.97 (1H, m), 6.92 (1H, dd, J = 1.
0 and 7.8Hz), 6.79 (1H, t, J = 7.8Hz), 3.82 (3H, s), 1.42 (18
H, s) IR (KBr, cm ^-1 ): 3624,3520,3515,2956,1643,1620,1546,1
477,1439,1363,1305,1259,1238,1069,984,774,727,698

Example 133 3-Methyl-6-isopropylsalicylaldehyde 3,5-di-tert-butyl-4-
Hydroxybenzoyl hydrazone (3-methyl-6-isopropy
lsalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhy
Drazone) Yield: 88% (property) pale yellow crystals (mp> 300 ℃) PMR ( DMSO-d 6, δ ppm):. 12.83 (1H, s), 11.87 (1H, s), 9.00
(1H, s), 7.69 (2H, s), 7.62 (1H, s), 7.14 (1H, d, J = 8.0Hz), 6.
76 (1H, d, J = 8.0Hz), 3.35-3.32 (1H, m), 2.17 (3H, s), 1.44 (1
8H, s), 1.24 (6H, d, J = 7.0Hz) IR (KBr, cm ^-1 ): 3620,3205,2961,1635,1600,1547,1458,1
436,1360,1304,1240,1115,962,811

Example 134 4,6-Diisopropoxysalicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (4,6-diisopropoxysalicyl)
aldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 83% (physical properties) colorless crystal (mp.> 300 ℃) PMR (DMSO-d ₆ , δ ppm): 12.64 (1H, s), 11.83 (1H, s), 8.76
(1H, s), 7.68 (2H, s), 7.54 (1H, s), 6.10-6.06 (2H, m), 4.73-
4.60 (2H, m), 1.44 (18H, s), 1.32 (1H, d, J = 6.0Hz), 1.28 (6H,
d, J = 6.0Hz) IR (KBr, cm ^-1 ): 3616,3208,3062,2973,1631,1601,1547,1
501,1435,1346,1324,1303,1239,1155,1114,1067,1023,9
72,930,908,813,708

Example 135 4-dimethylaminosalicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone
e 3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 78% (physical properties) Yellow crystal (mp. 255-272 ° C) PMR (DMSO-d ₆ , δ ppm): 11.62 (1H, s) , 11.58 (1H, s), 8.44
(1H, s), 7.65 (2H, s), 7.51 (1H, s), 7.19 (1H, d, J = 8.7Hz), 6.
30 (1H, dd, J = 2.4 and 8.7Hz), 6.17 (1H, d, J = 2.4Hz), 2.96
(6H, s), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3411,3221,2957,2911,1630,1600,1522,1
484,1435,1353,1306,1263,1239,1137,980,910,888,852,
822,791,717,700,647

Example 136 4-Di-n-propylaminosalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone
icylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydraz
one) Yield: 57% (property) pale yellow crystals (mp.243-248 ℃) PMR (DMSO- d 6, δ ppm): 11.55 (1H, s), 11.53 (1H, brs), 8.4
1 (1H, s), 7.65 (2H, s), 7.50 (1H, s), 7.15 (1H, d, J = 8.8Hz),
6.24 (1H, dd, J = 2.0 and 8.8Hz), 6.10 (1H, d, J = 2.0Hz), 3.3
0-3.20 (4H, m), 1.62-1.48 (4H, m), 1.43 (18H, s), 0.90 (6H,
t, J = 7.3Hz) IR (KBr, cm ^-1 ): 3624,3207,2958,2871,1632,1599,1519,1
434,1354,1304,1239,1134,1100,893,823,786,702,649

Example 137 3-Hydroxypicolinaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone
-butyl-4-hydroxybenzoylhydrazone) Yield: 51% (property) pale yellow crystals (mp.245-252 ℃) PMR (DMSO- d 6, δ ppm): 12.17 (1H,
s), 11.78 (1H, s), 8.19 (1H, d
d, J = 1.5 and 4.5 Hz), 7.72 (2
H, s), 7.65 (1H, s), 7.39 (1H,
d, J = 8.5 Hz), 7.33 (1H, dd, J =
4.5 and 8.5 Hz), 1.44 (18H,
s) IR (KBr, cm ^-1 ): 3447,3230,2
960, 2911, 1643, 1601, 1542, 1
445, 1330, 1304, 1237, 1178, 1
162,1096,887,807,756,703

Example 138 4-N-pyrrolidinosalicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone
e 3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 66% (physical properties) Yellow crystals (mp. 295-298 ° C) PMR (DMSO-d ₆ , δ ppm): 11.66 (1H, s) , 11.54 (1H, s), 8.42
(1H, s), 7.65 (2H, s), 7.50 (1H, s), 7.17 (1H, d, J = 8.8Hz), 6.
15 (1H, dd, J = 2.2 and 8.8Hz), 6.02 (1H, d, J = 2.2Hz), 3.32-
3.23 (4H, m), 2.00-1.92 (4H, m), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3606,3444,3207,2958,1631,1595,1551,1
523,1485,1434,1355,1344,1307,1253,1 238,1160,1143,1119,1087,961,897,828,780,702

Example 139 4-N-piperidinosalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone
3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 84% (physical properties) pale yellow crystal (mp.273-278 ° C) PMR (DMSO-d ₆ , δ ppm): 11.60 (1H, s) , 11.56 (1H, s), 8.44
(1H, s), 7.65 (2H, s), 7.50 (1H, s), 7.20 (1H, d, J = 8.8Hz), 6.
49 (1H, dd, J = 2.2 and 8.8Hz), 6.36 (1H, d, J = 2.2Hz), 3.30-
3.23 (4H, m), 1.61-1.56 (6H, m), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3585,3444,2953,1629,1599,1556,1515,1
435,1352,1305,1239,1121,1024,974,667,648

Example 140 2-Hydroxy-6-methylnicotinaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone (2-hydroxy-6
-Methylnicotinaldehyde 3,
5-di-t-butyl-4-hydroxyben
Zoylhydrazone) Yield: 50% (property) pale yellow crystals (mp> 280 ℃) PMR ( DMSO-d 6, δ ppm):. 11.97 (1H, s), 11.52 (1H, s), 8.60
(1H, s), 7.93 (1H, d, J = 6.8Hz), 7.64 (2H, s), 7.47 (1H, s), 6.
15 (1H, d, J = 6.8Hz), 2.24 (3H, s), 1.44 (18H, s) IR (KBr, cm ^-1 ): 3627,3444,2956,1650,1633,1621,1564,1
484,1435,1354,1307,1240,1162,1105,1070,971,889,77
6,697,582

Example 141 4-N-morpholinosalicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone
3,5-di-t-butyl- 4-hydroxybenzoylhydrazone) Yield: 82% (Physical Properties) colorless crystals (mp.295-298 ℃) PMR (DMSO- d 6, δ ppm): 11.66 (1H, s), 11.62 (1H, s), 8.47
(1H, s), 7.66 (2H, s), 7.53 (1H, s), 7.26 (1H, d, J = 8.8Hz), 6.
53 (1H, dd, J = 1.6 and 8.8Hz), 6.42 (1H, d, J = 1.6Hz), 3.75-
3.70 (4H, m), 3.25-3.17 (4H, m), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3610,3444,2953,1632,1600,1556,1516,1
434,1358,1306,1246,1238,1121,1045,978,896,784,701,
664

Example 142 4- (4-Ethyl-1-piperazinyl) salicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone (4- (4-ethyl-
1-piperazinyl) salicylaldehyde 3,5-di-t-butyl-4-hyd
Roxybenzoylhydrazone) Yield: 52% (property) pale green crystals (mp.250-262 ℃) PMR (DMSO- d 6, δ ppm): 11.64 (1H, s), 11.59 (1H, s), 8.46
(1H, s), 7.65 (2H, s), 7.53 (1H, brs), 7.23 (1H, d, J = 8.8Hz),
6.52 (1H, dd, J = 2.0 and 8.8Hz), 6.40 (1H, d, J = 2.0Hz), 3.2
7-3.20 (4H, m), 2.50-2.44 (4H, m), 2.36 (2H, q, J = 7.1Hz), 1.
43 (18H, s), 1.04 (3H, t, J = 7.1Hz) IR (KBr, cm ^-1 ): 3606,3444,3219,2958,2911,2876,2824,1
630,1602,1556,1515,1435,1357,1305,1239,1200,1152,1
124,1025,979,889,846,776,701

Example 143 4-N-piperidino-6
Hydroxysalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone (4-N-piperidin
o-6-hydroxysalicylaldehyde 3,5-di-t-butyl-4-hydrox
ybenzoylhydrazone) Yield: 62% (physical properties) pale yellow crystal (mp.244-246 ° C) PMR (DMSO-d ₆ , δ ppm): 11.55 (1H, s), 10.95 (2H, brs), 8.7
6 (1H, s), 7.66 (2H, s), 7.49 (1H, s), 5.90 (2H, s), 3.25-3.17
(4H, m), 1.60-1.50 (6H, m), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3604,3444,3176,2953,1634,1602,1557,1
435,1325,1304,1238,1191,1123,989,703

Example 144 4-N-piperidino-6
Isopropoxysalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone (4-N-piper
idino-6-isopropoxysalicylaldehyde 3,5-di-t-butyl-4
-Hydroxybenzoylhydrazone) Yield: 73% (Physical properties) Light yellow crystal (mp.> 300 ℃) PMR (DMSO-d ₆ , δ ppm): 12.38 (1H, s), 11.68 (1H, s), 8.70
(1H, s), 7.66 (2H, s), 7.47 (1H, s), 6.06 (1H, d, J = 2.0Hz), 5.
98 (1H, d, J = 2.0Hz), 4.71 (1H, sept, J = 6.0Hz), 3.29-3.24 (4
H, m), 1.62-1.56 (6H, m), 1.43 (18H, s), 1.32 (6H, t, J = 6.0H
z) IR (KBr, cm ^-1 ): 3592,3444,2953,1630,1598,1556,1435,1
345,1304,1237,1202,1121,1071,1024,996,805,708

Example 145 4- (N-methoxycarbonylmethyl) cyclopentylaminosalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone (4- (N-methoxycarbonylmethyl) cyclopentylamido)
nosalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylh
Ydrazone) Yield: 60% (property) pale yellow crystals (mp.215-220 ℃) PMR (DMSO- d 6, δ ppm): 11.59 (1H, s), 11.57 (1H, s), 8.43
(1H, s), 7.65 (2H, s), 7.51 (1H, s), 7.19 (1H, d, J = 8.8Hz),
6.27 (1H, dd, J = 2.0 and 8.8Hz), 6.17 (1H, d, J = 2.0Hz), 4.2
7-4.15 (1H, m), 4.08 (2H, s), 3.68 (3H, s), 1.95-1.85 (2H,
m), 1.72-1.38 (6H, m), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3594,3444,3226,2957,1738,1630,1601,1
515,1435,1358,1304,1239,1147,961,789,703

Example 146 4-Isopropoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (4-isopropox)
ysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchro
man-2-acetylhydrazone) Compound 6-hydroxy-2,5, synthesized in Reference Example 2.
7,8-tetramethylchroman-2-acetohydrazide
0.84 g (3 mmol) and 0.54 g (3 mmol) of 4-isopropoxysalicylaldehyde are dissolved in 20 ml of ethanol, and
For 7 hours. The solvent was distilled off, and the residue was crystallized by adding a mixed solvent of hexane: ethyl acetate = 1: 1, and collected by filtration. Dry under reduced pressure to give 1.05 g of the title compound (yield
80%). (Physical Properties) colorless crystals (mp.199-204 ℃) PMR (DMSO- d 6, δ ppm): 11.46,11.17 (1H, each-s), 11.45,
10.18 (1H, each-s), 8.23,8.13 (1H, each-s), 7.41,7.36 (2
H, each-s), 7.34,7.28 (1H, each-d, J = 8.3Hz), 6.48-6.37 (2
H, m), 4.63,4.55 (1H, each-sept, J = 5.8Hz), 2.91-2.40 (2H,
m), 2.06-1.77 (11H, m), 1.36-1.32 (3H, m), 1.27,1.26 (6H, e
(ach-d, J = 5.8Hz)

Examples 147 to 161 The following compounds were prepared in substantially the same manner as in Example 146 except that 4-isopropoxysalicylaldehyde was replaced with another aldehyde compound. Example 147 3-Isopropoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
hyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetyl
hydrazone Yield: 82% (physical properties) Colorless crystals (mp. 150-154 ° C) PMR (DMSO-d ₆ , δ ppm): 11.59, 11.29 (1H, each-s), 10.91,
9.18 (1H, each-s), 8.33,8.30 (1H, each-s), 7.09,7.02 (1H,
each-dd, J = 1.5and8.1Hz), 7.00,6.96 (1H, each-dd, J = 1.5a
nd8.1Hz), 6.81,6.73 (1H, each-t, J = 8.1Hz), 4.58-4.49 (1
H, m), 2.91-2.43 (4H, m), 2.06-1.77 (11H, m), 1.35,1.345 (3
H, each-s), 1.27, (6H, d, J = 5.9Hz)

Example 148 2-Hydroxy-3-methoxycinnamaldehyde 6-hydroxy-2,5,7,
8-tetramethylchroman-2-acetylhydrazone (2
-hydroxy-3-methoxycinnamaldehyde 6-hydroxy-2,5,7,8
-tetramethylchroman-2-acetylhydrazone) Yield: 78% (physical properties) Pale yellow crystals (mp. 118-126 ° C) PMR (DMSO-d ₆ , δ ppm): 11.17, 11.11 (1H, each-s), 9.11,
9.06 (1H, each-s), 7.90,7.76 (1H, each-s), 7.77,7.75 (1H,
each-s), 7.19-7.05 (2H, m), 6.99-6.72 (3H, m), 3.82,3.81
(3H, each-s), 2.62-2.47 (2H, m), 2.87,2.49 (1H, each-d, J =
13.5Hz), 2.79,2.41 (1H, each-d, J = 13.5Hz), 2.06-1.94 (10
H, m), 1.87-1.75 (1H, m), 1.34,1.32 (3H, each-s) IR (KBr, cm ^-1 ): 3400,3260,2920,1664,1619,1589,1547,1
478,1467,1440,1365,1261,1220,1086,1070,919,775,728

Example 149 3-Methyl-6-isopropylsalicylaldehyde 6-hydroxy-2,5,7,
8-tetramethylchroman-2-acetylhydrazone (3
-methyl-6-isopropylsalicylaldehyde 6-hydroxy-2,5,
7,8-tetramethylchroman-2-acetylhydrazone) Yield: 75% (property) pale yellow crystals (mp.120-123 ℃) PMR (DMSO- d 6, δ ppm): 12.54 (1H, s), 11.62 (1H , s) 8.74 (1
H, s), 7.44 (1H, s), 7.14 (1H, d, J = 7.8Hz), 6.74 (1H, d, J = 7.8
Hz), 3.19 (1H, sept, J = 6.8Hz), 2.65-2.44 (4H, m), 2.14 (3H,
s), 2.04 (6H, s), 1.96 (3H, s), 2.00-1.80 (2H, m), 1.35 (3H,
s), 1.18-1.25 (6H, m) IR (KBr, cm ^-1 ): 3232,2964,2926,1663,1597,1535,1458,1
382,1337,1317,1253,1240,1192,1178,1084,967,815,645

Example 150 4,6-Diisopropoxysalicylaldehyde 6-hydroxy-2,5,7,8-
Tetramethylchroman-2-acetylhydrazone (4,6-d
iisopropoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetra
methylchroman-2-acetylhydrazone) Yield: 52% (physical properties) Orange oil PMR (DMSO-d ₆ , δ ppm): 12.21 (1H, s), 11.48 (1H, s), 8.50
(1H, s), 7.42 (1H, s), 6.07 (1H, d, J = 2.0Hz), 6.05 (1H, d, J =
2.0Hz), 4.65 (2H, sept, J = 6.0Hz), 2.65-2.38 (4H, m), 2.05
(3H, s), 2.03 (3H, s), 1.97 (3H, s), 2.10-1.78 (2H, m), 1.34
(3H, s), 1.29 (6H, d, J = 6.0Hz), 1.26 (6H, d, J = 6.0Hz)

Example 151 4-Dimethylaminosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (4-dimethyla
minosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylc
hroman-2-acetylhydrazone) Yield: 46% (property) pale brown crystals (mp.211-216 ℃) PMR (DMSO- d 6, δ ppm): 11.31,11.07 (1H, each-s), 11.37,
10.16 (1H, each-s), 8.29,8.15 (1H, each-s), 7.42,7.37 (1
H, each-s), 7.19,7.18 (1H, each-d, J = 8.0Hz), 6.28,6.24 (1
H, each-dd, J = 2.0 and 8.0Hz), 6.14,6.11 (1H, each-d, J =
2.0Hz), 2.95, 2.92 (6H, each-s), 2.65-2.39 (4H, m), 2.06-
1.77 (11H, m), 1.34,1.33 (3H, each-s) IR (KBr, cm ^-1 ): 3397,3266,2931,1663,1633,1595,1524,1
443,1361,1266,1218,1173,1140,1112,1084,1007,979,97
3,827,793,716,650,602

Example 152 4-Di-n-propylaminosalicylaldehyde 6-hydroxy-2,5,7,8
-Tetramethylchroman-2-acetylhydrazone (4-d
in-propylaminosalicylaldehyde 6-hydroxy-2,5,7,8-t
etramethylchroman-2-acetylhydrazone) Yield: 72% (property) pale brown crystals (mp.110-113 ℃) PMR (DMSO- d 6, δ ppm): 11.25,11.04 (1H, each-s), 11.31,
10.09 (1H, each-s), 8.12,8.04 (1H, each-s), 7.40,7.35 (1
H, each-s), 7.14,7.12 (1H, each-d, J = 8.0Hz), 6.23-6.15 (1
H, m), 6.08-6.05 (1H, m), 3.28-3.17 (4H, m), 2.65-2.37 (4H, m
m), 2.06-1.77 (11H, m), 1.60-1.47 (4H, m), 1.34,1.33 (3H, e
ach-s), 0.89 (6H, t, J = 7.3Hz) IR (KBr, cm ^-1 ): 3444,3226,2960,2931,2872,1632,1598,1
556,1519,1455,1416,1359,1235,1211,1134,1086,1006,9
20,827,787,751,648

Example 153 3-Hydroxypicolinaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
naldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-a
cetylhydrazone) Yield: 67% (physical properties) Yellow crystals (mp. 190-195 ° C) PMR (DMSO-d ₆ , δ ppm): 11.93, 11.61 (1H, each-s), 11.51,
10.35 (1H, each-s), 8.34,8.24 (1H, each-s), 8.20-8.12 (1
H, m), 7.45-7.12 (3H, m), 2.97-2.47 (4H, m), 2.07-1.80 (11
H, m), 1.35,1.33 (3H, each-s) IR (KBr, cm ^-1 ): 3444,3208,2929,1685,1557,1446,1418,1
374,1298,1256,1178,1088,1059,1032,807,733,696,682,
560

Example 154 4-Pyrrolidinosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (4-pyrrolidinosa
licylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman
-2-acetylhydrazone) Yield: 85% (property) pale yellow crystals (mp.273-278 ℃) PMR (DMSO- d 6, δ ppm): 11.27,11.04 (1H, each-s), 11.41,
10.19 (1H, each-s), 8.13,8.05 (1H, each-s), 7.40,7.36 (1
H, each-s), 7.16,7.14 (1H, each-d, J = 8.8Hz), 6.13,6.09 (1
H, each-dd, J = 2.0 and 8.8Hz), 5.99,5.96 (1H, each-d, J =
2.0Hz), 3.30-3.20 (4H, m), 2.83-2.30 (4H, m), 2.07-1.77 (1
1H, m), 1.34,1.33 (3H, each-s) IR (KBr, cm ^-1 ): 3444,3195,3041,2969,2936,2922,1632,1
597,1525,1418,1377,1359,1348,1253,1231,1177,1161,1
142,1117,1085,821,787,648

Example 155 4-Piperidinosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (4-piperidinosal
icylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-
2-acetylhydrazone) Yield: 69% (Physical Properties) colorless crystals (mp.225-228 ℃) PMR (DMSO- d 6, δ ppm): 11.33,11.09 (1H, each-s), 11.31,
10.07 (1H, each-s), 8.14,8.07 (1H, each-s), 7.39,7.34 (1
H, each-s), 7.18 (1H, d, J = 8.8Hz), 6.47,6.42 (1H, each-dd,
J = 2.0 and 8.8Hz), 6.33,6.31 (1H, each-d, J = 2.0Hz), 3.29
-3.17 (4H, m), 2.86-2.37 (4H, m), 2.07-1.78 (11H, m), 1.60-
1.55 (6H, m), 1.34 (3H, s) IR (KBr, cm ^-1 ): 3444,2932,1663,1631,1599,1556,1516,1
451,1358,1241,1220,1121,1087,1023,971,791

Example 156 2-Hydroxy-6-methylnicotinaldehyde 6-hydroxy-2,5,7,8
-Tetramethylchroman-2-acetylhydrazone (2-h
ydroxy-6-methylnicotinaldehyde 6-hydroxy-2,5,7,8-t
etramethylchroman-2-acetylhydrazone) Yield: 24% (property) pale yellow crystals (mp.176-178 ℃) PMR (DMSO- d 6, δ ppm): 11.95,11.91 (1H, each-s), 11.26,
11.22 (1H, each-s), 8.25,8.04 (1H, each-s), 7.85,7.35 (1
H, each-d, J = 7.5Hz), 7.41,7.34 (1H, each-s), 6.12,5.98 (1
H, each-d, J = 7.5Hz), 2.70-2.48 (2H, m), 3.02,2.48 (1H, eac
hd, J = 13.5Hz), 2.74,2.40 (1H, each-d, J = 13.5Hz), 2.22,
2.20 (3H, each-s), 2.07-1.70 (11H, m), 1.37,1.33 (3H, each
-s) IR (KBr, cm ^-1 ): 3418,2933,1651,1645,1557,1470,1463,1
455,1379,1256,1209,1132,1088,1061,777,584

Example 157 4-morpholinosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
icylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-
2-acetylhydrazone) Yield: 79% (property) pale yellow crystals (mp.212-214 ℃) PMR (DMSO- d 6, δ ppm): 11.40,11.14
(1H, each-s), 11.37, 10.14 (1
H, each-s), 8.18,8.10 (1H, ea
ch-s), 7.41, 7.36 (1H, each-
s), 7.25, 7.23 (1H, reach-d, J =
8.8 Hz), 6.51, 6.46 (1H, each-
dd, J = 2.0 and 8.8 Hz), 6.39,
6.34 (1H, each-d, J = 2.0Hz),
3.75-3.68 (4H, m), 3.22-3.10
(4H, m), 2.90-2.40 (4H, m), 2.
07-1.78 (11H, m), 1.34 (3H, s) IR (KBr, cm ^-1 ): 3459, 3227, 2
972, 2929, 1659, 1628, 1556, 1
514, 1505, 1454, 1253, 1234, 1
192, 1118, 1086, 1047, 981, 89
4,840,788,667,625

Example 158 4- (4-Ethyl-1-piperazinyl) salicylaldehyde 6-hydroxy-2,
5,7,8-Tetramethylchroman-2-acetylhydrazone (4- (4-ethyl-1-piperazi)
nyl) salicylaldehyde 6-hyd
roxy-2,5,7,8-tetramethylc
roman-2-acetylhydrazine yield: 65% (physical properties) pale pink crystal (mp. 208-222 ° C) PMR (DMSO-d ₆ , δ ppm): 11.37, 11.11 (1H, each-s), 11.33,
10.10 (1H, each-s), 8.16,8.08 (1H, each-s), 7.41,7.36 (1
H, each-s), 7.22,7.21 (1H, each-d, J = 8.8Hz), 6.50,6.45 (1
H, each-dd, J = 2.0 and 8.8Hz), 6.37,6.33 (1H, each-d, J =
2.0Hz), 3.26-3.14 (4H, m), 2.70-2.30 (10H, m), 2.06-1.76
(11H, m), 1.34 (3H, s), 1.03 (3H, t, J = 7.3Hz) IR (KBr, cm ^-1 ): 3455,3303,2971,2935,2827,1670,1629,1
601,1557,1515,1450,1380,1356,1217,1201,1161,1124,1
087,1058,1025,980,779,646

Example 159 4-Piperidino-6-hydroxysalicylaldehyde 6-hydroxy-2,5,
7,8-tetramethylchroman-2-acetylhydrazone (4-piperidino-6-hydroxysalicylaldehyde 6-hydroxy
-2,5,7,8-tetramethylchroman-2-acetylhydrazone) Yield: 50% (Physical properties) Light yellow crystal (mp. 240-245 ° C) PMR (DMSO-d ₆ , δ ppm): 11.27, 11.11 (1H , each-s), 10.78,
10.33 (1H, each-s), 8.44,8.34 (1H, each-s), 7.40,7.36 (1
H, each-s), 5.88,5.87 (2H, each-s), 3.23-3.15 (4H, m), 2.8
5-2.35 (4H, m), 2.06-1.76 (11H, m), 1.60-1.50 (6H, m), 1.3
4,1.29 (3H, each-s) IR (KBr, cm ^-1 ): 3814,3312,2933,285
3,1639,1597,1526,1452,1417,1255,1202,1121,1085,106
0,855,811

Example 160 4-Piperidino-6-isopropoxysalicylaldehyde 6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone (4-piperidino-6-isopropoxysalicylaldehyde 6-
hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazo
ne) Yield: 76% (property) pale pink crystals (mp.192-195 ℃) PMR (DMSO- d 6, δ ppm): 11.33,11.16 (1H, each-s), 11.96,
11.00 (1H, each-s), 8.44,8.38 (1H, each-s), 7.39,7.34 (1
H, each-s), 6.04 (1H, d, J = 2.0Hz), 5.95 (1H, d, J = 2.0Hz), 4.
66 (1H, sept, J = 6.0Hz), 3.30-3.22 (4H, m), 2.80-2.37 (4H,
m), 2.08-1.77 (11H, m), 1.34 (3H, s), 1.28 (6H, t, J = 6.0Hz) IR (KBr, cm- ¹ ): 3396,3339,2976,2933,1675,1626 , 1596,1
544,1505,1452,1383,1343,1261,1235,1203,1173,1121,1
087,1062,997,931,923,860,812,474

Example 161 4- (N-methoxycarbonylmethyl) cyclopentylaminosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (4- (N-methoxycarbonylmet)
hyl) cyclopentylaminosalicylaldehyde 6-hydroxy-2,5,
7,8-tetramethylchroman-2-acetylhydrazone) Yield: 43% (physical properties) Pale purple oil PMR (DMSO-d ₆ , δ ppm): 11.32, 11.10 (1H, each-s), 11.33,
10.10 (1H, each-s), 8.14,8.06 (1H, each-s), 7.42,7.36 (1
H, each-s), 7.19,7.17 (1H, each-d, J = 8.8Hz), 6.25,6.21 (1
H, each-dd, J = 2.0 and 8.8Hz), 6.14,6.10 (1H, each-d, J =
2.0Hz), 4.25-4.10 (1H, m), 4.08-4.02 (2H, m), 3.68 (3H, s),
2.90-2.38 (4H, m), 2.06-1.78 (13H, m), 1.72-1.39 (6H, m),
1.34,1.33 (3H, each-s)

Example 162 o-Vaniline 3,5-diisopropyl-4-hydroxybenzoylhydrazone (ov
anillin 3,5-diisopropyl-4-hydroxybenzoylhydrazone) Compound 3,5-diisopropyl- synthesized in Reference Example 16.
0.47 g (2 mmol) of 4-hydroxybenzohydrazide and o
-0.30 g (2 mmol) of vanillin was dissolved in 20 ml of ethanol, and the mixture was stirred at 60 ° C for 3 hours. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 0.22 g (yield: 30%) of the title compound.

(Physical properties) Light yellow crystal (mp. 218-223 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.79 (1H, s), 11.20 (1 H, s), 8.80
(1H, s), 8.66 (1H, s), 7.63 (2H, s), 7.11 (1H, d, J = 7.8Hz),
7.02 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 7.8Hz), 3.82 (3H, s),
3.42-3.27 (2H, m), 1.21 (12H, d, J = 6.8Hz) IR (KBr, cm ^-1 ): 3465,3216,3061,2961,1635,1606,1576,1
543,1465,1358,1303,1251,1210,1159,1095,1078,982,94
4,835,778,732

Examples 163 to 166 The following compounds were prepared in substantially the same manner as in Example 162 except that o-vanillin was replaced with another aldehyde compound. Example 163 4-diethylaminosalicylaldehyde 3,5-diisopropyl-4-hydroxybenzoylhydrazone
opyl-4-hydroxybenzoylhydrazone) Yield: 64% (physical properties) Yellow crystal (mp. 135-138 ° C) PMR (DMSO-d ₆ , δ ppm): 11.59 (1H, s), 11.50 (1H, s), 8.72
(1H, s), 8.44 (1H, s), 7.60 (2H, s), 7.16 (1H, d, J = 8.8Hz), 6.
24 (1H, dd, J = 2.2 and 8.8Hz), 6.13 (1H, d, J = 2.2Hz), 3.40-
3.28 (6H, m), 1.21 (12H, d, J = 6.8Hz), 1.12 (6H, t, J = 7.0Hz) IR (KBr, cm ^-1 ): 3418,2966,1633,1601,1519,1470 , 1355,1
295,1249,1206,1133,963,787,733

Example 164 4-dimethylaminosalicylaldehyde 3,5-diisopropyl-4-hydroxybenzoylhydrazone
e 3,5-diisopropyl-4-hydroxybenzoylhydrazone) Yield: 65% (physical properties) Yellow crystal (mp.235-252 ° C) PMR (DMSO-d ₆ , δ ppm): 11.63 (1H, s), 11.53 (1H , s), 8.74
(1H, s), 8.46 (1H, s), 7.60 (2H, s), 7.19 (1H, d, J = 8.8Hz),
6.31 (1H, dd, J = 2.2 and 8.8Hz), 6.17 (1H, d, J = 2.2Hz), 3.4
0-3.27 (2H, m), 2.96 (6H, s), 1.21 (12H, d, J = 6.8Hz) IR (KBr, cm- ¹ ): 3417,2962,1632,1602,1523,1469,1444, 1
356,1302,1263,1209,1137,1072,979,825,733

Example 165 4-Isopropoxysalicylaldehyde 3,5-diisopropyl-4-hydroxybenzoylhydrazone
3,5-diisopropyl-4-hydroxybenzoylhydrazone) Yield: 75% (property) pale yellow crystals (mp.249-256 ℃) PMR (DMSO- d 6, δ ppm): 11.72 (1H, s), 11.68 (1H , s), 8.77
(1H, s), 8.55 (1H, s), 7.62 (2H, s), 7.35 (1H, d, J = 8.8Hz), 6.
48 (1H, dd, J = 1.8 and 8.8Hz), 6.45 (1H, d, J = 1.8Hz), 4.65
(1H, sept, J = 6.3Hz), 3.40-3.27 (2H, m), 1.28 (6H, d, J = 6.3H
z), 1.21 (12H, d, J = 6.8Hz) IR (KBr, cm ^-1 ): 3419,3218,2962,1634,1605,1538,1508,1
468,1358,1333,1295,1255,1203,1113,1075,992,966,93
3,843,835,805,740,643

Example 166 4-Piperidino-6-isopropoxysalicylaldehyde 3,5-diisopropyl-4-hydroxybenzoylhydrazone (4-piperidino-
6-isopropoxysalicylaldehyde 3,5-diisopropyl-4-hydr
Oxybenzoylhydrazone) Yield: 91% (property) pale yellow crystals (mp.260-290 ℃) PMR (DMSO- d 6, δ ppm): 12.42 (1H, s), 11.65 (1H, s), 8.72
(1H, s), 8.71 (1H, s), 7.61 (2H, s), 6.06 (1H, d, J = 2.0Hz), 5.
97 (1H, d, J = 2.0Hz), 4.72 (1H, sept, J = 6.0Hz), 3.40-3.30 (2
H, m), 3.30-3.23 (4H, m), 1.62-1.55 (6H, m), 1.32 (6H, d, J =
6.0Hz), 1.21 (12H, d, J = 7.0Hz) IR (KBr, cm ^-1 ): 3418,3212,2962,2936,1631,1601,1553,1
465,1347,1206,1119,995,817,734

Example 167 o-Vaniline 3- (3,5
-Di-t-butyl-4-hydroxyphenyl) propionylhydrazone (o-vanillin 3- (3,5-di-t-butyl-4-hydr)
(oxyphenyl) propionylhydrazone) Compound 3- (3,5-di-t-butyl-4-hydroxyphenyl) propionohydrazide synthesized in Reference Example 17
1.17 g (4 mmol) and 0.61 g (4 mmol) of o-vanillin were dissolved in 20 ml of ethanol, and the mixture was stirred at room temperature for 8 hours. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (1.22 g).
(Yield: 72%) was obtained. (Physical properties) Colorless crystal (mp.175-185 ° C) PMR (DMSO-d ₆ , δ ppm): 11.58,11.25 (1H, each-s), 10.92,
9.48 (1H, each-s), 8.34,8.28 (1H, each-s), 7.23,7.08 (1H, each-s)
each-dd, J = 1.5 and 8.1Hz), 7.05-6.94 (1H, m), 6.97,6.95
(2H, each-s), 6.83,6.77 (1H, each-t, J = 8.1Hz), 6.70,6.67
(1H, each-s), 3.81 (3H, s), 2.85-2.75 (3H, m), 2.55-2.43 (1
H, m), 1.364,1.357 (18H, each-s)

Examples 168 to 170 The following compounds were prepared in substantially the same manner as in Example 167 except that o-vanillin was replaced with another aldehyde compound. Example 168 4-Diethylaminosalicylaldehyde 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionylhydrazone (4-diethylaminosalicylal)
dehyde 3- (3,5-di-t-butyl-4-hydroxyphenyl) propionyl
hydrazone) Yield: 72% (physical properties) Light brown crystal (mp. 180-182 ° C) PMR (DMSO-d ₆ , δ ppm): 11.28, 10.99 (1H, each-s), 11.33,
10.15 (1H, each-s), 8.11,8.04 (1H, each-s), 7.25,7.14 (1
H, each-d, J = 8.8Hz), 6.97,6.94 (2H, each-s), 6.69,6.67 (1
H, each-s), 6.23,6.20 (1H, each-dd, J = 2.3 and 8.8Hz), 6.
09,6.07 (1H, each-d, J = 2.3Hz), 3.45-3.30 (4H, m), 2.83-2.
38 (4H, m), 1.37,1.36 (18H, each-s), 1.10,1.096 (6H, each-s
t, J = 7.0Hz) IR (KBr, cm ^-1 ): 3589,2965,2871,1664,1632,1600,1559,1
527,1401,1355,1246,1129,1016,962,826,784

Example 169 Pyridoxal 3- (3,3)
5-di-t-butyl-4-hydroxyphenyl) propionyl hydrazone (pyridoxal 3- (3,5-di-t-butyl-4-hyd)
roxyphenyl) propionylhydrazone) Yield: 44% (property) of yellow crystals (mp.205-220 ℃) PMR (DMSO- d 6, δ ppm): 13.00 (1H, brs), 12.56,11.92 (1H,
each-s), 8.67,8.51 (1H, each-s), 8.22,8.20 (1H, each-s),
6.97,6.96 (2H, each-s), 6.78-6.67 (1H, m), 4.76,4.73 (2H,
each-s), 2.61 (3H, s), 2.90-2.55 (4H, m), 1.36 (18H, s) IR (KBr, cm ^-1 ): 3380,2956,1697,1542,1474,1435,1363, 1
233,1167,1120,1059,1039,769

Example 170 4-Piperidinosalicylaldehyde 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionylhydrazone (4-piperidinosal)
icylaldehyde 3- (3,5-di-t-butyl-4-hydroxyphenyl) pro
Pionylhydrazone) Yield: 88% (property) pale yellow crystals (mp.195-197 ℃) PMR (DMSO- d 6, δ ppm): 11.35,11.05 (1H, each-s), 11.32,
10.14 (1H, each-s), 8.15,8.08 (1H, each-s), 7.30,7.19 (1
H, each-d, J = 8.8Hz), 6.97,6.94 (2H, each-s), 6.69,6.66 (1
H, each-s), 6.47,6.44 (1H, each-dd, J = 2.0 and 8.8Hz), 6.
34,6.31 (1H, each-d, J = 2.0Hz), 3.28-3.18 (4H, m), 2.82-2.
40 (4H, m), 1.61-1.55 (6H, m), 1.37,1.36 (18H, each-s) IR (KBr, cm ^-1 ): 3444,3195,2952,2862,1660,1631,1600,1
557,1519,1435,1385,1220,1163,1121,1024,972,770,568

Example 171 o-Vaniline 3,5-di-
t-butyl-4-hydroxycinnamoylhydrazone (o
-vanillin 3,5-di-t-butyl-4-hydroxycinnamoylhydrazo
ne) Under a stream of argon, 0.83 g (3 mmol) of 3,5-di-t-butyl-4-hydroxycinnamic acid and 0.50 g (3 mmol) of o-vanillin hydrazone were added to a 10 ml solution of methylene chloride, and 0.60 g (6 mmol) of triethylamine was added. And bis (2-oxo-3-
Oxazolidinyl) phosphinic chloride (bis (2-oxo
-3-oxazolidinyl) phosphinic chloride) 0.76g (3mmol)
Was added at room temperature, and the mixture was further stirred at room temperature for 12 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. The solvent eluted with chloroform: methanol = 20: 1 was evaporated, recrystallized from toluene, and dried under reduced pressure to obtain 0.37 g (yield: 28%) of the title compound. (Physical properties) Yellow crystal (mp.238-245 ° C) PMR (DMSO-d ₆ , δ ppm): 11.77 (1H, brs), 10.96 (1H, brs),
8.39 (1H, s), 7.58 (1H, d, J = 16.0Hz), 7.45-7.30 (3H, m), 7.1
3 (1H, d, J = 8.0Hz), 7.01 (1H, d, J = 8.0Hz), 6.85 (1H, t, J = 8.0Hz)
Hz), 6.50 (1H, d, J = 16.0Hz), 3.82 (3H, s), 1.42 (18H, s) IR (KBr, cm ^-1 ): 3444,3197,2956,1651,1621,1616,1463 , 1
426,1360,1253,1207,1196,1119,1091,1080,975,733

Example 172 4-Diethylaminosalicylaldehyde 3,5-di-tert-butyl-4-hydroxycinnamoylhydrazone
de 3,5-di-t-butyl-4-hydroxycinnamoylhydrazone) 3,5-di-t-butyl-4-hydroxycinnamic acid 0.4
7 g (1.7 mmol), 0.42 g (2 mmol) of 4-diethylaminosalicylaldehyde hydrazone and 3- (diethylphosphoryloxy) -1,2,3-benzotriazine-4 (3
H) -one (3- (diethylphosphoryloxy) -1,2,3-benzotri
azin-4 (3H) -one) 0.60 g (2 mmol) of dimethylformamide
After adding 0.40 g (4 mmol) of triethylamine to the 10 ml solution at room temperature, the mixture was further stirred at room temperature for 18 hours. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and saturated saline, dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. Chloroform: methanol = 30:
The solvent was distilled off from one eluted part, and hexane: ethyl acetate = 1: 1.
Further crystallization was performed, and the crystals were collected by filtration. The crystals collected by filtration were dried under reduced pressure to give the title compound (0.33 g, yield 42%).

(Physical properties) Yellow crystal (mp. 240-250 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.48 (1H, s), 11.37 (1 H, s), 8.17
(1H, s), 7.51 (1H, d, J = 16.0Hz), 7.37 (1H, s), 7.36 (2H, s),
7.16 (1H, d, J = 9.0Hz), 6.48 (1H, d, J = 16.0Hz), 6.24 (1H, dd,
J = 2.0 and 9.0Hz), 6.11 (1H, d, J = 2.0Hz), 3.35 (4H, q, J = 7.
1Hz), 1.42 (18H, s), 1.11 (6H, t, J = 7.1Hz) IR (KBr, cm ^-1 ): 3444,3207,2965,1632,1594,1519,1426,1
355,1242,1208,1133,1022,787

Example 173 o-Vaniline 3- (3,5
-Diisopropyl-4-hydroxyphenyl) propionylhydrazone (o-vanillin 3- (3,5-diisopropyl-4-hyd
roxyphenyl) propionylhydrazone) Compound 3- (3,5-diisopropyl-4-hydroxyphenyl) propionohydrazide synthesized in Reference Example 18
0.79 g (3 mmol) and 0.46 g (3 mmol) of o-vanillin in 2-
It was dissolved in 20 ml of propanol and heated under reflux for 8 hours. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound 1.0
3 g (86% yield) was obtained. (Physical properties) Colorless crystal (mp.85-88 ° C) PMR (DMSO-d ₆ , δ ppm): 11.58,11.25 (1H, each-s), 10.93,
9.50 (1H, each-s), 8.33,8.28 (1H, each-s), 7.80,7.78 (1H, each-s)
each-s), 7.23,7.07 (1H, each-dd, J = 1.5 and 8.0Hz), 7.0
0,6.96 (1H, each-dd, J = 1.5 and 8.0Hz), 6.86-6.74 (3H,
m), 3.81,3.80 (3H, each-s), 3.26 (2H, sept, J = 7.0Hz), 2.84
-2.74 (2H, m), 2.50-2.43 (2H, m), 1.13,1.12 (12H, each-s) IR (KBr, cm ^-1 ): 3444,3252,2960,2867,1670,1609,1470, 1
255,1203,1153,1078,778,732,564

Example 174 4-Diethylaminosalicylaldehyde 3- (3,5-diisopropyl-4-hydroxyphenyl) propionylhydrazone (4-diethylam
inosalicylaldehyde 3- (3,5-diisopropyl-4-hydroxyphe
nyl) propionylhydrazone) The title compound was prepared in substantially the same manner as in Example 173 except that o-vanillin was replaced with 4-diethylaminosalicylaldehyde. Yield: 77% (property) pale yellow crystals (mp.179-183 ℃) PMR (DMSO- d 6, δ ppm): 11.34,10.98 (1H, each-s), 11.27,
10.16 (1H, each-s), 8.11,8.04 (1H, each-s), 7.78 (1H, s),
7.24,7.12 (1H, each-d, J = 9.0Hz), 6.85,6.82 (2H, each-s),
6.23,6.21 (1H, each-dd, J = 2.5 and 9.0Hz), 6.09,6.07 (1
H, each-d, J = 2.5Hz), 3.40-3.20 (6H, m), 2.82-2.70 (2H, m),
2.45-2.38 (2H, m), 1.16-1.08 (18H, m) IR (KBr, cm ^-1 ): 3500,2964,1662,1632,1599,1557,1520,1
471,1401,1355,1247,1196,1128,1077,1012,787

Examples 175 to 183 The following compounds were prepared in substantially the same manner as in Example 1 or 2, except that benzaldehyde or 4-fluorobenzaldehyde was replaced with another aldehyde compound or ketone compound. Example 175 6-Isopropoxy-4-morpholinosalicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (6-isopropoxy)
-4-morpholinosalicylaldeh
ide 3,5-di-t-butyl-4-hydr
Oxybenzoylhydrazone) Yield: 96% (Physical Properties) colorless crystals (mp> 300 ℃) PMR ( DMSO-d 6, δ ppm):. 12.43 (1H, s), 11.72 (1H, s), 8.72
(1H, s), 7.66 (2H, s), 7.50 (1H, brs), 6.12 (1H, d, J = 1.0Hz),
6.01 (1H, d, J = 1.0Hz), 4.73 (1H, sept, J = 5.9Hz), 3.74-3.69
(4H, m), 3.24-3.18 (4H, m), 1.43 (18H, s), 1.31 (6H, d, J = 5.9
Hz) IR (KBr, cm ^-1 ): 3601,3444,3207,2955,1630,1598,1553,1
506,1446,1435,1347,1332,1303,1239,1201,1121,1071,1
007,973,923,886,798,709,672,582,548

Example 176 4-N- (isopropoxycarbonylmethyl) isopropylaminosalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone (4-N- (isopropoxycarbonylmethyl) isoprop
ylaminosalicylaldehyde 3,5-di-t-butyl-4-hydroxyben
Zoylhydrazone) Yield: 80% (property) pale yellow crystals (mp.209-213 ℃) PMR (DMSO- d 6, δ ppm): 11.59 (2H, s), 8.43 (1H, s), 7.65
(2H, s), 7.50 (1H, brs), 7.18 (1H, d, J = 8.8Hz), 6.22 (1H, dd,
J = 1.6 and 8.8Hz), 6.11 (1H, d, J = 1.6Hz), 4.96 (1H, sept, J
= 6.4Hz), 4.17 (1H, sept, J = 6.4Hz), 4.00 (2H, s), 1.43 (18H,
s), 1.22 (6H, d, J = 6.4Hz), 1.15 (6H, d, J = 6.4Hz) IR (KBr, cm- ¹ ): 3596,3212,2969,1745,1632,1601,1557,1
518,1465,1435,1402,1359,1305,1251,1239,1205,1182,1
144,1106,1075,955,937,901,833,787,707,646

Example 177 4-N- (methoxycarbonylmethyl) isopropylamino salicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (4-N- (methoxycarbonylmethyl) isopropylamino
salicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhyd
razone) Yield: 68% (physical properties) pale yellow crystal (mp. 201-203 ° C) PMR (DMSO-d ₆ , δ ppm): 11.58 (1H, s), 11.57 (1H, s), 8.43
(1H, s), 7.65 (2H, s), 7.51 (1H, s), 7.18 (1H, d, J = 8.8Hz), 6.
23 (1H, dd, J = 2.0 and 8.8Hz), 6.11 (1H, d, J = 2.0Hz), 3.82
(3H, s), 4.17 (1H, sept, J = 6.3Hz), 4.07 (2H, s), 3.68 (3H,
s), 1.42 (18H, s), 1.14 (6H, d, J = 6.3Hz) IR (KBr, cm ^-1 ): 3618,3444,3219,2956,1754,1632,1601,1
552,1516,1434,1359,1305,1238,1203,1187,1172,1140,1
078,954,906,889,785,703,648

Example 178 4-Isopropoxy-6
Morpholinosalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone (4-isopropoxy-
6-morpholinosalicylaldehyde 3,5-di-t-butyl-4-hydro
(xybenzoylhydrazone) Yield: 96% (Physical properties) Pale yellow crystal (mp.> 300 ℃) PMR (DMSO-d ₆ , δ ppm): 12.58 (1H, s), 11.80 (1H, s), 8.73
(1H, s), 7.63 (2H, s), 7.56 (1H, s), 6.22 (1H, d, J = 2.5Hz), 6.
14 (1H, d, J = 2.5Hz), 4.66 (1H, sept, J = 5.9Hz), 3.81-3.75 (4
H, m), 2.91-2.85 (4H, m), 1.44 (18H, s), 1.24 (6H, d, J = 5.9H
z) IR (KBr, cm ^-1 ): 3609,3444,2958,2912,1636,1621,1598,1
567,1556,1338,1302,1237,1211,1179,1161,1116,1029,1
011,871,831,706

Example 179 5-Diethylaminosalicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone
3,5-di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 84% (physical properties) Yellow crystal (mp. 280-288 ° C) PMR (DMSO-d ₆ , δ ppm): 11.76 (1H, s), 10.59 (1H, s), 8.59 (1
H, s), 7.68 (2H, s), 7.54 (1H, s), 6.83-6.73 (3H, m), 3.24 (4
H, q, J = 6.8Hz), 1.44 (18H, s), 1.05 (6H, t, J = 6.8Hz) IR (KBr, cm- ¹ ): 3444,3235,2967,1641,1600,1580,1549 , 1
498,1435,1359,1304,1274,1236,1181,1141,1119,890,84
3,779,736,698

Example 180 3,5-Dibromosalicylaldehyde 3,5-dibromosalicylaldehyde 3,5-dibromosalicylaldehyde 3,5-
di-t-butyl-4-hydroxybenzoylhydrazone) Yield: 82% (physical properties) pale yellow crystal (mp.> 300 ° C) PMR (DMSO-d ₆ , δ ppm): 12.88 (1H, brs), 12.26 (1H, brs),
8.53 (1H, s), 7.78 (1H, d, J = 2.5Hz), 7.735 (1H, d, J = 2.5Hz),
7.70 (2H, s), 7.62 (1H, s), 1.44 (18H, s) IR (KBr, cm- ¹ ): 3619,3218,3055,2958,1639,1600,1537,1
444,1422,1338,1302,1237,1163,1120,1107,980,950,88
9,863,739,711,684

Example 181 3-methoxy-5-piperidinomethylsalicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (3-methoxy-5-p
iperidinomethylsalicylaldehyde 3,5-di-t-butyl-4-hy
Droxybenzoylhydrazone) Yield: 51% (property) pale yellow crystals (mp.193-213 ℃) PMR (DMSO- d 6, δ ppm): 11.78 (1H, brs), 10.87 (1H, brs),
8.62 (1H, brs), 7.67 (2H, s), 7.57 (1H, brs), 7.04 (1H, s), 6.
92 (1H, s), 3.81 (3H, s), 3.35 (2H, s), 2.36-2.26 (4H, m), 1.5
5-1.40 (6H, m), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3444,2937,1645,1539,1464,1435,1392,1
369,1301,1263,1236,1162,1115,1039,1010,992,889,86
5,844,701

Example 182 3-Methoxy-5-morpholinomethylsalicylaldehyde 3,5-di-tert-butyl-4-hydroxybenzoylhydrazone (3-methoxy-5-m
orpholinomethylsalicylaldehyde 3,5-di-t-butyl-4-hy
droxybenzoylhydrazone) Yield: 67% (physical properties) pale yellow crystal (mp.208-218 ° C) PMR (DMSO-d ₆ , δ ppm): 11.79 (1H, brs), 10.90 (1H, brs),
8.63 (1H, brs), 7.67 (2H, s), 7.55 (1H, brs), 7.06 (1H, s), 6.
95 (1H, s), 3.82 (3H, s), 3.61-3.55 (4H, m), 3.40 (2H, s), 2.3
9-2.32 (4H, m), 1.43 (18H, s) IR (KBr, cm ^-1 ): 3444,3235,2957,1642,1548,1463,1455,1
435,1392,1364,1237,1162,1114,1069,1002,912,867,702

Example 183 5- (4-Ethyl-1-piperazinyl) methyl-3-methoxysalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone (5- (4-ethyl-1-piperazinyl) ) methyl-3-methoxy
salicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhyd
Razone) Yield: 63% (property) pale yellow crystals (mp.201-210 ℃) PMR (DMSO- d 6, δ ppm): 11.78 (1H, brs), 10.92 (1H, brs),
8.62 (1H, brs), 7.68 (2H, s), 7.56 (1H, brs), 7.03 (1H, s), 6.
93 (1H, s), 3.82 (3H, s), 3.39 (2H, s), 2.46-2.25 (10H, m), 1.
43 (18H, s), 0.98 (3H, t, J = 7.3Hz) IR (KBr, cm ^-1 ): 3444,3252,2955,2813,1646,1539,1463,1
454,1435,1393,1365,1302,1236,1164,1118,1004,943,88
8,803

Example 184 6-Isopropoxy-4-
Morpholinosalicylaldehyde 6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone (6-isopropoxy-4-morpholinosalicylaldehyde 6-
hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazo
ne) Compound 6-hydroxy-2,5, synthesized in Reference Example 2
7,8-tetramethylchroman-2-acetohydrazide
1.11 g (4 mmol) and 1.06 g (4 mmol) of 6-isopropoxy-4-morpholinosalicylaldehyde were added to 2-propanol 3
The mixture was dissolved in 0 ml and heated under reflux for 18 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. Ethyl acetate: n-hexane = 3: 2 The eluted part was evaporated,
Ethyl acetate was added for crystallization and collected by filtration. Drying under reduced pressure gave 1.57 g (yield 75%) of the title compound.

(Physical properties) Colorless crystals (mp. 207-210 ° C.) PMR (DMSO-d ₆ , δ ppm): 12.01 (1H, s), 11.37 (1H, s), 8.46
(1H, s), 7.39 (1H, s), 6.10 (1H, d, J = 1.6Hz), 6.00 (1H, d, J =
1.6Hz), 4.68 (1H, sept, J = 5.9Hz), 3.73-3.67 (4H, m), 3.22-
3,17 (4H, m), 2.65-2.38 (4H, m), 2.05 (3H, s), 2.035 (3H, s),
1.97 (3H, s), 2.04-1.95 (1H, m), 1.90-1.78 (1H, m), 1.34 (3H
H, s), 1.28 (6H, d, J = 5.9Hz) IR (KBr, cm ^-1 ): 3418,1973,2857,1676,1625,1598,1549,1
505,1447,1377,1338,1267,1236,1197,1172,1124,1113,1
087,1062,1006,930,922,884,671

Examples 185 to 188 Example 184 was repeated except that 6-isopropoxy-4-morpholinosalicylaldehyde was replaced by another aldehyde compound.
The following compounds were prepared in substantially the same manner as described above. Example 185 4-N- (isopropoxycarbonylmethyl) isopropylaminosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-
Acetylhydrazone (4-N- (isopropoxycarbonylmethyl) i
sopropylaminosalicylaldehyde 6-hydroxy-2,5,7,8-tet
ramethylchroman-2-acetylhydrazone) Yield: 97% (physical properties) Pale purple amorphous solid PMR (DMSO-d ₆ , δ ppm): 11.34, 10.1
1 (1H, each-s), 11.32, 11.08
(1H, etch-s), 8.13, 8.06 (1H,
each-s), 7.40,7.34 (1H, each
-S), 7.18, 7.16 (1H, reach-d, J
= 8.8 Hz), 6.20, 6.17 (1H, each)
−dd, J = 2.5 and 8.8 Hz), 6.08,
6.07 (1H, each-d, J = 2.5Hz),
5.00-4.90 (1H, m), 4.20-4.07
(1H, m), 3.99, 3.95 (2H, each-
s), 2.84-2.39 (4H, m), 2.07-
1.78 (11H, m), 1.34, 1.33 (3H,
each-s), 1.27, (6H, d, J = 6.4H)
z), 1.14 (6H, d, J = 6.4 Hz)

Example 186 4-N- (methoxycarbonylmethyl) isopropylaminosalicylaldehyde 6
-Hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (4-N- (methoxy
carbonylmethyl) isopropyla
minosalicylaldehyde 6-hyd
roxy-2,5,7,8-tetramethylc
roman-2-acetylhydrazine) Yield: 45% (physical properties) Light purple amorphous solid PMR (DMSO-d ₆ , δ ppm): 11.33, 10.11 (1H, each-s), 11.3
2,11.08 (1H, each-s), 8.14,8.06 (1H, each-s), 7.41,7.36
(1H, each-s), 7.19,7.176 (1H, each-d, J = 8.8Hz), 6.22,6.1
8 (1H, each-dd, J = 2.0 and 8.8Hz), 6.085,6.05 (1H, each-dd
d, J = 2.0Hz), 4.21-4.08 (1H, m), 4.06,4.02 (2H, each-s), 3.
68 (3H, s), 2.84-2.39 (4H, m), 2.06-1.78 (11H, m), 1.34,1.3
3 (3H, each-s), 1.13 (6H, d, J = 6.4Hz)

Example 187 4-Isopropoxy-6-
Morpholinosalicylaldehyde 6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone (4-isopropoxy-6-morpholinosalicylaldehyde 6-
hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazo
ne) Yield: 86% (property) pale yellow crystals (mp.122-124 ℃) PMR (DMSO- d 6, δ ppm): 12.21,11.17 (1H, each-s), 11.50,
11.41 (1H, each-s), 8.52,8.41 (1H, each-s), 7.41,7.35 (1
H, each-s), 6.19,6.16 (1H, each-d, J = 2.0Hz), 6.12,6.10 (1
H, each-d, J = 2.0Hz), 4.64 (1H, sept, J = 6.3Hz), 3.80-3.74
(4H, m), 2.87-2.80 (4H, m), 2.63-2.41 (4H, m), 2.07-1.80 (1
1H, m), 1.34 (3H, s), 1.26 (6H, d, J = 6.3Hz) IR (KBr, cm ^-1 ): 3418,2974,2929,2857,1669,1653,1622,1
597,1567,1452,1373,1343,1333,1260,1213,1180,1160,1
113,1010,923,871,832

Example 188 5-Diethylaminosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone
inosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylch
roman-2-acetylhydrazone) Yield: 45% (Physical properties) Yellowish brown amorphous solid PMR (DMSO-d ₆ , δ ppm): 11.50, 11.28 (1H, each-s), 10.3
8,9.26 (1H, each-s), 8.29,8.20 (1H, each-s), 7.40,7.34 (1
H, each-s), 6.94-6.64 (3H, m), 3.27-3.15 (4H, m), 3.00-2.4
3 (4H, m), 2.07-1.79 (11H, m), 1.35,1.33 (3H, each-s), 1.06
-0.98 (6H, m)

Example 189 3,5-Dibromosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (3,5-dibromosa
licylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman
2-acetylhydrazone) Compound 6-hydroxy-2,5 synthesized in Reference Example 2.
7,8-tetramethylchroman-2-acetohydrazide
1.67 g (6 mmol) and 3,5-dibromosalicylaldehyde
Dissolve 1.68 g (6 mmol) in 30 ml of ethanol, and add
Stirred for hours. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (2.61 g, yield 80%). (Physical properties) pale yellow crystal (mp.222-228 ° C) PMR (DMSO-d ₆ , δ ppm): 12.60,10.73 (1H, each-s), 12.0
0,11.59 (1H, each-s), 8.27,8.13 (1H, each-s), 7.77,7.61
(2H, each-s), 7.41,7.27 (1H, each-s), 2.98-2.48 (4H, m),
2.06-1.79 (11H, m), 1.35 (3H, s) IR (KBr, cm ^-1 ): 3448,3198,3059,2970,2939,1666,1609,1
560,1444,1378,1345,1251,1195,1172,1085,926,859,73
8,687

Examples 190 to 192 The following compounds were prepared in substantially the same manner as in Example 189 except that 3,5-dibromosalicylaldehyde was replaced with another aldehyde compound. Example 190 3-methoxy-5-piperidinomethylsalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (3-metho
xy-5-piperidinomethylsalicylaldehyde 6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone) Yield: 68% (property) pale yellow crystals (mp.162-170 ℃) PMR (DMSO- d 6, δ ppm): 11.53,11.30 (1H, each- s), 10.6
2,9.34 (1H, each-s), 8.33,8.26 (1H, each-s), 7.41,7.37 (1
H, each-s), 7.03,7.01 (1H, each-d, J = 1.2Hz), 6.91,6.85 (1
H, each-d, J = 1.2Hz), 3.80,3.79 (3H, each-s), 3.32,3.30 (2
H, each-s), 2.93-2.42 (4H, m), 2.36-2.25 (4H, m), 2.05-1.7
8 (11H, m), 1.55-1.34 (6H, m), 1.35 (3H, s) IR (KBr, cm ^-1 ): 3433,3197,3054,2934,1661,1463,1373,1
262,1197,1162,1109,1087,1037,991,950,855,779,753,7
31

Example 191 3-Methoxy-5-morpholinomethylsalicylaldehyde 6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetylhydrazone (3-methoxy-5-morpholinomethylsalicylaldehyde
6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydr
azone) Yield: 82% (physical properties) Colorless crystals (mp. 146-150 ° C) PMR (DMSO-d ₆ , δ ppm): 11.53, 11.30 (1H, each-s), 10.6
3,9.37 (1H, each-s), 8.33,8.25 (1H, each-s), 7.41,7.36 (1
H, each-s), 7.05,7.03 (1H, each-d, J = 1.2Hz), 6.93,6.87 (1
H, each-d, J = 1.2Hz), 3.81,3.80 (3H, each-s), 3.60-3.53 (4
H, m), 3.37,3.34 (2H, each-s), 2.92-2.43 (4H, m), 2.37-2.3
0 (4H, m), 2.05-1.78 (11H, m), 1.34 (3H, s) IR (KBr, cm ^-1 ): 3427,3200,2931,1662,1557,1456,1368,1
262,1196,1163,1113,1087,1033,1004,914,866,794,752,
731

Example 192 5- (4-Ethyl-1-piperazinyl) methyl-3-methoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone (5- (4- ethyl-1-piperaziny
l) methyl-3-methoxysalicylaldehyde 6-hydroxy-2,5,7,
8-tetramethylchroman-2-acetylhydrazone) Yield: 73% (property) pale yellow crystals (mp.175-182 ℃) PMR (DMSO- d 6, δ ppm): 11.53,11.30 (1H, each-s), 10.6
4,9.36 (1H, each-s), 8.33,8.26 (1H, each-s), 7.41,7.39 (1
H, each-s), 7.02 (1H, d, J = 1.2Hz), 6.92,6.85 (1H, each-d, J
= 1.2Hz), 3.80,3.79 (3H, each-s), 3.36,3.33 (2H, each-s),
2.92-2.24 (12H, m), 2.05-1.78 (11H, m), 1.35 (3H, s), 1.00-
0.94 (3H, m) IR (KBr, cm ^-1 ): 3427,3196,2971,2933,2821,1680,1661,1
557,1463,1377,1263,1198,1162,1087,1009,803

Example 193 N ′-(2-hydroxy-
4-Isopropoxybenzyl) -3,5-di-t-butyl-4-hydroxybenzohydrazide (N '-(2-hydroxy-4
-isopropoxybenzyl) -3,5-di-t-butyl-4-hydroxybenzohy
drazide) 4-Isopropoxysalicylaldehyde 3,5-di-t
-Butyl-4-hydroxybenzoylhydrazone 3.98 g
30 ml of an aqueous solution of 12.0 g (mmol) of sodium borohydride was added dropwise to a 70 ml solution of (9.3 mmol) in methanol under ice-cooling.
After stirring under ice-cooling for an hour, the mixture was stirred at room temperature for 16 hours. The solvent was distilled off, water was added to the residue, the mixture was neutralized with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. Water was added to the crystals and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. Hexane in the residue:
Crystallization was performed by adding a mixed solvent of ethyl acetate = 2: 1, which was collected by filtration. Drying under reduced pressure gave 2.91 g (yield 73%) of the title compound.

(Physical properties) Colorless crystals (mp. 149-153 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.97 (1H, d, J = 5.4 Hz), 9.71 (1H,
s), 7.58 (2H, s), 7.38 (1H, s), 7.03 (1H, d, J = 8.3Hz), 6.345
(1H, d, J = 2.5Hz), 6.29 (1H, dd, J = 2.5 and 8.3Hz), 5.31 (1
H, q, J = 5.4Hz), 4.49 (1H, sept, J = 5.8Hz), 3.84 (2H, d, J = 5.4
Hz), 1.40 (18H, s), 1.24 (6H, d, J = 5.8) IR (KBr, cm ^-1 ): 3634,3284,2960,2872,1628,1586,1540,1
506,1430,1313,1240,1160,1120,1105,992,924,888,843,
800,698,635,

Example 194 N '-(4-diethylamino-2-hydroxybenzyl) -3,5-di-t-butyl-4-hydroxybenzohydrazide (N'-(4-diethylam
ino-2-hydroxybenzyl) -3,5-di-t-butyl-4-hydroxybenzo
hydrazide) 4-diethylaminosalicylaldehyde 3,5-di-t
-Butyl-4-hydroxybenzoylhydrazone 1.32 g
(3 mmol) and 0.754 g of sodium cyanoborohydride (12 m
mol) in THF (30 ml) at room temperature was added dropwise with p-toluenesulfonic acid in THF (10 ml). After stirring for 3 hours at room temperature,
The mixture was acidified with concentrated hydrochloric acid, and the solvent was distilled off. The residue was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. Ethyl acetate layer with water,
After washing with a saturated saline solution, it was dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the hexane: ethyl acetate = 1: 1 eluate was evaporated to give 0.23 g (yield 17%) of the title compound. (Physical properties) Light brown amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.96 (1H, brs), 9.33 (1H, s), 7.59
(2H, s), 7.35 (1H, brs), 6.90 (1H, d, J = 8.3Hz), 6.14 (1H, d, J
= 2.5Hz), 6.07 (1H, dd, J = 2.5 and 8.3Hz), 5.23-5.14 (1H,
m), 3.82-3.78 (2H, m), 3.26 (4H, q, J = 7.1Hz), 1.40 (18H, s),
1.07 (6H, t, J = 7.1Hz)

Example 195 N ′-[2-hydroxy-
4-N- (methoxycarbonylmethyl) cyclopentylaminobenzyl] -3,5-di-t-butyl-4-hydroxybenzohydrazide (N '-[2-hydroxy-4-N- (methoxyc
arbonylmethyl) cyclopentylaminobenzyl) -3,5-di-t-but
yl-4-hydroxybenzohydrazide) 4-N- (methoxycarbonylmethyl) cyclopentylaminosalicylaldehyde 3,5-di-t-butyl-4
1.06 g (2 mmol) of hydroxybenzoylhydrazone and 0.503 g (8 mmol) of sodium cyanoborohydride in THF20
The ml solution was adjusted to pH 4 with a 1N hydrochloric acid solution, stirred at room temperature for 3 hours, acidified with concentrated hydrochloric acid, and the solvent was distilled off. The residue was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and hexane: ethyl acetate = 1: 1.
The solvent was distilled off from the eluted portion to obtain 0.5 g (yield 47%) of the title compound.

(Physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.97 (1H, brs), 9.41 (1H, s), 7.58
(2H, s), 7.36 (1H, s), 6.92 (1H, d, J = 8.3Hz), 6.14 (1H, d, J =
2.5Hz), 6.09 (1H, dd, J = 2.5 and 8.3Hz), 5.25-5.17 (1H,
m), 4.12-4.00 (1H, m), 3.95 (2H, s), 3.65 (3H, s), 1.92-1.78
(2H, m), 1.71-1.35 (6H, m), 1.40 (18H, s)

Example 196 N '-(5-bromo-2-
(Hydroxy-3-methoxybenzyl) -3,5-di-t
-Butyl-4-hydroxybenzohydrazide (N '-(5-bro
mo-2-hydroxy-3-methoxybenzyl) -3,5-di-t-butyl-4-hyd
roxybenzohydrazide) 5-bromo-3-methoxysalicylaldehyde 3,5-
Di-t-butyl-4-hydroxybenzoylhydrazone
30 ml of an aqueous solution of 9.55 g (25 mmol) of sodium borohydride was added dropwise to a solution of 2.39 g (5 mmol) in 70 ml of methanol under ice-cooling.
After stirring for 1 hour under ice-cooling, the mixture was stirred at room temperature for 16 hours. The solvent was distilled off, water was added to the residue, acidified with concentrated hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was crystallized by adding a mixed solvent of hexane: ethyl acetate = 1: 1, and collected by filtration. Dry under reduced pressure, 1.83 g of the title compound (76% yield)
I got

(Physical properties) Colorless crystal (mp. 214-220 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.45 (1H, d, J = 6.0 Hz), 9.35 (1H,
s), 7.56 (2H, s), 7.36 (1H, s), 7.03-6.98 (2H, m), 5.46 (1H,
q, J = 6.0Hz), 3.92 (2H, d, J = 6.0Hz), 3.80 (3H, s), 1.40 (18H,
s) IR (KBr, cm ^-1 ): 3627,3293,3268,2956,1628,1600,1581,1
538,1486,1272,1239,1161,1119,1095,996,874,837,747,
699,654

Example 197 N '-(3,5-dibromo-2-hydroxybenzyl) -3,5-di-t-butyl-4-hydroxybenzohydrazide (N'-(3,5-dibromo-2
-hydroxybenzyl) -3,5-di-t-butyl-4-hydroxybenzohydra
zide) 3,5-dibromosalicylaldehyde 3,5-di-t-
1.56 g of butyl-4-hydroxybenzoylhydrazone (2.
961 mmol) in THF (50 ml) was added with sodium triacetoxyborohydride (2.51 g, 11.84 mmol), and the mixture was stirred at room temperature for 17 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and dried over magnesium sulfate.
The solvent was distilled off. After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Drying under reduced pressure gave 1.32 g (yield 84%) of the title compound. (Physical properties) Colorless crystal (mp.244-246 ° C) PMR (DMSO-d ₆ , δ ppm): 11.14 (1H, brs), 10.19 (1H, s), 7.
60 (3H, s), 7.44 (1H, brs), 7.35 (1H, s), 5.72 (1H, brs), 4.02
(2H, s), 1.40 (18H, s) IR (KBr, cm ^-1 ): 3618,3294,3239,2959,1631,1599,1530,1
458,1432,1362,1342,1313,1276,1238,1155,1120,1089,1
026,989,956,899,858,771,685

Example 198 N′-pyridoxyl-3,
5-di-t-butyl-4-hydroxybenzohydrazide
(N'-pyridoxyl-3,5-di-t-butyl-4-hydroxybenzohydrazi
de) Pyridoxal 3,5-di-t-butyl-4-hydroxybenzoylhydrazone 2.25 g (5 mmol) in 50 ml of THF was added to 3.71 g (17.5 g) of sodium triacetoxyborohydride.
mmol) and stirred at room temperature for 17 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue and extracted with ethyl acetate. After washing the ethyl acetate layer with water and saturated saline,
After drying over magnesium sulfate, the solvent was distilled off. The precipitated crystals were collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to give the title compound (1.62 g, yield 78%).

(Physical properties) Colorless crystal (mp. 243-247 ° C.) PMR (DMSO-d ₆ , δ ppm): 10.52 (1H, brs), 10.19 (1H, s), 7.
86 (1H, s), 7.61 (2H, brs), 7.45 (1H, brs), 5.62-5.55 (1H,
m), 5.08 (1H, t, J = 5.0Hz), 4.49 (2H, d, J = 5.0Hz), 4.09 (2H,
d, J = 5.6Hz), 2.36 (3H, s), 1.41 (18H, s) IR (KBr, cm ^-1 ): 3311,3284,3107,2962,1637,1601,1567,1
433,1418,1361,1326,1302,1255,1237,1115,1097,1019,8
96,768,707

Example 199 N′-pyridoxyl-3,
5-di-t-butyl-4-hydroxybenzohydrazide hydrochloride (N'-pyridoxyl-3,5-di-t-butyl-4-hydroxybenz
ohydrazide hydrochloride) To a solution of 1.77 g (4.26 mmol) of the compound synthesized in Example 198 in 20 ml of methanol was added 1.27 ml of a 4N hydrochloric acid-ethyl acetate solution, and the mixture was stirred at room temperature, and then ethyl acetate was added. The precipitated crystals were collected by filtration and dried under reduced pressure to give 1.83 g of the title compound (yield
95%). (Physical Properties) colorless crystals (mp.210-233 (dec) ℃) PMR (DMSO-d 6, δ ppm): 10.37 (1H, brs), 8.13 (1H, s), 7.6
1 (2H, s), 7.50 (1H, s), 4.69 (2H, s), 4.22 (2H, s), 2.60 (3H,
s), 1.40 (18H, s) IR (KBr, cm ^-1 ): 3623,3265,2957,2710,1638,1627,1600,1
469,1432,1391,1314,1242,1159,1120,1097,1014,887,85
5,766,742

Example 200 N '-(2-hydroxy-
3-methoxybenzyl) -3,5-di-t-butyl-4
-Hydroxybenzohydrazide (N '-(2-hydroxy-3-metho
xybenzyl) -3,5-di-t-butyl-4-hydroxybenzohydrazide) sodium triacetoxyborohydride in a solution of 3.98 g (10 mmol) of o-vanillin 3,5-di-t-butyl-4-hydroxybenzoylhydrazone in 40 ml of THF 4.24g (20mmo
l) was added and the mixture was stirred at room temperature for 17 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue and extracted with chloroform. After washing the chloroform layer with water and saturated saline,
After drying over magnesium sulfate, the solvent was distilled off. After dissolving the residue in ethyl acetate, isopropyl ether was added for crystallization, and the crystals were collected by filtration. Dry under reduced pressure to give the title compound
3.32 g (81% yield) was obtained.

(Physical properties) Colorless crystal (mp.185-188 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.99 (1H, d, J = 5.8 Hz), 9.10 (1H,
s), 7.58 (2H, s), 7.38 (1H, brs), 6.86 (1H, dd, J = 1.0 and 8.
0Hz), 6.82 (1H, dd, J = 1.0 and 8.0Hz), 6.71 (1H, t, J = 8.0H
z), 5.45-5.38 (1H, m), 3.94 (2H, d, J = 6.3Hz), 3.78 (3H, s),
1.39 (18H, s) IR (KBr, cm ^-1 ): 3626,3274,2954,2872,1633,1600,1589,1
525,1481,1430,1391,1361,1348,1311,1273,1239,1162,1
120,1083,1027,991,956,889,841,772,732,697,634

Example 201 N '-(2-hydroxy-
3-methoxybenzyl) -3,5-di-t-butyl-4
-Hydroxybenzohydrazide methanesulfonate
(N '-(2-hydroxy-3-methoxybenzyl) -3,5-di-t-butyl-4-h
ydroxybenzohydrazide methanesulfonate) A solution of 0.2 g (0.5 mmol) of the compound synthesized in Example 200, 2 ml of ethyl acetate and 58 mg (0.6 mmol) of methanesulfonic acid was stirred at room temperature for 1 hour. The solvent was distilled off, and the precipitated crystals were collected by filtration from a mixed solvent of hexane: ethyl acetate = 2: 1. Drying under reduced pressure gave 196 mg (79% yield) of the title compound. (Physical properties) Colorless crystal (mp. 205-207 ° C (dec)) PMR (DMSO-d ₆ , δ ppm): 11.20 (1H, b
rs), 7.68 (1H, s), 7.59 (2H,
s), 7.00 (1H, dd, J = 1.5 and)
8.0 Hz), 6.93 (1H, dd, J = 1.5 a)
nd 8.0 Hz), 6.80 (1H, dd, J = 8.
0 and 8.0 Hz), 4.29 (2H, s),
3.82 (3H, s), 2.33 (3H, s), 1.4
0 (18H, s) IR (KBr, cm ^-1 ): 3589, 3423, 2
960, 1667, 1600, 1560, 1494, 1
439, 1390, 1328, 1276, 1242, 1
205, 1157, 1044, 972, 925, 88
9,774,733,554,534

Example 202 N '-(2-hydroxy-
3-methoxybenzyl) -3,5-di-t-butyl-4
-Hydroxythiobenzohydrazide (N '-(2-hy
droxy-3-methoxybenzyl) -3,
5-di-butyl-4-hydroxythithi
Obenzohydrazide 3,5-di-t-butyl-4-hydroxythiobenzohydrazide 560 mg (2 mmol), o-vanillin 304 mg (2 mmol)
To a solution of 20 ml of 1,2-dichloroethane and 1,2-dichloroethane, 636 mg (3 mmol) of sodium triacetoxyborohydride was added, followed by stirring at room temperature for 17 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, the hexane: ethyl acetate = 2: 1 eluted portion was evaporated, and the residue was subjected to hexane: ethyl acetate = 4: 4.
Crystallization was carried out by adding the mixed solvent of No. 1 and it was collected by filtration. Drying under reduced pressure gave 260 mg (31% yield) of the title compound.

(Physical properties) Light yellow crystal (mp.183-186 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.82-11.74 (1H, m), 8.83 (1H, br)
s), 7.45 (2H, s), 7.37 (1H, brs), 7.02-6.94 (1H, m), 6.88 (2
H, d, J = 7.8Hz), 6.72 (1H, t, J = 7.8Hz), 4.12 (2H, d, J = 6.8H
z), 3.78 (3H, s), 1.39 (18H, s) IR (KBr, cm ^-1 ): 3562,3412,3189,2956,1593,1480,1423,1
348,1279,1222,1110,1088,1007,890,841,782,714

Example 203 N′-pyridoxyl-3,
5-di-t-butyl-4-hydroxythiobenzohydrazide (N'-pyridoxyl-3,5-di-t-butyl-4-hydroxythiobenz
ohydrazide) 3,5-di-t-butyl-4-hydroxythiobenzohydrazide 0.84 g (3 mmol), pyridoxal 0.61 g (3 mmo
l), 1,2-dichloroethane (20 ml) and THF (20 ml) were added to sodium triacetoxyborohydride (1.90 g, 9 ml).
mol) and the mixture was stirred at room temperature for 48 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and chloroform:
The solvent was distilled off from the eluted portion of methanol = 10: 1. After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Dry under reduced pressure to give 0.4 g of the title compound (yield 31
%).

(Physical properties) Colorless crystals (mp. 190-192 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.72 (1H, brs), 9.24 (1H, brs),
7.90 (1H, s), 7.49 (2H, s), 7.39 (1H, s), 7.01 (1H, brs), 5.24
(1H, brs), 4.60 (2H, s), 4.25 (2H, s), 2.37 (3H, s), 1.39 (18
H, s) IR (KBr, cm ^-1 ): 3417,3176,2957,1430,1360,1223,1155,1
120,1033,1017,888

Example 204 N '-(2-hydroxy-
3-methoxybenzyl) -3,5-diisopropyl-4
-Hydroxybenzohydrazide (N '-(2-hydroxy-3-metho
xybenzyl) -3,5-diisopropyl-4-hydroxybenzohydrazide) 2.78 g (7.5 mmol) of o-vanillin 3,5-diisopropyl-4-hydroxybenzoylhydrazone in THF 100 ml
4.24 g of sodium triacetoxyborohydride (20
mmol) and stirred at room temperature for 17 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Dry under reduced pressure to give the title compound (2.65 g, yield 95).
%).

(Physical properties) Light purple crystal (mp. 170-171 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.97 (1H, d, J = 6.3 Hz), 9.13 (1H,
s), 8.58 (1H, brs), 7.52 (2H, s), 6.86 (1H, dd, J = 1.0 and 6.
8Hz), 6.82 (1H, dd, J = 1.0 and 6.8Hz), 6.71 (1H, t, J = 6.8H
z), 5.41 (1H, q, J = 6.3Hz), 3.95 (2H, d, J = 6.3Hz), 3.79 (3H,
s), 3.29 (2H, sept, J = 6.8Hz), 1.17 (12H, d, J = 6.8Hz) IR (KBr, cm- ¹ ): 3439,3294,2964,1631,1587,1468,1441,1
308,1266,1242,1127,1160,1075,770,732

Example 205 N '-(2-hydroxy-
3-methoxybenzyl) -3,5-diisopropyl-4
-Hydroxybenzohydrazide methanesulfonate
(N '-(2-hydroxy-3-methoxybenzyl) -3,5-diisopropyl-4-
(Hydroxybenzohydrazide methanesulfonate) A solution of 1.49 g (4 mmol) of the compound synthesized in Example 204, 30 ml of ethyl acetate and 0.39 g (4 mmol) of methanesulfonic acid was stirred at room temperature for 1 hour. The solvent was distilled off, and the precipitated crystals were collected by filtration from a mixed solvent of hexane: ethyl acetate = 2: 1.
Drying under reduced pressure gave 1.40 g (yield 75%) of the title compound.

(Physical properties) Colorless crystal (mp. 180-185 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.21 (1H, brs), 8.93 (1H, brs),
7.52 (2H, s), 7.01 (1H, d, J = 7.8Hz), 6.93 (1H, d, J = 7.8Hz),
6.80 (1H, t, J = 7.8Hz), 4.31 (2H, s), 3.82 (3H, s), 3.32 (2H, s
ept, J = 6.8Hz), 2.33 (3H, s), 1.17 (12H, d, J = 6.8Hz) IR (KBr, cm ^-1 ): 3452,2964,1670,1603,1493,1468,1441,1
383,1314,1276,1194,1150,1048,931,775,733

Example 206 N'-pyridoxyl-3,
5-diisopropyl-4-hydroxybenzohydrazide hydrochloride (N'-pyridoxyl-3,5-diisopropyl-4-hydroxyben
zohydrazide hydrochloride) Pyridoxal 3,5-diisopropyl-4-hydroxybenzoylhydrazone 2.89 g (7.5 mmol) of THF 100m
l 8.48 g of sodium triacetoxyborohydride in solution
(40 mmol) was added and the mixture was stirred at room temperature for 17 hours. The solvent was distilled off, water was added to the residue, and the mixture was acidified with concentrated hydrochloric acid, and then chloroform was added. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (2.65 g, yield 83%). (Physical properties) pale yellow crystal (mp.175-213 ° C) PMR (DMSO-d ₆ , δ ppm): 10.38 (1H, s), 8.74 (1H, brs), 8.13
(1H, s), 7.55 (2H, s), 4.69 (2H, s), 4.23 (2H, s), 3.32 (2H, se
pt, J = 6.8Hz), 2.60 (3H, s), 1.18 (12H, d, J = 6.8Hz) IR (KBr, cm ^-1 ): 3223,3082,2963,2870,1619,1554,1540,1
468,1431,1408,1389,1312,1295,1214,1200,1149,1052,1
017,909,858,774

Example 207 N ′-(2,5-dihydroxy-3,4-dimethoxy-6-methylbenzyl)-
3,5-di-t-butyl-4-hydroxybenzohydrazide (N '-(2,5-dihydroxy-3,4-dimethoxy-6-methylbenzy
l) -3,5-di-t-butyl-4-hydroxybenzohydrazide) 2,5-dihydroxy-3,4-dimethoxy-6-methylbenzaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone 2.09 g (4.56 mmol) in THF
Add 50 ml sodium triacetoxyborohydride solution
3.86 g (18.24 mmol) was added, and the mixture was stirred at room temperature for 17 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue and extracted with chloroform. The chloroform layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the hexane: ethyl acetate = 1: 1 eluate was distilled off.
After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Dry under reduced pressure to give the title compound 0.5
3 g (yield 25%) was obtained.

(Physical properties) Pale orange crystal (mp. 190-192 ° C.) PMR (DMSO-d ₆ , δ ppm): 10.15 (1H, d, J)
= 6.0 Hz), 8.72 (1H, s), 7.97 (1
H, s), 7.60 (2H, s), 7.38 (1H,
s), 5.12 (1H, q, J = 6.0 Hz), 3.9
1 (2H, d, J = 6.0 Hz), 3.74 (3H,
s), 3.73 (3H, s), 2.17 (3H, s),
1.40 (18H, s) IR (KBr, cm ^-1 ): 3418, 3076, 2
955,1642,1468,1428,1313,1
240, 1120, 1098, 1073, 1025, 9
66,915,888

Example 208 N '-(2-hydroxy-
3-methoxy-5-piperidinomethylbenzyl) -3,
5-di-t-butyl-4-hydroxybenzohydrazide (N '-(2-hydroxy-3-methyoxy-
5-piperidinomethylbenzyl)
-3,5-di-t-butyl-4-hydroxy
Benzohydrazide) To a solution of 2.76 g (5.57 mmol) of 3-methoxy-5-piperidinomethylsalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone in 100 ml of THF was added 4.72 g of sodium triacetoxyborohydride. (22.28 mmol)
Was added and stirred at room temperature for 17 hours. After neutralization with saturated aqueous sodium bicarbonate,
The solvent was distilled off. Water was added to the residue and extracted with chloroform. The chloroform layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and chloroform:
The eluted part of methanol = 9: 1 was distilled off. After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Drying under reduced pressure gave 1.50 g (yield 54%) of the title compound.

(Physical properties) Light yellow crystal (mp. 115-118 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.97 (1H, d, J = 5.0 Hz), 8.96 (1H, s),
7.57 (2H, s), 7.36 (1H, s), 6.76 (1H, d, J = 1.2Hz), 6.70 (1H,
d, J = 1.2Hz), 5.42-5.35 (1H, m), 3.91 (2H, d, J = 5.4Hz), 3.77
(3H, s), 3.27 (2H, s), 2.29-2.20 (4H, m), 1.46-1.30 (6H, m),
1.39 (18H, s) IR (KBr, cm ^-1 ): 3636,3292,2936,1632,1601,1538,1497,1
454,1455,1430,1391,1366,1342,1299,1238,1159,1119,1
097,1039,992,862

Example 209 N ′-(2-hydroxy-
3-methoxy-5-morpholinomethylbenzyl) -3,
5-di-t-butyl-4-hydroxybenzohydrazide
(N '-(2-hydroxy-3-methoxy-5-morpholinomethylbenzyl)
-3,5-di-t-butyl-4-hydroxybenzohydrazide) 3-methoxy-5-morpholinomethylsalicylaldehyde 3,5-di-t-butyl-4-hydroxybenzoylhydrazone 1.16 g (2.33 mmol) in THF 50 ml Into, 1.98 g (9.32 mmol) of sodium triacetoxyborohydride
Was added and stirred at room temperature for 17 hours. After neutralization with saturated aqueous sodium bicarbonate,
The solvent was distilled off. Water was added to the residue and extracted with chloroform. The chloroform layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and chloroform:
The eluted part of methanol = 9: 1 was distilled off. After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Drying under reduced pressure gave 1.0 g (yield 85%) of the title compound.

(Physical properties) Colorless crystals (mp. 116-120 ° C.) IR (KBr, cm ⁻¹ ): 3627,3292,2955,1632,1601,1538,1498,1
455,1430,1392,1349,1330,1298,1238,1154,1116,1070,1
035,1009,910,889,865,795

Example 210 N '-[5- (4-Ethyl-1-piperazinyl) methyl-2-hydroxy-3-methoxybenzyl] -3,5-di-t-butyl-4-hydroxybenzohydrazide (N '-[5- (4-ethyl-1-piperaziny
l) methyl-2-hydroxy-3-methoxybenzyl] -3,5-di-t-butyl
-4-hydroxybenzohydrazide) 5- (4-ethyl-1-piperazinyl) methyl-3-methoxysalicylaldehyde 3,5-di-t-butyl-4
To a solution of 2.25 g (4.3 mmol) of -hydroxybenzoylhydrazone in 50 ml of THF was added 3.64 g (17.2 mmol) of sodium triacetoxyborohydride and the mixture was stirred at room temperature for 17 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue and extracted with chloroform. Chloroform layer with water,
After washing with a saturated saline solution, it was dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the chloroform: methanol = 10: 1 eluted portion was distilled off. After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Drying under reduced pressure gave 0.96 g (42% yield) of the title compound.

(Physical properties) Colorless crystal (mp. 119-125 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.97 (1H, d, J = 5.8 Hz), 8.98 (1H, s),
7.57 (2H, s), 7.37 (1H, brs), 6.76 (1H, d, J = 1.2Hz), 6.70 (1
H, d, J = 1.2Hz), 5.40 (1H, q, J = 5.8Hz), 3.91 (2H, d, J = 5.8H
z), 3.77 (3H, s), 3.30 (2H, s), 2.40-2.10 (10H, m), 1.39 (18
H, s), 0.95 (3H, t, J = 7.1Hz) IR (KBr, cm ^-1 ): 3294,2954,2875,2814,1634,1601,1498,1
430,1392,1359,1344,1301,1238,1162,1121,1097,1013,9
41,889,858,801,695

Example 211 N ′-(2-hydroxy-
3-methoxybenzyl) -6-hydroxy-2,5
7,8-tetramethylchroman-2-acetohydrazide
(N '-(2-hydroxy-3-methoxybenzyl) -6-hydroxy-2,5,7,8-
tetramethylchroman-2-acetohydrazide) o-vanillin 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone 2.06 g (5 mmo
To a solution of l) in 50 ml of methanol was added dropwise 20 ml of an aqueous solution of 6.19 g (mmol) of sodium borohydride under ice-cooling, and the mixture was further stirred for 1 hour under ice-cooling, followed by stirring at room temperature for 16 hours. The solvent was distilled off, water was added to the residue, and the mixture was neutralized with concentrated hydrochloric acid. Ethyl acetate was added, the insolubles were collected by filtration, and the mixture was washed with water and ethyl acetate. Drying under reduced pressure gave 1.62 g (78% yield) of the title compound.

(Physical properties) Colorless crystal (mp. 178-180 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.40 (1H, d, J =
5.9 Hz), 8.98 (1 H, s), 7.36 (1
H, s), 6.84 (1H, dd, J = 1.5 and
7.8 Hz), 6.78 (1H, dd, J = 1.5)
and 7.8 Hz), 6.69 (1H, dd, J =
7.8 and 7.8 Hz), 5.32 (1H, q,
J = 5.9 Hz), 3.91-3.79 (2H, m),
3.77 (3H, s), 2.61-2.40 (2H,
m), 2.33 (1H, d, J = 13.2 Hz);
23 (1H, d, J = 13.2 Hz), 2.04 (3
H, s), 2.01 (3H, s), 1.99 (3H,
s), 1.93-1.84 (1H, m), 1.76-
1.67 (1H, m), 1.27 (3H, s) IR (KBr, cm ^-1 ): 3483,3265,3
225, 3080, 2939, 1634, 1555, 1
480, 1441, 1378, 1335, 1281, 1
258,1229,1201,1184,1091,1
070, 1010, 943, 928, 858, 775,
735,597

Example 212 N ′-(2-hydroxy-
4-isopropoxybenzyl) -6-hydroxy-2,
5,7,8-Tetramethylchroman-2-acetohydrazide (N ′-(2-hydroxy-4-isopro
(oxybenzyl) -6-hydroxy-2,
5,7,8-tetramethylchroman-
2-acetohydrazide) 4-isopropoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone 9.00 g of sodium borohydride in a 60 ml methanol solution of 3.00 g (6.8 mmol) of methanol (mmol) aqueous solution 20
After stirring for 1 hour under ice-cooling, the mixture was
Stirred for hours. The solvent was distilled off, water was added to the residue, acidified with concentrated hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Dry under reduced pressure, 2.33 g of the title compound (77% yield)
I got

(Physical properties) Colorless crystals (mp. 157-162 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.61 (1H, s), 9.40 (1H, d, J = 6.3 Hz),
7.37 (1H, s), 6.98 (1H, d, J = 8.3Hz), 6.315 (1H, d, J = 2.5Hz),
6.27 (1H, dd, J = 2.5 and 8.3Hz), 5.23 (1H, q, J = 6.3Hz), 4.4
7 (1H, sept, J = 5.9Hz), 3.81-3.69 (2H, m), 2.60-2.40 (2H,
m), 2.33 (1H, d, J = 13.2 Hz), 2.22 (1H, d, J = 13.2 Hz), 2.04 (3
H, s), 2.01 (3H, s), 1.96 (3H, s), 1.92-1.82 (1H, m), 1.76-1.
66 (1H, m), 1.26 (3H, s), 1.23 (6H, d, J = 5.9Hz)

Example 213 N ′-[2-hydroxy-
4-N- (isopropoxycarbonylmethyl) isopropylaminobenzyl] -6-hydroxy-2,5,7,
8-tetramethylchroman-2-acetohydrazide (N'-
[2-hydroxy-4-N- (isopropoxycarbonylmethyl) isopropyl
aminobenzyl] -6-hydroxy-2,5,7,8-tetramethylchroman-
2-acetohydrazide)) 4-N- (isopropoxycarbonylmethyl) isopropylaminosalicylaldehyde 6-hydroxy-2,
To a solution of 1.5 g (2.93 mmol) of 5,7,8-tetramethylchroman-2-acetylhydrazone in 50 ml of methanol was added dropwise 20 ml of an aqueous solution of 4.5 g (118 mmol) of sodium borohydride under ice-cooling, and further ice-cooled for 1 hour. After stirring, the mixture was stirred at room temperature for 16 hours. The solvent was distilled off, water was added to the residue, acidified with concentrated hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the hexane: ethyl acetate = 1: 1 eluate was distilled off to give 0.30 g (yield: 20%) of the title compound as a pale pink amorphous solid.

(Physical properties) Pale pink amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.39 (1H, d, J = 5.5 Hz), 9.32 (1H, s),
7.37 (1H, s), 6.86 (1H, d, J = 8.8Hz), 6.06 (1H, d, J = 2.5Hz),
6.00 (1H, dd, J = 2.5 and 8.8Hz), 5.13 (1H, q, J = 5.5Hz), 4.9
3 (1H, sept, J = 6.0Hz), 4.00 (1H, sept, J = 6.6Hz), 3.85 (2H,
s), 3.77-3.65 (2H, m), 2.60-2.40 (2H, m), 2.33 (1H, d, J = 13.
7Hz), 2.23 (1H, d, J = 13.7Hz), 2.04 (3H, s), 2.01 (3H, s), 1.9
6 (3H, s), 1.94-1.84 (1H, m), 1.76-1.67 (1H, m), 1.28 (3H, m
s), 1.20 (6H, d, J = 6.0Hz), 1.11 (6H, d, J = 6.6Hz)

Example 214 N ′-[2-hydroxy-
4-N- (methoxycarbonylmethyl) cyclopentylaminobenzyl] -6-hydroxy-2,5,7,8-
Tetramethylchroman-2-acetohydrazide (N '-[2-h
ydroxy-4-N- (methoxycarbonylmethyl) cyclopentylamino
benzyl] -6-hydroxy-2,5,7,8-tetramethylchroman-2-ace
tohydrazide)) 4-N- (methoxycarbonylmethyl) cyclopentylaminosalicylaldehyde 6-hydroxy-2,5,
2.4 g (4.48 mmol) of 7,8-tetramethylchroman-2-acetylhydrazone and sodium cyanoborohydride
A solution of 1.13 g (17.92 mmol) in 30 ml of THF was adjusted to pH 4 with a 1N hydrochloric acid solution and stirred at room temperature for 6 hours. The mixture was acidified with concentrated hydrochloric acid, and the solvent was distilled off. The residue was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off.
The residue was subjected to silica gel column chromatography, and the eluted portion of hexane: ethyl acetate = 1: 2 was distilled off to obtain 0.3 g (yield: 12%) of the title compound as a pale orange amorphous solid.

(Physical properties) Pale orange amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.39 (1H, d, J = 5.0 Hz), 9.31 (1H, s),
7.36 (1H, s), 6.87 (1H, d, J = 8.3Hz), 6.116 (1H, d, J = 2.5Hz),
6.07 (1H, dd, J = 2.5 and 8.3Hz), 5.13 (1H, q, J = 5.0Hz), 4.1
1-4.00 (1H, m), 3.94 (2H, s), 3.77-3.66 (2H, m), 3.65 (3H,
s), 2.60-2.42 (2H, m), 2.33 (1H, d, J = 13.5Hz), 2.23 (1H, d, J
= 13.5Hz), 2.04 (3H, s), 2.01 (3H, s), 1.97 (3H, s), 1.94-1.3
8 (10H, m), 1.28 (3H, s)

Example 215 N ′-(5-bromo-2-
(Hydroxy-3-methoxybenzyl) -6-hydroxy-2,5,7,8-tetramethylchroman-2-acetohydrazide (N '-(5-bromo-2-hydroxy-3-methoxybenzyl)-
6-hydroxy-2,5,7,8-tetramethylchroman-2-acetohydraz
ide) 5-Bromo-3-methoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-
To a solution of 2.46 g (5 mmol) of acetylhydrazone in 50 ml of 1,2-dichloroethane were added 2.12 g (10 mmol) of sodium triacetoxyborohydride and 50 ml of THF, and the mixture was stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. The residue was dissolved in 300 ml of ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Dry under reduced pressure to give the title compound 1.7
0 g (yield 69%) was obtained.

(Physical properties) Light yellowish brown solid (mp. 103-107 ° C.) PMR (DMSO-d ₆ , δ ppm): 9.38 (1H, d, J = 6.0 Hz), 9.20 (1H, s),
7.36 (1H, s), 6.99 (2H, s), 5.40 (1H, q, J = 6.0Hz), 3.90-3.77
(5H, m), 2.60-2.40 (2H, m), 2.32 (1H, d, J = 13.5Hz), 2.21 (1
H, d, J = 13.5Hz), 2.04 (3H, s), 2.01 (3H, s), 1.95 (3H, s), 1.9
1-1.83 (1H, m), 1.75-1.65 (1H, m), 1.26 (3H, s) IR (KBr, cm ^-1 ): 3287,2934,1645,1538,1489,1378,1354,1
296,1232,1087,922,853,832,749,573

Example 216 N ′-(3,5-dibromo-2-hydroxybenzyl) -6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetohydrazide (N '-(3,5-dibromo-2-hydroxybenzyl) -6-hydroxy-2,
5,7,8-tetramethylchroman-2-acetohydrazide) 3,5-dibromosalicylaldehyde 6-hydroxy-
To a solution of 1.6 g (2.98 mmol) of 2,5,7,8-tetramethylchroman-2-acetylhydrazone in 50 ml of THF was added 2.52 g (11.92 mmol) of sodium triacetoxyborohydride and the mixture was stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and hexane: ethyl acetate =
The 1: 1 eluate was distilled off to give 1.45 g (yield 90%) of the title compound as a colorless amorphous solid.

(Physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 10.80 (1H, brs), 9.63 (1H, s), 7.60-
7.55 (1H, m), 7.40-7.30 (2H, m), 5.71 (1H, brs), 3.98-3.89
(2H, m) 2.57-2.40 (2H, m), 2.35 (1H, d, J = 14.0Hz), 2.25 (1H,
d, J = 14.0Hz), 2.04 (3H, s), 2.01 (3H, s), 1.95 (3H, s), 1.96-
1.84 (1H, m), 1.77-1.68 (1H, m), 1.28 (3H, s) IR (KBr, cm ^-1 ): 3296,2927,1660,1538,1459,1378,1339,1
255,1154,1086,1059,1035,1007,920,858,685

Example 217 N ′-(2-hydroxy-
4-isopropoxy-6-morpholinobenzyl) -6
Hydroxy-2,5,7,8-tetramethylchroman-
2-acetohydrazide (N '-(2-hydroxy-4-isopropoxy-6-
morpholinobenzyl) -6-hydroxy-2,5,7,8-tetramethylchr
oman-2-acetohydrazide) 4-isopropoxy-6-morpholinosalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone 2.86 g (5.47 mmol) of 1,
To a solution of 2-dichloroethane (50 ml) was added sodium triacetoxyborohydride (4.64 g, 21.88 mmol), and the mixture was stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. Ethyl acetate layer with water,
After washing with a saturated saline solution, it was dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the hexane: ethyl acetate = 1: 1: 1 eluate was distilled off to give 0.2 g of the title compound as a pale yellow amorphous solid (yield 7
%).

(Physical properties) Light yellow amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.51 (1H, s), 9.39 (1H, s), 7.38 (1H,
s), 6.00 (1H, s), 5.96 (1H, s), 5.45-5.30 (1H, m), 4.92 (1H, s
ept, J = 5.8Hz), 3.85-3.70 (2H, m), 3.10-2.95 (4H, m), 2.62-
2.40 (2H, m), 2.32 (1H, d, J = 13.2Hz), 2.23 (1H, d, J = 13.2H
z), 2.04 (3H, s), 2.02 (3H, s), 1.97 (3H, s), 1.94-1.84 (1H,
m), 1.77-1.67 (1H, m), 1.65-1.40 (6H, m), 1.27 (3H, s), 1.24
(6H, d, J = 5.8Hz)

Example 218 N ′-(2-hydroxy-
4,6-diisopropoxybenzyl) -6-hydroxy-2,5,7,8-tetramethylchroman-2-acetohydrazide (N '-(2-hydroxy-4,6-diisopropoxybenzyl) -6
-hydroxy-2,5,7,8-tetramethylchroman-2-acetohydrazi
ne) 4,6-diisopropoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-
To a solution of 2.49 g (5 mmol) of acetylhydrazone in 50 ml of THF was added 4.22 g (20 mmo) of sodium triacetoxyborohydride.
l) was added and the mixture was stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the hexane: ethyl acetate = 1: 1 eluate was distilled off to give 0.61 g (yield: 24%) of the title compound as a pale yellow amorphous solid.

(Physical properties) Pale yellow amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.75 (1H, s), 9.39 (1H, s), 7.37 (1H,
s), 5.97 (2H, s), 5.35 (1H, brs), 4.52-4.42 (2H, m), 3.82-3.
78 (2H, m), 2.62-2.40 (2H, m), 2.32 (1H, d, J = 13.2Hz), 2.23
(1H, d, J = 13.2Hz), 2.04 (3H, s), 2.01 (3H, s), 1.97 (3H, s),
1.94-1.84 (1H, m), 1.77-1.67 (1H, m), 1.27 (3H, s), 1.25 (6
(H, d, J = 5.8Hz), 1.23 (6H, d, J = 5.8Hz)

Example 219 N′-pyridoxyl-6
Hydroxy-2,5,7,8-tetramethylchroman-
2-acetohydrazide (N'-pyridoxyl-6-hydroxy-2,5,7,
8-tetramethylchroman-2-acetohydrazide) pyridoxal 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone 2.20 g (5 mm
ol) in 50 ml of THF was added 3.18 g (15 mmol) of sodium triacetoxyborohydride and stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. After dissolving the residue in ethyl acetate, hexane was added for crystallization, and the crystals were collected by filtration. Drying under reduced pressure gave 1.64 g (yield 76%) of the title compound.

(Physical properties) Colorless crystals (mp. 163-165 ° C.) PMR (DMSO-d ₆ , δ ppm): 10.42 (1H, s),
9.62 (1H, d, J = 4.0 Hz), 7.83 (1
H, s), 7.37 (1H, s), 5.65 (1H, d
d, J = 4.0 and 4.0 Hz), 5.04 (1
H, t, J = 5.5 Hz), 4.43 (2H, d, J =
4.0 Hz), 4.05 to 4.00 (2H, m), 2.
59-2.42 (2H, m), 2.36 (1H, d, J
= 13.5 Hz), 2.33 (3H, s), 2.26
(1H, d, J = 13.5 Hz), 2.04 (3H,
s), 2.01 (3H, s), 1.95 (3H, s),
1.95-1.86 (1H, m), 1.80-1.69
(1H, m), 1.28 (3H, s) IR (KBr, cm ^-1 ): 3273, 2931, ¹
646,1581,1456,1416,1379,1
288,1257,1236,1229,1086,1
061, 1033, 1007, 973, 934, 92
2,899,777

Example 220 N '-(2-hydroxy-
4,6-dimethoxybenzyl) -6-hydroxy-2,
5,7,8-Tetramethylchroman-2-acetohydrazide (N '-(2-hydroxy-4,6-dime
thoxybenzyl) -6-hydroxy-2,
5,7,8-tetramethylchroman-
2-acetohydrazide) 4.95 g (4 mmol) of 4,6-dimethoxysalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone was added to 3.39 g of sodium triacetoxyborohydride in 50 ml of THF. 16 mmol) and stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue and extracted with chloroform.
The chloroform layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the hexane: ethyl acetate = 1: 1 eluate was distilled off to give 0.64 g (yield 33%) of the title compound as a pale yellow amorphous solid.

(Physical properties) Pale yellow amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.82 (1H, s), 9.41 (1H, d, J = 5.8 Hz),
7.37 (1H, s), 6.01 (2H, s), 5.30 (1H, q, J = 5.8Hz), 3.80 (2H,
d, J = 5.8Hz), 3.71 (3H, s), 3.68 (3H, s), 2.60-2.40 (2H, m),
2.32 (1H, d, J = 13.5Hz), 2.21 (1H, d, J = 13.5Hz), 2.04 (3H,
s), 2.01 (3H, s), 1.96 (3H, s), 1.92-1.83 (1H, m), 1.78-1.65
(1H, m), 1.26 (3H, s) IR (KBr, cm ^-1 ): 3296,2934,1624,1593,1513,1456,1379,1
338,1255,1214,1202,1149,1109,1086,1057,1008,922,81
6

Example 221 N ′-(2,5-dihydroxy-3,4-dimethoxy-6-methylbenzyl) -6
-Hydroxy-2,5,7,8-tetramethylchroman-2-acetohydrazide (N '-(2,5-dihydroxy-3,4-dimet
hoxy-6-methylbenzyl) -6-hydroxy-2,5,7,8-tetramethyl
chroman-2-acetohydrazide) 2,5-dihydroxy-3,4-dimethoxy-6-methylbenzaldehyde 6-hydroxy-2,5,7,8-
Tetramethylchroman-2-acetylhydrazone 2.36 g
To a solution of (5 mmol) in 30 ml of THF was added 4.24 g (20 mmol) of sodium triacetoxyborohydride and the mixture was stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the eluted portion of hexane: ethyl acetate = 1: 2 was distilled off to obtain 1.56 g (66% yield) of a pale brown amorphous solid. After dissolving in ethyl acetate, 4N hydrochloric acid-ethyl acetate was added and hydrochloric acid chloride was performed to obtain 1.18 g (yield 70%) of pale yellow crystals.

(Physical properties) Light yellow crystal (mp. 139-144 ° C.) PMR (DMSO-d ₆ , δ ppm): 11.19 (1H, brs), 8.30 (1H, brs), 4.2
5-4.18 (2H, m), 3.76 (3H, s), 3.73 (3H, s), 2.58-2.40 (4H, m
m), 2.15 (3H, s), 2.05 (3H, s), 2.03 (3H, s), 1.98 (3H, s), 1.9
2-1.84 (1H, m), 1.80-1.70 (1H, m), 1.30 (3H, s) IR (KBr, cm- ¹ ): 3419,2938,1693,1496,1471,1434,1391,1
259,1192,1124,1100,1086,1060,1006,957,921,852

Example 222 N '-(2-hydroxy-
3-methoxy-5-piperidinomethylbenzyl) -6
Hydroxy-2,5,7,8-tetramethylchroman-
2-acetohydrazide (N '-(2-hydroxy-3-methoxy-5-pip
eridinomethylbenzyl) -6-hydroxy-2,5,7,8-tetramethyl
chroman-2-acetohydrazine) 3-methoxy-5-piperidinomethylsalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone 4.14 g (8.12 mmol) of TH
F 100 ml solution in sodium triacetoxyborohydride
6.89 g (32.48 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the chloroform: methanol = 9: 1 eluted portion was distilled off to obtain 0.93 g (yield: 22%) of the title compound as a pale yellow amorphous solid.

(Physical Properties) Light yellow amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.46 (1H, s), 9.17 (1H, brs), 7.39 (1
H, s), 7.01 (1H, s), 6.91 (1H, s), 5.34 (1H, brs), 3.85 (2H,
s), 3.80 (3H, s), 3.34 (2H, s), 2.60-2.40 (2H, m), 2.33 (1H,
d, J = 13.5Hz), 2.23 (1H, d, J = 13.5Hz), 2.04 (3H, s), 2.01 (3
H, s), 1.95 (3H, s), 1.92-1.82 (1H, m), 1.77-1.30 (7H, m), 1.
25 (3H, s) IR (KBr, cm ^-1 ): 3280,2935,1651,1500,1455,1378,1343,1
299,1254,1164,1088,1060,1037,935,856,753

Example 223 N ′-(2-hydroxy-
3-methoxy-5-morpholinomethylbenzyl) -6
Hydroxy-2,5,7,8-tetramethylchroman-
2-acetohydrazide (N '-(2-hydroxy-3-methoxy-5-mor
pholinomethylbenzyl) -6-hydroxy-2,5,7,8-tetramethyl
chroman-2-acetohydrazide) 3-methoxy-5-morpholinomethylsalicylaldehyde 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetylhydrazone 2.30 g (4.5 mmol) of TH
F 100 ml solution in sodium triacetoxyborohydride
3.8 g (18 mmol) was added and the mixture was stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the chloroform: methanol = 10: 1 eluted portion was distilled off to give 1.85 g (yield 80%) of the title compound as a colorless amorphous solid.

(Physical properties) Colorless amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.40 (1H, d, J = 5.8 Hz), 8.92 (1H, s),
7.38 (1H, s), 6.78 (1H, s), 6.70 (1H, s), 5.30 (1H, q, J = 5.8H
z), 3.88-3.78 (2H, m), 3.77 (3H, s), 3.57-3.52 (4H, m), 3.31
(2H, s), 2.60-2.40 (2H, m), 2.35-2.20 (6H, m), 2.04 (3H, s),
2.01 (3H, s), 1.95 (3H, s), 1.92-1.84 (1H, m), 1.76-1.67 (1
H, m), 1.26 (3H, s) IR (KBr, cm ^-1 ): 3388,2931,2863,1651,1499,1456,1378,1
349,1294,1254,1158,1114,1088,1035,1008,918,865,796

Example 224 N ′-[5- (4-Ethyl-1-piperazinyl) methyl-2-hydroxy-3-methoxybenzyl] -6-hydroxy-2,5,7,8-
Tetramethylchroman-2-acetohydrazide (N '-[5-
(4-ethyl-1-piperazino) methyl-2-hydroxy-3-methoxybe
nzyl] -6-hydroxy-2,5,7,8-tetramethylchroman-2-aceto
hydrazide) 5- (4-ethyl-1-piperazinyl) methyl-3-methoxysalicylaldehyde 6-hydroxy-2,5,
To a solution of 1.57 g (2.91 mmol) of 7,8-tetramethylchroman-2-acetylhydrazone in 100 ml of THF was added 2.47 g (11.64 mmol) of sodium triacetoxyborohydride and the mixture was stirred at room temperature for 15 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and chloroform: methanol = 1.
The 0: 1 eluted portion was distilled off to give the title compound as an amorphous solid.
1.10 g (70% yield) was obtained.

(Physical properties) Amorphous solid PMR (DMSO-d ₆ , δ ppm): 9.40 (1H, d, J = 5.8 Hz), 8.91 (1H, s),
7.39 (1H, s), 6.76 (1H, d, J = 1.2Hz), 6.67 (1H, d, J = 1.2Hz),
5.35-5.28 (1H, m), 3.87-3.75 (2H, m), 3.76 (3H, s), 3.30 (2
H, s), 2.60-2.18 (14H, m), 2.04 (3H, s), 2.01 (3H, s), 1.95 (3
H, s), 1.92-1.83 (1H, m), 1.76-1.66 (1H, m), 1.26 (3H, s), 0.
96 (3H, t, J = 7.1Hz) IR (KBr, cm ^-1 ): 3390,2934,2819,1651,1498,1455,1378,1
345,1297,1254,1162,1088,1012,939,922,855,801

Example 225 N′-pyridoxyl-2-
Hydroxy-5-methoxybenzohydrazide (N'-pyrido
xyl-2-hydroxy-5-methoxybenzohydrazide hydrochlorid
e) 2-hydroxy-5-methoxybenzohydrazide 1.82 g
(10 mmol) and 2.03 g (10 mmol) of pyridoxal were dissolved in 50 ml of ethanol, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, the residue was dissolved in THF (100 ml), and sodium triacetoxyborohydride (8.44 g, 40 mmol) was added, followed by stirring at room temperature for 17 hours. The solvent was distilled off, the residue was subjected to silica gel column chromatography, and chloroform: methanol =
The 10: 1 eluted portion was distilled off to obtain a pale yellow amorphous solid. After dissolving the residue in methanol, 4N hydrochloric acid-ethyl acetate solution was added to cause crystallization, and the crystals were collected by filtration. Dried under reduced pressure,
1.28 g (yield 35%) of the title compound were obtained.

(Physical properties) Yellow powder (mp. 190-200 ° C. (dec)) PMR (DMSO-d ₆ , δ ppm): 11.40 (1H, brs), 10.56 (1H, brs), 8.
15 (1H, s), 7.38 (1H, d, J = 3.4Hz), 7.02 (1H, dd, J = 3.4 and
8.8Hz), 6.90 (1H, d, J = 8.8Hz), 4.72 (2H, s), 4.30 (2H, s), 3.
73 (3H, s), 2.62 (3H, s) IR (KBr, cm ^-1 ): 3251,3048,2941,1607,1548,1491,1466,1
421,1335,1291,1207,1153,1079,1035,938,868,842,835,
759 Acylhydrazone derivative (I) obtained in the above example
Are shown in Tables 1 to 8.

[0379]

[Table 1]

[0380]

[0381]

[0382]

[0383]

[Table 2]

[0384]

[0385]

[0386]

[Table 3]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[Table 4]

[0395]

[Table 5]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[Table 6]

[0403]

[Table 7]

[0404]

[Table 8]

[0405]

Test Example 1 Acylhydrazone derivative (I)
The Maillard reaction inhibitory effect of the acylhydrazone derivative (I) was confirmed by the screening system described below.
Bovine serum albumin and glucose were dissolved in 0.5 M sodium phosphate buffer (pH 7.4) to a concentration of 5 μg / ml and 1 M, respectively. Furthermore, after dissolving the acylhydrazone derivative (I) shown in Table 9, the cells were cultured at 37 ° C. for 2 days. After the culture, the amount of AGE in the culture solution was quantified by a non-competitive ELISA method using an anti-AGE antibody (Wako Pure Chemical Industries, Ltd.). Non-competitive EL
The ISA method is based on the method of Horiuchi et al. (Horiuchi S. et al., J.
Biol. Chem., 266, 7329-7332 (1991)).

The inhibition rate of the acylhydrazone derivative (I) was calculated by the following equation. Inhibition ratio (%) = [[(Ca-Cb)-(Da-Db)] / (Ca-Cb)] × 100 Ca: AG in (bovine serum albumin + glucose) culture solution
E amount Cb: AGE amount in (bovine serum albumin) culture solution Da: (bovine serum albumin + glucose + acylhydrazone derivative (I)) AGE amount in culture solution Db: (bovine serum albumin + acylhydrazone derivative (I)) ) Amount of AGE in culture solution AG of acylhydrazone derivative (I) at various concentrations
E The IC50 value was determined by examining the production inhibitory effect. In addition, the same test was performed for aminoguanidine as a control. Table 9 shows the results.

[0408]

[Table 9]

Test Example 2 Acylhydrazone derivative (I)
The anti-oxidative action of the acylhydrazone derivative (I) was confirmed by a screening system for examining the inhibitory effect of lipid peroxide production as described below. Rat kidney tissue was washed with 50 mM cold potassium phosphate buffer containing 0.142 M sodium chloride (pH 7.
4) After homogenization in the mixture and centrifugation at 1000 × g for 10 minutes, the supernatant was used as rat kidney homogenate. 2mg / ml
The acylhydrazone derivative (I) shown in Table 10 was dissolved in 3 ml of the rat kidney homogenate at a concentration of 1 μM. After heating this solution at 37 ° C. for 15 minutes, 600 μl of a 35% perchloric acid aqueous solution was added, and centrifuged at 14000 × g for 10 minutes. The production amount of lipid peroxide was measured according to the TBA method.
That is, 1.5 ml of 0.5% aqueous solution of 2-thiobarbituric acid (TBA) was added to 3 ml of the obtained supernatant, and the mixture was heated at 100 ° C. for 15 minutes. After cooling the reaction solution, it was colorimetrically measured at 532 nm. A methanol solution of 1,1,3,3-tetraethoxypropane was used as a standard solution.

The inhibition rate of the acylhydrazone derivative (I) was calculated by the following equation. Inhibition rate (%) = [[(Ta-Tb)-(ta-tb)] / (Ta-Tb)] × 100 Ta: TBA value after heating rat kidney homogenate Tb: before heating rat kidney homogenate TBA value of ta: TBA value after heating (rat kidney homogenate + acylhydrazone derivative (I)) tb: TBA value before heating (rat kidney homogenate + acylhydrazone derivative (I)) A similar test was performed for guanidine (1 × 10 ⁻⁴ M). Table 10 shows the results.

[0411]

[Table 10]

Test Example 3 Acylhydrazone derivative (I)
The effect of diabetic nephropathy on the diabetic nephropathy was tested using the compound of Example 33. Diabetic rats were treated with male Wistar rats (6 weeks old) at 50 m of streptozotocin (STZ).
Rats having a blood glucose level of 200 mg / dl or more after 24 hours were prepared. The STZ diabetic rats were divided into two groups, and the test substance administration group (n
= 6), 100 mg / kg of the compound suspended in a 0.5% aqueous methylcellulose solution was administered to a diabetic control group (n
= 6), 5 ml of 0.5% aqueous methylcellulose solution
/ Kg. In addition, untreated rats of the same age and the same age were treated as normal control group (n = 6), and 5 ml / kg of 0.5% aqueous methylcellulose solution was administered. The administration method was gavage once a day for 3 weeks. Three weeks after administration, urinary albumin excretion was quantified by ELISA. The results are shown in FIG.

As shown in FIG. 1, urine albumin excretion was increased in the diabetic control group as compared with the normal control group. On the other hand, the test substance administration group was found to have an effect of suppressing urinary albumin excretion as compared with the diabetic control group. The inhibitory effect was 57% lower than that of the diabetic control group.

Test Example 4 Acute toxicity test A single oral administration toxicity test was carried out using the compound of Example 33. 0.5% in 3-4 male SD rats per group
The compound suspended in an aqueous methylcellulose solution was orally administered. The administration dose is 500 mg / kg, 1000 m
g / kg, 2000mg / kg, dose volume is 10ml
/ Kg. Observation of general symptoms and weight measurement,
An anatomical examination was performed 14 days after administration. As a result, no death due to medication was observed, and no change was observed in any of the general symptoms, changes in body weight, and anatomical examination.

Test Example 5 Ames Test “Guidelines for Test Methods for Drug Toxicity” (September 1, 1989)
One day, using the compound of Example 97, a reverse mutation test (Ames 'tes test (Ames' tes test)
t)). That is, the compound was added to four strains of Salmonela typhimurium and cultured, and then seeded on a medium, and the number of revertant colonies in the medium was observed. Regardless of the presence or absence of S9Mix (preparation of S9 fraction from rat liver enzymatically induced by phenobarbital and 6-benzoflavone), none of the bacterial species resulted in an increase in the number of revertant colonies. Therefore, the mutagenicity of the compound was determined to be negative.

[0416]

The acylhydrazone derivative (I) and the pharmaceutical composition thereof are useful as Maillard reaction inhibitors and anti-active oxidants, and are particularly effective for various complications of diabetes and diseases such as senile diseases.

[Brief description of the drawings]

FIG. 1 is a graph showing the amount of albumin excreted in urine.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/31 A61K 31/31 31/35 ADP 31/35 ADP 31/40 ADS 31/40 ADS 31/44 31/44 31 / 445 ABL 31/445 ABL 31/47 31/47 31/495 AGZ 31/495 AGZ 31/535 31/535 C07C 235/16 C07C 235/16 A 243/38 243/38 243/40 243/40 251/68 251/68 251/76 251/76 251/80 251/80 251/84 251/84 251/86 251/86 251/88 251/88 255/66 255/66 259/10 259/10 327/56 327 / 56 C07D 213/42 C07D 213/42 213/64 213/64 213/65 213/65 215/14 215/14 295/12 295/12 AZ 307/52 307/52 311/72 101 311/72 101 333 / 22 333/22 405/12 213 405/12 213 215 215 407/12 307 407/12 307 409/12 311 409/12 311 (72) Inventor Rie Shibayama 5-3 Tsurugaoka, Oimachi, Iruma-gun, Saitama Number 1 No. Nisshin Flour Milling Co., Ltd.

Claims (8)

[Claims] 1. The following formula (I): X—W—Y wherein X is the following formula (A): (In the formula, R ¹ and R ² are the same or different, and are C _1-4-
Represents an alkyl group, R ³ represents a hydrogen atom or a C _1-4 -alkyl group, and n ¹ represents 0 to 2. A group represented by the following formula (B): (Wherein, R ⁴ and R ⁵ are the same or different, and are C _1-4-
Represents an alkyl group, and R ⁶ represents a hydrogen atom or a C _1-4 -alkyl group. A group represented by the following formula (C): (Wherein R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and represent a C _1-4 -alkyl group, R ¹¹ represents a hydrogen atom or a C _1-4 -alkyl group, and n ² represents 0 to 3), or the following formula (D): (Wherein, R ²⁷ represents a C _1-4 -alkyl group, and R ²⁸ represents a hydrogen atom, a halogen atom, a hydroxyl group or a C _1-4 -alkoxy group); Group, thienyl group, pyrrolyl group, pyridyl group, 2-hydroxy-6
-Methylpyridin-3-yl group, C _1-4 -alkyl group,
The following formula (E): (Wherein, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, C _1-4-
Alkoxy, C _1-4 -alkyl-carbonyloxy, nitro, cyano, phenyl, morpholino,
A pyrrolidino group, a piperidino group, a piperazino group or an amino group (the nitrogen atom in the piperazino group or the amino group is a C _1-4 -alkyl group, a C _5-8 -cycloalkyl group and a C _5-8 -cycloalkyl group;
₁ selected from _1-4 -alkoxy-carbonylmethyl groups
Or it may be substituted by two groups. ) Or a nitrogen-containing heterocyclic-substituted methyl group, and R ¹² and R ¹³ , or R
¹⁵ and R ¹⁶ may together form a fused 6-membered ring. A group represented by the following formula (F): (Wherein, R ¹⁷ , R ¹⁸ and R ¹⁹ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group), a group represented by the following formula (G): (Wherein R ²⁰ and R ²¹ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group), or a group represented by the following formula (H): (Wherein, R ²² , R ²³ and R ²⁴ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group); W represents the following formula (J): 9 (Wherein R ²⁵ and R ²⁶ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group, and R ²⁶ is a trimethylene group in cooperation with R ¹⁶ in the above formula (E). And Z ¹ represents an oxygen atom or a sulfur atom.), A group represented by the following formula (K): (Wherein, Z ² represents an oxygen atom or a sulfur atom), a group represented by the following formula (L): (Wherein Z ³ and Z ⁴ are the same or different and each represent an oxygen atom or a sulfur atom), a group represented by the following formula (M): (Wherein, Z ⁵ represents an oxygen atom or a sulfur atom), a group represented by the following formula (N): (Wherein Z ⁶ and Z ⁷ are the same or different and each represent an oxygen atom or a sulfur atom), a group represented by the following formula (O): (Wherein, Z ⁸ and Z ⁹ are the same or different and each represent an oxygen atom or a sulfur atom), represented by the following formula (P): -CH = NN-CH- (P) Or a group represented by the following formula (Q): (In the formula, Z ¹⁰ represents an oxygen atom or a sulfur atom.) Or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The pharmaceutical composition according to claim 1, which is a Maillard reaction inhibitor. 3. The pharmaceutical composition according to claim 1, which is an antireactive oxygen drug. 4. The following formula (I ′): X—W—Y, wherein X is the following formula (A): (In the formula, R ¹ and R ² are the same or different, and are C _1-4-
Represents an alkyl group, R ³ represents a hydrogen atom or a C _1-4 -alkyl group, and n ¹ represents 0 to 2. And a group represented by the following formula (B): (Wherein, R ⁴ and R ⁵ are the same or different, and are C _1-4-
Represents an alkyl group, and R ⁶ represents a hydrogen atom or a C _1-4 -alkyl group. A group represented by the following formula (C): (Wherein R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and represent a C _1-4 -alkyl group, R ¹¹ represents a hydrogen atom or a C _1-4 -alkyl group, and n ² represents 0 to 3), or the following formula (D): (Wherein, R ²⁷ represents a C _1-4 -alkyl group, and R ²⁸ represents a hydrogen atom, a halogen atom, a hydroxyl group or a C _1-4 -alkoxy group); Group, thienyl group, pyrrolyl group, pyridyl group, 2-hydroxy-6
-Methylpyridin-3-yl group, C _1-4 -alkyl group,
The following formula (E): (Wherein, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, C _1-4-
Alkoxy, C _1-4 -alkyl-carbonyloxy, nitro, cyano, phenyl, morpholino,
A pyrrolidino group, a piperidino group, a piperazino group or an amino group (the nitrogen atom in the piperazino group or the amino group is a C _1-4 -alkyl group, a C _5-8 -cycloalkyl group and a C _5-8 -cycloalkyl group;
₁ selected from _1-4 -alkoxy-carbonylmethyl groups
Or it may be substituted by two groups. ) Or a nitrogen-containing heterocyclic-substituted methyl group, and R ¹² and R ¹³ , or R
¹⁵ and R ¹⁶ may together form a fused 6-membered ring. A group represented by the following formula (F): (Wherein R ¹⁷ , R ¹⁸ and R ¹⁹ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group), a group represented by the following formula (G): (Wherein R ²⁰ and R ²¹ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group) or a group represented by the following formula (H): (Wherein, R ²² , R ²³ and R ²⁴ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group); W represents the following formula (J): Embedded image (Wherein R ²⁵ and R ²⁶ are the same or different and each represent a hydrogen atom or a C _1-4 -alkyl group, and Z ¹ represents an oxygen atom or a sulfur atom); ): Embedded image (Wherein Z ² represents an oxygen atom or a sulfur atom), a group represented by the following formula (L): (Wherein Z ³ and Z ⁴ are the same or different and each represent an oxygen atom or a sulfur atom), a group represented by the following formula (M): (Wherein, Z ⁵ represents an oxygen atom or a sulfur atom), a group represented by the following formula (N): (Wherein Z ⁶ and Z ⁷ are the same or different and each represent an oxygen atom or a sulfur atom), a group represented by the following formula (O): (Wherein, Z ⁸ and Z ⁹ are the same or different and each represent an oxygen atom or a sulfur atom), a group represented by the following formula (P):-
CH = NN—CH— a group represented by (P) or the following formula (Q): (In the formula, Z ¹⁰ represents an oxygen atom or a sulfur atom.) Provided that X is 3,5-di-t-butyl-4
A hydroxyphenyl group, and Y is a phenyl group or 2
-Hydroxyphenyl group, and W is -CONH
Except when it is NHCO-. Or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 4, wherein in the formula (I ′), W is a group represented by the formula (J) or a pharmaceutically acceptable salt thereof. 6. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein in the formula (I ′), W is a group represented by the formula (K). 7. The compound according to claim 4, wherein in the formula (I ′), X is a group represented by the formula (A) or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 4, wherein X in the formula (I ′) is a group represented by the formula (C), or a pharmaceutically acceptable salt thereof.