JPH1087485A - Agent for suppressing death of nerve cell - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent exhibiting an effect to suppress the death of nerve cell and useful for the treatment of Alzheimer's disease, etc., by using a chromone derivative known as a pharmaceutical agent such as aldose reductase inhibitor. SOLUTION: This agent contains a chromone derivative of the formula (R<1> to R<4> are each H, OH, a 1-6C alkoxy, a 2-6C alkenyloxy, etc.; X is O atom, S atom, SO, etc.; R' is phenyl, an aralkyl or a heterocyclic group) or its pharmacologically permissible salt as an active component. The compound of the formula is e.g. 7-isopropoxy-2-[(4-isopropoxyphenyl)thio]-5,6-dimethoxy-4H- chromen-4-one. The active component is preferably administered at a daily rate of 30mg to 2g as the chromone derivative of the formula I in several divided doses. The agent is effective for the treatment of Alzheimer's disease, Down's syndrome, vascular dementia, Parkinson's disease, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a nerve cell death inhibitor which is a remedy for diseases caused by cell death of nerve cells.

[0002]

2. Description of the Related Art In recent years, neural tissue death and neurotrophic factors (N
The relationship with the Eurotropic Factor (NTF) has received attention. In other words, nerve cells are nerve growth factors (Nerv
When e Growth Factor (NGF) is no longer available (or lacks nerve growth factor), it has been confirmed that nerve cells develop some suicide mechanism and lead to cell death [Journal of Cell Biology] (Journal of Cell Biolog
y), 106, 829-844, 1988]. Also,
Recently, B.C.L-2 (B), an oncogene product, has been used as a biological substance that saves nerve cells from cell death by suppressing the expression of such suicide mechanisms.
cl-2) has been found [Science
nce), 258, 302-304, 1992].

[0003] To develop a medicament having an effect of rescuing nerve cell death induced by the inability to receive neurotrophic factors such as nerve growth factor (or lack of neurotrophic factor) (inhibiting nerve cell death). If such a compound can be used, it can be used for the treatment of many diseases, and the development of a compound having an inhibitory effect on nerve cell death has been desired. On the other hand, as a chromone derivative, the following formula (Ia):

[0004]

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[0005] (wherein, R ² and R ⁴ are the same or different, a hydroxyl group, C _1-6 - alkoxy groups, C _2-6 - represents an alkenyloxy group or an acyloxy group, R ³ is a hydrogen atom or a C _1-6 - alkoxy group, X is an oxygen atom, a sulfur atom, -SO-, SO ₂ - represents or -NH- and, R ⁵
Represents a substituted or unsubstituted phenyl group, aralkyl group or heterocyclic group. Is known and reported to be useful as a drug such as an aldose reductase inhibitor (for example, WO92 / 09594, WO9)
3/24477, JP-A-1-228914). However, there is no report that the chromone derivative represented by the formula (Ia) has a nerve cell death inhibitory effect.

[0006]

An object of the present invention is to provide a novel pharmaceutical use of a known or novel chromone derivative, that is, to provide a neuronal cell death inhibitor containing the chromone derivative as an active ingredient.

[0007]

According to the present invention, there is provided the following formula (I):

[0008]

Embedded image

(Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a hydroxyl group, a C _1-6 -alkoxy group, a C _2-6 -alkenyloxy group, an acyloxy group or X represents a substituted or unsubstituted C _1-6 -alkyl group;
Oxygen atom, sulfur atom, -SO-, SO ₂ - or -N
Represents H-, R ⁵ represents a substituted or unsubstituted phenyl group, an aralkyl group or a heterocyclic group. ) Or a pharmaceutically acceptable salt thereof as an active ingredient.

Examples of C _1-6 -alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
Examples include a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a 1-ethylpropyloxy group, and a hexyloxy group. C _2-6 - The alkenyloxy group, for example vinyloxy group, allyloxy group, prenyloxy group (3-methyl-2-butenyloxy group). Examples of the acyloxy group include an aliphatic acyloxy group having 2 to 6 carbon atoms such as an acetoxy group, a propionyloxy group, an isobutyryloxy group, a pivaloyloxy group, an acryloxy group and a methacryloxy group; a benzoyloxy group, anisoyloxy group, Toluoyloxy group,
An aromatic acyloxy group such as a 4- (4-methylpiperazinomethyl) benzoyloxy group is exemplified.

Examples of the C _1-6 -alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group,
Pentyl group, isopentyl group, 1-ethylpropyl group,
A hexyl group. The C _1-6 -alkyl group represented by R ¹ , R ² , R ³ or R ⁴ is a suitable substituent, preferably a halogen atom, an amino group, a hydroxyl group, a carboxyl group, a C _1-6 -alkoxy group. , An acyloxy group, a heterocyclic group (preferably a heterocyclic group containing a nitrogen atom, for example, a pyridyl group, a benzimidazolyl group, a benzthiazolyl group, a thiazolinyl group, a thiadiazolyl group, a 1-pyrrolidinyl group). The aralkyl group represented by R ⁵ includes, for example, a benzyl group and a phenethyl group, and the heterocyclic group is preferably a heterocyclic group containing a nitrogen atom, for example, a pyridyl group, a benzimidazolyl group,
A benzothiazolyl group, a thiazolinyl group, a thiadiazolyl group, and a 1-pyrrolidinyl group.

The phenyl group, aralkyl group or heterocyclic group represented by R ⁵ is a suitable substituent, preferably C _1-6-
Alkyl group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxyl group, a hydroxymethyl group, a methylenedioxy group, C _1-6 - alkoxy groups, C _2-6 - alkenyloxy groups, C _1-6 - alkoxy - Carbonyl group, tert-
Butyldimethylsilyloxy group, the acyloxy group,
Acyloxy groups derived from amino acids (glycyloxy group, β-
An aspartyloxy group), and the following formula (II): R ⁶ O— (where R ⁶ is a carboxy-C _1-6 -alkyl group, a carboxy-C _2-6 -alkenyl group, a C _1-6 -alkoxy- C _1-6 -alkyl group, C _1-6 -alkoxy-carbonyl group, C _1-6 -alkylthio-C _1-6 -alkyl group, C
_1-6 - alkylsulphinyl -C _1-6 - alkyl groups, C
_1-6 - alkylsulphonyl -C _1-6 - alkyl groups, C
_1-6 - alkylsulfonyl group, C _1-6 - alkyl - carbonyloxy -C _1-6 - alkyl group, C _1-6 - alkoxy - carbonyl -C _1-6 - alkyl group, C _1-6 - alkoxy - Carbonyl-C _2-6 -alkenyl group, having 3 to 3 carbon atoms
6 branched alkyl groups, C 2-6 aliphatic acyl groups, C _1-6 -alkoxy-carbonyl groups, substituted or unsubstituted carbamoyl groups, substituted or unsubstituted thiocarbamoyl groups, substituted or unsubstituted 1-piperidinylcarbonyl group, substituted or unsubstituted 1-pyrrolidinylcarbonyl group, substituted or unsubstituted 1-piperazinylcarbonyl group, substituted or unsubstituted morpholinocarbonyl group, substituted or unsubstituted benzene Sulfonyl group,
Alkenyl group having 2 to 6 carbon atoms, 2-acetoxy-2-methyl-propionyl group, a benzoyl group, C _1-6 - alkoxy - benzoyl, nitrobenzoyl group, acetoxymethyl benzoyl, aminobenzoyl group, morpholino-methylbenzoyl group, thiophene Represents a carbonyl group, a furoyl group, a pyridinecarbonyl group, a phenoxycarbonyl group or a diphenoxyphosphoryl group. ) May be substituted with at least one substituent selected from the groups represented by

A carboxy-C _1-6 -alkyl group represented by R ⁶ in the formula (II), a C _1-6 -alkoxy-C
_1-6 - alkyl group, C _1-6 - alkylthio -C _1-6 - alkyl group, C _1-6 - alkylsulphinyl -C _1-6 - alkyl group, C _1-6 - alkylsulphonyl -C _1-6 An alkyl group, a C _1-6 -alkylsulfonyl group, a C _1-6 -alkyl-carbonyloxy-C _1-6 -alkyl group and C
_1-6 - alkoxy - carbonyl -C _1-6 - in the alkyl group - the "C _1-6 alkyl" include methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group Tert-butyl group,
Pentyl group, isopentyl group, 1-ethylpropyl group,
A hexyl group.

A carboxy-C _2-6 -alkenyl group and C
“C _2-6 -alkenyl” in a _1-6 -alkoxy-carbonyl-C _2-6 -alkenyl group, and C _2-6
Examples of the alkenyl group include, for example, a vinyl group, an allyl group,
A prenyl group.

C _1-6 -alkoxy-C _1-6 -alkyl, C _1-6 -alkoxy-carbonyl, C _1-6 -alkoxy-carbonyl-C _1-6 -alkyl, C _1-6- Alkoxy-carbonyl-C _2-6 -alkenyl group, C _1-6
“C _1-6 -alkoxy” in —alkoxy-carbonyl group, C _1-6 -alkoxy-benzoyl group and C _1-6 -alkoxy-carbonyl group includes, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group , Butoxy, isobutoxy, sec-butoxy, tert-
Butoxy, pentyloxy, isopentyloxy, 1-ethylpropyloxy and hexyloxy groups.

[0016] C _1-6 - alkylthio -C _1-6 - in the alkyl group - as the "C _1-6 alkylthio", for example, methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec
-Butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, 1-ethylpropylthio group,
A hexylthio group. Examples of the branched alkyl group having 3 to 6 carbon atoms include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and 1-ethylpropyl. 2-6 carbon atoms
Examples of the aliphatic acyl group include an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, an acryloyl group, and a methacryloyl group.

[0017] As the substituted carbamoyl groups are, for example C _1-6 - alkyl group, a phenyl group, a pyridyl group, mono- or di-substituted carbamoyl groups are exemplified by piperidyl group, the C _1-6 - alkyl group , A phenyl group, a pyridyl group and a piperidyl group are a halogen atom such as a chlorine atom, a C _1-6 -alkoxy-carbonyl group, a C _1-6 -alkylthio group, a C _1-6 -alkoxy group, a C _1-6 -alkyl It may be substituted with at least one substituent selected from a group, a carboxy group, a hydroxyl group, a cyano group and a formyl group.

The substituted thiocarbamoyl group includes
For example, C _1-6 -alkyl group, phenyl group, pyridyl group,
A thiocarbamoyl group mono- or di-substituted with a piperidyl group; and the C _1-6 -alkyl group, phenyl group, pyridyl group and piperidyl group are a halogen atom such as a chlorine atom, a C _1-6 -alkoxy- Carbonyl group, C _1-6
It may be substituted with at least one substituent selected from -alkylthio, C _1-6 -alkoxy, C _1-6 -alkyl, carboxy, hydroxyl, cyano and formyl.

Examples of the substituted 1-piperidinylcarbonyl group include, for example, a mono-substituted hydroxyl group, a hydroxy-C _1-6 -alkyl group, a C _1-6 -alkoxy-C _1-6 -alkyl group and a carboxy group. And di-substituted 1-piperidinylcarbonyl groups. Examples of the substituted 1-pyrrolidinylcarbonyl group include a hydroxyl group and a hydroxy-
1 mono- or di-substituted C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl or carboxy.
-Pyrrolidinylcarbonyl group. Examples of the substituted 1-piperazinylcarbonyl group include mono- or di-substituted hydroxyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl, and carboxy groups. And a 1-piperazinylcarbonyl group. Examples of the substituted morpholinocarbonyl group include a hydroxyl group, a hydroxy-C _1-6 -alkyl group and a C _1-6
-Alkoxy-C _1-6 -alkyl groups and morpholinocarbonyl groups mono- or di-substituted by carboxy groups. Examples of the substituted or unsubstituted benzenesulfonyl group include a C _1-6 -alkyl group, a hydroxyl group, a hydroxy-C _1-6 -alkyl group, a C _1-6 -alkoxy-C _1-6
-A benzenesulfonyl group mono- or di-substituted by an alkyl group or a carboxy group.

Of the compounds represented by the above formula (I), R
A compound in which the phenyl group, aralkyl group or heterocyclic group represented by ⁵ is substituted with a group represented by the following formula (II): R ⁶ O— (wherein R ⁶ has the same meaning as described above) The medicinal substance is a compound in which a phenyl group, an aralkyl group or a heterocyclic group represented by R ⁵ in the formula (I) is substituted with a hydroxyl group, and the derivative has improved bioavailability of the medicinal substance. It is.

In view of the neuronal cell death inhibitory effect and bioavailability, R ⁶ in the above formula (II) is particularly preferably as follows. (1) methylthiomethyl group (2) ethoxycarbonyl group (3) N-ethylcarbamoyl group (4) N, N-dimethylcarbamoyl group (5) N- (2-hydroxyethyl) -N-methylcarbamoyl group The compound represented by 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,
Examples thereof include acid addition salts such as phosphate, sulfate, fumarate and maleate, and alkali metal salts such as sodium salt.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION Many of the compounds represented by the above formula (I) are known compounds and are described in WO 92/09594,
It can be produced according to the method described in WO93 / 24477 and JP-A-1-228914. On the other hand, among the compounds represented by the formula (I), a compound in which the phenyl group, aralkyl group or heterocyclic group represented by R ⁵ is substituted with a group represented by the formula (II) is a novel compound. A phenyl group represented by R ⁵ in the formula (I);
Compounds in which an aralkyl group or a heterocyclic group is substituted with a hydroxyl group, for example, 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H
The phenolic hydroxyl group of -chromen-4-one (5,6-dimethoxy-2- (4-hydroxyphenylthio) -7-isopropoxycyclomone described in Example 22 of WO92 / 09594) was converted into ether by a conventional method. It can be produced by esterification, esterification, carbonate esterification, carbamic acid esterification, thiocarbamic acid O-esterification, sulfonic acid esterification or phosphoric acid esterification.

When the substituent corresponding to R ⁶ contains a functional group involved in the above reaction, for example, a hydroxyl group or a carboxyl group in carbamic acid esterification, the functional group is protected with a suitable protecting group, and the carbamic acid is protected. After performing a reaction such as esterification, the protecting group is eliminated. Examples of the hydroxyl-protecting group include a tert-butyldimethylsilyl group, and examples of the carboxyl-protecting group include tert-butyldimethylsilyl.
-Butyl group. The product may be purified by a commonly used technique, for example, 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. Examples of elution solvents for column chromatography include chloroform, acetone, hexane, dichloromethane, ethyl acetate, and mixed solvents thereof.

The compound represented by the formula (I) and a pharmaceutically acceptable salt thereof (hereinafter, referred to as "chromone derivative (I)") have a neuronal cell death inhibitory effect and cannot receive a neurotrophic factor. (Or lack of neurotrophic factor)
Diseases attributed to neuronal cell death induced in some cases, such as Alzheimer's disease [Pro. N. A. S. (Pro.N.A.S.), 83, 9231-92
35, 1986], Down syndrome [Pro. N. A. S. (Pro.N.A.S.), 88, 1793-179.
7, 1991], vascular dementia [Journal of Neurosci., Vol. 11, No. 9,
2914-2919, 1991], Parkinson's disease [Nature, 350, 230-23]
2, 1991], amyotrophic lateral sclerosis [Ann. Neurol. 10, 499-50.
5,1981]. In addition, an acute toxicity test by oral administration of the chromone derivative (I) was performed using an ICR mouse, and no death occurred by oral administration of 1 g / kg. Thus, the chromone derivative (I) has extremely low toxicity and high safety.

The dosage and formulation of the chromone derivative (I) will be described below. The chromone derivative (I) can be administered to animals and humans as it is or together with conventional pharmaceutical carriers. 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 exhibit the intended effect as an oral preparation, it depends on the age, weight and degree of disease of the patient, but usually 30 mg to 2 g of the chromone derivative (I) is divided into several times a day for adults. Is 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. Specific examples are as follows.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol. [Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, low-substituted hydroxypropylcellulose.

[Surfactant] Sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate
80. [Lubricant] Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol. [Fluidity accelerator] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The chromone derivative (I) may be a suspension,
It can also be administered as an emulsion, syrup or elixir, and these various dosage forms may contain a flavoring agent and a coloring agent. In order to achieve the intended effect as a parenteral drug, it depends on the age, weight and degree of the disease of the patient, but is usually 0.1% to 600 mg per day as a chromone derivative (I) in adults by weight, Intravenous infusion, subcutaneous injection, and intramuscular injection are appropriate.

This parenteral preparation is produced according to a conventional method, and as a diluent, it is generally distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericide, a preservative and a stabilizer may be added. Also,
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.

[0031]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Production Examples and Examples, but the present invention is not limited thereto. Production Example 1 [4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] methyl pivalate pivaloyloxymethyl chloride 0.446 ml, NaI 464 m
g and acetone (10 ml) were stirred at room temperature overnight. Potassium carbonate
426 mg, 2-[(4-hydroxyphenyl) thio] -7
1.00 g of -isopropoxy-5,6-dimethoxy-4H-chromen-4-one was added, and the mixture was further stirred at room temperature for 5 hours.
Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to give 538.1 mg (yield) of the title compound.
42%).

¹ H-NMR (CDCl ₃ ) 7.55 (d, 8.8 Hz, 2H), 7.11
(d, 8.8Hz, 2H), 6.60 (s, 1H), 5.81 (s, 2H), 5.72 (s, 1H),
4.63 (hept, 5.9Hz, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 1.43
(d, 5.9Hz, 6H), 1.23 (s, 9H) FABMS 503 (MH ⁺ )

Production Example 2 7-Isopropoxy-2-
[(4-Isopropoxyphenyl) thio] -5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene -4-
ON 507.2 mg, isopropyl iodide 0.262 ml, potassium carbonate 362 mg, and DMF 5 ml were stirred at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain 554.4 mg (yield 98%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.48 (d, 8.8 Hz, 2H), 6.93
(d, 8.8Hz, 2H), 6.61 (s, 1H), 5.67 (s, 1H), 4.60 (m, 2H),
3.91 (s, 3H), 3.85 (s, 3H), 1.43 (d, 5.9Hz, 6H), 1.39 (d,
6.4Hz, 6H) EIMS 430 (M ⁺ ), 415,373

Production Example 3 2-[[4- (allyloxy)
Phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene- 4-
506.9 mg of ON, 0.227 ml of allyl bromide, 362 mg of potassium carbonate, and 5 ml of DMF were stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, flash column chromatography (hexane: ethyl acetate =
Purification by 3: 1) afforded 534.4 mg (95% yield) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.51 (d, 9.0 Hz, 2H), 6.98
(d, 9.0Hz, 2H), 6.61 (s, 1H), 6.16-5.98 (m, 1H), 5.66 (s,
1H), 5.44 (dd, 17.3Hz, 1.5Hz, 1H), 5.34 (dd, 10.5Hz, 1.5H
z, 1Hz), 4.60 (m, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 1.43
(d, 5.9Hz, 6H) EIMS 428 (M ⁺ ), 413,371

Production Example 4 Ethyl = [4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] acetate 2-[(4-hydroxyphenyl) Thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
521.1 mg of ON, 0.223 ml of ethyl bromoacetate, 370 mg of potassium carbonate, and 5.2 ml of DMF were stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 2: 1) to obtain 608.9 mg (yield: 96%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.53 (d, 8.8 Hz, 2H), 6.98
(d, 8.8Hz, 2H), 6.60 (s, 1H), 5.69 (s, 1H), 4.67 (s, 2H),
4.62 (hept, 6.4Hz, 1H), 4.30 (q, 6.8Hz, 2H), 3.91 (s, 3H),
3.84 (s, 3H), 1.43 (d, 6.4Hz, 6H), 1.32 (t, 6.8Hz, 3H) EIMS 474 (M ⁺ ), 459, 417

Production Example 5 Ethyl = (E) -3- [4-
[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy]
Acrylate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 510.4mg, Ethyl propionate 0.268ml, Triton B
(40% MeOH) 0.02 ml, THF 5.1 ml, and chloroform 6 ml were stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, it was purified by flash column chromatography (hexane: ethyl acetate = 3: 1),
523.4 mg (81% yield) of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) 7.80 (d, 12.2 Hz, 1H), 7.62
(d, 8.8Hz, 2H), 7.16 (d, 8.8Hz, 2H), 6.59 (s, 1H), 5.76 (s,
1H), 5.69 (d, 12.2Hz, 1H), 4.62 (hept, 5.9Hz, 1H), 4.22
(q, 6.8Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 1.43 (d, 5.9H
z, 6H), 1.31 (t, 6.8Hz, 3H) EIMS 486 (M ⁺ ), 471, 457

Production Example 6 [4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenoxy] acetic acid 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
767.1 mg of ON, 0.438 ml of t-butyl bromoacetate, 546 mg of potassium carbonate and 8 ml of DMF were stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1), and tert-butyl = [4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H).
-Chromen-2-yl) thio] phenoxy] acetate was obtained in an amount of 889.4 mg (89% yield). 889.4 mg of this compound, TFA 2.
3 ml of dichloromethane and 5 ml of dichloromethane were stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, recrystallization from ethanol gave 618.8 mg of the title compound.
(78% yield).

¹ H-NMR (CDCl ₃ ) 7.55 (d, 8.8 Hz, 2H), 7.07
(d, 8.8Hz, 2H), 6.67 (s, 1H), 5.72 (s, 1H), 4.65 (hept, 5.
9Hz, 1H), 4.56 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 1.45
(d, 5.9Hz, 6H) EIMS 446 (M ⁺ ), 431,389

Production Example 7 7-Isopropoxy-5,6-
Dimethoxy-2-[[4- (methoxymethoxy) phenyl] thio] -4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene -4-
N, N-diisopropylethylamine 0.4 ml (2.3 m3) in a solution of 500 mg (1.29 mmole) of dichloromethane in 5 ml of dichloromethane
mole) and chloromethyl methyl ether 0.15 ml (1.96
mmole) and stirred at room temperature for 16 hours. Further, N, N
-Diisopropylethylamine 0.2 ml and chloromethyl methyl ether 0.08 ml were added, and the mixture was stirred at room temperature for 4 hours.
Triethylamine was added, and the mixture was stirred at room temperature for 1 hour. Dichloromethane was added, and the mixture was washed with 2N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2), and recrystallized from ethyl acetate to give 310 mg (0.72 mmole, 5
6%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.51 (d, J = 8.9 Hz, 2H),
7.11 (d, J = 8.9 Hz, 2H), 6.62 (s, 1H), 5.67 (s, 1
H), 5.23 (s, 2H) 4.62 (hept, J = 6.1 Hz, 1H), 3.91
(s, 3H), 3.85 (s, 3H), 3.52 (s, 3H), 1.44 (d, J = 6.
1 Hz, 6H) EIMS 432 (M ⁺ ), 417, 375

Production Example 8 7-Isopropoxy-5,6-
Dimethoxy-2-[[4-[(methylthio) methoxy]
Phenyl] thio] -4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
In a solution of 500 mg (1.29 mmole) of DMF in 10 ml of 60% NaH 7
After adding 8 mg (1.9 mmole) and stirring at 0 ° C for 5 minutes, 0.14 ml (1.7 mmole) of chloromethylmethylsulfide was added and the mixture was stirred at 0 ° C for 24 hours. Water was added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2-2: 1) to give the title compound
0.48 g (1.07 mmole, 83%) was obtained as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.53 (d, J = 8.9 Hz, 2H),
7.04 (d, J = 8.9 Hz, 2H), 6.61 (s, 1H), 5.68 (s, 1
H), 5.19 (s, 2H) 4.62 (hept, J = 6.1 Hz, 1H), 3.91
(s, 3H), 3.85 (s, 3H), 2.29 (s, 3H), 1.43 (d, J = 6.
1 Hz, 6H) EIMS 448 (M ⁺ ), 433

Production Example 9 3- [4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] acrylic acid 2-[(4-hydroxyphenyl) ) Thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
On 600 mg of dichloromethane in 6 ml solution of propiolic acid
0.3 ml of tert-butyl and 0.03 ml of triton B (40% MeOH) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and after extraction with dichloromethane, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2), and tert-butyl = 3- [4-[(7
-Isopropoxy-5,6-dimethoxy-4-oxo-
610 mg (76% yield) of 4H-chromen-2-yl) thio] phenoxy] acrylate was obtained. 610 mg of this compound
To a solution of (1.18 mmole) in 5 ml of dichloromethane was added 1 ml (13 mmole) of trifluoroacetic acid, and the mixture was stirred at room temperature for 5 hours.
Water was added, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the crystals were collected by filtration and recrystallized from ethyl acetate to give 278 mg (0.61 mmol) of the title compound.
e, 51%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.87 (d, J = 12.1 Hz, 1
H), 7.63 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2
H), 6.59 (s, 1H) 5.79 (s, 1H), 5.68 (d, J = 12.1 Hz,
1H), 4.92 (hept, J = 6.0 Hz, 1H), 3.92 (s, 3H), 3.8
5 (s, 3H) 1.43 (d, J = 6.0 Hz, 6H) EIMS 458 (M ⁺ )

Production Example 10 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[(phenoxycarbonyl) oxy] phenyl] thio] -4H-chromen-4-
On 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
500 mg of ON, 0.194 ml of phenyl chloroformate, 0.357 ml of triethylamine and 5 ml of dichloromethane were stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (56%).
5 mg (86% yield) was obtained.

¹ H-NMR (CDCl ₃ ) 7.65 (d, 8.8 Hz, 2H), 7.50-
7.22 (m, 7H), 6.57 (s, 1H), 5.89 (s, 1H), 4.61 (hept, 6.1H
z, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 1.42 (d, 6.1Hz, 6H) EIMS 508 (M ⁺ ), 493, 451

Production Example 11 2-[[4-[(isobutoxycarbonyl) oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
On 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
520.6 mg, isobutyl chloroformate 0.208 ml, triethylamine 0.371 ml, dichloromethane 5.2 ml at room temperature.
Stirred for hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (615.4 mg, yield 94%).

¹ H-NMR (CDCl ₃ ) 7.61 (d, 8.8 Hz, 2H), 7.30
(d, 8.8Hz, 2H), 6.58 (s, 1H), 5.87 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 4.07 (d, 6.8Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H),
2.07 (m, 1H), 1.43 (d, 6.1 Hz, 6H), 1.02 (d, 6.8 Hz, 6H) EIMS 488 (M ⁺ ), 473, 431, 331

Production Example 12 2-[[4-[(ethoxycarbonyl) oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) ) Thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
211 mg, ethyl chloroformate 0.062 ml, triethylamine 0.378 ml and dichloromethane 5 ml were stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, recrystallized from ethanol to give the title compound 229m
g (yield 92%) was obtained.

¹ H-NMR (CDCl ₃ ) 7.61 (d, 8.6 Hz, 2H), 7.29
(d, 8.6Hz, 2H), 6.58 (s, 1H), 5.87 (s, 1H) 4.62 (m, 1H),
4.35 (q, 7.1Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 1.42 (d,
5.9Hz, 6H), 1.41 (t, 7.1Hz, 3H) EIMS 460 (M ⁺ ), 445, 431, 403

Production Example 13 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[(isopropoxycarbonyl) oxy] phenyl] thio] -4H-chromene-4
-One 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 503.9mg, isopropyl chlorocarbonate 238mg
, 0.27 ml of triethylamine and 5 ml of dichloromethane were stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound.
594.3 mg (96% yield) were obtained.

¹ H-NMR (CDCl ₃ ) 7.61 (d, 8.7 Hz, 2H), 7.30
(d, 8.7Hz, 2H), 6.58 (s, 1H), 5.87 (s, 1H), 5.00 (hept, 6.
3Hz, 1H), 4.62 (hept, 6.1Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3
H), 1.43 (d, 6.1Hz, 6H), 1.40 (d, 6.3Hz, 6H) EIMS 474 (M ⁺ ), 459,417,373,331

Production Example 14 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = acetate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 177mg, acetic anhydride 0.429ml, triethylamine 0.63
4 ml of dichloromethane and 5 ml of dichloromethane were stirred at room temperature for 0.5 hour.
Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the crystals were recrystallized from hexane-ethyl acetate to give the title compound 18
8 mg (96% yield) was obtained.

¹ H-NMR (CDCl ₃ ) 7.61 (d, 8.5 Hz, 2H), 7.20
(d, 8.5Hz, 2H), 6.59 (s, 1H), 5.85 (s, 1H), 4.62 (m, 1H),
3.92 (s, 3H), 3.85 (s, 3H), 2.33 (s, 3H), 1.43 (d, 5.9Hz, 6
H) EIMS 430 (M ⁺ ), 415, 373, 331

Production Example 15 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = nicotinate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 203 mg, nicotinic acid chloride hydrochloride 122 mg, triethylamine 0.364 ml, dichloromethane 5 ml at room temperature.
Stir for 5 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was recrystallized from ethyl acetate to give the title compound (240 mg, yield 93%).

¹ H-NMR (CDCl ₃ ) 9.41 (dd, 1.7 Hz, 0.6 Hz, 1
H), 8.89 (dd, 4.9Hz, 1.7Hz, 1H), 8.47 (dt, 8.1Hz, 1.7Hz, 1
H), 7.68 (d, 9.0Hz, 2H), 7.50 (ddd, 8.1Hz, 4.9Hz, 0.6Hz, 1
H), 7.36 (d, 9.0Hz, 2H), 6.60 (s, 1H), 5.89 (s, 1H), 4.63
(m, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 1.43 (d, 6.1Hz, 6H) EIMS 493 (M ⁺ ), 478, 450, 436

Production Example 16 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = pivalate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
210 mg, pivaloyl chloride 0.08 ml, triethylamine 0.377 ml, and dichloromethane 5 ml were stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, recrystallization from hexane-ethyl acetate gave 210 mg (82% yield) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.60 (d, 8.8 Hz, 2H), 7.17
(d, 8.8Hz, 2H), 6.58 (s, 1H), 5.83 (s, 1H), 4.62 (m, 1H),
3.92 (s, 3H), 3.85 (s, 3H), 1.43 (d, 6.1Hz, 6H), 1.37 (s, 9
H) FABMS 473 (MH ⁺ )

Production Example 17 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = benzoate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
On 500 mg, benzoyl chloride 0.18 ml, triethylamine 0.357 ml and dichloromethane 5 ml were stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound in 55%.
8.6 mg (88% yield) was obtained.

¹ H-NMR (CDCl ₃ ) 8.22 (m, 2H), 7.67 (m, 1H),
7.66 (d, 8.8Hz, 2H), 7.54 (m, 2H), 7.34 (d, 8.8Hz, 2H),
6.60 (s, 1H), 5.89 (s, 1H), 4.61 (hept, 5.9Hz, 1H), 3.93
(s, 3H), 3.85 (s, 3H), 1.43 (d, 5.9Hz, 6H) EIMS 492 (M ⁺ ), 477,435

Production Example 18 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = isobutyrate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
508.2 mg, isobutyryl chloride 0.166 ml, triethylamine 0.362 ml, dichloromethane 5 ml at room temperature.
Stirred for hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain 542.9 mg (yield 90%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.60 (d, 8.8 Hz, 2H), 7.20
(d, 8.8Hz, 2H), 6.60 (s, 1H), 5.83 (s, 1H), 4.61 (hept, 6.
1Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.82 (hept, 6.3Hz, 1
H), 1.43 (d, 6.1 Hz, 6H), 1.34 (d, 6.3 Hz, 6H) EIMS 458 (M ⁺ ), 443, 429, 401

Production Example 19 4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = propionate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
508.9 mg, propionyl chloride 0.137 ml, triethylamine 0.362 ml, dichloromethane 5 ml at room temperature
Stirred for hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain 498.9 mg (yield 86%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.59 (d, 8.8 Hz, 2H), 7.19
(d, 8.8Hz, 2H), 6.59 (s, 1H), 5.85 (s, 1H), 4.61 (hept, 6.
1Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.64 (q, 7.0Hz, 2H),
1.43 (d, 6.1Hz, 6H), 1.28 (t, 7.0Hz, 3H) EIMS 444 (M ⁺ ), 429,387,331

Production Example 20 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl p-anisate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
509.5 mg, 0.269 ml of p-anisoyl chloride, 0.362 ml of triethylamine and 5 ml of dichloromethane at room temperature.
Stir for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 2: 1) to obtain 642.8 mg (yield 94%) of the title compound.

¹ H-NMR (CDCl ₃ ) 8.16 (d, 9.0 Hz, 2H), 7.65
(d, 8.8Hz, 2H), 7.32 (d, 8.8Hz, 2H), 7.01 (d, 9.0Hz, 2H),
6.60 (s, 1H), 5.88 (s, 1H), 4.63 (hept, 6.1Hz, 1H), 3.92
(s, 3H) 3.91 (s, 3H), 3.85 (s, 3H), 1.43 (d, 6.1Hz, 6H) EIMS 522 (M ⁺ ), 507,465

Production Example 21 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = 2-acetoxy-2-methylpropionate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 504.8mg, 2-acetoxyisobutyryl chloride
0.372ml, triethylamine 0.540ml, dichloromethane
5 ml was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain 610.5 mg (yield: 91%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.60 (d, 8.3 Hz, 2H), 7.20
(d, 8.3Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 4.63 (hept, 5.
9Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.14 (s.3H), 1.70
(s, 6H), 1.43 (d, 5.9Hz, 6H) EIMS 516 (M ⁺ ), 501, 459, 399, 388

Production Example 22 4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = acrylate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
522.9 mg, acryloyl chloride 0.220 ml, triethylamine 0.560 ml, dichloromethane 5.2 ml at room temperature
Stir for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain 341 mg (57% yield) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.62 (d, 8.8 Hz, 2H), 7.25
(d, 8.8Hz, 2H), 6.64 (d, 17.1Hz, 1H), 6.59 (s, 1H), 6.34 (d
d, 17.1Hz, 10.3Hz, 1H), 6.07 (d, 10.3Hz, 1H), 5.86 (s, 1
H), 4.62 (hept, 5.9Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H),
1.43 (d, 5.9Hz, 6H) EIMS 442 (M ⁺ ), 427,385

Production Example 23 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = 4-nitrobenzoate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
ON 510.1 mg, p-nitrobenzoyl chloride 0.364
ml, triethylamine 0.362ml, dichloromethane 5.1ml
Was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was recrystallized from ethanol-chloroform to give the title compound (575 mg, yield 82%).

¹ H-NMR (CDCl ₃ ) 8.40 (s, 4H), 7.69 (d, 8.8 H
z, 2H), 7.36 (d, 8.8Hz, 2H), 6.61 (s, 1H), 5.87 (hept, 5.9
Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 1.44 (d, 5.9 Hz, 6H) EIMS 537 (M ⁺ ), 522, 480

Production Example 24 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = 2-thenoate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
514.1mg, 2-thiophenecarbonyl chloride
0.213ml, triethylamine 0.368ml, dichloromethane 6
ml was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain 632.3 mg (yield 95%) of the title compound.

¹ H-NMR (CDCl ₃ ) 8.01 (dd, 3.9 Hz, 1.5 Hz, 1
H), 7.71 (dd, 4.9Hz, 1.5Hz, 1H), 7.65 (d, 8.8Hz, 2H), 7.3
4 (d, 8.8Hz, 2H), 7.21 (dd, 4.9Hz, 3.9Hz, 1H), 6.59 (s, 1H
H), 5.89 (s, 1H), 4.63 (hept, 5.9Hz, 1H), 3.92 (s, 3H),
3.85 (s, 3H), 1.43 (d, 5.9Hz, 6H) EIMS 498 (M ⁺ ), 483,441

Production Example 25 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = 2-furoate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
501.8 mg, 0.191 ml of 2-furoyl chloride, 0.357 ml of triethylamine and 7 ml of dichloromethane at room temperature.
Stirred for hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain 561.2 mg (yield 90%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.71 (d, 1.7 Hz, 1 H), 7.65
(d, 8.7Hz, 2H), 7.43 (d, 3.6Hz, 1H), 7.33 (d, 8.7Hz, 2H),
6.63 (dd, 3.6Hz, 1.7Hz, 1H), 6.59 (s, 1H), 5.90 (s, 1H),
4.62 (hept, 6.0Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 1.43
(d, 6.0Hz, 6H) EIMS 482 (M ⁺ ), 467,425

Production Example 26 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = isonicotinate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 500mg, Isonicotinic acid chloride hydrochloride 276mg,
0.429 ml of triethylamine and 5 ml of dichloromethane were stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, recrystallization from ethyl acetate gave 514.8 mg (81% yield) of the title compound.

¹ H-NMR (CDCl ₃ ) 8.90 (d, 6.0 Hz, 2H), 8.02
(d, 6.0Hz, 2H), 7.69 (d, 8.7Hz, 2H), 7.35 (d, 8.7Hz, 2H),
6.60 (s, 1H), 5.88 (s, 1H), 4.63 (hept, 6.1Hz, 1H), 3.93
(s, 3H), 3.85 (s, 3H), 1.44 (d, 6.1Hz, 6H) EIMS 493 (M ⁺ ), 436

Production Example 27 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = 2-acetoxybenzoate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 512.3mg, acetylsalicyloyl chloride 393.3
mg, 0.274 ml of triethylamine and 5 ml of dichloromethane were stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to obtain 609.4 mg (yield 84%) of the title compound.

¹ H-NMR (CDCl ₃ ) 8.23 (dd, 7.9 Hz, 1.6 Hz, 1
H), 7.68 (td, 7.9Hz, 1.6Hz, 1H), 7.66 (d, 8.7Hz, 2H), 7.4
2 (td, 7.9Hz, 1.6Hz, 1H), 7.29 (d, 8.7Hz, 2H), 7.20 (dd, 7.
9Hz, 1.6Hz, 1H), 6.60 (s, 1H), 5.89 (s, 1H), 4.63 (hept,
6.1Hz, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 2.34 (s, 3H), 1.4
3 (d, 6.1Hz, 6H) EIMS 550 (M ⁺ ), 535

Production Example 28 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = anthranilate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
500.8 mg of ON, 231.6 mg of isatoic anhydride, 173.5 mg of 4-dimethylaminopyridine and 10 ml of DMF were stirred at 80 ° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate.
After concentration, the concentrate was purified by column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (463.7 mg, yield 71%).
Obtained.

¹ H-NMR (CDCl ₃ ) 8.08 (dd, 8.5 Hz, 1.6 Hz, 1
H), 7.66 (d, 8.7Hz, 2H), 7.62-7.26 (m, 3H), 6.77-6.70
(m, 2H), 6.60 (s, 1H), 5.89 (s, 1H), 4.63 (hept, 6.1Hz, 1
H), 3.92 (s, 3H), 3.85 (s, 3H), 1.43 (d, 6.1Hz, 6H) EIMS 507 (M ⁺ ), 492, 450

Production Example 29 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = 4- (morpholinomethyl)
Benzoate hydrochloride (1) Methyl 4- (morpholinomethyl) benzoate Methyl 4- (bromomethyl) benzoate 1.00 g
(4.37 mmole) in ethanol 10 ml solution triethylamine 1 ml (7.2 mmole) and morpholine 0.5 ml (5.75 mmole)
Was added and stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to make the aqueous layer basic, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off, the insoluble matter was removed by filtration, and the solvent was again distilled off to obtain 1.00 g (4.26 mmole, 97%) of methyl 4- (morpholinomethyl) benzoate as a colorless solid. ¹ H-NMR (CDCl ₃ ) 7.99 (d, J = 8.3 Hz, 2H), 7.41 (d, J =
8.3 Hz, 2H), 3.91 (s, 3H), 3.72 (t, J = 4.6 Hz, 4H)
3.55 (s, 2H), 2.45 (t, J = 4.6 Hz, 4H) EIMS 235 (M ⁺ ), 204, 149, 86

(2) 4- (morpholinomethyl) benzoyl chloride hydrochloride methyl 4- (morpholinomethyl) benzoate 1.00
g (4.3 mmole) was added to 2 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 3 hours. After cooling, the solvent was distilled off, and 3 ml of thionyl chloride was added.
The mixture was refluxed for 14 hours. After standing to cool, 4-
(Morpholinomethyl) benzoyl chloride hydrochloride 632
mg (2.3 mmole, 54%) was obtained as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) 11.74 (b
rs, 1H), 7.98 (d, J = 8.2H)
z, 2H), 7.78 (d, J = 8.2H)
z, 2H), 4.40 (d, J = 3.9 H
z, 2H) 3.699-3.78 (m, 4
H), 3.23-3.11 (m, 4H).

(3) 4-[(7-isopropoxy-5,
6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenyl = 4- (morpholinomethyl) benzoate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy- 4H-chromen-4-
To a solution of 500 mg (1.29 mmole) of ON in 5 ml of dichloromethane was added 500 mg (1.8 mmole) of 4- (morpholinomethyl) benzoyl chloride hydrochloride and 0.5 ml (3.6 mmole) of triethylamine, and the mixture was stirred at room temperature for 1 hour. After adding water, the mixture was extracted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 10), recrystallized from ethyl acetate, and purified with 4-[(7-isopropoxy-5,6).
-Dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenyl = 4- (morpholinomethyl) benzoate (636 mg, 1.07 mmole, 83%) was obtained as a colorless solid.

¹ H-NMR (CDCl ₃ ) 8.16 (d, J = 8.3 Hz, 2H),
7.65 (2H, d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2
H) 7.33 (d, J = 8.7 Hz, 2H), 6.60 (s, 1H), 5.88 (s, 1
H), 4.63 (hept, J = 6.0 Hz, 1H), 3.93 (s, 3H) 3.85
(s, 3H), 3.74 (t, J = 4.7 Hz, 4H), 3.60 (1H, s), 2.48
(t, J = 4.7 Hz, 4H), 1.43 (d, J = 6.0 Hz, 6H)) FABMS 592 (MH ⁺ )

(4) 4-[(7-isopropoxy-5,
6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenyl = 4- (morpholinomethyl) benzoate hydrochloride 4-[(7-isopropoxy-5,6-dimethoxy-4
-Oxo-4H-chromen-2-yl) thio] phenyl = 4- (morpholinomethyl) benzoate 400 mg (0.68
To a solution of mmole) in 5 ml of dichloromethane was added 10 ml of a methanol solution of hydrochloric acid. The solvent was distilled off, dichloromethane was added, the crystals were separated by filtration, washed with ether, and the title compound 405 was obtained.
mg (0.645 mmole, 95%) was obtained as a colorless solid.

¹ H-NMR (DMSO-d ₆ ) 8.24 (d, J = 8.2 Hz, 2
H), 7.86 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.7 Hz, 2H)
7.51 (d, J = 8.7 Hz, 2H), 7.02 (s, 1H), 5.69 (s, 1
H), 4.82 (hept, J = 6.0 Hz, 1H), 4.49 (brs, 2H) 4.1
7-3.74 (m, 4H), 3.74 (s, 3H), 3.73 (s, 3H), 3.37-
3.10 (m, 4H), 1.33 (d, J = 6.0 Hz, 6H)

Production Example 30 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = 3- (morpholinomethyl)
Benzoate hydrochloride (1) Methyl 3- (morpholinomethyl) benzoate Methyl 3-methylbenzoate 1.0 ml (7.2 mmole)
N-bromosuccinimide in 10 ml solution of carbon tetrachloride
1.5 g (8.4 mmole) and 0.1 g (0.4 mmole) of benzoyl peroxide
e) was added and the mixture was heated under reflux for 3 hours. After cooling, dichloromethane was added, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 1.81 g of methyl 3- (bromomethyl) benzoate as a colorless oil. This was dissolved in 15 ml of ethanol, and 1.5 ml of triethylamine (10.8
mmole) and 0.8 ml (9.2 mmole) of morpholine, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to make the aqueous layer basic, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3).
Methyl = 3- (morpholinomethyl) benzoate 1.03g
(4.38 mmole, 61%) was obtained as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.99 (s, 1H), 7.93 (d,
J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.40 (d, J =
7.6 Hz, 1H) 3.925 (s, 3H), 3.71 (t, J = 4.6 Hz, 4H),
3.54 (s, 2H), 2.45 (t, J = 4.6 Hz, 4H)

(2) 3- (morpholinomethyl) benzoyl chloride hydrochloride methyl 3- (morpholinomethyl) benzoate 1.03
g (4.4 mmole) was added to 2 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 3 hours. After cooling, the solvent was distilled off, 3 ml of thionyl chloride was added, and the mixture was refluxed for 16 hours. After allowing to cool, the mixture was filtered to obtain 1.09 g (3.95 mmole, 90%) of 3- (morpholinomethyl) benzoyl chloride hydrochloride as a colorless solid.

¹ H-NMR (DMSO-d ₆ ) 11.52 (brs, 1H), 8.18
(s, 1H), 8.01 (d, J = 7.8 Hz, 11H), 7.95 (d, J = 7.8
Hz, 1H) 7.59 (t, J = 7.8 Hz, 1H), 4.41 (d, J = 4.4 H
z, 2H), 3.98-3.75 (m, 4H), 3.24-3.12 (m, 4H)

(3) 4-[(7-isopropoxy-5,
6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenyl = 3- (morpholinomethyl) benzoate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy- 4H-chromen-4-
3- (morpholinomethyl) benzoyl chloride hydrochloride in a solution of 500 mg (1.29 mmole) of dichloromethane in 5 ml of dichloromethane
500 mg (1.8 mmole) and 0.5 ml of triethylamine (3.
6 mmole) and stirred at room temperature for 0.5 hour. Water and saturated aqueous sodium hydrogen carbonate were added, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and silica gel column chromatography (methanol: dichloromethane =
1:20) and recrystallized from ethyl acetate-hexane to give 4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenyl = 3. -(Morpholinomethyl) benzoate 711mg
(1.20 mmole, 93%) was obtained as a colorless solid.

¹ H-NMR (CDCl ₃ ) 8.16 (s, 1H), 8.11 (d,
J = 7.6 Hz, 1H), 7.69-7.64 (m, 3H), 7.50 (t, J = 7.6 H
z, 1H) 7.34 (d, J = 8.7 Hz, 2H), 6.60 (s, 1H), 5.88
(1H, s), 4.63 (hept, J = 6.0 Hz, 1H), 3.93 (s, 3H) 3.8
5 (s, 3H), 3.74 (t, J = 4.5Hz, 4H), 3.60 (s, 2H), 2.
49 (t, J = 4.5 Hz, 4H), 1.44 (d, J = 6.0 Hz, 6H) FABMS 592 (MH ⁺ )

(4) 4-[(7-isopropoxy-5,
6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenyl = 3- (morpholinomethyl) benzoate hydrochloride 4-[(7-isopropoxy-5,6-dimethoxy-4
-Oxo-4H-chromen-2-yl) thio] phenyl = 3- (morpholinomethyl) benzoate 400 mg (0.68
Ethyl acetate hydrochloride solution was added to a dichloromethane solution of (mmole), and the solvent was distilled off. After repeating this several times, the crystals were separated by filtration, washed with ether, and 463 mg of the title compound (quan
t.) was obtained as a colorless solid.

¹ H-NMR (DMSO-d ₆ ) 8.42 (s, 1H), 8.24
(d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.81 (d,
J = 8.6 Hz, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.52 (d, J
= 8.6Hz, 2H), 7.02 (s, 1H), 5.70 (s, 1H), 4.82 (hep
t, J = 6.0 Hz, 1H), 4.50 (brs, 2H), 4.04-3.79 (m, 4
H), 3.74 (s, 3H), 3.73 (s, 3H), 3.30-3.10 (m, 4H),
1.33 (d, J = 6.0 Hz, 6H)

Production Example 31 2-[[4-[[dimethyl (thiocarbamoyl)] oxy] phenyl] thio] -7
-Isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
547.5 mg of ON, 0.347 ml of N, N-dimethylthiocarbamoyl chloride, 113 mg of NaH (60% oil), and 5.5 ml of DMF were stirred at room temperature for 2 hours. 3N-HCl was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, it was purified by flash column chromatography (hexane: ethyl acetate = 2: 1),
513.2 mg (yield 77%) of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) 7.62 (d, 8.6 Hz, 2H), 7.16
(d, 8.6Hz, 2H), 6.57 (s, 1H), 5.85 (s, 1H), 4.61 (hept, 6.
1Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.47 (s, 3H), 3.38
(s, 3H), 1.42 (d, 6.1 Hz, 6H) EIMS 475 (M ⁺ ), 460, 418,
371

Production Example 32 2-[[4-[(Diphenoxyphosphoryl) oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
On 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
504.9 mg, diphenylphosphoryl azide
0.419 ml, triethylamine 0.359 ml, dichloromethane 5
ml was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain 717.3 mg (yield: 89%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.3 Hz, 2H), 7.40-
7.22 (m, 12H), 6.57 (s, 1H), 5.82 (s, 1H), 4.61 (hept, 6.4
Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 1.42 (d, 6.4 Hz, 6H) EIMS 620 (M ⁺ ), 605, 577, 563

Production Example 33 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl = p-toluenesulfonate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
502.8 mg of ON, 0.494 mg of tosyl chloride, 0.539 ml of triethylamine, and 5 ml of dichloromethane were stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound
5.0 mg (94% yield) was obtained.

¹ H-NMR (CDCl ₃ ) 7.74
(D, 8.5 Hz, 2H), 7.52 (d, 8.8H
z, 2H), 7.37 (d, 8.8 Hz, 2H),
7.09 (d, 8.5 Hz, 2H), 6.56 (s,
1H), 5.78 (s, 1H), 4.61 (hep
t, 6.1 Hz, 1H), 3.92 (s, 3H),
3.85 (s, 3H), 2.47 (s, 3H),
1.43 (d, 6.1 Hz, 6H) EIMS 542 (M ⁺ ), 527, 485

Production Example 34 4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenyl methanesulfonate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
ON 509.1 mg, mesyl chloride 0.122 ml, triethylamine 0.362 ml, dichloromethane 5 ml at room temperature
Stirred for 20 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, it was purified by flash column chromatography (dichloromethane: acetone = 20: 1).
536.7 mg (88% yield) of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) 7.64 (d, 8.8 Hz, 2H), 7.37
(d, 8.8Hz, 2H), 6.57 (s, 1H), 5.91 (s, 1H), 4.63 (hept, 6.
3Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.22 (s, 3H), 1.42
(d, 6.3Hz, 6H) EIMS 466 (M ⁺ ), 451,409

Production Example 35 2-[[4- (carbaniloyloxy) phenyl] thio] -7-isopropoxy-
5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 505.1 mg, phenyl isocyanate 0.169 ml, triethylamine 0.359 ml, dichloromethane 5 ml at room temperature
Stirred for hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, recrystallization from ethyl acetate-chloroform afforded 364.5 mg (55% yield) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.62 (d, 8.8 Hz, 2H), 7.50-
7.35 (m, 4H), 7.31 (d, 8.8Hz, 2H), 7.15 (m, 1H), 7.00 (br
s, 1H), 6.60 (s, 1H), 5.85 (s, 1H), 4.61 (hept, 6.1Hz, 1
H), 3.92 (s, 3H), 3.85 (s, 3H), 1.43 (d, 6.1 Hz, 6H) FABMS 508 (MH ⁺ )

Production Example 36 7-Isopropoxy-2-
[[4-[(isopropylcarbamoyl) oxy] phenyl] thio] -5,6-dimethoxy-4H-chromene-
4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 504.5 mg, isopropyl isocyanate 0.
153ml, triethylamine 0.360ml, dichloromethane 5m
l was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (hexane: ethyl acetate = 2: 1) to obtain 511.9 mg (yield 86%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.56 (d, 8.8 Hz, 2H), 7.24
(d, 8.8Hz, 2H), 6.60 (s, 1H), 5.82 (s, 1H), 4.92 (m, 1H),
4.61 (hept, 6.1Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 1.43
(d, 6.1Hz, 6H), 1.26 (d, 6.2Hz, 6H) FABMS 474 (MH ⁺ )

Production Example 37 2-[[4-[(Ethylcarbamoyl) oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl ) Thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
219 mg, 0.054 ml of ethyl isocyanate, 0.01 ml of triethylamine and 6 ml of dichloromethane were stirred at room temperature for 2 hours. After concentrating the reaction solution, recrystallized from ethyl acetate,
230 mg (89% yield) of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) 7.57 (d, 8.8 Hz, 2H), 7.23
(d, 8.8Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 5.11 (brt, 1H
H), 4.62 (m, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.33 (m, 2
H), 1.42 (d, 6.1Hz, 6H), 1.24 (t, 7.3Hz, 3H) FABMS 460 (MH ⁺ )

Production Example 38 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[(propylcarbamoyl) oxy] phenyl] thio] -4H-chromen-4-
On 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
602.7 mg of ON, 0.174 ml of n-propyl isocyanate, 0.043 ml of triethylamine and 6 ml of dichloromethane were stirred at room temperature for 2 hours. After the reaction solution was concentrated, it was purified by flash column chromatography (hexane: ethyl acetate = 2: 1) to obtain 548.1 mg (yield: 75%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.57 (d, 8.7 Hz, 2H), 7.23
(d, 8.7Hz, 2H), 6.59 (s, 1H) 5.83 (s, 1H), 5.16 (brt, 1H),
4.62 (hept, 6.1Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.25
(m, 2H), 1.62 (m, 2H), 1.43 (d, 6.1Hz, 6H), 0.99 (t, 7.4H
z, 3H) FABMS 474 (MH ⁺ )

Production Example 39 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[(methylcarbamoyl)
Oxy] phenyl] thio] -4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
504.2 mg of ON, 0.115 ml of methyl isocyanate, 0.036 ml of triethylamine and 5 ml of dichloromethane were stirred at room temperature for 1 hour. After the reaction solution was concentrated, it was purified by flash column chromatography (hexane: ethyl acetate = 1: 1) to obtain 534.8 mg (yield 92%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.23
(d, 8.7Hz, 2H), 6.59 (s, 1H), 5.82 (s, 1H), 5.09 (brd, 1H
H), 4.62 (hept, 6.1Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H),
2.92 (d.4.9Hz, 3H), 1.43 (d, 6.1Hz, 6H) FABMS 446 (MH ⁺ )

Production Example 40 2-[[4-[[(2-chloroethyl) carbamoyl] oxy] phenyl] thio]-
7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one
ON 587.2 mg, 2-chloroethyl isocyanate 0.194
ml, triethylamine 0.042 ml, and dichloromethane 6 ml were stirred at room temperature for 2 hours. After concentrating the reaction solution, flash column chromatography (dichloromethane: acetone =
20: 1) to give 614.3 mg (82% yield) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.59 (d, 8.8 Hz, 2H), 7.25
(d, 8.8Hz, 2H), 6.60 (s, 1H), 5.83 (s, 1H), 5.62 (brt, 1H
H), 4.62 (hept, 5.9Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H),
3.70-3.60 (m, 4H), 1.43 (d, 5.9Hz, 6H) FABMS 494 (MH ⁺ )

Production Example 41 Ethyl = N-[[4-[(7
-Isopropoxy-5,6-dimethoxy-4-oxo-
4H-chromen-2-yl) thio] phenoxy] carbonyl] glycinate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
Ethyl isocyanatoacetate 0.2 ml (1.78 mmole) in 5 ml dichloromethane solution of 500 mg (1.29 mmole)
And 0.02 ml (0.14 mmole) of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was recrystallized from ethyl acetate to give the title compound (598 mg, 1.15 mmole, 89%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.58 (2H, d, J = 8.7 Hz,
2H), 7.25 (d, J = 8.7 Hz, 2H), 6.58 (s, 1H), 5.85
(s, 1H) 5.63 (t, J = 5.1 Hz, 1H), 4.62 (hept, J = 6.0
Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.07 (d, J = 5.1 H
z, 2H) 3.92 (s, 3H), 3.85 (s, 3H), 1.43 (d, J = 6.0 H
z, 6H), 1.32 (t, J = 7.1 Hz, 3H) FABMS 518 (MH ⁺ ), 387

Production Example 42 Methyl = N-[[4-[(7
-Isopropoxy-5,6-dimethoxy-4-oxo-
4H-chromen-2-yl) thio] phenoxy] carbonyl] -L-methioninate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 507.3 mg, (S)-(-)-2-isocyanato-4- (methylthio) butyric acid methyl ester 297 mg, triethylamine 0.01
8 ml of dichloromethane and 5 ml of dichloromethane were stirred at room temperature for 2 hours. The reaction solution was concentrated, and purified by column chromatography (dichloromethane: acetone = 20: 1) to give the title compound as a 497.
7 mg (66% yield) were obtained.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.25
(d, 8.7Hz, 2H), 6.58 (s, 1H), 5.85 (s, 1H), 5.80 (m, 1H),
4.71-4.52 (m, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3
H), 2.61 (t, 7.3Hz, 2H), 2.40-2.00 (m, 2H), 2.14 (s, 3H),
1.43 (d, 6.1Hz, 6H) FABMS 578 (MH ⁺ )

Production Example 43 Diethyl = N-[[4-
[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy]
Carbonyl] -L-glutamate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
In a 5 ml dichloromethane solution of 500 mg (1.29 mmole) of diethyl 2-isocyanato-L-glutamate 0.4 m
l (1.7 mmole) and triethylamine 0.02 ml (0.14 mmo
le), and the mixture was stirred at room temperature for 1.5 hours. After adding dichloromethane, washing with 2N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off, recrystallized from ethyl acetate, and the title compound (595 mg, 0.96 mm
ole, 74%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.57 (d, J = 8.4 Hz, 2H),
7.25 (d, J = 8.4 Hz, 2H), 6.58 (s, 1H), 5.88 (s, 1H),
5.85 (s, 1H) 4.62 (hept, J = 6.0 Hz, 1H), 4.50-4.40
(m, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.16 (q, J = 7.2 Hz,
2H) 3.92 (s, 3H), 3.85 (s, 3H), 2.53-1.99 (m, 4H),
1.43 (d, J = 6.0 Hz, 6H), 1.32 (t, J = 7.2 Hz, 3H) 1.
27 (t, J = 7.2 Hz, 3H) FABMS 618 (MH ⁺ )

Production Example 44 Ethyl = 3-[[[4-
[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy]
Carbonyl] amino] propionate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
0.3 ml (2 mmole) of ethyl 3-isocyanatopropionate and 0.02 of triethylamine were added to a solution of 500 mg (1.29 mmole) of ON in 5 ml of dichloromethane.
ml (0.14 mmole) was added, and the mixture was stirred at room temperature for 2 hours. Dichloromethane was added, and the mixture was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and recrystallized from ethyl acetate to give the title compound (515 m).
g (0.97 mmole, 75%) was obtained as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.57 (d, J = 8.7 Hz, 2H),
7.24 (d, J = 8.7 Hz, 2H), 6.59 (s, 1H), 5.84 (s, 1
H), 5.68 (t, J = 6.0 Hz, 1H), 4.62 (hept, J = 6.0 Hz,
1H), 4.20 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.85 (s,
3H), 3.56 (q, J = 6.0 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2
H), 1.43 (d, J = 6.0 Hz, 6H), 1.30 (t, J = 7.2 Hz, 3H) FABMS 532 (MH ⁺ )

Production Example 45 2-[[4-[(dimethylcarbamoyl) oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl ) Thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
6.06 g, N, N-dimethylcarbamoyl chloride
2.87 ml and pyridine 60 ml were stirred at 50 ° C. for 7 hours. 250 ml of 3N-HCl was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was recrystallized from 40 ml of ethyl acetate-60 ml of hexane to obtain 5.78 g (yield 81%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.8 Hz, 2H), 7.23
(d, 8.8Hz, 2H), 6.60 (s, 1H), 5.82 (s, 1H), 4.61 (hept, 6.
1Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.12 (s, 3H), 3.03
(s, 3H), 1.43 (d, 6.1Hz, 6H) EIMS 459 (M ⁺ ), 444, 430, 416, 402

Production Example 46 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[(morpholinocarbonyl) oxy] phenyl] thio] -4H-chromen-4-
On 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
516.2mg, 4-morpholinecarbonyl chloride
0.466 ml and pyridine 5.2 ml were stirred at room temperature for 3 hours. After neutralizing the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, recrystallized from ethanol, the title compound was 534.3 mg (80% yield).
Obtained.

¹ H-NMR (CDCl ₃ ) 7.59 (d, 8.8 Hz, 2H), 7.23
(d, 8.8Hz, 2H), 6.60 (s, 1H), 5.81 (s, 1H), 4.62 (hept, 6.
4Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.77 (m, 4H), 3.70
(brs, 2H), 3.59 (brs, 2H), 1.42 (d, 6.4Hz, 6H) EIMS 501 (M ⁺ ), 486,444

Production Example 47 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[[(4-methyl-1-piperazinyl) carbonyl] oxy] phenyl] thio] -4
H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
On 511.2 mg, 4-methylpiperazinecarbonyl chloride 214 mg, triethylamine 0.274 ml, 4-dimethylaminopyridine 161 mg, dichloromethane 7 ml at 50 ° C.
Stirred for hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (dichloromethane: acetone = 2: 1) to obtain 612 mg (yield 90%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.22
(d, 8.7Hz, 2H), 6.60 (s, 1H), 5.82 (s, 1H), 4.62 (hept, 6.
0Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.65 (m, 4H), 2.48
(t, 5.1Hz, 4H), 2.36 (s, 3H), 1.43 (d, 6.0Hz, 6H) EIMS 514 (M ⁺ ), 499,457,444

Production Example 48 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[[(4-methyl-1-piperazinyl) carbonyl] oxy] phenyl] thio] -4
H-chromen-4-one hydrochloride 7-isopropoxy-5,6-dimethoxy-2-[[4
-[[(4-Methyl-1-piperazinyl) carbonyl] oxy] phenyl] thio] -4H-chromen-4-one 6
84.4 mg, methanol 6 ml and HCl-methanol 4 ml were stirred for 1 hour under ice cooling. Ether was added to the reaction mixture, and the mixture was further stirred for 1 hour.
81%).

¹ H-NMR (CDCl ₃ ) 7.61 (d, 8.6 Hz, 2H), 7.22
(d, 8.6Hz, 2H), 6.60 (s, 1H), 5.78 (s, 1H), 4.62 (hept, 6.
0Hz, 1H), 4.38 (m, 2H), 4.00 (m, 2H), 3.91 (s, 3H), 3.85
(s, 3H), 3.50 (m, 2H), 2.97 (m, 2H), 2.88 (brs, 3H), 1.43
(d, 6.0Hz, 6H) EIMS 514 (M ⁺ -HCl)

Production Example 49 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[(1-pyrrolidinylcarbonyl) oxy] phenyl] thio] -4H-chromene-
4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
ON 522.0mg, pyrrolidine carbonyl chloride 0.361
ml and pyridine 5.2 ml were stirred at 50 ° C. for 3 hours. After neutralizing the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (dichloromethane: acetone = 20: 1) to give 523.8 mg of the title compound (yield 80
%)Obtained.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.25
(d, 8.7Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.62-3.46 (m, 4H),
2.10-1.80 (m, 4H), 1.43 (d, 6.1 Hz, 6H) EIMS 485 (M ⁺ ), 470, 428

Production Example 50 2-[[4-[(Diethylcarbamoyl) oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) ) Thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
204 mg, N, N-diethylcarbamoyl chloride
0.333 ml and pyridine 5 ml were stirred at 50 ° C. for 7 hours. 3N-HCl was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentrating the reaction mixture, the mixture was purified by flash column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound in 20%.
7 mg (81% yield) was obtained.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.8 Hz, 2H), 7.23
(d, 8.8Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.43 (m, 4H), 1.42
(d, 6.1Hz, 6H), 1.25 (m, 6H) FABMS 488 (MH ⁺ )

Production Example 51 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[(N-methylcarbaniloyl) oxy] phenyl] thio] -4H-chromene-4
-One 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
508.1 mg of ON, 444 mg of N-methyl-N-phenylcarbamoyl chloride and 5 ml of pyridine were stirred at 50 ° C. for 4 hours. The reaction solution was neutralized with 3N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (585.1 mg, yield).
87%).

¹ H-NMR (CDCl ₃ ) 7.56 (d, 8.6 Hz, 2H), 7.47-
7.19 (m, 7H), 6.57 (s, 1H), 5.82 (s, 1H), 4.61 (hept, 6.1H
z, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.44 (s, 3H), 1.42 (d,
6.1Hz, 6H) EIMS 521 (M ⁺ ) 506, 464

Production Example 52 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[[N-methyl-N- (2
-Pyridyl) carbamoyl] oxy] phenyl] thio]
-4H-chromen-4-one (1) N-methyl-N- (2-pyridyl) carbamoyl chloride hydrochloride Under ice cooling, a solution of 5.94 g of triphosgene in 30 ml of benzene was added to
A solution of 3.09 ml of methylaminopyridine in 30 ml of benzene was added dropwise and stirred for 2 hours. The resulting solid was collected by filtration, washed with benzene, and dried to obtain 2.32 g of N-methyl-N- (2-pyridyl) carbamoyl chloride hydrochloride.

(2) 7-isopropoxy-5,6-dimethoxy-2-[[4-[[N-methyl-N- (2-pyridyl) carbamoyl] oxy] phenyl] thio] -4H
-Chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
500 mg of N-methyl-N- (2-pyridyl) carbamoyl chloride hydrochloride 2 g and pyridine 5 ml were stirred at room temperature for 24 hours. Water was added to the reaction solution, and extracted with ethyl acetate.
The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (dichloromethane: methanol = 100: 1) to give the title compound in 62%.
3.4 mg (93% yield) was obtained.

¹ H-NMR (CDCl ₃ ) 8.47 (m, 1H), 7.73 (m, 2H),
7.61 (d, 8.7Hz, 2H), 7.28 (d, 8.7Hz, 2H), 7.13 (dd, 8.4H
z, 4.2Hz, 1H), 6.59 (s, 1H), 5.84 (s, 1H), 4.62 (hept, 6.1
Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.63 (s, 3H), 1.43
(d, 6.1Hz, 6H)

Production Example 53 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[[N-methyl-N- (1
-Methyl-4-piperidinyl) carbamoyl) oxy]
Phenyl] thio] -4H-chromen-4-one hydrochloride (1) N-methyl-N- (1-methyl-4-piperidinyl) carbamoyl chloride hydrochloride Under ice cooling, 5.94 g of triphosgene was added to a 30 ml solution of benzene.
A solution of 4.37 ml of -methyl-4- (methylamino) piperidine in 30 ml of benzene was added dropwise and stirred for 2 hours. The resulting solid was collected by filtration, washed with benzene, dried and dried with N-methyl-N-
6.26 g of (1-methyl-4-piperidinyl) carbamoyl chloride hydrochloride was obtained.

(2) 7-isopropoxy-5,6-dimethoxy-2-[[4-[[N-methyl-N- (1-methyl-4-piperidinyl) carbamoyl) oxy] phenyl] thio] -4H -Chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
517.3 mg, N-methyl-N- (1-methyl-4-piperidinyl) carbamoyl chloride hydrochloride 1.40 g, triethylamine 1.84 ml, 4-dimethylaminopyridine 16
2 mg and 10 ml of dichloromethane were stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the concentrate was purified by column chromatography (dichloromethane: methanol = 30: 1), and 7-isopropoxy-5,6-dimethoxy-2-[[4-[[N-methyl-N- (1-methyl-4- 579.1 mg (yield of piperidinyl) carbonyl) oxy] phenyl] thio] -4H-chromen-4-one
80%).

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.22
(d, 8.7Hz, 2H), 6.60 (s, 1H), 5.82 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 4.08 (m, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.98-
2.93 (m, 5H), 2.31 (s, 3H), 2.17-1.77 (m, 6H), 1.43 (d, 6.
1Hz, 6H) EIMS 542 (M ⁺ ), 472,446,388

(3) 7-isopropoxy-5,6-dimethoxy-2-[[4-[[N-methyl-N- (1-methyl-4-piperidinyl) carbamoyl) oxy] phenyl] thio] -4H -Chromen-4-one hydrochloride 7-isopropoxy-5,6-dimethoxy-2 under ice-cooling
-[[4-[[N-methyl-N- (1-methyl-4-piperidinyl) carbamoyl) oxy] phenyl] thio]
To a solution of 522 mg of -4H-chromen-4-one in 5 ml of ethyl acetate was added 5 ml of hydrochloric acid-ethyl acetate, followed by stirring for 1 hour.
10 ml of ether was added, and the resulting crystals were collected by filtration and dried to give 474.7 mg of the title compound.

¹ H-NMR (DMSO-d ₆ ) 7.71 (d, 8.6 Hz, 2H), 7.3
5 (d, 8.6Hz, 2H), 7.01 (s, 1H), 5.60 (s, 1H), 4.81 (hept,
6.0Hz, 1H), 3.73 (s, 6H), 3.50-2.80 (m, 8H), 2.73 (s, 1.5
H), 2.70 (s, 1.5H), 2.30-1.80 (m, 4H), 1.32 (d, 6.0Hz, 6
H)

Production Example 54 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[[N- (2-methoxyethyl) -N-methylcarbamoyl] oxy] phenyl]
Thio] -4H-chromen-4-one To a solution of 646 mg (2.2 mmole) of triphosgene in 10 ml of benzene was added 1 ml (7.2 mmole) of triethylamine, and N- (2-methoxyethyl) -N-methylamine was added under ice cooling.
A 0.7 ml (6.5 mmole) solution of benzene in 5 ml was added dropwise over 30 minutes. The mixture was stirred for 1.5 hours. The solvent is distilled off and N
-(2-Methoxyethyl) -N-methylcarbamoyl chloride was obtained. There, 5 ml of pyridine and 2-[(4-
Hydroxyphenyl) thio] -7-isopropoxy-
5,6-dimethoxy-4H-chromen-4-one 500 mg
(1.29 mmole) and the mixture was stirred at room temperature for 17 hours. Dichloromethane was added, and the mixture was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 40) to give the title compound
0.63 g (1.2 mmole, 97%) was obtained as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.57 (d, J = 8.6 Hz, 2H),
7.39-7.26 (m, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 4.
62 (hept, J = 6.0 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3
H), 3.75-3.50 (m, 4H), 3.40 (s, 3H), 3.18 (s, 1.5
H), 3.08 (s, 1.5H), 1.43 (d, J = 6.0 Hz, 6H) EIMS 503 (M ⁺ )

Production Example 55 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[(N-methoxy-N-methylcarbamoyl) oxy] phenyl] thio] -4H-
To a solution of 1.92 g of chromen-4-one triphosgene in 30 ml of dichloromethane was added 2.6 ml of pyridine, and the mixture was stirred under ice-cooling for 20 minutes, and 628 mg of N, O-dimethylhydroxylamine hydrochloride in dichloromethane was added.
A 30 ml suspension was added dropwise over 30 minutes. Thereafter, the mixture was stirred at room temperature for 1 hour. Dichloromethane was added to the reaction solution, washed with water, and dried over anhydrous magnesium sulfate. Evaporate the solvent,
N-methoxy-N-methylcarbamoyl chloride
0.49 g (62% yield) was obtained. 0.49 g (3.98 mmo
To a solution of le) in 5 ml of pyridine was added 500 mg (1.29 mmole) of 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one. Stirred for hours. Add dichloromethane,
After washing with 2N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 40) to obtain 552 mg (quant.) Of the title compound as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.60 (d, J = 8.6 Hz, 2H),
7.28 (d, J = 8.6 Hz, 2H), 6.55 (s, 1H), 5.85 (s, 1
H), 4.62 (hept, J = 6.0 Hz, 1H), 3.92 (s, 3H), 3.85
(s, 3H), 3.82 (s, 3H), 3.31 (s, 3H), 1.43 (d, J = 6.
0 Hz, 6H) EIMS 475 (M ⁺ )

Production Example 56 N-[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] sarcosine (1) tert-butyl = N- (chloroformyl) sarcosinate To a solution of 1.63 g of triphosgene in 10 ml of dichloromethane was added 2.67 ml of pyridine under ice-cooling, and the mixture was stirred for 10 minutes.
A solution of 1 g of -butyl ester hydrochloride in 10 ml of dichloromethane was added dropwise, followed by stirring at room temperature for 2 hours. Add water to the reaction solution,
Extract with dichloromethane, wash the organic layer with saturated saline,
Drying over anhydrous sodium sulfate gave 1.12 g of tert-butyl N- (chloroformyl) sarcosinate. ¹ H-NMR (CDCl ₃ ) 4.08 (s, 1H), 4.02 (s, 1H), 3.20 (s, 1.5
H), 3.10 (s, 1.5H), 1.50 (s, 4.5H), 1.48 (s, 4.5H)

(2) tert-butyl = N-[[4-[(7
-Isopropoxy-5,6-dimethoxy-4-oxo-
4H-chromen-2-yl) thio] phenoxy] carbonyl] sarcosinate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
518.2 mg, tert-butyl N- (chloroformyl)
6 ml of sarcosinate and pyridine were stirred at room temperature for 20 hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 10: 7), and tert-butyl = N-[[4
-[(7-isopropoxy-5,6-dimethoxy-4-
776.7 mg of oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] sarcosinate (100% yield)
Obtained.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.24
(d, 8.7Hz, 1H), 7.17 (d, 8.7Hz, 1H), 6.58 (s, 1H), 5.85 (s,
0.5H), 5.83 (s, 0.5H), 4.62 (hept, 6.0Hz, 1H), 4.03 (s, 1H
H), 4.00 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.17 (s, 1.5
H), 3.07 (s, 1.5H), 1.51 (s, 4.5H), 1.50 (s, 4.5H), 1.42
(d, 6.0Hz, 6H) EIMS 559 (M ⁺ ), 502, 446, 331

(3) N-[[4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] sarcosine tert-butyl = N- [[4-[(7-isopropoxy-
5,6-dimethoxy-4-oxo-4H-chromene-2
-Yl) thio] phenoxy] carbonyl] sarcosinate 740 mg, trifluoroacetic acid 1 ml, dichloromethane 7 ml
Was stirred at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was recrystallized from ethyl acetate-hexane to give the title compound (551.3 mg, yield 83%).

¹ H-NMR (acetone-d ₆ ) 7.72 (d, 8.7 Hz, 1 H),
7.71 (d, 8.7Hz, 1H), 7.36 (d, 8.7Hz, 1H), 7.30 (d, 8.7Hz, 1H)
H), 6.84 (s, 1H), 5.70 (s, 0.5H), 5.68 (s, 0.5H), 4.81 (h
ept, 6.0Hz, 1H), 4.27 (s, 1H), 4.15 (s, 1H), 3.81 (s, 3H),
3.79 (s, 3H), 3.21 (s, 1.5H), 3.06 (s, 1.5H), 1.40 (d, 6.0
Hz, 6H) FABMS 504 (MH ⁺ )

Production Example 57 2-[[4-[[N- (2-
Hydroxyethyl) -N-methylcarbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-
Dimethoxy-4H-chromen-4-one (1) 2- (tert-butyldimethylsiloxy) -N-methylethylamine N-methylethanolamine 3.28 g, tert-butyldimethylsilyl chloride 13.16 g, triethylamine 12.08
ml and dichloromethane (60 ml) were stirred at room temperature for 24 hours. Water was added to the reaction solution, extracted with dichloromethane, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the concentrate was purified by column chromatography (dichloromethane: methanol = 4: 1) to obtain 1.79 g of 2- (tert-butyldimethylsiloxy) -N-methylethylamine (22% yield).
Obtained. ¹ H-NMR (CDCl ₃ ) 3.74 (t, 5.2Hz, 2H), 2.70 (t, 5.2Hz, 2H),
2.47 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H)

(2) N- [2- (tert-butyldimethylsiloxy) ethyl] -N-methylcarbamoyl chloride Under ice-cooling, 4.22 ml of pyridine was added to a solution of 2.58 g of triphosgene in 15 ml of dichloromethane, followed by stirring for 10 minutes. (Tert-butyldimethylsiloxy) -N-methylethylamine 1.6
A solution of 5 g of dichloromethane in 15 ml was added dropwise and stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with dichloromethane,
The organic layer was washed with brine and dried over anhydrous sodium sulfate to obtain 1.65 g of N- [2- (tert-butyldimethylsiloxy) ethyl] -N-methylcarbamoyl chloride.

¹ H-NMR (CDCl ₃ ) 3.81 (t, 5.4 Hz, 1 H), 3.80
(t, 5.4Hz, 1H), 3.58 (t, 5.4Hz, 1H), 3.50 (t, 5.4Hz, 1H),
3.21 (s, 1.5H), 3.11 (s, 1.5H), 0.89 (s, 9H), 0.07 (s, 3
H), 0.06 (s, 3H)

(3) 2-[[4-[[N- [2- (tert
-Butyldimethylsiloxy) ethyl] -N-methylcarbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio]- 7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
500 mg, N- [2- (tert-butyldimethylsiloxy) ethyl] -N-methylcarbamoyl chloride 974
mg and 5 ml of pyridine were stirred at room temperature for 24 hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, column chromatography (hexane: ethyl acetate = 2: 1)
2-[[4-[[N- [2- (tert-butyldimethylsiloxy) ethyl] -N-methylcarbamoyl] oxy] phenyl] thio] -7-isopropoxy-
5,6-Dimethoxy-4H-chromen-4-one was added to 793.
8 mg (100% yield) was obtained.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.22
(d, 8.7Hz, 1H), 7.21 (d, 8.7Hz, 1H), 6.59 (s, 1H), 5.83
(s, 0.5H), 5.82 (s, 0.5H), 4.62 (hept, 6.1Hz, 1H), 3.92
(s, 3H), 3.84 (s, 3H), 3.88-3.80 (m, 2H), 3.56 (t, 5.5Hz, 1
H), 3.47 (t, 5.5Hz, 1H), 3.19 (s, 1.5H), 3.09 (s, 1.5H),
1.43 (d, 6.1Hz, 6H), 0.92 (s, 9H), 0.092 (s, 3H), 0.090
(s, 3H) EIMS 603 (M ⁺ ), 588, 546

(4) 2-[[4-[[N- (2-hydroxyethyl) -N-methylcarbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene- 4-one 2-[[4-[[N- [2- (tert-butyldimethylsiloxy) ethyl] -N-methylcarbamoyl] oxy]
Phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 716.1 mg, 1% conc.H
10 ml of Cl-EtOH was stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline,
Dry over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (ethyl acetate: hexane = 5: 1) to obtain 467.5 mg (yield: 80%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.24
(d, 8.7Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 3.92 (s, 3H), 3.90-3.80 (m, 2H), 3.85 (s, 3H),
3.65-3.50 (m, 2H), 3.20 (s, 1.5H), 3.10 (s, 1.5H), 1.43
(d, 6.1Hz, 6H) EIMS 489 (M ⁺ ), 432 388, 373, 331

Production Example 58 2-[[4-[[N- (3-
Hydroxypropyl) -N-methylcarbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-
Dimethoxy-4H-chromen-4-one (1) 3- (tert-butyldimethylsiloxy) -N-methylpropylamine 3- (tert-butyldimethylsiloxy) -N-benzyl-N-methylpropylamine 5.49 g of methanol 120ml
To the solution, 500 mg of 20% Pd (OH) ₂ -C was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated.
Purification by column chromatography (dichloromethane: methanol = 4: 7) gave 2.14 g of 3- (tert-butyldimethylsiloxy) -N-methylpropylamine (56% yield).
Obtained.

¹ H-NMR (CDCl ₃ ) 3.69 (t, 6.2 Hz, 2H), 2.66
(t, 6.9Hz, 2H), 2.43 (s, 3H), 1.80-1.64 (m, 2H), 0.89 (s,
9H), 0.052 (s, 6H) EIMS 203 (M ⁺ ), 188, 146

(2) N- [3- (tert-butyldimethylsiloxy) propyl] -N-methylcarbamoyl chloride To a solution of 2.04 g of triphosgene in 15 ml of dichloromethane was added 2.78 ml of pyridine, and the mixture was stirred for 10 minutes. − (Tert−
Butyldimethylsiloxy) -N-methylpropylamine
A solution of 1.40 g of dichloromethane in 15 ml was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with dichloromethane, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and N- [3- (tert-butyldimethylsiloxy) was added.
Propyl] -N-methylcarbamoyl chloride to 1.75
g obtained.

¹ H-NMR (CDCl ₃ ) 3.70-3.24 (m, 4H), 3.14
(s, 1.5H), 3.05 (s, 1.5H), 1.90-1.70 (m, 2H), 0.90 (s, 9
H), 0.056 (s, 6H) FABMS 266 (MH ⁺ )

(3) 2-[[4-[[N- [3- (tert
-Butyldimethylsiloxy) propyl] -N-methylcarbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio]- 7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
510.9 mg, N- [3- (tert-butyldimethylsiloxy) propyl] -N-methylcarbamoyl chloride
606 mg and pyridine (5 ml) were stirred at room temperature for 20 hours and at 60 ° C for 2 hours. The reaction solution was neutralized with hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to give 2-[[4-[[N-
[3- (tert-butyldimethylsiloxy) propyl]-
N-methylcarbamoyl] oxy] phenyl] thio]-
742.4 mg (yield 91%) of 7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one was obtained.

¹ H-NMR (CDCl ₃ ) 7.57 (d, 8.7 Hz, 2H), 7.22
(d, 8.7Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.75-3.66 (m, 2H),
3.55-3.40 (m, 2H), 3.11 (s, 1.5H), 3.03 (s, 1.5H), 1.42
(d, 6.1Hz, 6H) FABMS 618 (MH ⁺ )

(4) 2-[[4-[[N- (3-hydroxypropyl) -N-methylcarbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene- 4-one 2-[[4-[[N- [3- (tert-butyldimethylsiloxy) propyl] -N-methylcarbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-
Dimethoxy-4H-chromen-4-one 697.7 mg, 1% co
nc. HCl-EtOH (10 ml) was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (ethyl acetate: hexane = 5: 1) to obtain 492.7 mg (yield 87%) of the title compound.

¹ H-NMR (CDCl ₃ ) 7.59 (d, 8.7 Hz, 2H), 7.22
(d, 8.7Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.85-3.50 (m, 4H),
3.12 (s, 2H), 3.04 (s, 1H), 2.00-1.80 (m, 2H), 1.42 (d, 6.
1Hz, 6H) FABMS 504 (MH ⁺ )

Production Example 59 [[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] methylamino] acetonitrile (1) [ N- (chloroformyl) -N-methylamino]
Acetonitrile Under ice-cooling, 5.78 ml of pyridine was added to a solution of 4.24 g of triphosgene in 30 ml of dichloromethane, and the mixture was stirred for 10 minutes. A solution of 1.00 g of methylaminoacetonitrile in 20 ml of dichloromethane was added dropwise, followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, extracted with dichloromethane, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and [N- (chloroformyl) -N
1.84 g of [-methylamino] acetonitrile was obtained. ¹ H-NMR (CDCl ₃ ) 4.46 (s, 0.6H), 4.35 (s, 1.4H), 3.30 (s,
2.1H), 3.20 (s, 0.9H) (2) [[[4-[(7-Isofluorooxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carboxynil] Methylamino] acetonitrile 2-[(4-humanperoxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
508.7 mg, 348 mg of [N- (chloroformyl) -N-methylamino] acetonitrile and 5 ml of pyridine at room temperature for 20 minutes.
Stirred for hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 7: 10) to give the title compound as 632.
6 mg (100% yield) was obtained.

¹ H-NMR (CDCl ₃ ) 7.61 (d, 8.7 Hz, 2H), 7.24
(d, 8.7Hz, 2H), 6.58 (s, 1H), 5.85 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 4.39 (s, 0.8H), 4.36 (s, 1.2H), 3.92 (s, 3H),
3.85 (s, 3H), 3.26 (s, 1.8H), 3.16 (s, 1.2H), 1.43 (d, 6.1
Hz, 6H) EIMS 484 (M ⁺ ), 469, 427

Production Example 60 [[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] methylamino] acetaldehyde (1) N -(2,2-Dimethoxyethyl) -N-methylcarbamoyl chloride Under ice cooling, to a solution of 4.98 g of triphosgene in 30 ml of dichloromethane was added 6.79 ml of pyridine, and the mixture was stirred for 10 minutes. The mixture was added dropwise and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and dried.
2.66 g of (2,2-dimethoxyethyl) -N-methylcarbamoyl chloride was obtained. ¹ H-NMR (CDCl ₃ ) 4.53 (t, 5.3 Hz, 1 H), 3.54 (d, 5.3 Hz, 1 H),
3.47 (d, 5.3Hz, 1H), 3.44 (s, 3H), 3.42 (s, 3H), 3.19 (s,
1.5H), 3.11 (s, 1.5H)

(2) 2-[[4-[[N- (2,2-dimethoxyethyl) -N-methylcarbamoyl] oxy]
Phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene- 4-
1.0174 g, N- (2,2-dimethoxyethyl) -N
-952 mg of methylcarbamoyl chloride, 10 ml of pyridine
Was stirred at room temperature for 20 hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 7: 10) to give 2-
[[4-[[N- (2,2-dimethoxyethyl) -N-
Methylcarbamoyl] oxy] phenyl] thio] -7-
1.4091 g (100% yield) of isopropoxy-5,6-dimethoxy-4H-chromen-4-one was obtained.

¹ H-NMR (CDCl ₃ ) 7.59 (d, 8.7 Hz, 2H), 7.23
(d, 8.7Hz, 2H), 6.59 (s, 1H), 5.83 (s, 0.5H), 5.82 (s, 0.5
H), 4.71-4.55 (m, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.53
(d, 5.4Hz, 1H), 3.45 (s, 3H), 3.44 (s, 3H), 3.43 (d, 5.4H
z, 1H), 3.17 (s, 1.5H), 3.08 (s, 1.5H), 1.43 (d, 6.1Hz, 6
H) EIMS 533 (M ⁺ ), 486, 444

(3) [[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenoxy] carbonyl] methylamino] acetaldehyde 2-[[4-[[N- (2,2-dimethoxyethyl)-
N-methylcarbamoyl] oxy] phenyl] thio]-
6 ml of trifluoroacetic acid was added to 1.29 g of 7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one and 12 ml of dichloromethane, followed by stirring at room temperature for 2 hours. The reaction solution was extracted with dichloromethane, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography (hexane: ethyl acetate = 7: 10)
To give 1.14 g (97% yield) of the title compound.

¹ H-NMR (CDCl ₃ ) 9.74 (s, 0.5 H), 9.68 (s, 0.
5H), 7.59 (d, 8.7Hz, 1H), 7.57 (d, 8.7Hz, 1H), 7.25 (d, 8.
7Hz, 1H), 7.17 (d, 8.7Hz, 1H), 6.59 (s, 1H), 5.84 (s, 0.5
H), 5.82 (s, 0.5H), 4.62 (hept, 6.1Hz, 1H), 4.30 (s, 1H),
4.29 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.19 (s, 1.5H),
3.09 (s, 1.5H), 1.42 (d, 6.1Hz, 6H) EIMS 487 (M ⁺ ), 472,430,388,373,331

Production Example 61 2-[[4-[[(4-hydroxypiperidino) carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H
-Chromen-4-one (1) 4- (tert-butyldimethylsiloxy) piperidine 4-Hydroxypiperidine A solution of 2.02 g (0.02 mole) of 20 ml of dichloromethane in 6 ml of triethylamine and te
rt-butyldimethylsilyl chloride 3.63 g (24 mmol
e) was added and the mixture was stirred at room temperature for 22 hours. Further, 6 ml of triethylamine and 3.58 of tert-butyldimethylsilyl chloride were added.
g was added and stirred at room temperature for 22 hours. Dichloromethane was added, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 4 to 1: 1) to obtain 4- (tert-butyldimethylsiloxy) piperidine.
2.58 g (12 mmole, 60%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) 3.78-3.67 (m, 1H), 3.12-3.01 (m, 2
H), 2.67-2.54 (m, 2H), 1.83-1.71 (s, 2H), 1.51-1.4
2 (s, 2H) EIMS 215 (M ⁺ ), 158

(2) 4- (tert-butyldimethylsiloxy) -1-piperidinylcarbonyl chloride triphosgene 1.91 g (6.43 mmole) of dichloromethane 20
Add 3 ml (37 mmole) of pyridine to the ml solution, and add
Stir for 2 hours. 1.38 g (6.42 mmole) of 4- (tert-butyldimethylsiloxy) piperidine in dichloromethane
A 30 ml suspension was added dropwise over 20 minutes. Thereafter, the mixture was stirred at room temperature for 1 hour. Dichloromethane was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. Evaporate the solvent,
1.96 g (quant.) Of 4- (tert-butyldimethylsiloxy) -1-piperidinylcarbonyl chloride was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) 4.07-3.97 (m, 1H), 3.78-3.57 (m, 4
H), 1.84-1.52 (m, 4H), 0.90 (s, 9H), 0.07 (s, 6H)

(3) 2-[[4-[[[4- (tert-butyldimethylsiloxy) piperidino] carbonyl] oxy] phenyl] thio "-7-isopropoxy-5,6-
Dimethoxy-4H-chromen-4-one 4- (tert-butyldimethylsiloxy) -1-piperidinylcarbonyl chloride In a solution of 1.96 g of pyridine in 10 ml of pyridine, 2- (2-[(4-hydroxyphenyl) thio]-
500 mg (1.29 mmole) of 7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one was added, and the mixture was added at room temperature for 19 hours.
Stirred for hours. Dichloromethane was added, and the mixture was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 50) to give 2-[[4-[[[4- (tert-butyldimethylsiloxy) piperidino] carbonyl] oxy] phenyl] thio. "-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 817 mg (quant.) Was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) 7.57 (d, J = 8.6 Hz, 2H),
7.21 (d, J = 8.6 Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1
H), 4.62 (hept, J = 6.0 Hz, 1H), 4.13-3.97 (m, 1H),
3.92 (s, 3H), 3.85 (s, 3H), 3.75-3.43 (m, 4H), 1.8
7-1.65 (m, 4H), 1.43 (d, J = 6.0 Hz, 6H), 0.92 (s, 9
H), 0.09 (s, 6H) EIMS 629 (MH ⁺ ), 614, 572

(4) 2-[[4-[[(4-hydroxypiperidino) carbonyl] oxy] phenyl] thio]-
7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[[4-[[[4- (tert-butyldimethylsiloxy) piperidino] carbonyl] oxy] phenyl] thio "-7-iso Propoxy-5,6-dimethoxy-4H
-Chromen-4-one 764 mg (1.2 mmole) in 1% c.HCl
It was dissolved in 10 ml of ethanol solution and stirred at room temperature for 6 hours. The solvent was distilled off, and the residue was recrystallized from ethyl acetate to give the title compound (349 mg, 0.68 mmole, 57%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.58 (d, J = 8.7 Hz, 2H),
7.22 (d, J = 8.7 Hz, 2H), 6.59 (s, 1H), 5.82 (s, 1
H), 4.62 (hept, J = 6.0 Hz, 1H), 4.02-3.93 (m, 3H),
3.92 (s, 3H), 3.85 (s, 3H), 3.55-3.34 (m, 2H), 2.0
5-1.94 (m, 2H), 1.76-1.53 (m, 2H), 1.43 (d, J = 6.0
Hz, 6H) EIMS 515 (MH ⁺ ), 458, 572

Production Example 62 2-[[4-[[[2- (Hydroxymethyl) piperidino] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one (1) 2-[(tert-butyldimethylsiloxy) methyl] piperidine (±) -2-piperidinemethanol 2.01 g (18 mmole)
5 ml of triethylamine in a 20 ml solution of dichloromethane
(36 mmole) and tert-butyldimethylsilyl chloride
4.0 g (27 mmole) was added, and the mixture was stirred at room temperature for 17 hours. Dichloromethane was added, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and silica gel column chromatography (methanol: dichloromethane = 1: 4-
1: 1), followed by silica gel column chromatography (methanol: dichloromethane = 1: 20 to 1: 1).
Purification in 1) gave 3.58 g (15.6 mmole, 89%) of 2-[(tert-butyldimethylsiloxy) methyl] piperidine as a colorless oil. ¹ H-NMR (CDCl ₃ ) 3.52 (dd, J = 9.6, 4.0 Hz, 1H), 3.40
(dd, J = 9.6, 4.0 Hz, 1H), 3.11-3.00 (m, 1H), 2.73-2.
48 (m, 2H), 1.82-0.92 (m, 6H), 0.89 (s, 9H), 0.05
(s, 6H)

(2) 2-[(tert-butyldimethylsiloxy) methyl] -1-piperidinecarbonyl chloride triphosgene 1.92 g (6.46 mmole) of dichloromethane 20
Add 3 ml (37 mmole) of pyridine to the ml solution, and add
Stirred for minutes. A solution of 1.41 g (6.2 mmole) of 2-[(tert-butyldimethylsiloxy) methyl] piperidine in 20 ml of dichloromethane was added dropwise over 15 minutes. Thereafter, the mixture was stirred at room temperature for 1 hour. Dichloromethane was added, washed with water, and dried over anhydrous magnesium sulfate. Evaporate the solvent,
2-[(tert-butyldimethylsiloxy) methyl] -1
1.8 g of -piperidinecarbonyl chloride was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) 4.48-3.58 (m, 3H), 1.92-1.21 (m, 6
H), 0.92 (s, 3.8H), 0.90 (s, 5.2H), 0.10 (s, 2.5
H), 0.07 (s, 3.5H)

(3) 2-[[4-[[[2-[(tert-
Butyldimethylsiloxy) methyl] piperidino] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one To 1.8 g of the brown oil obtained in the above (2), 2 -[(4-hydroxyphenyl) thio] -7-isopropoxy-5,
6-Dimethoxy-4H-chromen-4-one 500 mg (1.
29 mmole) and 5 ml of pyridine were added, and the mixture was stirred at room temperature for 17 hours. Dichloromethane was added, and the mixture was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate.
The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4).
[[4-[[[2-[(tert-butyldimethylsiloxy) methyl] piperidino] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 334 mg (0.52 mmole 40%)
Was obtained as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.57
(D, J = 8.7 Hz, 2H), 7.22
(D, J = 8.7 Hz, 2H), 6.59
(S, 1H), 5.83 (s, 1H), 4.
62 (hept, J = 6.1 Hz, 1H),
4.41 (brs, 1H), 4.20-4.07
(M, 1H), 3.92 (s, 3H),
3.85 (s, 3H), 3.79-3.70
(M, 2H), 1.93-1.59 (m, 6
H), 1.42 (d, J = 6.1 Hz, 6
H), 0.90 (s, 9H), 0.08
(S, 6H) EIMS 643 (M ⁺ -1), 586.

(4) 2-[[4-[[[2- (Hydroxymethyl) piperidino] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[[4-[[[2-[(tert-butyldimethylsiloxy) methyl] piperidino] carbonyl] oxy]
Phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 470 mg (0.73 mmol
Dissolve e) in 10 ml of 1% c.HCl in ethanol and add 1.
Stir for 5 hours. The solvent was distilled off and recrystallized from ethyl acetate-hexane to give 275 mg (0.52 mmole, 71
%) As a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.57 (d, J = 8.7 Hz, 2H),
7.22 (d, J = 8.7 Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1
H), 4.62 (hept, J = 6.1 Hz, 1H), 4.53-4.27 (m, 1H),
4.18-4.07 (m, 1H), 3.99-3.89 (m, 1H), 3.91 (s, 3H),
3.84 (s, 3H), 3.74 (dd, J = 11.2, 5.9 Hz, 1H), 3.13
(brs, 1H), 1.85-1.52 (m, 6H), 1.43 (d, J = 6.0 Hz, 6
H) EIMS 529 (M ⁺ ), 388, 331

Production Example 63 2-[[4-[[[2- (2
-Hydroxyethyl) piperidino] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-
Dimethoxy-4H-chromen-4-one (1) 2- [2- (tert-butyldimethylsiloxy) ethyl] piperidine 2-piperidine Ethanol 5 ml (36 mmol) in a solution of 2.22 g (17 mmole) of ethanol in 20 ml of dichloromethane.
e) and 4.0 g of tert-butyldimethylsilyl chloride (2
7 mmole) and stirred at room temperature for 20 hours. Dichloromethane was added, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 4 to 1: 1), and further purified by silica gel column chromatography (methanol: dichloromethane = 1: 9 to 1: 2). 3.95 g (16.2 mmole, 95%) of-[2- (tert-butyldimethylsiloxy) ethyl] piperidine was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) 3.72 (t, J = 6.1 Hz, 1H), 3.11-3.05
(m, 1H), 2.73-2.58 (m, 2H), 1.82-1.09 (m, 8H), 0.8
9 (s, 9H), 0.05 (s, 6H)

(2) 2- [2- (tert-butyldimethylsiloxy) ethyl] -1-piperidinecarbonyl chloride triphosgene 1.91 g (6.43 mmole) of dichloromethane 20
Add 3 ml (37 mmole) of pyridine to the ml solution, and add
Stirred for 0 minutes. A solution of 2.0 g (8.2 mmole) of 2- [2- (tert-butyldimethylsiloxy) ethyl] piperidine in 20 ml of dichloromethane was added dropwise over 20 minutes. Thereafter, the mixture was stirred at room temperature for 1 hour. Dichloromethane was added, washed with water, and dried over anhydrous magnesium sulfate. Evaporate the solvent,
2- [2- (tert-butyldimethylsiloxy) ethyl]
2.3 g of -1-piperidinecarbonyl chloride was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) 4.62 (brs, 1H), 4.20 (d, J = 13.3 Hz,
1H), 3.65 (td, J = 6.3, 1.4 Hz, 2H), 3.28-2.85 (m,
1H), 2.12-1.40 (m, 8H)

(3) 2-[[4-[[[2- [2- (te
rt-butyldimethylsiloxy) ethyl] piperidino] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one To 2.3 g of the brown oil obtained in the above (2) , 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,
6-dimethoxy-4H-chromen-4-one 700 mg (1.
8 mmole) and 10 ml of pyridine were added, and the mixture was stirred at room temperature for 44 hours. Dichloromethane was added, and the mixture was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate.
The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3).
[[4-[[[2- [2- (tert-butyldimethylsiloxy) ethyl] piperidino] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 1.09 g (1.65 mmole 92
%) As a colorless oil.

¹ H-NMR (CDCl ₃ ) 7.57 (d, J = 8.6 Hz, 2H),
7.20 (d, J = 8.6 Hz, 2H), 6.59 (s, 1H), 5.85 (s, 1
H), 4.62 (hept, J = 6.1 Hz, 1H), 4.60-4.40 (m, 1H),
4.28-4.07 (m, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.7
6-3.61 (m, 2H), 2.12-1.51 (m, 8H), 1.42 (d, J = 6.1
Hz, 6H), 0.88 (s, 9H), 0.05 (s, 6H) EIMS 657 (M ⁺ ), 600

(4) 2-[[4-[[[2- (2-hydroxyethyl) piperidino] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4 -One 2-[[4-[[[2- [2- (tert-butyldimethylsiloxy) ethyl] piperidino] carbonyl] oxy]
Phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 1.085 g (1.65 mmol)
e) was dissolved in 20 ml of 1% c.
Stir for 5 hours. The solvent was distilled off, and silica gel column chromatography (ethyl acetate: hexane = 2: 1 to 4:
Purify in 1) to give the title compound 619 mg (1.14 mmole, 69%)
Was obtained as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.58 (d, J = 8.6 Hz, 2H),
7.21 (d, J = 8.6 Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1
H), 4.62 (hept, J = 6.1 Hz, 1H), 4.68-4.56 (m, 1H),
4.24-4.17 (m, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.6
9-3.46 (m, 2H), 3.17-2.92 (m, 1H), 2.13-2.00 (m, 1
H), 1.86-1.61 (m, 6H), 1.43 (d, J = 6.1 Hz, 6H) EIMS 543 (M ⁺ ), 373, 331

Production Example 64 1-[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl]-
L-proline (1) tert-butyl = 1- (chloroformyl) -L-prolinate triphosgene 1.92 g (6.46 mmole) of dichloromethane 20
2.6 ml (32 mmole) of pyridine was added to the ml solution, and the mixture was stirred for 10 minutes under ice cooling. A solution of L-proline tert-butyl ester 1.1 g (6.5 mmole) in dichloromethane 20 ml was added to 10
In minutes. Thereafter, the mixture was stirred at room temperature for 1 hour. Dichloromethane was added, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 1.57 g (quant.) Of tert-butyl = 1- (chloroformyl) -L-prolinate as a brown oily substance. ¹ H-NMR (CDCl ₃ ) 4.45-4.30 (m, 1H), 3.85-3.50 (m, 2
H), 2.38-1.90 (m, 4H), 1.49 (s, 4.5H), 1.47 (s, 4.
5H)

(2) tert-butyl = 1-[[4-[(7
-Isopropoxy-5,6-dimethoxy-4-oxo-
4H-chromen-2-yl) thio] phenoxy] carbonyl] -L-prolinate 2-[(4-hydroxyphenyl) thiol was added to a solution of 1.57 g of tert-butyl-1- (chloroformyl) -L-prolinate in 10 ml of pyridine. ] -7-Isopropoxy-5,6
-Dimethoxy-4H-chromen-4-one 500 mg (1.29
mmole) and stirred at room temperature for 22 hours. Dichloromethane was added, and the mixture was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. Evaporate the solvent,
Purification by silica gel column chromatography (methanol: dichloromethane = 1: 20), crude tert-butyl = 1
-[[4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] -L-prolinate 0.51 g (q
uant.) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) 7.56 (d, J = 8.7 Hz, 2H),
7.25 (d, J = 8.7 Hz, 0.8H), 7.21 (d, J = 8.7 Hz, 1.2
H), 6.58 (s, 1H), 5.85 (s, 0.4H), 5.84 (s, 0.6H),
4.68-4.27 (m, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 3.7
9-3.47 (m, 2H), 2.38-1.75 (m, 4H), 1.49-1.41 (m, 1
5H) EIMS 629 (MH ⁺ ), 614, 572

(3) 1-[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] -L-proline tert-butyl = 1-[[4-[(7-isopropoxy-
5,6-dimethoxy-4-oxo-4H-chromene-2
-Yl) thio] phenoxy] carbonyl] -L-prolinate 1 ml (13 mmole) of trifluoroacetic acid was added to a solution of 0.51 g (0.87 mmole) of dichloromethane in 5 ml of dichloromethane, and the solution was added at room temperature.
Stirred for days. Water was added, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the crystals were collected by filtration and recrystallized from ethyl acetate-hexane to give 245 mg (0.46 mmole, 53%) of the title compound as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.58 (d, J = 8.7 Hz, 1H),
7.54 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.2
3 (d, J = 8.7 Hz, 1H), 6.60 (s, 0.5H), 6.59 (s, 0.5
H), 5.86 (s, 0.5H), 5.77 (s, 0.5H), 4.68-4.47 (m,
2H), 3.92 (s, 1.5H), 3.91 (s, 1.5H), 3.84 (s, 3H),
3.81-3.53 (m, 2H), 2.59-2.01 (m, 4H), 1.43 (d, J =
6.0 Hz, 6H) EIMS 529 (M ⁺ ), 157, 331

Production Example 65 2-[[4-[[[(S)-
2- (hydroxymethyl) -1-pyrrolidinyl] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one (1) (S) -2-[(tert -Butyldimethylsiloxy) methyl] pyrrolidine (S) -2-pyrrolidinemethanol 2.01 g (20 mmole)
7 ml of triethylamine in a 20 ml solution of dichloromethane
(50 mmole) and tert-butyldimethylsilyl chloride
6.1 g (42 mmole) was added, and the mixture was stirred at room temperature for 18 hours. Dichloromethane was added, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and silica gel column chromatography (methanol: dichloromethane = 1: 4-
1: 1), and 3.86 g of (S) -2-[(tert-butyldimethylsiloxy) methyl] pyrrolidine (10 mmole,
90%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) 3.60
(Dd, J = 10.0, 5.0 Hz, 1
H), 3.53 (dd, J = 10.0, 5.0
Hz, 1H), 3.25-3.12 (m, 1
H), 3.06-2.80 (m, 2H), 1.
88-1.67 (m, 3H), 1.53-1.3
9 (m, 1H), 0.90 (s, 9H),
0.06 (s, 6H)

(2) (S) -2-[(tert-butyldimethylsiloxy) methyl] -1-pyrrolidinecarbonyl chloride 1.91 g (6.43 mmole) of dichloromethane 20
Add 3 ml (37 mmole) of pyridine to the ml solution, and add
Stirred for 0 minutes. A solution of 1.6 g (7.4 mmole) of (S) -2-[(tert-butyldimethylsiloxy) methyl] pyrrolidine in 20 ml of dichloromethane was added dropwise over 20 minutes. Thereafter, the mixture was stirred at room temperature for 1 hour. Dichloromethane was added, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain (S) -2-[(tert-butyldimethylsiloxy) methyl] -1-pyrrolidinecarbonyl chloride as a brown oil. ¹ H-NMR (CDCl ₃ ) 4.07-3.49 (m, 5H), 2.12-1.82 (m, 4
H), 0.89 (s, 9H), 0.05 (s, 6H)

(3) 2-[[4-[[[(S) -2-
(Tert-butyldimethylsiloxymethyl) -1-pyrrolidinyl] carbonyl] oxy] phenyl] thio] -7-
Isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy was added to the brown oil obtained in the above (2). -4H-chromen-4-one 500 mg (1.29 mmo
le) and 5 ml of pyridine were added, and the mixture was stirred at room temperature for 24 hours.
Dichloromethane was added, and the mixture was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 2-[[4-
[[[(S) -2- (tert-butyldimethylsiloxymethyl) -1-pyrrolidinyl] carbonyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 723 mg (1.15 mmole, 8
9%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.57 (d, J = 8.6 Hz, 2H),
7.23 (d, J = 8.6 Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1
H), 4.62 (hept, J = 6.1 Hz, 1H), 4.20-3.92 (m, 1H),
3.92 (s, 3H), 3.85 (s, 3H), 3.78-3.50 (m, 4H), 2.17
-1.87 (m, 4H), 1.43 (d, J = 6.1 Hz, 6H), 0.90 (s, 9
H), 0.07 (s, 6H)

(4) 2-[[4-[[[(S) -2-
(Hydroxymethyl) -1-pyrrolidinyl] carbonyl] oxy] phenyl] thio] -7-isopropoxy-
5,6-dimethoxy-4H-chromen-4-one 2-[[4-[[[(S) -2- (tert-butyldimethylsiloxymethyl) -1-pyrrolidinyl] carbonyl] carbonyl]
[Oxy] phenyl] thio] -7-isopropoxy-5,
6-dimethoxy-4H-chromen-4-one 723 mg
(1.2 mmole) was dissolved in 10 ml of a 1% c.HCl ethanol solution and stirred at room temperature for 1.5 hours. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-hexane to give 241 mg (0.4 mg) of the title compound.
7 mmole, 41%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.59 (d, J = 8.6 Hz, 2H),
7.26 (d, J = 8.6 Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1
H), 4.62 (hept, J = 6.0 Hz, 1H), 4.30-3.99 (m, 1H),
3.92 (s, 3H), 3.85 (s, 3H), 3.75-3.57 (m, 4H), 2.17
-1.86 (m, 4H), 1.43 (d, J = 6.0 Hz, 6H) EIMS 515 (M ⁺ )

Production Example 66 7-Isopropoxy-5,6
-Dimethoxy-2-[[4-[[[(S) -2- (methoxymethyl) -1-pyrrolidinyl] carbonyl] oxy] phenyl] thio] -4H-chromen-4-one (1) (S)- 2- (methoxymethyl) -1-pyrrolidinecarbonyl chloride Under ice cooling, to a solution of 2.62 g of triphosgene in 20 ml of dichloromethane, 3.58 ml of pyridine was added and stirred for 10 minutes, and then (S) -2- (methoxymethyl) pyrrolidine was added.
A solution of 1.02 g of dichloromethane in 20 ml was added dropwise and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate to obtain 1.52 g of (S) -2- (methoxymethyl) -1-pyrrolidinecarbonyl chloride. ¹ H-NMR (CDCl ₃ ) 4.30-4.05 (m, 1H), 3.75-3.40 (m, 4H),
3.37 (s, 1.2H), 3.35 (s, 1.8H), 2.15-1.80 (m, 4H)

(2) 7-isopropoxy-5,6-dimethoxy-2-[[4-[[[(S) -2- (methoxymethyl) -1-pyrrolidinyl] carbonyl] oxy] phenyl] thio]- 4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
On 500 mg, (S) -2- (methoxymethyl) -1-pyrrolidinecarbonyl chloride 457 g and pyridine 5 ml were stirred at room temperature for 20 hours and at 60 ° C. for 2 hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, column chromatography (dichloromethane: acetone = 15: 1)
And 565.6 mg (83% yield) of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.25
(d, 8.7Hz, 2H), 6.59 (s, 1H), 5.82 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 4.25-4.20 (m, 1H), 3.92 (s, 3H), 3.85 (s, 3H),
3.70-3.45 (m, 4H), 3.38 (s, 3H), 2.15-1.85 (m, 4H), 1.43
(d, 6.1Hz, 6H) EIMS 529 (M ⁺ ) 514

Production Example 67 Diethyl = [[[4-[(7
-Isopropoxy-5,6-dimethoxy-4-oxo-
4H-Chromen-2-yl) thio] phenoxy] carbonyl] imino] diacetate (1) Diethyl = [(chloroformyl) imino] diacetate To a solution of 1.57 g of triphosgene in 5 ml of dichloromethane was added 2.14 ml of pyridine under ice-cooling. After stirring for 10 minutes, a solution of 1 g of diethyl iminodiacetic acid in 5 ml of dichloromethane was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate to obtain 1.51 g of diethyl = [(chloroformyl) imino] diacetate. ¹ H-NMR (CDCl ₃ ) 4.31-4.15
(M, 8H), 1.31 (t, 7.1 Hz, 3H),
1.29 (t, 7.1 Hz, 3H)

(2) Diethyl = [[[4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H-
Chromen-2-yl) thio] phenoxy] carbonyl]
Imino] diacetate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
500 mg of ON, 1.40 g of diethyl = [(chloroformyl) imino] diacetate and 6 ml of pyridine were stirred at room temperature for 24 hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give 484.
4 mg (62% yield) was obtained.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.22
(d, 8.7Hz, 2H), 6.58 (s, 1H), 5.84 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 4.32-4.20 (m, 8H), 3.92 (s, 3H), 3.84 (s, 3H),
1.42 (d, 6.1Hz, 6H), 1.32 (t, 7.1Hz, 3H), 1.30 (t, 7.1Hz, 3
H)

Production Example 68 [[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] imino] diacetonitrile (1) [ (Chloroformyl) imino] diacetonitrile In a 10 ml dioxane solution of 3.12 g of triphosgene under ice-cooling,
After adding 4.25 ml of pyridine and stirring for 10 minutes, a solution of 1 g of iminodiacetonitrile in 10 ml of dioxane was added dropwise, and the mixture was stirred at room temperature for 72 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and [(chloroformyl) imino] diacetonitrile was added.
2.04 g was obtained. ¹ H-NMR (CDCl ₃ ) 4.61 (s, 2H), 4.50 (s, 2H) EIMS 157 (M ⁺ ), 130, 122

(2) [[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenoxy] carbonyl] imino] diacetonitrile 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
518.2 mg of ON, 700 mg of [(chloroformyl) imino] diacetonitrile and 5 ml of pyridine were stirred at room temperature for 2 hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (dichloromethane: acetone = 12: 1) to give the title compound (598.7 m).
g (88% yield).

¹ H-NMR (acetone-d ₆ ) 7.79 (d, 8.7 Hz, 2H),
7.47 (d, 8.7Hz, 2H), 6.84 (s, 1H), 5.75 (s, 1H), 4.90-4.6
0 (m, 5H), 3.82 (s, 3H), 3.79 (s, 3H), 1.40 (d, 6.0Hz, 6H) EIMS 509 (M ⁺ ), 494,452

Production Example 69 [[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] imino] diacetate (1) diacetic acid -tert-butyl = [(chloroformyl) imino]
Diacetate Under ice-cooling, 3.56 ml of pyridine was added to a solution of 2.18 g of triphosgene in 20 ml of dichloromethane, and the mixture was stirred for 10 minutes. A solution of 1.80 g of di-tert-butyl iminodiacetate in 20 ml of dichloromethane was added dropwise, followed by stirring at room temperature for 2 hours. . Water was added to the reaction solution, extracted with dichloromethane, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and di-tert-butyl was added.
2.11 g of [(chloroformyl) imino] diacetate was obtained. ¹ H-NMR (CDCl ₃ ) 4.16 (s, 2H), 4.10 (s, 2H), 1.49 (s, 9
H), 1.47 (s, 9H)

(2) di-tert-butyl = [[[4-[(7
-Isopropoxy-5,6-dimethoxy-4-oxo-
4H-chromen-2-yl) thio] phenoxy] carbonyl] imino] diacetate 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
516.3mg, di-tert-butyl = [(chloroformyl)
Imino] diacetate 818mg, pyridine 5ml at room temperature
Stirred for hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 3: 1), and di-tert-butyl was purified.
872 mg of [[[4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl) thio] phenoxy] carbonyl] imino] diacetate.
(99% yield).

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.21
(d, 8.7Hz, 2H), 6.58 (s, 1H), 5.86 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 4.13 (s, 2H), 4.11 (s, 2H), 3.92 (s, 3H), 3.84
(s, 3H), 1.50 (s, 9H), 1.49 (s, 9H), 1.42 (d, 6.1Hz, 6H) FABMS 660 (MH ⁺ )

(3) [[[4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromene-
2-yl) thio] phenoxy] carbonyl] imino] diacetate di-tert-butyl = [[[4-[(7-isopropoxy-
5,6-dimethoxy-4-oxo-4H-chromene-2
-Yl) thio] phenoxy] carbonyl] imino] diacetate (835.9 mg), trifluoroacetic acid (2 ml) and dichloromethane (6 ml) were stirred at room temperature for 20 hours. Add water to the reaction solution,
The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, recrystallization from ethyl acetate-hexane gave 526.8 mg (76% yield) of the title compound.

¹ H-NMR (acetone-d ₆ ) 7.72 (d, 8.7 Hz, 2H),
7.33 (d, 8.7Hz, 2H), 6.83 (s, 1H), 5.72 (s, 1H), 4.80 (hep
t, 6.1Hz, 1H), 4.39 (s, 2H), 4.28 (s, 2H), 3.81 (s, 3H),
3.79 (s, 3H), 1.39 (d, 6.1Hz, 6H) FABMS 548 (MH ⁺ )

Production Example 70 2-[[4-[[N, N-bis (2-hydroxyethyl) carbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4 -One (1) N-benzyl-2,2'-bis (tert-butyldimethylsiloxy) diethylamine N-benzyl-N, N-bis (2-hydroxyethyl)
Amine 6.09 g, imidazole 12.74 g, tert. In DMF 120 ml
14.10 g of -butyldimethylsilyl chloride was added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 50: 1), and N-benzyl-
There was obtained 11.04 g (yield 84%) of 2,2′-bis (tert-butyldimethylsiloxy) diethylamine.

¹ H-NMR (CDCl ₃ ) 7.40-7.20 (m, 5H), 3.71
(s, 2H), 3.66 (t, 6.6Hz, 4H), 2.67 (t, 6.6Hz, 4H), 0.87
(s, 18H), 0.02 (s, 12H) EIMS 423 (M ⁺ ), 408, 366, 278

(2) 2,2'-bis (tert-butyldimethylsiloxy) diethylamine N-benzyl-2,2'-bis (tert-butyldimethylsiloxy) diethylamine 11.04 g of methanol 330 ml
To the solution, 1.1 g of 20% Pd (OH) ₂ -C was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated.
Column chromatography (hexane: ethyl acetate = 1
0: 7) to give 8.45 g (97% yield) of 2,2'-bis (tert-butyldimethylsiloxy) diethylamine.

¹ H-NMR (CDCl ₃ ) 3.75 (t, 5.2 Hz, 4H), 2.76
(t, 5.2Hz, 4H), 0.90 (s, 18H), 0.06 (s, 12H) EIMS 333 (M ⁺ ), 318,276,188

(3) N, N-bis [2- (tert-butyldimethylsiloxy) ethyl] carbamoyl chloride Under ice-cooling, 2.91 ml of pyridine was added to a solution of 1.78 g of triphosgene in 20 ml of dichloromethane, followed by stirring for 10 minutes. 2'-bis (tert-butyldimethylsiloxy) diethylamine
A solution of 2.00 g of dichloromethane in 20 ml was added dropwise and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and 2.43 g of N, N-bis [2- (tert-butyldimethylsiloxy) ethyl] carbamoyl chloride was added. Obtained.

¹ H-NMR (CDCl ₃ ) 3.85-3.77 (m, 4H), 3.68
(t, 5.0Hz, 2H), 3.58 (t, 5.0Hz, 2H), 0.90 (s, 9H), 0.89
(s, 9H), 0.068 (s, 6H), 0.058 (s, 6H) FABMS 396 (MH ⁺ )

(4) 2-[[4-[[N, N-bis [2
-(Tert-butyldimethylsiloxy) ethyl] carbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[(4-hydroxyphenyl) thio] -7 -Isopropoxy-5,6-dimethoxy-4H-chromene-4-
568.3 mg, N, N-bis [2- (tert-butyldimethylsiloxy) ethyl] carbamoyl chloride 1.14
g and pyridine (6 ml) were stirred at room temperature for 20 hours and at 50 ° C for 3 hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (hexane: ethyl acetate = 3: 1) to give 2-[[4-[[N, N-
Bis [2- (tert-butyldimethylsiloxy) ethyl]
Carbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-
1.0295 g (94% yield) of ON was obtained.

¹ H-NMR (CDCl ₃ ) 7.58 (d, 8.7 Hz, 2H), 7.21
(d, 8.7Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.88-3.70 (m, 4H),
3.64 (t, 5.6Hz, 2H), 3.53 (t, 5.6Hz, 2H), 1.43 (d, 6.1Hz, 6
H), 0.91 (s, 18H), 0.087 (s, 6H), 0.081 (s, 6H) FABMS 748 (MH ⁺ )

(5) 2-[[4-[[N, N-bis (2
-Hydroxyethyl) carbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2-[[4-[[N, N-bis [2- (tert- Butyldimethylsiloxy) ethyl] carbamoyl] oxy] phenyl] thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 974.3 mg, 1% conc. HCl-E
10 ml of tOH was stirred at room temperature for 1 hour. Add water to the reaction solution,
The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (ethyl acetate) to give 479.3 mg of the title compound.
(71% yield).

¹ H-NMR (CDCl ₃ ) 7.59 (d, 8.7 Hz, 2H), 7.24
(d, 8.7Hz, 2H), 6.60 (s, 1H), 5.80 (s, 1H), 4.62 (hept, 6.
1Hz, 1H), 3.96-3.90 (m, 4H), 3.91 (s, 3H), 3.84 (s, 3H),
3.70-3.58 (m, 4H), 1.43 (d, 6.1Hz, 6H) FABMS 520 (MH ⁺ )

Production Example 71 7-Isopropoxy-5,6
-Dimethoxy-2-[[4- (methylsulfonylmethoxy) phenyl] thio] -4H-chromen-4-one 7-isopropoxy-5,6-dimethoxy-2-[[4- [(Methylthio) methoxy] phenyl] thio] -4H-chromen-4-one 2.00 g (4.4 g
A solution of 776 mg (4.49 mmole) of m-chlorobenzoic acid in 15 ml of dichloromethane was added dropwise to a solution of 6 mmole) in 20 ml of dichloromethane, and the mixture was stirred at room temperature for 3 hours. Since the raw material did not disappear, 779 mg (4.50 mmole) of m-chlorobenzoic acid was added.
Was added and the mixture was stirred at room temperature for 20 hours. Dichloromethane was added, washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1 to methanol: dichloromethane = 1: 20) and recrystallized from ethyl acetate-hexane to give 345 mg (0.72 mmole, 16 %) As a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.59 (d, J = 8.9 Hz, 2H),
7.15 (d, J = 8.9 Hz, 2H), 6.60 (s, 1H), 5.68 (s, 1
H), 5.03 (s, 2H), 4.62 (hept, J = 6.1 Hz, 1H), 3.91
(s, 3H), 3.85 (s, 3H), 3.07 (s, 3H), 1.43 (d, J = 6.
1 Hz, 6H) FABMS 481 (MH ⁺ )

Production Example 72 7-Isopropoxy-5,6
-Dimethoxy-2-[[4- (methylsulfinylmethoxy) phenyl] thio] -4H-chromen-4-one 7-isopropoxy-5,6-dimethoxy-2-[[4- [(Methylthio) methoxy] phenyl] thio] -4H-chromen-4-one 500 mg (1.12
A solution of 200 mg (1.16 mmole) of m-chlorobenzoic acid in 5 ml of dichloromethane was added dropwise to a solution of 5 mmol of (mmole) in dichloromethane and stirred at room temperature for 23 hours. Dichloromethane was added, washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 20) to give the title compound (303 mg, 0.65 mmol).
e, 58%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) 7.57 (d, J = 8.9 Hz, 2H),
7.15 (d, J = 8.9 Hz, 2H), 6.61 (s, 1H), 5.67 (s, 1
H), 5.05 (d, J = 10.4 Hz, 1H), 4.96 (d, J = 10.4 Hz, 1
H), 4.63 (hept, J = 6.1 Hz, 1H), 3.91 (s, 3H), 3.85
(s, 3H), 2.75 (s, 3H), 1.44 (d, J = 6.1 Hz, 6H) FABMS 465 (MH ⁺ )

Production Example 73 2-[(4-hydroxyphenyl) thio] -4H-chromen-4-one (1) 2-Methylthio-4H-chromen-4-one Potassium hydride (35% oil 1ml) in THF 5ml
And 21.8-hydroxyacetophenone
g, 18-crown-6 351 mg of THF 5 ml solution was added dropwise,
Stir for 1 hour. 1.59 ml of carbon disulfide is added to this solution,
Stirred at room temperature for 20 hours. Thereafter, 1 ml of methyl iodide was added, and the mixture was stirred for 1 hour. Water was slowly added to the reaction solution, and the mixture was extracted twice with ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was subjected to column chromatography (hexane: ethyl acetate =
3: 1) to give 2-methylthio-4H-chromene-
238.1 mg (yield 47%) of 4-one was obtained.

¹ H-NMR (CDCl ₃ ) 8.18 (dd, 8.8 Hz, 2.0 Hz,
1H), 7.64 (ddd, 8.8Hz, 8.6Hz, 2.0Hz, 1H), 7.38
(m, 2H), 6.22 (s, 1H), 2.55 (s, 3H) EIMS 192 (M ⁺ ), 177

(2) 2-Methylsulfinyl-4H-chromen-4-one 226 mg of 2-methylthio-4H-chromen-4-one, 724 mg of oxone, 6 ml of methanol and 6 ml of water were stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 199.9 mg of 2-methylsulfinyl-4H-chromen-4-one (yield: 81%). ¹ H-NMR (CDCl ₃ ) 8.24 (dd, 8.8Hz, 2.0Hz, 1H), 7.80-
7.45 (m, 3H), 6.98 (s, 1H), 2.30 (s, 3H)

(3) 2-[(4-hydroxyphenyl)
Thio] -4H-chromen-4-one 2-methylsulfinyl-4H-chromen-4-one 19
0 mg, 173 mg of 4-hydroxybenzenethiol, 189 mg of potassium carbonate and 5 ml of acetone were stirred at room temperature for 2 hours.
Dilute hydrochloric acid was added to the reaction solution, and the resulting solid was collected by filtration and recrystallized from methanol to obtain 79.2 mg (yield 37%) of the title compound.

¹ H-NMR (DMSO-d ₆ ) 10.28 (s, 1H), 7.97
(dd, 7.8Hz, 1.6Hz, 1H), 7.77 (ddd, 8.6Hz, 7.2Hz,
1.6Hz, 1H), 7.59-7.38 (m, 4H), 6.96 (d, 8.6Hz, 2
H), 5.62 (s, 1H) EIMS 270 (M ⁺ ), 253, 237, 150

Production Example 74 2-[(4-hydroxyphenyl) thio] -5-methoxy-4H-chromen-4-one (1) 5-methoxy-2-methylthio-4H-chromen-4-one Under ice-cooling , Potassium hydride (35% oil 1ml) in THF 5ml
And 22.1 g of 2'-hydroxy-6'-methoxyacetophenone and 288 mg of 18-crown-6 in 5 m of THF.
l The solution was added dropwise and stirred for 1 hour. 1.30 ml of carbon disulfide was added to this solution, and the mixture was stirred at room temperature for 20 hours. Thereafter, 1 ml of methyl iodide was added, and the mixture was stirred for 1 hour. Water was slowly added to the reaction solution, and the mixture was extracted twice with ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (hexane: ethyl acetate = 1: 1).
165.4 mg of -methylthio-4H-chromen-4-one
(34% yield).

¹ H-NMR (CDCl ₃ ) 7.51 (t, 8.5 Hz, 1H), 6.
97 (dd, 8.5Hz, 1.0Hz, 1H), 6.80 (dd, 8.5Hz, 1.0Hz,
1H), 6.11 (s, 1H), 3.97 (s, 3H), 2.50 (s, 3H) EIMS 222 (M ⁺ ), 205, 193, 176

(2) 5-methoxy-2-methylsulfinyl-4H-chromen-4-one 5-methoxy-2-methylthio-4H-chromen-4-one
ON 152.1mg, Oxone 295mg, Methanol 5ml, Water 5m
l was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5-methoxy-2-methylsulfinyl-4H-chromen-4-.
On was obtained in an amount of 105 mg (yield: 64%). ¹ H-NMR (CDCl ₃ ) 7.61 (t, 8.3 Hz, 1H), 7.03 (dd, 8.3H
z, 1.0Hz, 1H), 6.88 (dd, 8.3Hz, 1.0Hz, 1H), 6.84
(s, 1H), 4.00 (s, 3H), 2.96 (s, 3H)

(3) 2-[(4-hydroxyphenyl)
Thio] -5-methoxy-4H-chromen-4-one 90.6 mg of 5-methoxy-2-methylsulfinyl-4H-chromen-4-one, 4-hydroxybenzenethiol
72 mg, potassium carbonate 79 mg and acetone 3 ml were stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to the reaction solution, and the resulting solid was collected by filtration and recrystallized from hexane-ethyl acetate to give the title compound (44.8 mg, yield 39%). ¹ H-NMR (DMSO-d ₆ ) 10.25 (s, 1H), 7.63 (t, 8.4 Hz, 1
H), 7.51 (d, 8.7Hz, 2H), 7.06-6.95 (m, 4H), 5.44
(s, 1H), 3.82 (s, 3H) EIMS 300 (M ⁺ ), 283, 271, 254

Production Example 75 2-[(4-hydroxyphenyl) thio] -6-methoxy-4H-chromen-4-one (1) 6-methoxy-2-methylthio-4H-chromen-4-one Under ice-cooling , Potassium hydride (35% oil 1ml) in THF 5ml
And 29.5 mg of 2′-hydroxy-5′-methoxyacetophenone and 262 mg of 18-crown-6 in 5 m of THF.
l The solution was added dropwise and stirred for 1 hour. 1.18 ml of carbon disulfide was added to this solution, and the mixture was stirred at room temperature for 20 hours. Thereafter, 1 ml of methyl iodide was added, and the mixture was stirred for 1 hour. Water was slowly added to the reaction solution, and the mixture was extracted twice with ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (hexane: ethyl acetate = 3: 1) to give 6-methoxy-2
239.1 mg of -methylthio-4H-chromen-4-one
(54% yield). ¹ H-NMR (CDCl ₃ ) 7.54 (d, 2.9 Hz, 1H), 7.34 (d, 9.3H
z, 1H), 7.21 (dd, 9.3Hz, 2.9Hz, 1H), 6.21 (s, 1H),
3.89 (s, 3H), 2.54 (s, 3H) EIMS 222 (M ⁺ ), 207, 150

(2) 6-methoxy-2-methylsulfinyl-4H-chromen-4-one 6-methoxy-2-methylthio-4H-chromen-4-one
ON 226.3mg, Oxone 439mg, Methanol 6ml, Water 6m
l was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 6-methoxy-2-methylsulfinyl-4H-chromen-4-.
On was obtained 224.5 mg (94% yield). ¹ H-NMR (CDCl ₃ ) 7.59 (d, 3.0Hz, 1H), 7.42 (d, 9.0H
z, 1H), 7.31 (dd, 9.0Hz, 3.0Hz, 1H), 6.94 (s, 1H),
3.91 (s, 3H), 2.98 (s, 3H)

(3) 2-[(4-hydroxyphenyl)
Thio] -6-methoxy-4H-chromen-4-one 211 mg of 6-methoxy-2-methylsulfinyl-4H-chromen-4-one, 4-hydroxybenzenethiol
171 mg, potassium carbonate 188 mg, acetone 5 ml at room temperature
Stirred for hours. Dilute hydrochloric acid was added to the reaction solution, and the resulting solid was collected by filtration and recrystallized from methanol to give the title compound (145.7).
mg (54% yield). ¹ H-NMR (DMSO-d ₆ ) 10.28 (s, 1H), 7.56-7.49 (m, 3H),
7.38-7.31 (m, 2H), 6.96 (d, 8.7Hz, 2H), 5.60 (s, 1
H), 3.83 (s, 3H) EIMS 300 (M ⁺ ), 285, 270

Production Example 76 2-[(4-hydroxyphenyl) thio] -7-methoxy-4H-chromen-4-one (1) 7-methoxy-2-methylthio-4H-chromen-4-one Under ice-cooling , Potassium hydride (35% oil 1ml) in THF 5ml
And 310 mg of 2'-hydroxy-4'-methoxyacetophenone, 494 mg of 18-crown-6 in 5 ml of THF.
The solution was added dropwise and stirred for 1 hour. Add carbon disulfide to this solution
3.4 ml was added and the mixture was stirred at room temperature for 20 hours. Thereafter, 1 ml of methyl iodide was added, and the mixture was stirred for 1 hour. Water was slowly added to the reaction solution, and the mixture was extracted twice with ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was subjected to column chromatography (hexane:
The mixture was purified with ethyl acetate = 2: 1) to obtain 230.3 mg of 7-methoxy-2-methylthio-4H-chromen-4-one (yield).
55%). ¹ H-NMR (CDCl ₃ ) 8.07 (d, 8.8 Hz, 1H), 6.95 (dd, 8.8H
z, 2.4Hz, 1H), 6.82 (d, 2.4Hz, 1H), 6.15 (s, 1H),
3.90 (s, 3H), 2.53 (s, 3H) EIMS 222 (M ⁺ ), 207, 179, 150

(2) 7-methoxy-2-methylsulfinyl-4H-chromen-4-one 7-methoxy-2-methylthio-4H-chromen-4-one
ON 205.8mg, Oxone 570mg, Methanol 6ml, Water 6m
l was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 7-methoxy-2-methylsulfinyl-4H-chromene-4-
191.3 mg (87% yield) of ON was obtained. ¹ H-NMR (CDCl ₃ ) 8.14 (d, 9.0Hz, 1H), 7.03 (dd, 9.0H
z, 2.2Hz, 1H), 6.89 (d, 2.2Hz, 1H), 6.88 (s, 1H),
3.92 (s, 3H), 2.97 (s, 3H)

(3) 2-[(4-hydroxyphenyl)
Thio] -7-methoxy-4H-chromen-4-one 183.9 mg of 7-methoxy-2-methylsulfinyl-4H-chromen-4-one, 146 mg of 4-hydroxybenzenethiol, 160 mg of potassium carbonate and 5 ml of acetone were added at room temperature. Stir for 2 hours. Dilute hydrochloric acid was added to the reaction solution, and the resulting solid was collected by filtration and recrystallized from methanol to give the title compound as 188.
5 mg (81% yield) was obtained.

¹ H-NMR (DMSO-d ₆ ) 10.27 (s, 1H), 7.86
(d, 8.8Hz, 1H), 7.52 (d, 8.7Hz, 2H), 7.11 (d, 2.3H
z, 1H), 7.04 (dd, 8.8Hz, 2.3Hz, 1H), 6.95 (d, 8.7H
z, 2H), 5.52 (s, 1H), 3.88 (s, 3H) EIMS 300 (M ⁺ ), 151

Production Example 77 5-Hydroxy-2-[(4
-Hydroxyphenyl) thio] -7-isopropoxy-
6-methoxy-8- (1-pyrrolidinylmethyl) -4H
-Chromen-4-one (1) 5-hydroxy-7-isopropoxy-6-methoxy-2-propylthio-4H-chromen-4-one 5-hydroxy-7-isopropoxy-2- (4-isopropoxyphenoxy ) -6-Methoxy-4H-chromen-4-one (compound of Example 4 in WO92 / 09594) A solution of 1.48 g, propanethiol 0.7 ml, sodium hydroxide 496 mg and DMSO 12 ml was stirred at room temperature for 1 hour.
Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (hexane: ethyl acetate = 100: 17).
5-hydroxy-7-isopropoxy-6-methoxy-
1.08 g of 2-propylthio-4H-chromen-4-one
(81% yield).

¹ H-NMR (CDCl ₃ ) 12.59 (s, 1H), 6.38 (s,
1H), 6.10 (s, 1H), 4.63 (m, 1H), 3.86 (s, 3H), 3.
01 (t, 7.3Hz, 2H), 1.79 (m, 2H), 1.42 (d, 5.9Hz, 6
H), 1.08 (t, 7.3Hz, 3H) EIMS 324 (M ⁺ ), 281, 267

(2) 5-hydroxy-7-isopropoxy-6-methoxy-2-propylthio-8- (1-pyrrolidinylmethyl) -4H-chromen-4-one 5-hydroxy-7-isopropoxy- 6-methoxy-
2-propylthio-4H-chromen-4-one 61 mg, pyrrolidine 0.157 ml, paraformaldehyde 56 mg, acetic acid 0.
A mixed solution of 5 ml and 2 ml of ethanol was stirred at 70 ° C. for 20 hours. The reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate) to give 5-hydroxy-7-isopropoxy-6-methoxy-2-propylthio-8- (1-pyrrolidinylmethyl)- 26 mg (yield 35%) of 4H-chromen-4-one was obtained.

¹ H-NMR (CDCl ₃ ) 12.86 (s, 1H), 6.13 (s,
1H), 4.92 (m, 1H), 3.89 (s, 3H), 3.80 (s, 2H), 3.
09 (t, 7.0Hz, 2H), 2.56 (m, 4H), 1.80-1.65 (m, 6
H), 1.31 (d, 6.4Hz, 6H), 1.08 (t, 7.3Hz, 3H) EIMS 407 (M ⁺ ), 337, 295

(3) 5-hydroxy-7-isopropoxy-6-methoxy-2-propylsulfinyl-8-
(1-Pyrrolidinylmethyl) -4H-chromen-4-one Under ice cooling, 5-hydroxy-7-isopropoxy-6-methoxy-2-propylthio-8- (1-pyrrolidinylmethyl) -4H- 187 mg of chromen-4-one was dissolved in 10% sulfuric acid, and a solution of 212 mg of oxone in 10% sulfuric acid was added thereto, followed by stirring at room temperature for 20 hours. The reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 5-hydroxy-7-isopropoxy-6-methoxy-2-propylsulfinyl-8- (1
-Pyrrolidinylmethyl) -4H-chromen-4-one
174 mg (88% yield) were obtained.

(4) 5-hydroxy-2-[(4-hydroxyphenyl) thio] -7-isopropoxy-6-methoxy-8- (1-pyrrolidinylmethyl) -4H-chromen-4-one 5 -Hydroxy-7-isopropoxy-6-methoxy-
169 mg of 2-propylsulfinyl-8- (1-pyrrolidinylmethyl) -4H-chromen-4-one, 101 mg of 4-hydroxybenzenethiol, 110 mg of potassium carbonate and 10 ml of acetone were stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (chloroform: methanol = 30: 1).
g (yield 70%) was obtained.

¹ H-NMR (CDCl ₃ ) 7.36 (d, 8.8 Hz, 2H), 6.
77 (d, 8.8Hz, 2H), 5.78 (s, 1H), 4.93 (m, 1H), 3.86
(s, 5H), 2.58 (m, 4H), 1.76 (m, 4H), 1.29 (d, 6.4
Hz, 6H) EIMS 457 (M ⁺ ), 388, 345, 331

Experimental Example 1 Neuronal Cell Death Inhibitory Effect of Chromone Derivatives This experiment was performed by PD Martin (PD Mart).
In) et al. [Journal of Cell Biology
y), 106, 829-844, 1988]. That is, the superior cervical sympathetic ganglion (Superior Cervical ganglion) extracted from a rat fetus on the 21st day of fetal life
Ganglion, SCG) was pre-cultured for 7 days in a culture solution supplemented with mouse nerve growth factor (NGF) at a concentration of 50 ng / ml, followed by a 2-day culture period.
If 50 ng / ml NGF is present, the neurons are alive, but if no NGF is present, all neurons will die. In the absence of NGF, protein synthesis and RN
When A synthesis is inhibited, all nerve cells survive. In this case, it can be considered that the nerve cells are alive because the protein that causes cell death is not synthesized. On the other hand, in the presence of NGF, it is considered that synthesis of a protein that causes cell death and its cell death effect are suppressed.

(1) Dissection and collection of SCG Dissection buffer: Hanks 'Balanced Salt Solution [Hanks' Balanced Salt]
Solution (HBSS), Sigma (Sigma)
a) 1 L of 15 mM Hepes (HEP)
ES, Wako) solution (pH 7.2), 0.22 μm
Sterilized through a filter (hereinafter “HBSS solution”)
Was used. Rat: Specific Pathogen Free (sp
effective pathogen free, SPF)
Of Wistar strain (Japan SLC) was purchased and used on day 21 of pregnancy.

Method: A rat on the 21st day of pregnancy was anesthetized with ether for about 5 minutes, and then placed on a dissecting table, and the left and right carotid arteries were cut and bled. After spray disinfection of the abdomen with 70% alcohol, a large incision was made on the skin with dissecting scissors, and the exposed peritoneum was cut in small cross sections (about 2 cm) together with the abdominal muscle to expose the abdominal cavity. The right and left uterine horns containing about 10 fetuses on average were taken out with flame-sterilized forceps and sterile dissecting scissors.
It was placed in a 0 mm petri dish (Falcon). The uterine and fetal membranes were cut in a petri dish, the fetuses separated from each placenta were removed one by one, and the fetuses were collected in another Petri dish containing a new HBSS solution. The upper part of the fetus was cut off from the chest, and after penetrating the jaw from the abdomen with a syringe needle, the fetus was fixed on a wax table facing up. The skin, muscles and glands from the chest to the neck are removed with sterile tweezers and sterile dissection scissors while absorbing the exuding body fluid and blood with sterile gauze. There is a bar-shaped slightly hard SCG. One pair of this SCG per fetus was collected in a 35 mm petri dish containing HBSS solution for all fetuses.

(2) Collection of SCG nerve cells, seeds, and culture method Cell culture solution: Minimum Essential Medium
m, Gibco) with 10 fetal calf serum (Flow)
In addition, penicillin G potassium (Meiji Seika) and streptomycin (Manyu Pharmaceutical Co., Ltd.) are respectively 100 units (units) / ml and 100 μg / ml, uridine (Uridine, Sigma) and fluorodeoxyuridine (Fluorodeoxyuridine, respectively).
Sigma) were added so that the concentration of each was 20 μM (hereinafter referred to as “culture solution (A)”).

SCG neurons: For SCG neurons: Excess connective tissue around each SCG was removed with sterile forceps under a stereomicroscope (Nikon) and washed three times with fresh HBSS solution in a Petri dish. After that, SCGs were added to 1 ml of HBSS solution containing collagenase (Wako) at a concentration of 1 mg / ml,
Incubated for 0 minutes. During that time, the liquid was stirred 2-3 times. Then, SCGs were reduced to 70 to 8 using a Pasteur pipette whose tip area was further narrowed by a burner.
SCG neurons were dissociated by moving in and out 0 times. The cell concentration of this SCG nerve cell suspension was determined by the cell count method using trypan blue staining.

Method: Mouse 2.5S nerve growth factor (NG
F, Takara Shuzo) was added to the culture solution (A) at a concentration of 50 ng / ml (hereinafter, referred to as “culture solution (B)”), and 600 μl of SCG equivalent to 1/2 to 1/3 was used. A dilution containing the cells was made. This cell suspension was transferred to a collagen-coated 24-well cell culture plate (Coas
tar, cat. No. 1 in 25820 col1)
600 μl of seeds were seeded per well, and culture was started at 37 ° C. under 5% carbon dioxide (CO ₂ ). Thereafter, preculture was performed for 7 days while replacing the entire amount of the culture solution (B) every other day.

(3) Sample assay method On day 7 of the preculture, the culture solution (B) was discarded, and then a sufficient amount of anti-mouse to neutralize NGF in the culture solution (B) remaining in the well. A solution obtained by adding the NGF antibody to the culture solution (A) (hereinafter referred to as “culture solution (C)”. Antibody concentration: 4.17 μl / m
A solution prepared by dissolving various chromone derivatives in 1) was placed in a well, and the culture was further continued for 2 days. The chromone derivative was weighed and dissolved so that the concentration in the culture solution (C) became 50 μg / ml. Culture solution without chromone derivative (C)
A control group was obtained by culturing the cells. After completion of the 2-day culture test, the number of surviving cells and the number of dead cells in each well were counted under a microscope by the cell count method using trypan blue staining, and the ratio of the number of dead cells was calculated.

The results are shown in Table 1.

[0271]

[Table 1]

As is clear from the results shown in Table 1, 100% of the cells died in the control group, whereas the chromone derivative-added group suppressed the cell death. That is, it was confirmed that the chromone derivative used in the present invention had a remarkable nerve cell death inhibitory effect. Therefore, it is confirmed that the chromone derivative used in the present invention is useful as a neuronal cell death inhibitor which can be used for treatment of Alzheimer's disease, Down's syndrome, vascular dementia, Parkinson's disease, amyotrophic lateral sclerosis and the like. Was.

Experimental Example 2 Bioavailability of Chromone Derivatives (1) Experimental Animal Male Wistar rats (Charles River Japan, 8 weeks old) were used after fasting for about 18 hours. In addition,
The animals were preliminarily reared for at least one week at a temperature of 23 ± 2 ° C. and a humidity of 55 ± 10% before being subjected to the experiment. Rats feed on solid feed (MF,
Oriental Yeast Co., Ltd.). The number of animals subjected to the test was 3 per group. (2) Administration method Various chromone derivatives were suspended in 1% Tween 80 physiological saline and administered by oral gavage with a metal probe at a dose of 100 mg / kg / 10 ml.

(3) Measurement of Plasma 2-[(4-Hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one Concentration Various chromone derivatives were orally administered to rats. Thereafter, blood was collected with time and 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H in plasma
-Chromen-4-one concentration was measured using high performance liquid chromatography (HPLC).

(I) Blood Collection and Preparation of Plasma In an experiment of oral administration of a chromone derivative, rats were subjected to a heparin saline solution (200 U / m
l) A cannula filled with was filled and fixed in a Bollman cage. After awakening from anesthesia, administer the chromone derivative, and after administration from the cannula 5, 15, 30, 45, 60, 90, 12
Blood samples were collected at 0, 180, 240, and 360 minutes, about 350 μl with time. Also, 2-[(4-hydroxyphenyl)
Thio] -7-isopropoxy-5,6-dimethoxy-4
In the experiment of oral administration of H-chromen-4-one, blood was collected from the tail vein at time of about 30, 50, 60 and 120 minutes after administration, about 350 μl each. Blood obtained is 3000 rpm, 10 minutes, 4
Plasma was obtained by centrifugation at ° C. Of these, 50 μl was used for plasma concentration measurement.

(Ii) Preparation of calibration curve 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-dimethoxy-4H-chromene-4-
A 100 μg / ml methanol solution was prepared, and this solution was serially diluted with methanol to obtain 10, 5, 1, 0.1, 0.05 and
Standard solutions at concentrations of 0.01 μg / ml or 10, 2, 0.4, 0.08 and 0.016 μg / ml were prepared. To 50 μl of blank plasma, 150 μl of an internal standard substance (butyl p-hydroxybenzoate 100 μg / ml in methanol), and further to 2-[(4-hydroxyphenyl) thio] -7-isopropoxy-5,6-
Dimethoxy-4H-chromen-4-one standard solution 50 μ
l was shaken for 20 minutes after addition. After that, 3000rpm, 4 ℃
, And the supernatant was transferred to another tube and evaporated to dryness using a freeze-centrifugal dryer. 1% methanolic phosphate 1
Redissolve in 00μl (shake for 3 minutes, sonicate for 3 minutes)
Then, 40 μl was injected into the HPLC.

(Iii) Pretreatment of sample 50 μl of rat plasma was mixed with 150 μl of an internal standard substance (butyl p-hydroxybenzoate 100 μg / ml in methanol) and HP
After adding 50 μl of methanol for LC, the mixture was shaken for 20 minutes. Thereafter, the mixture was centrifuged at 3000 rpm at 4 ° C. for 20 minutes, the supernatant was transferred to another tube, and evaporated to dryness using a freeze centrifugal dryer. 1
The mixture was redissolved in 100 µl of methanol (% shaking for 3 minutes and sonicated for 3 minutes), and 40 µl was injected into HPLC.

(Iv) HPLC analysis conditions-instrument-Pump LC-10AD (Shimadzu) UV detector SPD-10A (Shimadzu) System controller SCL-10A (Shimadzu) Auto injector SIL-10A (Shimadzu) Column oven CTO-6A (Shimadzu) Degasser DGU-4A (Shimadzu) Sample cooler SAMPLE COOLER (Shimadzu) Recorder C-R7A plus (Shimadzu) -Condition- Column TSK gel ODS-80TM 4.6 × 150mm (Tosoh Corporation) Using guard column Temperature 40 ° C Mobile phase composition ratio 55% Acetonitrile Flow rate 1 ml / min UV wavelength 303nm

(4) Calculation of Pharmacokinetic Coefficients The maximum plasma concentration (Cmax) and the time to reach the maximum plasma concentration (Tmax) were determined from the actually measured values. Further, the area under the time-plasma concentration curve (AUC0-lim) up to the final measurement point and the area under the time-plasma concentration curve up to infinity (AUC0-inf) were calculated by the trapezoidal method. Time up to 120 minutes after administration of various chromone derivatives-area under the plasma concentration curve (AUC0 _0-120min ) (μ
g · min / ml) are shown in Table 2.

[0280]

[Table 2]

As is clear from the results shown in Table 2, the chromone derivatives shown in the table are 2-[(4-
Hydroxyphenyl) thio] -7-isopropoxy-
It was confirmed that the bioavailability of 5,6-dimethoxy-4H-chromen-4-one was improved.

EXPERIMENTAL EXAMPLE 3 Nerve Conduction Velocity Improving Effect of Chromone Derivatives A nerve conduction test (the latest medicine, vol. 50, 771-780) which is said to be the most useful means for diagnosing peripheral neuropathy complicated at a high rate in diabetic patients. , 1995) for various chromone derivatives. (1) Diabetes-induced Wistar male rats (Charles River Japan, 8 weeks old) were treated with 10 mM citrate buffer (pH
Streptozotocin (STZ) 65 dissolved in 4.5)
mg / kg was administered via the tail vein to induce diabetes. S
Two weeks after TZ administration, the blood glucose level was 300 mg / dl or more.
TZ diabetic rats were used. The number of animals to be tested is 1
There were eight cases in the group. (2) Drug administration The chromone derivative was 1% Tween 80 at a concentration of 1 mg / kg.
And orally administered for 4 weeks from 2 weeks after STZ administration. A mouse to which 1% Tween 80 containing no chromone derivative was similarly administered was used as a diabetes control.

(3) Measurement of nerve conduction velocity (MNCV) The method of Miyoshi and Goto (Electroncephalogaphy and Clinical)
Neurophysiology, 35, 125-131, 197
MNCV of rat tail nerve was measured according to 3). After anesthesia by intraperitoneal administration of Nembutal 50 mg / kg, the tail nerve was used as the nerve to be examined, the first stimulation point 1 cm from the anus, the second stimulation point 5 cm from the anus, and the recording point 3 cm further. And the MNCV was measured. MN
CV was determined by the following equation.

MNCV (m / sec) = D (mm) / (L2−L1 (msec)) D; distance between first stimulus point and second stimulus point L1; conduction time from first stimulus point to recording point L2 Conduction time from the second stimulus point to the recording point. The tail is kept in a 37 ° C. paraffin incubator, and a temperature sensor (thermosensitive needle THR) is placed 3 to 4 cm from the anus.
-NST, Shibaura Electronics), Animal BranketControll
er (ATB-1100, Nihon Kohden) with tail temperature of 37
° C. As the MNCV measuring instrument, Neuropack MEB-5304 (Nihon Kohden) was used. Table 3 shows the results.

[0285]

[Table 3]

As is clear from the results shown in Table 3, it was confirmed that the chromone derivative improved the nerve conduction velocity in diabetic rats, and was shown to be effective for peripheral neuropathy accompanying diabetic patients.

Example 1 According to the above-mentioned prescription,-was uniformly mixed, and the mixture was compression-molded with a tableting machine to obtain a tablet of 200 mg per tablet. One tablet contains 20 mg of the compound obtained in Production Example 8, and 10 to 25 tablets per day for an adult are taken several times.

Embodiment 2 According to the above formula, a part of the mixture was uniformly mixed, compression-molded, pulverized, mixed with the remaining amount, and compression-molded with a tablet machine to obtain a tablet of 200 mg per tablet. . One tablet contains 20 mg of the compound obtained in Production Example 45, and 10 to 25 tablets per day for an adult are divided into several doses.

Embodiment 3 According to the above formula, and are uniformly mixed, mashed by a conventional method, granulated by an extruder, dried,
After crushing, and were mixed, the mixture was compression-molded with a tableting machine to obtain a tablet of 200 mg per tablet. One tablet contains 20 mg of the compound obtained in Production Example 37, and the adult daily dose is 10 to 10 mg.
Take 25 tablets several times.

Embodiment 4 According to the above-mentioned prescription, 〜 was uniformly mixed, compression-molded by a compression molding machine, pulverized by a crusher, and sieved to obtain granules. 1 g of this granule contains the compound obtained in Production Example 12.
It contains 100mg, and adults take 2-5g a day in several doses.

Embodiment 5 According to the above-mentioned formula, was mixed uniformly and wetted. The mixture was granulated by an extrusion granulator, dried and sieved to obtain granules. 1 g of this granule contains 100 mg of the compound obtained in Production Example 57 (4), and 2 to 5 g of an adult per day.
Take several times.

Embodiment 6 Mix uniformly according to the above formula, and add 200 mg to 2
No. capsules. One capsule contains 20 mg of the compound obtained in Production Example 34, and 10 to 25 capsules per day for an adult are divided into several doses.

[0293]

EFFECTS OF THE INVENTION The nerve cell death inhibitor of the present invention includes Alzheimer's disease, Down's syndrome, vascular dementia, Parkinson's disease,
It is effective for treating diseases such as amyotrophic lateral sclerosis and peripheral neuropathy.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/535 ABJ A61K 31/535 ABJ // C07D 311/54 C07D 311/54 405/12 207 405/12 207 211 211 (72 Inventor Shunji Sato 3586 Yoshiwara, Ami-cho, Inashiki-gun, Ibaraki Pref.

Claims (6)

[Claims] (1) The following formula (I): (Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are each a hydrogen atom, a hydroxyl group, a C _1-6 -alkoxy group, a C _2-6
-Represents an alkenyloxy group, an acyloxy group or a substituted or unsubstituted C _1-6 -alkyl group, wherein X is an oxygen atom,
Sulfur atom, -SO-, SO ₂ - or an -NH-,
R ⁵ represents a substituted or unsubstituted phenyl group, aralkyl group or heterocyclic group. Or a pharmaceutically acceptable salt thereof as an active ingredient. 2. In the formula (I), R ¹ is a hydrogen atom, R ² is an isopropoxy group, R ³ and R ⁴ are methoxy groups, R ⁵ is a 4-[(methylthio) methoxy] phenyl group, and X is 2. The nerve cell death inhibitor according to claim 1, which is a sulfur atom. 3. In the formula (I), R ¹ is a hydrogen atom, R ² is an isopropoxy group, R ³ and R ⁴ are methoxy groups, R ⁵ is a 4-[(ethoxycarbonyl) oxy] phenyl group, X The nerve cell death inhibitor according to claim 1, wherein is a sulfur atom. 4. In the above formula (I), R ¹ is a hydrogen atom, R ² is an isopropoxy group, R ³ and R ⁴ are methoxy groups, R ⁵ is a 4-[(ethylcarbamoyl) oxy] phenyl group, X The nerve cell death inhibitor according to claim 1, wherein is a sulfur atom. 5. In the above formula (I), R ¹ is a hydrogen atom, R ² is an isopropoxy group, R ³ and R ⁴ are methoxy groups, R ⁵ is a 4-[(dimethylcarbamoyl) oxy] phenyl group, X The nerve cell death inhibitor according to claim 1, wherein is a sulfur atom. 6. In the formula (I), R ¹ is a hydrogen atom, R ² is an isopropoxy group, R ³ and R ⁴ are methoxy groups, and R ⁵ is 4-[[N- (2-hydroxyethyl)- N
The nerve cell death inhibitor according to claim 1, wherein the -methylcarbamoyl] oxy] phenyl group and X are sulfur atoms.