JP2005314240A - Coumarin derivative and maillard reaction inhibitor containing the derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a coumarin derivative useful as a Maillard reaction inhibitor and its pharmaceutically acceptable salt. <P>SOLUTION: The coumarin derivative has an excellent action to inhibit saccharifying crossliking of a protein by the Maillard reaction, and accordingly is useful for the prophylaxis or therapy of diseases caused by the saccharifying crosslinking of a protein, for example, diabetic complication such as diabetic neuropathy, dialysis complication such as dialysis-related amyloidosis or a disease or impairment caused by aging, and can be also utilized as a cosmetic for skin-aging prevention and a skin-whitening effect by inhibiting crosslinking formation of collagen which causes hardening of the skin, formation of wrinkles and the like and discoloration of the skin. Furthermore, this compound is useful as a discoloration/deterioration inhibitor added to cosmetics and foods containing proteins and amino acids. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a coumarin derivative useful as a Maillard reaction inhibitor and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, a cosmetic, and a discoloration / deterioration inhibitor.

In 1912 Maillard reported focusing on the phenomenon that a mixture of amino acids and reducing sugars turns brown when heated [Maillard, LC, Compt. Rend. Soc. Biol., Vol.72, p599 (1912) ]. This was due to the reaction between amino acids and sugars, and it was suggested that this reaction could occur in vivo. Leads to 1968, Raba (Rahbar) is Hb · _1c is a component of hemoglobin, was reported to be increased in diabetic patients [Rahbar, S., Clin. Chim. Acta., Vol.22, p296 (1968) ]. Later, the chemical structure of this Hb · _1c is that glucose is bound to the chain N-terminal valine in the form of Amadori rearrangement [Koenig, RJ et al., J. Biol. Chem., Vol.252, p2992 (1977 )) And that this reaction occurs non-enzymatically (Stevens, VJ et al., J. Biol. Chem., Vol. 252, p2998 (1977)), etc. Was confirmed to be happening in

  The mechanism of the Maillard reaction in vivo has been reported by Brownlee et al. [Brownlee, M. et al., Science, vol.232, p1629 (1986)]. That is, first, an aldehyde group of glucose reacts with an amino group in a protein to form a Schiff base. Since this Schiff base is unstable, it quickly undergoes an intramolecular rearrangement reaction and is non-enzymatically converted to an Amadori rearrangement product. Further, this Amadori rearrangement product gradually undergoes a dehydration reaction and changes to a new glucose derivative, which proceeds to the stage of irreversibly cross-linking with an amino group such as a protein molecule to form a bridge. Through such a process, a protein polymer is mainly formed, and a late reaction product AGE (Advanced Glycation End products) of Maillard reaction is generated. As AGE is produced, the biological adaptability of the protein is reduced and the solubility is lowered, making it less susceptible to the action of proteases. Furthermore, fluorescence is eventually produced and the color becomes brown.

  The Maillard reaction is a phenomenon that is also seen in healthy individuals, but it is prominently observed in diabetic patients whose blood glucose levels are elevated and in protein sites with slow turnover. For example, in hemoglobin of diabetic mice, glycation of 2.7 times that of normal mice occurs [Monnier, VM et al., The Maillard Reaction in Foods and Nutrition, ACS Symposium Series, vol. 215, p432, Am. Chem. Soc., Washington DC (1983)]. Serum albumin has also been reported to increase glycation in diabetic patients [Guhrow, CE et al., Proc. Natl. Acad. Sci. U.S. vol. 76, p4258 (1979)]. Furthermore, repeated iv glycated serum protein in mice over 12 weeks has been shown to show typical diabetic kidney injury [Monnier, VM et al., Clin. Endocrinol. Metab., Vol. 11, p431 (1982)].

  The ocular lens crystallin is a special protein that does not turn over at all once biosynthesized. When glycation occurred in this crystallin, it was confirmed that the conformation was changed and an S—S bond involving an enzyme was formed in the intramolecular SH group, resulting in a high molecular weight. In diabetic cataracts in rats, binding to glucose is up to 10 times that of normal, and intramolecular SS binding has also been shown to increase [Monnier, VM et al., Clin. Endocrinol. Metab., Vol. 11, p431 (1982)]. Along with this glycation of crystallin, polymerization, insolubilization, fluorescence generation and yellow-brown coloration occur, and these changes are in good agreement with lens changes with age [Chiou, SH et al., J. Biol. Chem., Vol. 256, p5176 (1981)].

  Collagen and elastin present in connective tissue are rich in lysine and hydroxylysine, and are proteins with slow turnover. Conjugates with glucose have been found in the glomerular basement membrane, skin, and tendons [ Monnier, VM et al., Maillard Reactions in Food, Prog. Food Nutr. Sci., Vol.5, p315, Pergamon Press London), and also thought to be related to vascular wall hardening (Rosenburg, H. et al., Biochem. Biophys. Res. Commun., Vol. 91, p498 (1979)]. Further, glycation of neuromyelin protein is considered as a cause of diabetic neurological disease [Monnier, V. M. et al., Clin. Endocrinol. Metab. Vol. 11, p431 (1982)]. Thus, the Maillard reaction is considered to be involved not only in various complications of diabetes but also in various diseases associated with aging (aging).

  In recent years, a search for a substance that inhibits the Maillard reaction has been made in the background as described above. For example, Brownley et al. Have shown that aminoguanidine blocks the Maillard reaction in vitro and that administration of aminoguanidine to diabetic rats suppresses AGE formation in the arterial wall [Brownlee, M. et al. et al., Science, vol.232, p1629 (1986)]. The mechanism of action is that the amino group of aminoguanidine, which is a nucleophilic hydrazide compound (the amino group bonded to the guanidino group) blocks the active carbonyl group in the Amadori rearrangement product, and the Amadori rearrangement product is further crosslinked and polymerized. It is suggested that this is due to the fact that

  Furthermore, a composition comprising a compound having an active nitrogen-containing group (guanidino group or amino group bonded to a guanidino group) capable of reacting with an active carbonyl group in the Amadori rearrangement product suppresses the formation of a secondary glycation end product. Specifically, a compound selected from aminoguanidine, .-hydrazinohistidine, lysine and a mixture thereof (see Patent Document 1), and a novel guanidyl derivative (see Patent Document 2) are disclosed. Has been.

  On the other hand, as a Maillard reaction inhibitor having no active nitrogen-containing group capable of reacting with an active carbonyl group, an active ingredient is baicalin, which is a flavonoid contained in yellow rice (see Patent Document 3), and proanthocyanidin is an active ingredient. Various Maillard reaction inhibitors are disclosed, such as those having an aurone skeleton (see Patent Document 5), those having a phenylpropenoic acid derivative as an active ingredient (see Patent Document 6), and the like. .

  The present invention relates to a coumarin derivative, but it has been known that a coumarin derivative has been useful as a pharmaceutical so far. For example, a drug having an anti-HIV-1 action (see Patent Document 7), an antiviral agent ( Patent Literature 8), liver disease therapeutic agents (see Patent Literature 9), hypoglycemic agents (see Patent Literature 10), and the like are disclosed. Thus, coumarin derivatives have been reported to have various pharmacological actions, but there has been no report that they have an action of inhibiting glycation cross-linking of proteins by Maillard reaction.

JP-A-62-142114 Japanese Patent Laid-Open No. 9-59258 JP-A-3-240725 JP-A-6-336430 JP-A-9-241165 JP 2000-256259 A JP 2000-178267 A JP 11-158169 A JP 11-29471 A Japanese Patent Laid-Open No. 10-16796

  An object of the present invention is to provide a novel Maillard reaction inhibitor that does not have an active nitrogen-containing group that can react with an active carbonyl group, that is, does not have a guanidino group or an aminoguanidino group, and is different from conventional compounds such as an aurone skeleton or a phenylpropenoic acid derivative. An object of the present invention is to provide a coumarin derivative useful as an agent and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition, a cosmetic, and a discoloration / deterioration inhibitor containing the compound as an active ingredient.

  As a result of intensive studies to find a novel compound having an excellent protein glycation cross-linking inhibitory effect, the present inventors have found that the coumarin derivative of the present invention has an excellent protein glycation cross-linking inhibitory effect, which can be applied to pharmaceuticals, cosmetics, and discoloration. -The present invention was completed by finding it useful as a deterioration inhibitor and the like.

  As is apparent from the results of the pharmacological test described below, the coumarin derivative of the present invention has an excellent action of inhibiting glycation cross-linking of proteins due to Maillard reaction, so that diseases caused by glycation cross-linking of proteins, such as diabetic neuropathy, etc. It is useful for the prevention or treatment of diabetes complications, dialysis complications such as dialysis amyloidosis, or diseases and functional disorders caused by aging. It can also be used as a cosmetic for the purpose of preventing skin aging and skin beautification by suppressing collagen cross-linking and skin coloration, which cause skin hardening and wrinkle formation. Furthermore, the compound of the present invention is useful as a discoloration / deterioration preventing agent added to cosmetics and foods containing proteins and amino acids.

〔式中、R₁’は−NH−Ｘ又はCO−Y；Xは水素、アセチル基又はベンジル基；Yはアルキル基、フェニル基、水酸基、アルコキシ基又はアミノ基若しくはアルキル基で置換されていてもよいアミノ基；R₂’は水素；R₃’は水酸基又はアセトキシ基；R₅’は水素；R₄’及びR₆’は各々同一又は異なって水素、アリル基、（N, N-ジアルキルアミノ）アルキル基、ピペリジノアルキル基、モルホリノアルキル基、イミダゾリルアルキル基又は（無置換若しくは置換ピペラジノ）アルキル基を表す。但し、Xが水素若しくはアセチル基又はYがアルコキシ基のときは、R₄’又はR₆’は水素以外の基を表す。〕 The present invention is a compound represented by the following general formula (I ′) and a pharmaceutically acceptable salt thereof.

[Wherein R ₁ ′ is —NH—X or CO—Y; X is hydrogen, acetyl group or benzyl group; Y is substituted with an alkyl group, phenyl group, hydroxyl group, alkoxy group, amino group or alkyl group; R ₂ ′ is hydrogen; R ₃ ′ is a hydroxyl group or acetoxy group; R ₅ ′ is hydrogen; R ₄ ′ and R ₆ ′ are the same or different and each represents hydrogen, an allyl group, (N, N-dialkyl An amino) alkyl group, a piperidinoalkyl group, a morpholinoalkyl group, an imidazolylalkyl group, or a (unsubstituted or substituted piperazino) alkyl group; However, when X is hydrogen or an acetyl group or Y is an alkoxy group, R ₄ ′ or R ₆ ′ represents a group other than hydrogen. ]

〔式中、R₁は−NH−Ｘ、−CO−Y又は水酸基；Xは水素、アセチル基又はベンジル基；Yはアルキル基、フェニル基、水酸基、アルコキシ基又はアミノ基若しくはアルキル基で置換されていてもよいアミノ基；R₂は水素；R₃は水酸基、メトキシ基又はアセトキシ基；R₅は水素；R₄及びR₆は各々同一又は異なって水素、アリル基、（N, N−ジアルキルアミノ）アルキル基、ピペリジノアルキル基、モルホリノアルキル基、イミダゾリルアルキル基又は（無置換若しくは置換ピペラジノ）アルキル基を表す。〕 Moreover, this invention is a Maillard reaction inhibitor which contains at least 1 type of the compound represented by the following general formula (I) as an active ingredient.

[Wherein R ₁ is —NH—X, —CO—Y or a hydroxyl group; X is hydrogen, acetyl group or benzyl group; Y is an alkyl group, phenyl group, hydroxyl group, alkoxy group, amino group or alkyl group; R ₂ is hydrogen; R ₃ is a hydroxyl group, a methoxy group or an acetoxy group; R ₅ is hydrogen; R ₄ and R ₆ are the same or different and each represents hydrogen, an allyl group, (N, N-dialkyl) An amino) alkyl group, a piperidinoalkyl group, a morpholinoalkyl group, an imidazolylalkyl group, or a (unsubstituted or substituted piperazino) alkyl group; ]

In the general formulas (I ′) and (I), the alkyl group in Y of R ₁ ′ and R ₁ is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1 , 2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2, 2 -Dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1 , 2, 2-trimethylpropyl group, 1-ethyl-1-methyl Rupuropiru group, a 1-ethyl-2-methylpropyl group. Further, the alkoxy group in Y is a linear or branched alkoxy group having 1 to 6 carbon atoms, and specifically includes each alkoxy group corresponding to each of the above alkyl groups.

R ₄ ′ and R ₆ ′ and R ₄ and R ₆ are the same or different and each represents hydrogen, allyl group, (N, N-dialkylamino) alkyl group, piperidinoalkyl group, morpholinoalkyl group, imidazolylalkyl group or ( Represents an unsubstituted or substituted piperazino) alkyl group, and examples of the “alkyl group” in each of these substituents include the same alkyl groups as those described above for Y of R ₁ ′ and R ₁ . In addition, regarding “dialkyl” of “(N, N-dialkylamino) alkyl group”, the two alkyl groups may be the same or different.

〔式中R₇は水素又はアルキル基を表す。〕
R₇におけるアルキル基も上記R₁’及びR₁のYにおけるアルキル基と同様のものを挙げることができる。 The unsubstituted or substituted piperazino group of the “(unsubstituted or substituted piperazino) alkyl group” is represented by the following general formula (II).

[Wherein R ₇ represents hydrogen or an alkyl group. ]
As the alkyl group for R _7, the same alkyl groups as those for R ₁ ′ and Y of R ₁ can be exemplified.

Among the compounds of the present invention, preferred compounds are as follows.
8-Acetoxy-3-acetylamino-2H-1-benzopyran-2-one [Compound 1]
8-Acetoxy-3-benzoylamino-2H-1-benzopyran-2-one [Compound 2]
8-Hydroxy-2-oxo-2H-1-benzopyran-3-carboxylic acid [Compound 3]
3-Acetylamino-8-methoxy-2H-1-benzopyran-2-one [Compound 4]
Ethyl 8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate [Compound 5]
3-Acetyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 6]
3-Benzoyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 7]
3-Acetylamino-8-hydroxy-2H-1-benzopyran-2-one [Compound 8]
3-Benzoylamino-8-hydroxy-2H-1-benzopyran-2-one [Compound 9]
3, 8-Dihydroxy-2H-1-benzopyran-2-one [Compound 10]
3-Hydroxy-8-methoxy-2H-1-benzopyran-2-one [Compound 11]
N, N-Dimethyl-8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxamide [Compound 12]
8-Hydroxy-2-oxo-2H-1-benzopyran-3-carboxamide [Compound 13]
Ethyl 7-[(N, N-dimethylamino) methyl] -8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate [Compound 14]
Ethyl 7-[(N, N-diethylamino) methyl] -8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate [Compound 15]
Ethyl 8-hydroxy-2-oxo-7- (piperidinomethyl) -2H-1-benzopyran-3-carboxylate [Compound 16a]
Ethyl 5, 7-bis (piperidinomethyl) -8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate [Compound 16b]
Ethyl 8-hydroxy-7- (morpholinomethyl) -2-oxo-2H-1-benzopyran-3-carboxylate [Compound 17]
5, 7-bis (piperidinomethyl) -8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylic acid dihydrochloride [Compound 18]
3-Acetylamino-7- (N, N-dimethylamino) methyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 19]
3-Acetylamino-7- (N, N-diethylamino) methyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 20]
3-Acetylamino-8-hydroxy-7- (piperidinomethyl) -2H-1-benzopyran-2-one [Compound 21]
3-Acetylamino-8-hydroxy-7- (morpholinomethyl) -2H-1-benzopyran-2-one [Compound 22]
3-Acetylamino-5,7-bis (N, N-dimethylaminomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 23]
3-Acetylamino-5,7-bis (N, N-diethylaminomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 24]
3-Acetylamino-5,7-bis (piperidinomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 25]
3-Acetylamino-5,7-bis (morpholinomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 26]
3-Acetylamino-5,7-bis [(N-ethyl-N-methylamino) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 27]
3-Acetylamino-5,7-bis (N, N-dipropylaminomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 28]
3-Acetylamino-5,7-bis [(N-methyl-N-propylamino) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 29]
3-Acetylamino-5,7-bis [(N-ethyl-N-propylamino) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 30]
3-Acetylamino-5,7-bis [(N-butyl-N-methylamino) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 31]
3-Acetylamino-5,7-bis (N, N-dibutylaminomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 32]
3-Acetylamino-7-allyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 33]
3-Acetylamino-8-hydroxy-7- [3- (imidazol-2-yl) propyl] -2H-1-benzopyran-2-one [Compound 34]
3-Acetylamino-8-hydroxy-7- (3-piperidinopropyl) -2H-1-benzopyran-2-one [Compound 35]
3-Acetylamino-7- [3- (N, N-dimethylamino) propyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 36]
3-Acetylamino-7- [3- (N, N-diethylamino) propyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 37]
3-Acetylamino-7- [3- (N-ethyl-N-propylamino) propyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 38]
3-Acetylamino-7- [3- (N, N-dipropylamino) propyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 39]
3-Acetylamino-8-hydroxy-7- (3-morpholinopropyl) -2H-1-benzopyran-2-one [Compound 40]
3-Acetylamino-5,7-bis [(4-methylpiperazinyl) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 41]
8-Hydroxy-2-oxo-2H-1-benzopyran-3-carboxyhydrazide [Compound 42]
3-Acetylamino-5- (N, N-diethylamino) methyl-8-hydroxy-7- (3-piperidinopropyl) -2H-1-benzopyran-2-one [Compound 43]
3-Acetylamino-5,7-diallyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 44]
3-Acetylamino-5,7-bis (3-piperidinopropyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 45]

  The manufacturing method of this invention compound is shown below. The compounds of the present invention represented by the general formulas (I ′) and (I) can be produced according to the method described below, but based on the basic skeleton or the kind of substituent other than the following method. It can be manufactured by applying various synthesis methods using the characteristics.

スキームI中のR₁乃至R₆は前記一般式（I）と同じ置換基を表す。R₈は水酸基、アルコキシ基、アラルキルオキシ基等の求核試薬によって容易に置換しうる脱離基を表す。
一般式（III）の化合物に、一般式（IV）の活性メチレンを有する化合物、例えばアセト酢酸エチル、プロピオニル酢酸エチルなどの・-ケト酸、シアノ酢酸エチル、マロン酸ジエチル及びN-アセチルグリシンなどを、塩基の存在下、室温下又は加熱下で反応させることによって、本発明化合物を得るための原料化合物又は本発明化合物を直接製造することができる（スキームI）。 <Manufacturing method 1>

R _{1 to} R _{6 in} Scheme I represent the same substituent as in the general formula (I). R ₈ represents a leaving group that can be easily substituted with a nucleophilic reagent such as a hydroxyl group, an alkoxy group, an aralkyloxy group, and the like.
A compound having the active methylene of the general formula (IV) is added to the compound of the general formula (III), for example, ethyl acetoacetate, ethyl propionylacetate, etc. The starting compound for obtaining the compound of the present invention or the compound of the present invention can be produced directly by reacting in the presence of a base at room temperature or under heating (Scheme I).

  Examples of the solvent include aromatic hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and diethyl ether, and amides such as dimethylformamide and dimethylacetamide. Examples of the solvent include alcohol solvents such as methanol and ethanol. Further, high boiling solvents such as sulfolane, dimethyl sulfoxide and N-methylpyrrolidone, acetic anhydride, acetic acid or pyridine may be used. Solvents can be used alone or in admixture of two or more, and can be appropriately selected according to the type of raw material compound. Bases include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate, or aniline, pyridine, morpholine, piperidine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine. And organic bases such as 4-dimethylaminopyridine.

スキームII中のR₁乃至R₆は前記一般式（I）と同じ置換基を表す。R₈は水酸基、アルコキシ基、アラルキルオキシ基等の求核試薬によって容易に置換しうる脱離基を表す。
一般式（V）の化合物に、一般式（VI）の活性メチレンを有する化合物、例えばアセト酢酸エチル、プロピオニル酢酸エチルなどの・-ケト酸エステルを、縮合剤の存在下で反応させることにより、本発明化合物を得るための原料化合物又は本発明化合物を直接製造することができる（スキームII）。 <Manufacturing method 2>

R _{1 to} R _{6 in} Scheme II represent the same substituent as in the general formula (I). R ₈ represents a leaving group that can be easily substituted with a nucleophilic reagent such as a hydroxyl group, an alkoxy group, an aralkyloxy group, and the like.
By reacting the compound of the general formula (V) with a compound having an active methylene of the general formula (VI), for example, a keto acid ester such as ethyl acetoacetate or ethyl propionylacetate in the presence of a condensing agent, The starting compound for obtaining the inventive compound or the present compound can be directly produced (Scheme II).

  Examples of the solvent include aromatic hydrocarbon solvents such as benzene, toluene, xylene, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform, 1, 2- Halogenated hydrocarbon solvents such as dichloroethane, and amide solvents such as dimethylformamide and dimethylacetamide. Further, acetic acid or water may be used. Solvents can be used alone or in admixture of two or more, and can be appropriately selected according to the type of raw material compound. Examples of the condensing agent include acids such as sulfuric acid, phosphorus pentoxide, hydrochloric acid, and phosphorus oxychloride, and Lewis acids such as aluminum chloride, zinc chloride, tin chloride, and titanium chloride.

The compound of the general formula (I) obtained by the above production method 1 or 2 is further led to the target compound of the present invention by an organic synthesis reaction such as a hydrolysis reaction, a reduction reaction, an alkylation reaction, an acylation reaction, or a Mannich reaction. It is possible. For example, a compound having an acetoxy group at R ₃ can be converted to a compound having a hydroxyl group by a reaction such as acid or alkali hydrolysis.

スキームIII中のR₂乃至R₆は前記一般式（I）と同じ置換基を表す。R₉は水酸基、アルコキシ基、アラルキルオキシ基等の求核試薬によって容易に置換しうる脱離基を表す。R₁₀及びR₁₁は同一又は異なって水素又はアルキル基を表すが、アルキル基は上記R₁のYにおけるアルキル基と同様のものを挙げることができる。
上記製造方法１又は2で得られた一般式（I）の化合物が、R₁にカルボキシル基又はアルコキシカルボニル基を有する場合は、本製造方法3によりカルバモイル基又は窒素上の水素がアルキル基で置換したカルバモイル基を有する一般式（I-2）の化合物へと導くことができる。すなわち、一般式（I-1：R₉は水酸基）の化合物から誘導できるカルボン酸の反応性誘導体、又は一般式（I-1：R₉は水酸基、アルコキシ基、アラルキルオキシ基等の求核試薬によって容易に置換しうる脱離基）の化合物と、一般式（VII）の化合物を反応させることにより製造することができる（スキームIII）。 <Manufacturing method 3>

R _{2 to} R _{6 in} Scheme III represent the same substituent as in the general formula (I). R ₉ represents a leaving group that can be easily substituted with a nucleophilic reagent such as a hydroxyl group, an alkoxy group, an aralkyloxy group, and the like. R ₁₀ and R ₁₁ are the same or different and each represents hydrogen or an alkyl group, and examples of the alkyl group include the same alkyl groups as those described above for Y in R ₁ .
When the compound of the general formula (I) obtained by the above production method 1 or 2 has a carboxyl group or an alkoxycarbonyl group in R ₁ , the carbamoyl group or hydrogen on nitrogen is substituted with an alkyl group by this production method 3 To a compound of the general formula (I-2) having a carbamoyl group. That is, a reactive derivative of a carboxylic acid that can be derived from a compound of the general formula (I-1: R ₉ is a hydroxyl group), or a nucleophilic reagent such as a general formula (I-1: R ₉ is a hydroxyl group, an alkoxy group, an aralkyloxy group, etc. Can be prepared by reacting a compound of general formula (VII) with a compound of a leaving group that can be easily substituted by (Scheme III).

  Examples of the reactive derivative of carboxylic acid include acid halides, acid anhydrides, active esters, and acid azides. Specifically, examples of the acid halide include acid chloride and acid bromide. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used, and as the mixed acid anhydride, a mixed acid anhydride with a chlorocarbonic acid alkyl ester such as ethyl chlorocarbonate or isobutyl chlorocarbonate, benzyl chlorocarbonate Mixed acid anhydrides with chlorocarbonic acid aralkyl esters such as, mixed acid anhydrides with chlorocarbonic acid aryl esters such as phenyl chlorocarbonate, mixed acid anhydrides with alkanoic acids such as isovaleric acid and pivalic acid It is done. Active esters include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide Ester, N-hydroxy-5-norbornene-2,3-dicarboximide ester, N-hydroxypiperidine ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester, 2-hydroxy-4,5-dichlorophenyl ester, 2- Examples thereof include hydroxypyridine ester, 2-pyridylthiol ester, 1-benzotriazolyl ester and the like. Such reactive derivatives of carboxylic acids can be obtained from the corresponding carboxylic acids by known methods.

  When the acid halide or acid anhydride is reacted with the compound of the general formula (VII), the reaction can be performed in the presence of a base, in a solvent, or at room temperature. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and 4-dimethylaminopyridine. A base. Examples of the solvent include aromatic hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, chloroform and 1,2-dichloromethane, Examples thereof include amide solvents such as dimethylformamide and dimethylacetamide, and basic solvents such as pyridine. These solvents can be used alone or in admixture of two or more, and can be appropriately selected according to the type of the raw material compound.

When R _{9 of the} alkyl ester, ie the compound of the general formula (I-1) is represented by an alkoxy group, in the presence of an equimolar to excess of the corresponding amine, ie the amine of the general formula (VII) The reaction can be performed. Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane, amide solvents such as dimethylformamide and dimethylacetamide, alcohol solvents such as methanol, ethanol and isopropanol. These solvents can be used alone or in admixture of two or more, and can be appropriately selected according to the type of the raw material compound. Depending on the case, it can also be heated for a short time at around 100 ° C. without solvent or after evaporation of the solvent. In the case of other ester derivatives such as aralkyl esters, the same method can be used.

When R ₉ is a hydroxyl group, the amine represented by formula (VII) is preferably reacted in the presence of a condensing agent in an inert solvent at room temperature or under heating. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(-dimethylaminopropyl) carbodiimide (EDC) or its hydrochloride (EDC HCl), benzotriazole-1- Il-tris (dimethylamino) phosphonium hexafluorophosphide salt (BOP), diphenylphosphonyl azide (DPPA), 1,1′-carbonylbis-1H-imidazole (CDI), and the like. In some cases, additives such as N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3, 4-dihydro-1, 2,3-benzotriazine (HOOBt) May be used. Examples of the solvent include aromatic hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, chloroform and 1,2-dichloromethane, Examples thereof include amide solvents such as dimethylformamide and dimethylacetamide, and basic solvents such as pyridine. These solvents can be used alone or in admixture of two or more, and can be appropriately selected according to the type of the raw material compound.

スキームIV中のR₁、R₂、R₃及びR₅は前記一般式（I）と同じ置換基を表す。R₁₀及びR₁₁は、同一又は異なってアルキル基を示すか、又は、R₁₀とR₁₁が結合する窒素原子と一緒になって、下記一般式（VIII）の5又は6員環を形成する。

一般式（VIII）中、Wは−CH₂−、−CH₂CH₂−、−CH₂O−、−CH₂NH−又はCH₂N(R₁₂)−を表す。R₁₂は水素又はアルキル基を表す。ここで示されるアルキル基は上記R₁のYにおけるアルキル基と同様のものを挙げることができる。 <Manufacturing method 4>

R ₁ , R ₂ , R ₃ and R _{5 in} Scheme IV represent the same substituent as in the general formula (I). R ₁₀ and R ₁₁ are the same or different and each represents an alkyl group, or together with the nitrogen atom to which R ₁₀ and R ₁₁ are bonded, form a 5- or 6-membered ring of the following general formula (VIII) .

In the general formula (VIII), W is _{-CH 2 -, - CH 2 CH} 2 -, - CH 2 O -, - CH 2 NH- or CH ₂ N (R ₁₂₎ - represents a. R ₁₂ represents hydrogen or an alkyl group. Examples of the alkyl group shown here include the same alkyl groups as those described above for Y of R ₁ .

When the compound of the general formula (I) obtained by the above production method 1 or 2 has a hydroxyl group or an alkoxy group in R ₃ , R ₄ or R ₄ of the compound of the general formula (I) is produced by the production method _4. And a compound having a (N, N-dialkylamino) alkyl group at R ₆ . That is, by reacting a compound of the general formula (I-3) with formalin or paraformaldehyde and an amine represented by the general formula (VII) in an inert solvent at room temperature or under heating, the general formula (I-4 ) Can be prepared (Scheme IV).

  Examples of the inert solvent include aromatic hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, and amides such as dimethylformamide and dimethylacetamide. Examples of the solvent include alcohol solvents such as methanol, ethanol and isopropanol. These solvents can be used alone or in admixture of two or more, and can be appropriately selected according to the type of the raw material compound.

上記式中、R₁、R₂及びR₅は前記一般式（I）と同じ置換基を表す。一般式（I-6）の化合物は、クライゼン転位反応を用いて、一般式（I-5）の化合物を不活性溶媒中加熱することにより製造できる（スキームV）。 <Manufacturing method 5>

In the above formula, R ₁ , R ₂ and R ₅ represent the same substituent as in the general formula (I). The compound of general formula (I-6) can be produced by heating the compound of general formula (I-5) in an inert solvent using a Claisen rearrangement reaction (Scheme V).

Examples of the inert solvent include high-boiling solvents such as N, N-dimethylaniline N, N-diethylaniline, N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, and N-methylpyrrolidone. The compound of the general formula (I-5) can be produced from a compound of the general formula (I) in which R ₃ is a hydroxyl group and R ₄ and R ₆ are hydrogen by a known method used for allylation of a phenolic hydroxyl group. it can. Further, from the compound of the general formula (I-6), another allyl group can be introduced at the position of R _{6 in} the general formula (I) in the same manner as in Production Method 5, that is, the general formula (I -7) can be produced.

In general formula (I-7), R ₁ , R ₂ and R ₅ represent the same substituents as in general formula (I). The allyl group in the compounds of the general formulas (I-6) and (I-7) can be converted to a 3-hydroxypropyl group by using a known reaction such as hydroboration. The hydroxyl group at the 3-position of the 3-hydroxypropyl group is represented by the general formula (VII) in Scheme IV after conversion to a leaving group that can be easily substituted by a nucleophile such as halogen or methanesulfonyl group. By substituting with an amine, a compound having a 3- (N, N-dialkylamino) propyl group at R ₄ or R ₄ and R ₆ in the general formula (I) can be produced. These series of reactions can be carried out using reagents, solvents and conditions generally used in organic synthesis reactions.

  The compound of the present invention includes various salts when pharmaceutically acceptable salts exist, such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyanic acid, boron. Acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-toluenesulfonic acid, Addition salts with acids with naphthalene sulfonic acid, sulfanilic acid, etc., or salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, or metals such as aluminum, or bases such as ammonia and organic amines The salt with a kind can be mentioned. These salts can be produced from each free compound or converted to each other by known methods.

  In addition, when existing in the form of a stereoisomer such as a cis-trans isomer, an optical isomer, a conformer, a hydrate or a metal complex compound, any stereoisomer, hydrate and complex compound thereof. The present invention also includes. That is, the compound of the present invention has a double bond in the molecule and has a geometric isomer, but in the present invention, any single isomer (E isomer or Z isomer) may be used. However, it may be a mixture of two types (EZ isomer mixture). Furthermore, the present invention also includes a solvent mixture of these compounds with a solvent such as water, methanol, ethanol, acetonitrile, or the like, that is, a pharmaceutically acceptable solvate such as a hydrate, methanolate, ethanolate, acetonate or the like. .

  The compound of the present invention can be made into a pharmaceutical by combining with a suitable pharmaceutical carrier or diluent, can be formulated by any usual method, and is solid, semi-solid, liquid or gas for oral or parenteral administration. Can be prescribed in the dosage form. In formulating, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, or may be used as a compounding agent with other pharmaceutically active ingredients.

  For oral administration, as it is or with suitable additives such as lactose, mannitol, corn starch, potato starch and other conventional excipients, binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch and gelatin , Corn starch, potato starch, disintegrants such as potassium carboxymethylcellulose, lubricants such as talc and magnesium stearate, other bulking agents, wetting agents, buffering agents, preservatives, fragrances, etc. It can be a granule or a capsule.

  The injection may be an aqueous solvent or non-aqueous solvent such as distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol, or a solution or suspension. Depending on the type of disease, dosage forms other than those described above that are optimal for treatment, such as ointments, creams, gels, liquids for external use, eye drops, eye drops, suppositories, inhalants, It can be formulated into aerosols.

  The desired dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period, etc., but in order to obtain the desired effect, generally 0.01 to 100 mg / Kg of the compound of the present invention is administered to an adult. It can be orally administered in 1 to several times a day, preferably 0.05 to 25 mg / Kg in 1 to several times a day. In the case of parenteral administration (for example, injection), the daily dose is preferably a dose level of 3 to 1/10 of each dose.

  Moreover, this invention compound can be mix | blended with various cosmetic bases, and it can be set as cosmetics, such as a milky lotion, a cream, a lotion, a pack, a foundation, and a washing | cleaning agent. The cosmetic base can be selected according to the use mode described above, for example, purified water, buffer solution, lower alcohol, polyhydric alcohol, fats and oils, powder, surfactant, water-soluble polymer, cosmetic ingredient, Ultraviolet absorbers, thickeners, pigments, preservatives, fragrances, antioxidants, and the like can be used.

  The cosmetics may be combined with various active ingredients in addition to the compound of the present invention, and the content of the compound of the present invention is, for example, 0.001 to 10% by weight, preferably 0.01 to 5% in the cosmetic composition. Can do.

  Hereinafter, the present invention will be described in more detail based on examples. In addition, about the manufacturing method of the raw material compound used in the following examples, it described as a reference example.

  Anhydrous sodium sulfate was used for drying of the organic solvent performed in the following Reference Examples and Examples. Further, the organic solvent was distilled off using a rotary evaporator under reduced pressure unless otherwise specified. The final product was dried for 12 hours at 50 ° C. using a vacuum dryer in the presence of phosphorus pentoxide.

Example 1 8-Acetoxy-3-acetylamino-2H-1-benzopyran-2-one [Compound 1]
2,3-dihydroxybenzaldehyde (10.0 g, 72.1 mmol), N-acetylglycine (13.0 g, 111.0 mmol), sodium acetate (3.0 g, 36.2 mmol) and acetic anhydride (50 mL) were stirred at 50 ° C. for 7 hours. . The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration and recrystallized from water-ethanol-acetone to obtain 3.3 g (17%) of Compound 1.
¹ H-NMR (DMSO-d ₆ ) ...: 2.18 (s, 3H), 2.39 (s, 3H), 7.34, 7.34 (dx2, 2H, J = 8.0 Hz), 7.61 (dd, 2H, J = 8.0, 8.0 Hz), 8.65 (s, 1H), 9.81 (s, 1H).

Example 2 8-Acetoxy-3-benzoylamino-2H-1-benzopyran-2-one [Compound 2]
2,3-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), hippuric acid (9.7 g, 54.1 mmol), sodium acetate (2.3 g, 28.0 mmol) and acetic anhydride (30 mL) were stirred at 50 ° C. for 10 hours. The reaction solution was added to ice water, and the precipitated crystals were collected by filtration, washed with water and methanol, and dried to obtain 7.1 g (63%) of Compound 2.
¹ H-NMR (DMSO-d ₆ ) ・ ・: 2.41 (s, 3H), 7.38-7.70 (m, 6H), 7.97 (d, 2H, J = 8.0 Hz), 8.66 (s, 1H), 9.81 ( brs, 1H).

Example 3 8-Hydroxy-2-oxo-2H-1-benzopyran-3-carboxylic acid [Compound 3]
A mixture of 2,3-dihydroxybenzaldehyde (4.8 g, 34.8 mmol), malonic acid (97.2 g, 69.2 mmol), aniline (3 drops) and pyridine (5 mL) was heated to a homogeneous solution, and then at room temperature. Left for 20 hours. 2 mol / L hydrochloric acid was added, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 0.9 g (13%) of Compound 3.
Mp. 290-291-C. (Dec.). MS (EI) m / z: 206 (M ⁺ ) .IR (KBr): 1739, 1608, 1473, 1433, 1295, 1203 cm ^-1 . ¹ H- NMR (DMSO-d ₆ ) ・: 7.20 (d, 2H, J = 8.0 Hz), 7.32 (dd, 1H, J = 8.0, 8.0 Hz), 8.69 (s, 1H), 10.35 (s, 1H), 13.20 (s, 1H).

Example 4 3-Acetylamino-8-methoxy-2H-1-benzopyran-2-one [Compound 4]
Orthovanillin (5.0 g, 32.9 mmol), N-acetylglycine (5.8 g, 49.5 mmol), sodium acetate (4.0 g, 48.8 mmol) and acetic anhydride (30 mL) were stirred at 50 ° C. for 30 hours. The filtrate obtained by removing insolubles by filtration was concentrated, and the residue was dissolved in ether. The organic layer was washed with 10% aqueous sodium hydroxide solution and water and dried, and then ether was distilled off. The residual crystals were recrystallized from water-ethanol and dried to obtain 1.5 g (20%) of Compound 4.
Mp. 245-246 ー C. MS (EI) m / z: 233 (M ⁺ ). IR (KBr): 3337, 1712, 1684, 1540, 1360, 1251, 1149 cm ⁻¹ . ¹ H-NMR (DMSO -d ₆ ) ・ ・: 2.15 (s, 3H), 3.89 (s, 3H), 7.16-7.25 (m, 3H), 8.57 (s, 1H), 9.75 (s, 1H).

Example 5 Ethyl 8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate [Compound 5]
2,3-dihydroxybenzaldehyde (10.0 g, 70.4 mmol), diethyl malonate (12.1 mL, 79.6 mmol), piperidine (0.5 mL, 4.7 mmol) and ethanol (150 mL) were heated to reflux for 22 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with water and dried, and then ethyl acetate was distilled off. The precipitated crystals were collected by filtration, washed with ether and dried to obtain 14.6 g (86%) of Compound 5.
. Mp 180-181 over C. MS (EI) m / z :. 234 (M +) IR (KBr):. 3301, 1748, 1696, 1472, 1229 cm -1 1 H-NMR (DMSO-d 6)・: 1.31 (t, 3H, J = 7.0 Hz), 4.30 (q, 2H, J = 7.0 Hz), 7.21-7.34 (m, 3H), 8.69 (s, 1H), 10.50 (s, 1H).

Example 6 3-Acetyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 6]
2,3-dihydroxybenzaldehyde (1.0 g, 7.2 mmol), ethyl acetoacetate (0.9 mL, 7.2 mmol), piperidine (3 drops) and ethanol (20 mL) were heated to reflux for 0.5 hours. The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration, washed with ethanol, and dried to obtain 1.5 g (97%) of Compound 6.
Mp. 261-262 ー C. MS (EI) m / z: 204 (M ⁺ ). IR (KBr): 3248, 1696, 1601, 1473, 1372, 1297, 1223 cm ⁻¹ . ¹ H-NMR (DMSO -d ₆ ) ...: 2.59 (s, 3H), 7.20-7.22 (m, 2H), 7.35-7.37 (m, 1H), 8.59 (s, 1H), 10.40 (brs, 1H).

Example 7 3-Benzoyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 7]
2,3-dihydroxybenzaldehyde (1.0 g, 7.2 mmol), ethyl benzoyl acetate (1.2 mL, 7.2 mmol), piperidine (3 drops) and ethanol (20 mL) were heated to reflux for 0.5 hour. The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration, washed with ethanol, and dried to obtain 1.53 g (70%) of Compound 7.
. Mp 214-215 over C. MS (EI) m / z :. 266 (M +) IR (KBr):. 3250, 1697, 1652, 1602, 1294, 1237 cm -1 1 H-NMR (DMSO-d ₆ ) ・ ・: 7.21-7.28 (m, 3H), 7.55 (dd, 2H, J = 7.5, 7.5 Hz), 7.70 (dd, 1H, J = 7.5, 7.5 Hz), 7.93 (d, 2H, J = 7.5 Hz), 8.37 (s, 1H), 10.37 (s, 1H).

Example 8 3-Acetylamino-8-hydroxy-2H-1-benzopyran-2-one [Compound 8]
8-acetoxy-3-acetylamino-2H-1-benzopyran-2-one of Example 1 [Compound 1] (18.0 g, 68.9 mmol) and sodium methoxide (1.9 g, 34.5 mmol) were mixed with anhydrous methanol (200 mL). ) And stirred at room temperature under an argon atmosphere for 2 hours. 10% hydrochloric acid was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and hot 50% ethanol, and dried to obtain 13.5 g (90%) of Compound 8.
Mp. 269-270 ー C. MS (EI) m / z: 219 (M ⁺ ). IR (KBr): 3329, 1704, 1658, 1540, 1362 cm ⁻¹ . ¹ H-NMR (DMSO-d ₆ )・ ・: 2.17 (s, 3H), 6.99 -7.13 (m, 3H), 8.55 (s, 1H), 9.73 (s, 1H).

Example 9 3-Benzoylamino-8-hydroxy-2H-1-benzopyran-2-one [Compound 9]
To a solution of 8-acetoxy-3-benzoylamino-2H-1-benzopyran-2-one [Compound 2] (5.0 g, 16.2 mmol) of Example 2 suspended in methanol (80 mL), 1 mol / L water was added. An aqueous sodium oxide solution (30 mL) was added, and the reaction mixture was stirred until it became homogeneous. 5% Hydrochloric acid was added to make the solution acidic, and the precipitated crystals were collected by filtration, washed with water, and dried to give 3.3 g (76%) of Compound 9.
. Mp 194-195 over C. MS (EI) m / z :. 281 (M +) IR (KBr):. 1643, 1579, 1481, 1284 cm -1 1 H-NMR (DMSO-d 6) ·· : 6.40 (dd, 1H, J = 8.0, 8.0 Hz), 6.64 (d, 1H, J = 8.0 Hz), 6.81 (d, 1H, J = 8.0 Hz), 7.33 (s, 1H), 7.45-7.56 ( m, 4H), 7.98 (d, 2H, J = 7.5 Hz), 9.50-11.50 (br, 1H).

Example 10 3, 8-dihydroxy-2H-1-benzopyran-2-one [Compound 10]
8-acetoxy-3-acetylamino-2H-1-benzopyran-2-one [Compound 1] (2.3 g, 8.8 mmol) of Example 1 was added to 3 mol / L hydrochloric acid (50 mL) and heated to reflux for 1 hour. . The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration, washed with water, recrystallized from 50% ethanol, and dried to obtain 1.1 g (74%) of Compound 10.
. Mp 223-224 over C. MS (EI) m / z :. 178 (M +) IR (KBr):. 3185, 1685, 1292, 1267, 1215, 1159 cm -1 1 H-NMR (DMSO-d ₆ ) ...: 6.88 (dd, 1H, J = 1.0, 7.5 Hz), 6.94 (dd, 1H, J = 1.0, 7.5 Hz), 7.06 (s, 1H), 7.06 (dd, 1H, J = 7.5, 7.5 Hz), 10.02 (brs, 1H), 10.25 (brs, 1H).

Example 11 3-Hydroxy-8-methoxy-2H-1-benzopyran-2-one [Compound 11]
3-Acetylamino-8-methoxy-2H-1-benzopyran-2-one [Compound 4] (450 mg, 1.9 mmol) of Example 4 was added to 3 mol / L-hydrochloric acid (40 mL) and heated under reflux for 2 hours. did. The tar-like solid was removed by filtration and allowed to cool. The precipitated crystals were collected by filtration, washed with water and dried to obtain 250 mg (28%) of Compound 11.
¹ H-NMR (DMSO-d ₆ ): 3.89 (s, 3H), 7.07 (d, 1H, J = 8.0 Hz), 7.09 (s, 1H), 7.09 (d, 1H, J = 8.0 Hz) , 7.21 (dd, 1H, J = 8.0, 8.0 Hz), 10.36 (brs, 1H).

Reference Example 1 Ethyl 8- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxylate Example 7 (13.0 g, 55.5 mmol) in methylene chloride (150 mL) under ice-cooling Methoxymethyl chloride (8.4 mL, 111.0 mmol) and N, N-diisopropyl-N-ethylamine (13.9 mL, 111.0 mmol) were sequentially added. After stirring at room temperature for 2 hours, ice water was added to the reaction solution. The organic layer was separated, washed with saturated brine, and dried. Hexane was added to the residue obtained by evaporating the solvent, and the precipitated crystals were collected by filtration and dried to obtain 14.3 g (92%) of the compound.
¹ H-NMR (DMOS-d ₆ ) ・ ・: 1.41 (t, 3H, J = 7.0 Hz), 3.55 (s, 3H), 4.42 (q, 2H, J = 7.0 Hz), 5.31 (s, 2H) , 7.24-7.25 (m, 2H), 7.43-7.45 (m, 1H), 8.50 (s, 1H).

Reference Example 2 8- (Methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxylic acid Ethyl 8- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3- of Reference Example 1 To a solution of carboxylate (14.0 g, 50.3 mmol) in ethanol (80 mL) was added 3 mol / L aqueous sodium hydroxide solution (84 mL), and the mixture was stirred at room temperature for 8 hr. The reaction solution was concentrated to about half volume and acidified with 10% hydrochloric acid while adding ice. The precipitated crystals were collected by filtration, washed with water and dried to obtain 11.7 g (93%) of the title compound.
¹ H-NMR (DMSO-d ₆ ) ...: 3.45 (s, 3H), 5.35 (s, 2H), 7.31-7.34 (m, 1H), 7.49-7.54 (m, 2H), 8.72 (s, 1H ), 13.30 (brs, 1H).

Reference Example 3 N, N-Dimethyl-8- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxamide 8- (methoxymethoxy) -2-oxo-2H-1- of Reference Example 2 To a solution of benzopyran-3-carboxylic acid (1.0 g, 4.0 mmol) and 50% N, N-dimethylamine aqueous solution (0.5 mL, 4.8 mmol) in methylene chloride (50 mL) was added WSC · HCl (0.9 g , 4.8 mmol). After removing the ice bath and stirring for 6 hours, ice water was added to the reaction solution. The separated organic layer was washed with water, saturated brine and dried. Ether was added to the residual oily substance after evaporation of the solvent for crystallization, and the residue was collected by filtration and washed with ether to obtain 0.5 g (46%) of the title compound.
¹ H-NMR (CDCl ₃ ): 3.02 (s, 3H), 3.12 (s, 3H), 3.55 (s, 3H), 5.32 (s, 2H), 7.18 (d, 1H, J = 8.0 Hz) , 7.22 (dd, 1H, J = 8.0, 8.0 Hz), 7.41 (d, 1H, J = 8.0 Hz), 7.90 (s, 1H).

Example 12 N, N-dimethyl-8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxamide [Compound 12]
N, N-dimethyl-8- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxamide (1.3 g, 4.7 mmol) of Reference Example 3 was added to 4 mol / L-HCl / dioxane (20 mL). And stirred at room temperature for 15 hours. The precipitated crystals were collected by filtration, washed with ether, and recrystallized from 50% ethanol to obtain 0.7 g (63%) of Compound 12.
. Mp 223-224 over C. MS (EI) m / z :. 233 (M +) IR (KBr):. 1709, 1636, 1611, 1581, 1293 cm -1 1 H-NMR (DMSO-d 6)・ ・: 2.93 (s, 3H), 2.98 (s, 3H), 7.15-7.20 (m, 3H), 8.12 (s, 1H), 10.30 (s, 1H).

Reference Example 4 Succinimide 8- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxylate 8- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3- of Reference Example 2 To a solution of carboxylic acid (0.8 g, 3.2 mmol) and N_hydroxysuccinimide (0.7 g, 3.6 mmol) in methylene chloride (25 mL) was added WSC · HCl (0.4 g, 3.5 mmol) under ice cooling. After removing the ice bath and stirring for 3 hours, ice water was added to the reaction solution. The separated organic layer was washed with water, saturated brine and dried. The residue obtained by evaporating the solvent was crystallized by adding hexane, filtered, washed with hexane, and dried to obtain 0.7 g (60%) of the title compound.
¹ H-NMR (CDCl ₃ ): 2.91 (s, 4H), 3.55 (s, 3H), 5.33 (s, 2H), 7.30 (d, 2H, J = 8.0 Hz), 7.55 (dd, 1H, J = 8.0, 8.0 Hz), 8.78 (s, 1H).

Reference Example 5 8- (Methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxamide Succinimide of Reference Example 4- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxy A rate (650 mg, 1.9 mmol) and 28% aqueous ammonia (0.6 mL, 9.4 mmol) were added to THF (15 mL), and the mixture was stirred at room temperature for 16 hours. The residue obtained by evaporating THF was dissolved in ethyl acetate, washed with water and saturated brine, and dried. After the solvent was distilled off, hexane was added to the residue, and the precipitated crystals were collected by filtration and dried to obtain 0.3 g (69%) of the title compound.
¹ H-NMR (DMSO-d ₆ ): 3.45 (s, 3H), 5.36 (s, 2H), 7.35 (dd, 1H, J = 8.0, 8.0 Hz), 7.52 (d, 1H, J = 8.0 Hz), 7.59 (d, 1H, J = 8.0 Hz), 8.84 (s, 1H).

Example 13 8-Hydroxy-2-oxo-2H-1-benzopyran-3-carboxamide [Compound 13]
8- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxamide (300 mg, 1.2 mmol) of Reference Example 5 was dissolved in 4 mol / L-HCl / dioxane (12 mL), and at room temperature. Stir for 19 hours. The reaction solution was treated in the same manner as in Example 12 to obtain 100 mg (42%) of Compound 13.
. Mp> 300 over C. MS (EI) m / z :. 205 (M +) IR (KBr):. 1710, 1665, 1574, 1472, 1295 cm -1 1 H-NMR (DMSO-d 6) ·・: 7.23-7.24 (m, 2H), 7.34-7.36 (m, 1H), 7.90 (s, 1H), 8.10 (s, 2H), 8.67 (s, 1H), 10.47 (s, 1H).

Example 14 Ethyl 7-[(N, N-dimethylamino) methyl] -8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate [Compound 14]
Ethyl 8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate of Example 5 [Compound 5] (850 mg, 3.6 mmol), paraformaldehyde (220 mg, 7.3 mmol) and 50% N, N -An aqueous dimethylamine solution (0.74 mL, 7.3 mmol) was added to ethanol (30 mL), and the mixture was heated to reflux for 14 hours. The reaction solution was diluted with ethyl acetate, washed and dried with water and saturated brine, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain 220 mg (21%) of Compound 14 as crystals.
. Mp 113-114 over C. MS (EI) m / z :. 291 (M +) IR (KBr):. 1745, 1589, 1457, 1248, 1057 cm -1 1 H-NMR (DMSO-d 6)・ ・: 1.31 (t, 3H, J = 7.0 Hz), 2.30 (s, 6H), 4.29 (q, 2H, J = 7.0 Hz), 7.16 (d, 1H, J = 8.0 Hz), 7.28 (d, 1H, J = 8.0 Hz), 8.68 (s, 1H).

Example 15 Ethyl 7-[(N, N-diethylamino) methyl] -8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate [Compound 15]
Ethyl 8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate of Example 5 [Compound 5] (4.6 g, 19.7 mmol), paraformaldehyde (1.3 g, 43.3 mmol), N, N-diethylamine In a similar manner to Example 14, 0.7 g (11%) of Compound 15 was obtained as crystals from (4.1 mL, 39.5 mmol) and ethanol (100 mL).
. Mp 119-120 over C. MS (EI) m / z :. 319 (M +) IR (KBr):. 1748, 1714, 1241, 1053 cm -1 1 H-NMR (CDCl 3) ···: 1.15 (t, 6H, J = 7.0 Hz), 1.40 (t, 3H, J = 7.0 Hz), 3.91 (s, 2H), 2.68 (q, 2H, J = 7.0 Hz), 4.40 (q, 2H, J = 7.0 Hz), 6.92 (d, 1H, J = 8.0 Hz), 6.97 (d, 1H, J = 8.0 Hz), 8.45 (s, 1H).

Example 16 Ethyl 8-hydroxy-2-oxo-7- (piperidinomethyl) -2H-1-benzopyran-3-carboxylate [Compound 16a] and ethyl 5,7-bis (piperidinomethyl) -8-hydroxy-2 -Oxo-2H-1-benzopyran-3-carboxylate [Compound 16b]
Ethyl 8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate of Example 5 [Compound 5] (8.0 g, 34.2 mmol), paraformaldehyde (2.0 g, 66.6 mmol) and piperidine (7.3 mL, 68.3 mmol) was added to ethanol (180 mL), and the mixture was heated to reflux for 12 hours. The reaction solution was concentrated, and ethyl acetate was added to the residue. The organic layer was washed with water and saturated brine, dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain 1.3 g (12%) and 2.5 g (17%) of compounds 16a and 16b, respectively.
16a:. Mp 171-172 over C. MS (EI) m / z :. 331 (M +) IR (KBr):. 2929, 1752, 1250, 1205 cm -1 1 H-NMR (CDCl 3) ·· : 1.40 (t, 3H, J = 7.0 Hz), 1.55-1.60 (m, 2H), 1.67-1.69 (m, 4H), 2.60-2.70 (m, 4H), 3.81 (s, 2H), 4.41 (q , 2H, J = 7.0 Hz), 6.90 (d, 1H, J = 8.0 Hz), 6.98 (d, 1H, J = 8.0 Hz), 8.45 (s, 1H).
16b: Mp. 178-179 ー C. MS (EI) m / z: 428 (M ⁺ ). IR (KBr): 2929, 1758, 1591, 1235, 1041 cm ⁻¹ . ¹ H-NMR (CDCl ₃ )・ ・: 1.41 (t, 3H, J = 7.0 Hz), 1.52-1.54 (m, 6H), 1.65-1.68 (m, 6H), 2.33-2.50 (m, 8H), 3.54 (s, 2H), 3.76 (s, 2H), 4.40 (q, 2H, J = 7.0 Hz), 6.75 (s, 1H), 9.15 (s, 1H).

Example 17 Ethyl 8-hydroxy-7- (morpholinomethyl) -2-oxo-2H-1-benzopyran-3-carboxylate [Compound 17]
Ethyl 8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate of Example 5 [Compound 5] (900 mg, 3.8 mmol), paraformaldehyde (240 mg, 8.0 mmol), morpholine (0.7 mL, 7.7 mmol) and ethanol (30 mL) were obtained in the same manner as in Example 14 to obtain 140 mg (11%) of Compound 17 as crystals. However, purification by silica gel column chromatography used hexane: ethyl acetate = 1: 2 as a solvent.
. Mp 168-169 over C. MS (EI) m / z :. 333 (M +) IR (KBr):. 1753, 1734, 1255, 1043 cm -1 1 H-NMR (CDCl 3) ·: 1.41 ( t, 3H, J = 7.0 Hz), 2.59-2.68 (m, 4H), 3.74-3.81 (m, 4H), 3.85 (s, 2H), 4.41 (q, 2H, J = 7.0 Hz), 6.95 (d , 1H, J = 8.0 Hz), 7.02 (d, 1H, J = 8.0 Hz), 8.45 (s, 1H).

<Example 18> 5,7-bis (piperidinomethyl) -8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylic acid / dihydrochloride [Compound 18]
Ethyl 5, 7-bis (piperidinomethyl) -8-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate [Compound 16b] (500 mg, 1.2 mmol) from Example 16 was concentrated hydrochloric acid (15 mL). And heated at reflux for 4 hours. The reaction solution was concentrated, ether and acetone were added to the residue, and the crystals were collected by filtration to obtain 380 mg (69%) of Compound 18.
. Mp 223-224 over C. IR (KBr):. 3106 , 1754, 1459, 1233 cm -1 1 H-NMR (DMSO-d 6) ··: 1.74-1.80 (m, 10H), 2.96-3.02 ( m, 4H), 3.30-3.38 (m, 6H), 4.34 (s, 2H), 4.55 (s, 2H), 7.96 (s, 1H), 8.90 (s, 1H), 10.40 (brs, 1H), 10.70 (brs, 1H), 11.20 (brs, 1H), 13.60 (brs, 1H).

Example 19 3-Acetylamino-7- (N, N-dimethylamino) methyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 19]
3-Acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (1.0 g, 4.6 mmol), 37% formalin (0.4 mL, 4.6 mmol) and 50% N, N -Dimethylamine aqueous solution (0.5 mL, 4.6 mmol) was added to ethanol (20 mL), and the mixture was heated to reflux for 19 hours. The residue obtained by evaporating ethanol under reduced pressure was dissolved in ethyl acetate, washed with water and saturated brine, and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to obtain 0.38 g (30%) of Compound 19 as crystals.
. Mp 208-209 over C. MS (EI) m / z :. 276 (M +) IR (KBr):. 3334, 1714, 1684, 1533, 1505, 1359, 1244, 1141 cm -1 1 H-NMR (DMSO-d ₆ ) ・ ・: 2.16 (s, 3H), 2.29 (2, 6H), 7.02-7.03 (m, 2H), 8.53 (s, 1H), 9.71 (s, 1H).

Example 20 3-Acetylamino-7- (N, N-diethylamino) methyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 20]
3-Acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (3.0 g, 13.7 mmol), paraformaldehyde (0.9 g, 30.0 mmol) and N, N-diethylamine ( 2.9 mL, 27.4 mmol) was added to ethanol (80 mL), heated under reflux for 14 hours, and then treated in the same manner as in Example 31. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1). Thus, 0.9 g (21%) of Compound 20 was obtained as crystals.
. Mp 160-161 over C. MS (SIMS) m / z :. 305 (M + 1) + IR (KBr):. 3316, 1716, 1684, 1503, 1359 cm -1 1 H-NMR (CDCl 3)・ ・: 1.15 (t, 6H, J = 7.0 Hz), 2.23 (s, 3H), 2.68 (q, 4H, J = 7.0 Hz), 3.89 (s, 2H), 6.87-6.89 (m, 2H), 8.20 (s, 1H), 8.59 (s, 1H).

Example 21 3-Acetylamino-8-hydroxy-7- (piperidinomethyl) -2H-1-benzopyran-2-one [Compound 21]
3-acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (1.5 g, 6.8 mmol), paraformaldehyde (0.4 g, 13.3 mmol) and piperidine (1.5 mL, 13.7 mmol) was added to ethanol (50 mL) and heated to reflux for 23 hours. The residue obtained by evaporating ethanol under reduced pressure was dissolved in ethyl acetate, washed with water and saturated brine, and dried. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain 0.3 g (13%) of Compound 21.
. Mp 210-211 over C. MS (EI) m / z :. 316 (M +) IR (KBr):. 3339, 2945, 1718, 1684, 1535, 1507, 1373, 1360 cm -1 1 H-NMR (DMSO-d ₆ ) ・ ・: 1.45-1.56 (m, 6H), 2.16 (s, 3H), 2.48-2.51 (m, 4H), 3.79 (s, 2H), 7.01-7.02 (m, 2H), 8.52 (s, 1H), 9.70 (s, 1H).

Example 22 3-Acetylamino-8-hydroxy-7- (morpholinomethyl) -2H-1-benzopyran-2-one [Compound 22]
3-Acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (3.5 g, 16.0 mmol), paraformaldehyde (1.0 g, 33.3 mmol) and morpholine (2.8 mL, 32.0 mmol) was added to ethanol (100 mL), heated under reflux for 14 hours, and then post-treated in the same manner as in Example 19. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to give compound 22. 1.28 g (25%) was obtained as crystals.
. Mp 222-223 over C. MS (EI) m / z :. 318 (M +) IR (KBr):. 3328, 1707, 1681, 1534, 1374, 1117 cm -1 1 H-NMR (CDCl 3)・ ・: 2.24 (s, 1H), 2.62 (brs, 4H), 3.79 (brs, 4H), 3.83 (s, 2H), 6.91-6.93 (m, 2H), 8.30 (s, 1H), 8.60 (s , 1H).

Example 23 3-Acetylamino-5,7-bis (N, N-dimethylaminomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 23]
3-Acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (2.0 g, 9.1 mmol), 37% formalin (4.0 mL, 45.6 mmol) and 50% N, N -A dimethylamine aqueous solution (4.6 mL, 45.6 mmol) was added to ethanol (50 mL), and the mixture was heated to reflux for 24 hours. Ether was added to the residue obtained by evaporating ethanol, and the crystals were collected by filtration and recrystallized from water-ethanol to obtain 1.7 g (56%) of Compound 23.
. Mp 216-217 over C. MS (EI) m / z :. 333 (M +) IR (KBr):. 3322, 2778, 1714, 1684, 1533, 1486, 1371 cm -1 1 H-NMR (DMSO -d ₆ ) ・ ・: 2.13 (s, 6H), 2.16 (s, 3H), 2.28 (s, 6H), 3.41 (s, 2H), 3.71 (s, 2H), 6.92 (s, 1H), 8.94 (s, 1H), 9.67 (s, 1H).

Example 24 3-Acetylamino-5,7-bis (N, N-diethylaminomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 24]
3-Acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (2.0 g, 9.1 mmol), 37% formalin (4.0 mL, 45.6 mmol) and N, N-diethylamine (4.8 mL, 45.6 mmol) was added to ethanol (50 mL) and heated to reflux for 30 hours. Ether was added to the residue obtained by distilling off ethanol, and the precipitated crystals were collected by filtration, recrystallized from water-ethanol and dried to obtain 0.7 g (21%) of Compound 24.
. Mp 195-196 over C. MS (EI) m / z :. 389 (M +) IR (KBr):. 3321, 1715, 1686, 1531, 1486, 1375, 1244 cm -1 1 H-NMR (DMSO -d ₆ ) ・ ・: 0.99 (t, 6H, J = 7.0 Hz), 1.05 (t, 6H, J = 7.0 Hz), 2.15 (s, 3H), 2.41 (q, 4H, J = 7.0 Hz), 2.59 (q, 4H, J = 7.0 Hz), 3.55 (s, 2H), 3.87 (s, 2H), 6.95 (s, 1H), 9.04 (s, 1H), 9.64 (s, 1H).

Example 25 3-Acetylamino-5,7-bis (piperidinomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 25]
3-acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (1.0 g, 4.6 mmol), 37% formalin (2.9 mL, 36.5 mmol) and piperidine (3.9 mL, A solution of 36.5 mmol) in ethanol (50 mL) was heated to reflux for 22 hours and allowed to cool. The precipitated crystals were collected by filtration and washed with ethanol to obtain 1.4 g (37%) of Compound 25.
. Mp 163-164 over C. MS (EI) m / z :. 413 (M +) IR (KBr):. 2936, 1718, 1688, 1527, 1482, 1369, 1149 cm -1 1 H-NMR (CDCl ₃ ) ・ ・: 1.54-1.68 (m, 12H), 2.23 (s, 3H), 2.40-2.50 (m, 8H), 3.51 (s, 2H), 3.76 (s, 2H), 6.80 (s, 1H) , 8.15 (s, 1H), 9.09 (s, 1H).

Example 26 3-Acetylamino-5,7-bis (morpholinomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 26]
3-acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [compound 8] (2.0 g, 9.1 mmol), 37% formalin (4.0 mL, 45.6 mmol) and morpholine (4.0 mL, 45.6 mmol) was added to ethanol (50 mL), and the mixture was heated to reflux for 30 hours. After allowing to cool, the precipitated crystals were collected by filtration and washed with ethanol to obtain 3.2 g (85%) of Compound 26.
. Mp 219-220 over C. MS (EI) m / z :. 417 (M +) IR (KBr):. 3319, 2848, 1717, 1592, 1116 cm -1 1 H-NMR (CDCl 3) ·· : 2.24 (s, 3H), 2.44-4.50 (m, 4H), 2.59-2.65 (m, 4H), 3.58 (s, 2H), 3.66-3.72 (m, 4H), 3.74-3.82 (m, 4H) , 3.80 (s, 2H), 6.80 (s, 1H), 8.10 (s, 1H), 9.15 (s, 1H).

Example 27 3-Acetylamino-5,7-bis [(N-ethyl-N-methylamino) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 27]
3-acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (5.0 g, 22.8 mmol), 37% formalin (10.0 mL, 114.1 mmol) and N-ethyl-N -Methylamine (9.8 mL, 114.1 mmol) was added to ethanol (200 mL), and the mixture was heated to reflux for 18 hours. Ethanol was added to the residue obtained by distilling off ethanol, and the precipitated crystals were collected by filtration, recrystallized from ethanol-petroleum ether and dried to obtain 3.7 g (45%) of Compound 27.
. Mp 178-179 over C. MS (EI) m / z :. 361 (M +) IR (KBr):. 3324, 1714, 1684, 1531, 1484, 1371 cm -1 1 H-NMR (DMSO-d ₆ ) ・ ・: 1.08 (t, 6H, J = 7.0 Hz), 2.03 (s, 3H), 2.16 (s, 3H), 2.26 (s, 3H), 2.41 (q, 2H, J = 7.0 Hz), 2.52 (q, 2H, J = 7.0 Hz), 3.46 (s, 2H), 3.79 (s, 2H), 6.92 (s, 1H), 8.97 (s, 1H), 9.65 (s, 1H).

Example 28 3-Acetylamino-5,7-bis (N, N-dipropylaminomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 28]
3-Acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (3.0 g, 13.7 mmol), 37% formalin (15.0 mL, 109.5 mmol) and N, N-di Propylamine (9.6 mL, 109.5 mmol) was added to a mixed solution of ethanol (40 mL) and DMF (40 mL), and the mixture was heated to reflux for 22 hours. The residue obtained by distilling off ethanol was dissolved in chloroform, washed with water and saturated brine, and the solvent was dried. Petroleum ether and ether were added to the residue obtained by evaporating the solvent, and the precipitated crystals were collected by filtration, recrystallized from ethanol-petroleum ether and dried to obtain 2.9 g (47%) of Compound 28.
. Mp 159-160 over C. MS (EI) m / z :. 445 (M +) IR (KBr):. 3327, 2958, 1718, 1685, 1529, 1480, 1377, 1241 cm -1 1 H-NMR (DMSO-d ₆ ) ... 0.74 (t, 6H, J = 7.5 Hz), 0.84 (t, 6H, J = 7.5 Hz), 1.39-1.46 (m, 4H), 1.47-1.53 (m, 4H) , 2.15 (s, 3H), 2.31 (t, 4H, J = 7.5 Hz), 2.46 (t, 4H, J = 7.5 Hz), 3.57 (s, 2H), 3.83 (s, 2H), 6.97 (s, 1H), 8.97 (s, 1H), 9.60 (s, 1H).

Example 29 3-Acetylamino-5,7-bis [(N-methyl-N-propylamino) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 29]
3-acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (3.6 g, 16.4 mmol), 37% formalin (11.6 mL, 131.4 mmol), N-methyl-N From a mixed solution of -propylamine (13.4 mL, 131.4 mmol) and ethanol (50 mL) -DMF (50 mL), 4.7 g (73%) of Compound 29 as crystals was obtained in the same manner as in Example 28.
. Mp 153-154 over C. MS (EI) m / z :. 389 (M +) IR (KBr):. 3330, 2968, 1718, 1682, 1530 cm -1 1 H-NMR (DMSO-d 6)・ ・: 0.79-0.89 (m, 6H), 1.49-1.54 (m, 4H), 2.04 (s, 3H), 2.15 (s, 3H), 2.28 (s, 3H), 2.30-2.50 (m, 4H) , 3.47 (s, 2H), 3.78 (s, 2H), 6.92 (s, 1H), 8.97 (s, 1H), 9.63 (s, 1H).

Example 30 3-Acetylamino-5,7-bis [(N-ethyl-N-propylamino) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 30]
3-acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (3.0 g, 13.7 mmol), 37% formalin (9.6 mL, 109.5 mmol), N-ethyl-N From a mixed solution of -propylamine (13.2 mL, 109.5 mmol) and ethanol (40 mL) -DMF (40 mL), 3.9 g (67%) of Compound 30 as crystals was obtained in the same manner as in Example 28.
. Mp 147-148 over C. MS (EI) m / z :. 417 (M +) IR (KBr):. 3324, 2962, 1717, 1686, 1531 cm -1 1 H-NMR (CDCl 3) ·· : 0.93 (t, 3H, J = 7.0 Hz), 0.92 (t, 3H, J = 7.0 Hz), 1.08 (t, 3H, J = 7.0 Hz), 1.12 (t, 3H, J = 7.0 Hz), 1.40 -1.50 (m, 2H), 1.55-1.64 (m, 2H), 2.21 (s, 3H), 2.37 (t, 3H, J = 7.0 Hz), 2.52 (t, 3H, J = 7.0 Hz), 2.60 ( q, 2H, J = 7.0 Hz), 2.64 (t, 2H, J = 7.0 Hz), 3.63 (s, 2H), 8.85 (s, 2H), 6.84 (s, 1H), 8.06 (s, 1H), 9.10 (s, 1H).

Example 31 3-Acetylamino-5,7-bis [(N-butyl-N-methylamino) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 31]
3-Acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (3.0 g, 13.7 mmol), 37% formalin (9.6 mL, 109.5 mmol), N-butyl-N -From a mixed solution of methylamine (12.9 mL, 109.5 mmol) and ethanol (40 mL) -DMF (40 mL), 3.9 g (67%) of Compound 31 as crystals was obtained in the same manner as in Example 28.
. Mp 144-145 over C. MS (EI) m / z :. 417 (M +) IR (KBr):. 3328, 2957, 1714, 1686, 1529 cm -1 1 H-NMR (DMSO-d 6)・ ・: 0.79-0.89 (m, 6H), 1.22-1.30 (m, 4H), 1.44-1.49 (m, 4H), 2.06 (s, 3H), 2.15 (s, 3H), 2.30 (s, 3H) , 2.30-2.33 (m, 2H), 2.45-2.48 (m, 2H), 3.47 (s, 2H), 3.78 (s, 2H), 6.92 (s, 1H), 8.95 (s, 1H), 9.63 (s , 1H).

Example 32 3-Acetylamino-5,7-bis (N, N-dibutylaminomethyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 32]
3-acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (2.0 g, 9.1 mmol), 37% formalin (6.4 mL, 73.0 mmol), N, N-di From a mixed solution of butylamine (13.2 mL, 38.0 mmol) and ethanol (40 mL) -DMF (40 mL), 2.7 g (59%) of Compound 32 as crystals was obtained in the same manner as in Example 28.
. Mp 153-154 over C. MS (EI) m / z :. 501 (M +) IR (KBr):. 3410, 1713, 1686, 1535 cm -1 1 H-NMR (DMSO-d 6) ·· : 0.73-0.79 (m, 6H), 0.81-0.91 (m, 6H), 1.17-1.26 (m, 8H), 1.37-1.48 (m, 8H), 2.14 (s, 3H), 2.33-2.35 (m, 4H), 3.56 (s, 2H), 3.83 (s, 2H), 6.97 (s, 1H), 8.94 (s, 1H), 9.61 (s, 1H).

Reference Example 6 3-Acetylamino-8-allyloxy-2H-1-benzopyran-2-one 3-acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] 2.0 g, 9.1 mmol), allyl bromide (1.2 mL, 13.7 mmol) and anhydrous potassium carbonate (1.9 g, 13.7 mmol) were added to DMF (20 mL), and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water, and the precipitated crystals were collected by filtration, washed with water and hot ethanol, and dried to obtain 2.1 g (90%) of the title compound as crystals.
¹ H-NMR (DMSO-d ₆ ) ・ ・: 2.17 (s, 3H), 4.71-4.72 (m, 2H), 5.31-5.33 (m, 2H), 5.45-5.48 (m, 1H), 6.00-6.02 (m, 1H), 7.19-7.25 (m, 3H), 8.54 (s, 1H), 9.77 (s, 1H).

Example 33 3-Acetylamino-7-allyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 33]
3-acetylamino-8-allyloxy-2H-1-benzopyran-2-one (1.0 g, 3.9 mmol) of Reference Example 6 was added to N, N-dimethylaniline (15 mL), and the mixture was heated to reflux for 5 hours. After standing to cool, the solution diluted with ether was washed with dilute hydrochloric acid and water, and then the solvent was dried. The solvent was distilled off and the precipitated crystals were recrystallized from ethanol and dried to obtain 0.6 g (56%) of Compound 33.
. Mp 206-207 over C. MS (EI) m / z :. 259 (M +) IR (KBr):. 3343, 1707, 1668, 1536, 1373 cm -1 1 H-NMR (DMSO-d 6)・ ・: 2.16 (s, 3H), 3.40-3.41 (m, 2H), 5.02-5.07 (m, 2H), 5.85-6.05 (m, 1H), 7.04 (d, 1H, J = 8.0 Hz), 7.08 (d, 1H, J = 8.0 Hz), 8.54 (s, 1H), 9.71 (s, 1H), 9.74 (s, 1H).

Reference Example 7 3-acetylamino-7-allyl-8- (methoxymethoxy) -2H-1-benzopyran-2-one 3-acetylamino-7-allyl-8-hydroxy-2H-1 of Example 33 -Benzopyran-2-one [Compound 33] (1.1 g, 4.2 mmol) and N, N-diisopropyl-N-ethylamine (1.5 mL, 8.5 mmol) were dissolved in methylene chloride (30 mL), and methoxy under ice-cooling. Methyl chloride (0.7 mL, 8.5 mmol) was added. After removing the ice bath and stirring at room temperature for 15 hours, the reaction solution was washed with water and saturated brine. Ether was added to the residue obtained by drying and evaporating the solvent. The precipitated crystals were collected by filtration and dried to obtain 0.9 g (66%) of the title compound as crystals.
¹ H-NMR (DMSO-d ₆ ): 2.16 (s, 3H), 3.55 (s, 3H), 4.71-4.72 (m, 2H), 5.15 (s, 2H), 5.31-5.33 (m, 1H ), 5.45-5.48 (m, 1H), 6.00-6.02 (m, 1H), 7.19-7.25 (m, 2H), 8.54 (s, 1H), 9.77 (s, 1H).

Reference Example 8 3-acetylamino-7- (3-hydroxopropyl) -8- (methoxymethoxy) -2H-1-benzopyran-2-one
To a solution of 3-acetylamino-7-allyl-8- (methoxymethoxy) -2H-1-benzopyran-2-one (5.5 g, 18.1 mmol) of Reference Example 7 in anhydrous THF (100 mL) under ice-cooling. 1 mol / L BH ₃ -THF solution (20 mL, 20.0 mmol) was added, and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. Subsequently, 3 mol / L aqueous sodium hydroxide solution (18 mL) and 30% aqueous hydrogen peroxide (20 mL) were sequentially added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 1.1 g (19%) of the title compound as crystals.
¹ H-NMR (DMSO-d ₆ ): 1.68-1.74 (m, 2H), 2.15 (s, 3H), 2.72 (t, 2H, J = 8.0 Hz), 3.40-3.48 (m, 2H), 3.55 (s, 3H), 4.50 (t, 1H, J = 8.0 Hz), 5.17 (s, 2H), 7.17 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0 Hz), 8.55 (s, 1H), 9.72 (s, 1H).

Reference Example 9 3-acetylamino-7- [3- (methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one 3-acetylamino-7- of Reference Example 8 To a solution of (3-hydroxopropyl) -8- (methoxymethoxy) -2H-1-benzopyran-2-one (100 mg, 0.3 mmol) in methylene chloride (10 mL) was added triethylamine (0.1 mL, 0.6 mmol) and methanesulfonyl chloride (30 · L) were sequentially added, followed by stirring at 0 ° C. for 1 hour. Methylene chloride was added to the reaction solution, washed with water and saturated brine, and dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give 100 mg (81%) of the title compound as crystals.
¹ H-NMR (DMSO-d ₆ ): 1.98-2.03 (m, 2H), 2.09 (s, 3H), 2.81 (t, 2H, J = 8.0 Hz), 3.18 (s, 3H), 3.57 ( s, 3H), 4.24 (t, 2H, J = 6.0 Hz), 5.20 (s, 2H), 7.21 (d, 1H, J = 8.0 Hz), 7.40 (d, 1H, J = 8.0 Hz), 8.57 ( s, 1H), 9.73 (s, 1H).

Reference Example 10-1 3-acetylamino-7- [3- (imidazol-2-yl) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one 3-acetyl in Reference Example 9 Amino-7- [3- (methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (100 mg, 0.3 mmol) and imidazole (37 mg, 0.6 mmol) were added to toluene ( 15 mL) and heated to reflux for 16 hours. The residue obtained by concentrating the reaction solution was dissolved in chloroform, washed with water and saturated brine, and dried, and then the solvent was distilled off. The residual oil was crystallized from ether, and the crystals were collected by filtration, washed with ether and dried to give 60 mg (65%) of the title compound.
¹ H-NMR (DMSO-d ₆ ) ...: 1.99-2.04 (m, 2H), 2.16 (s, 3H), 2.66 (t, 2H, J = 8.0 Hz), 3.46 (s, 3H), 4.02 ( t, 2H, J = 7.0 Hz), 5.13 (s, 2H), 6.90 (s, 1H), 7.18 (d, 1H, J = 8.0 Hz), 7.21 (s, 1H), 7.39 (d, 1H, J = 8.0 Hz), 7.65 (s, 1H), 8.56 (s, 1H), 9.75 (s, 1H).

Example 34 3-Acetylamino-8-hydroxy-7- [3- (imidazol-2-yl) propyl] -2H-1-benzopyran-2-one [Compound 34]
Of 3-acetylamino-7- [3- (imidazol-2-yl) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (100 mg, 0.3 mmol) of Reference Example 10-1 To a methylene chloride (15 mL) solution was added 4 mol / L HCl / dioxane (0.7 mL, 3.0 mmol), and the mixture was stirred at room temperature for 19 hours. The precipitated 34 hydrochloride was collected by filtration and washed with ether. The obtained hydrochloride was dissolved in water and neutralized with a saturated aqueous solution of sodium bicarbonate. The precipitated crystals were collected by filtration, washed with water, and dried to obtain 50 mg (57%) of Compound 34 as crystals.
. Mp 254-255 over C. MS (EI) m / z :. 327 (M +) IR (KBr):. 3346, 1695, 1674, 1529, 1379, 1245 cm -1 1 H-NMR (DMSO-d ₆ ) ・ ・: 1.97-2.03 (m, 2H), 2.16 (s, 3H), 2.61 (t, 2H, J = 8.0 Hz), 3.98 (t, 2H, J = 7.0 Hz), 6.90 (s, 1H ), 7.06-7.07 (m, 2H), 7.19 (s, 1H), 7.65 (s, 1H), 8.54 (s, 1H), 9.71 (s, 1H), 9.77 (s, 1H).

Reference Example 10-2 3-acetylamino-8- (methoxymethoxy) -7- (3-piperidinopropyl) -2H-1-benzopyran-2-one 3-acetylamino-7- of Reference Example 9 [3- (Methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (5.0 g, 12.5 mmol) and piperidine (3.3 mL, 31.3 mmol) in toluene (60 mL) In addition, the mixture was heated to reflux for 14 hours. The reaction solution was treated in the same manner as in Reference Example 10-1 to obtain 3.8 g (78%) of the title compound as crystals.
¹ H-NMR (DMSO-d ₆ ): 1.35-1.37 (m, 2H), 1.47-1.49 (m, 4H), 1.70-1.72 (m, 2H), 2.16 (s, 3H), 2.24-2.30 (m, 6H), 2.69-2.71 (m, 2H), 3.56 (s, 3H), 5.18 (s, 2H), 7.19 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0 Hz), 8.56 (s, 1H), 9.72 (s, 1H).

Example 35 3-Acetylamino-8-hydroxy-7- (3-piperidinopropyl) -2H-1-benzopyran-2-one [Compound 35]
3-acetylamino-8- (methoxymethoxy) -7- (3-piperidinopropyl) -2H-1-benzopyran-2-one (3.7 g, 9.5 mmol) of Reference Example 10-2 in methylene chloride (25 4 mol / L-HCl / dioxane (24 mL, 95.0 mmol) was added to the solution, and the mixture was stirred at room temperature for 23 hours. The precipitated hydrochloride was treated in the same manner as in Example 34 to obtain 2.3 g (70%) of compound 35 as crystals.
. Mp 183-184 over C. MS (EI) m / z :. 344 (M +) IR (KBr):. 3379, 2937, 1671, 1583, 1375 cm -1 1 H-NMR (DMSO-d 6)・ ・: 1.42-1.50 (m, 2H), 1.57-1.63 (m, 4H), 1.78-1.84 (m, 2H), 2.16 (s, 3H), 2.23 (t, 2H, J = 6.5 Hz), 2.37 -2.44 (m, 4H), 2.66 (t, 2H, J = 6.5 Hz), 7.00 (d, 1H, J = 8.0 Hz), 7.06 (d, 1H, J = 8.0 Hz), 8.51 (s, 1H) , 9.66 (s, 1H).

Reference Example 10-3 3-acetylamino-7- [3- (N, N-dimethylamino) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one Acetylamino-7- [3- (methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (0.5 g, 1.2 mmol) and 50% N, N-dimethylamine aqueous solution ( 0.4 mL, 4.2 mmol) was added to toluene (25 mL), and the mixture was heated to reflux for 18 hours. The reaction solution was treated in the same manner as in Reference Example 10-1 to obtain 0.2 g (39%) of the title compound as crystals.
¹ H-NMR (CDCl ₃ ): 1.76-1.84 (m, 2H), 2.15 (s, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 2.34 (t, 2H, J = 7.0 Hz), 2.78 (t, 2H, J = 8.0 Hz), 3.67 (s, 3H), 5.24 (s, 2H), 7.15 (d, 1H, J = 8.0 Hz), 7.19 (d, 1H, J = 8.0 Hz), 8.00 (s, 1H), 8.63 (s, 1H).

Example 36 3-Acetylamino-7- [3- (N, N-dimethylamino) propyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 36]
3-acetylamino-7- [3- (N, N-dimethylamino) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (170 mg, 0.5 mmol) of Reference Example 10-3 To a methylene chloride (10 mL) solution was added 4 mol / L-HCl / dioxane (1.2 mL, 4.9 mmol), and the mixture was stirred at room temperature for 22 hours. The precipitated hydrochloride was treated in the same manner as in Example 34 to obtain 100 mg (67%) of compound 36 as crystals.
. Mp 217-218 over C. MS (EI) m / z :. 304 (M +) IR (KBr):. 3354, 1674, 1527 cm -1 1 H-NMR (CDCl 3) ··: 1.88-1.94 (m, 2H), 2.22 (s, 3H), 2.28 (t, 2H, J = 6.0 Hz), 2.34 (s, 6H), 2.79 (d, 2H, J = 6.5 Hz), 6.92 (d, 1H, J = 8.0 Hz), 6.99 (d, 1H, J = 8.0 Hz), 8.05 (s, 1H), 8.60 (s, 1H).

Reference Example 10-4 3-acetylamino-7- [3- (N, N-diethylamino) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one 3-acetyl of Reference Example 9 Amino-7- [3- (methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (5.0 g, 12.5 mmol) and N, N-diethylamine (4.4 mL, 43.8 mmol) ) Was added to toluene (60 mL) and heated to reflux for 18 hours. The reaction solution was treated in the same manner as in Reference Example 10-1 to obtain 3.3 g (69%) of the title compound as crystals.
¹ H-NMR (CDCl ₃ ) ... 1.02 (t, 3H, J = 8.0 Hz), 1.77-1.83 (m, 2H), .2.24 (s, 3H), 2.52 (t, 2H, J = 8.0 Hz) ), 2.54 (q, 2H, J = 8.0 Hz), 2.75 (t, 2H, J = 8.0 Hz), 3.67 (s, 3H), 5.23 (s, 2H), 7.15 (d, 1H, J = 8.0 Hz) ), 7.18 (d, 1H, J = 8.0 Hz), 8.00 (s, 1H), 8.63 (s, 1H).

Example 37 3-Acetylamino-7- [3- (N, N-diethylamino) propyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 37]
3-acetylamino-7- [3- (N, N-diethylamino) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (3.3 g, 8.6 mmol) of Reference Example 10-4 To the methylene chloride (50 mL) solution was added 4 mol / L-HCl / dioxane (21 mL, 86.0 mmol), and the mixture was stirred at room temperature for 22 hours. The precipitated hydrochloride was treated in the same manner as in Example 34 to obtain 2.0 g (71%) of compound 37 as crystals.
Mp. 140-141 ー C. MS (EI) m / z: 332 (M ⁺ ). IR (KBr): 3321, 2928, 1676, 1524, 1375 cm ⁻¹ . ¹ H-NMR (CDCl ₃ ) ・ ・: 1.11 (t, 6H, J = 7.0 Hz), 1.89-1.93 (m, 2H), 2.22 (s, 3H), 2.39 (t, 2H, J = 6.0 Hz), 2.68 (q, 4H, J = 7.0 Hz), 2.78 (t, 2H, J = 6.5 Hz), 6.90 (d, 1H, J = 8.0 Hz), 6.98 (d, 1H, J = 8.0 Hz), 8.08 (s, 1H), 8.59 (s, 1H).

Reference Example 10-5 3-Acetylamino-7- [3- (N-ethyl-N-propylamino) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one 3-acetylamino-7- [3- (methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (0.5 g, 1.2 mmol) and N-ethyl-N-propylamine (0.5 mL, 4.2 mmol) was added to toluene (25 mL), and the mixture was heated to reflux for 18 hours. The reaction solution was treated in the same manner as in Reference Example 10-1 to obtain 0.3 g (68%) of the title compound as crystals.
¹ H-NMR (CDCl ₃ ): 0.89 (t, 3H, J = 7.5 Hz), 1.04-1.07 (m, 2H), 1.48-1.50 (m, 2H), 1.80-1.90 (m, 2H), 2.24 (s, 3H), 2.53-2.57 (m, 2H), 2.76-2.79 (m, 4H), 2.78 (q, 2H, J = 7.5 Hz), 3.65 (s, 3H), 5.24 (s, 2H) , 7.15 (d, 1H, J = 8.0 Hz), 7.19 (d, 1H, J = 8.0 Hz), 8.01 (s, 1H), 8.63 (s, 1H).

Example 38 3-Acetylamino-7- [3- (N-ethyl-N-propylamino) propyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 38]
3-acetylamino-7- [3- (N-ethyl-N-propylamino) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one of Reference Example 10-5 (370 mg, 0.9 mmol) in methylene chloride (10 mL) was added 4 mol / L-HCl / dioxane (2.1 mL, 9.0 mmol), and the mixture was stirred at room temperature for 17 hours. The precipitated hydrochloride was treated in the same manner as in Example 34 to obtain 30 mg (10%) of compound 38 as crystals.
. Mp 97-98 over C. MS (EI) m / z :. 346 (M +) IR (KBr):. 1707, 1532, 1373, 1241 cm -1 1 H-NMR (CDCl 3) ··: 0.93 (t, 3H, J = 7.5 Hz), 1.10 (t, 3H, J = 5.0 Hz), 1.48-53 (m, 2H), 1.90-1.96 (m, 2H), 2.22 (s, 3H), 2.40 ( t, 2H, J = 6.0 Hz), 2.52 (t, 2H, J = 5.0 Hz), 2.69 (q, 2H, J = 7.5 Hz), 2.78 (t, 2H, J = 6.0 Hz), 6.91 (d, 1H, J = 8.0 Hz), 7.00 (d, 1H, J = 8.0 Hz), 8.07 (s, 1H), 8.59 (s, 1H).

Reference Example 10-6 3-acetylamino-7- [3- (N, N-dipropylamino) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one Reference Example 3-3 -Acetylamino-7- [3- (methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (0.5 g, 1.2 mmol) and N, N-dipropylamine (0.69 mL, 7.2 mmol) was added to toluene (25 mL), and the mixture was heated to reflux for 28 hours. The reaction solution was treated in the same manner as in Reference Example 10-1 to obtain 0.4 g (75%) of the title compound as crystals.
¹ H-NMR (CDCl ₃ ): 0.84-0.92 (m, 6H), 1.41-1.48 (m, 4H), 1.78-183 (m, 2H), 2.24 (s, 3H), 2.35-2.38 (m , 4H), 2.47-2.52 (m, 2H), 2.73-2.79 (m, 2H), 3.67 (s, 3H), 5.23 (s, 2H), 7.15 (d, 1H, J = 8.0 Hz), 7.18 ( d, 1H, J = 8.0 Hz), 8.10 (s, 1H), 8.63 (s, 1H).

Example 39 3-Acetylamino-7- [3- (N, N-dipropylamino) propyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 39]
3-acetylamino-7- [3- (N, N-dipropylamino) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (370 mg, 0.9 mmol) of Reference Example 10-6 ) In methylene chloride (15 mL) was added 4 mol / L-HCl / dioxane (2.1 mL, 9.0 mmol), and the mixture was stirred at room temperature for 17 hours. The precipitated hydrochloride was treated in the same manner as in Example 34 to obtain 100 mg (30%) of compound 39 as crystals.
. Mp 97-98 over C. MS (EI) m / z :. 360 (M +) IR (KBr):. 1699, 1535, 1456, 1360 cm -1 1 H-NMR (CDCl 3) ··: 0.92 (t, 6H, J = 7.5 Hz), 11.51-11.55 (m, 2H), 1.89-1.94 (m, 2H), 2.21 (s, 3H), 2.40 (t, 4H, J = 5.0 Hz), 2.52 ( t, 2H, J = 5.0 Hz), 2.78 (t, 2H, J = 6.0 Hz), 6.90 (t, 2H, J = 6.0 Hz), 6.90 (d, 1H, J = 8.0 Hz), 6.98 (d, 1H, J = 8.0 Hz), 8.10 (s, 1H), 8.59 (s, 1H).

Reference Example 10-7 3-acetylamino-8- (methoxymethoxy) -7- (3-morpholinopropyl) -2H-1-benzopyran-2-one 3-acetylamino-7- [3 of Reference Example 9 -(Methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (0.4 g, 1.0 mmol) and morpholine (0.2 mL, 2.5 mmol) were added to toluene (20 mL), Heated to reflux for 18 hours. The reaction solution was treated in the same manner as in Reference Example 10-1 to obtain 0.2 g (59%) of the title compound as crystals.
¹ H-NMR (CDCl ₃ ): 1.81-1.89 (m, 2H), 2.24 (s, 3H), 2.39 (t, 2H, J = 7.5 Hz), 2.42-2.44 (m, 4H), 2.79 ( t, 2H, J = 8.0 Hz), 3.67 (s, 3H), 3.70-3.72 (m, 4H), 5.24 (s, 2H), 7.14 (d, 1H, J = 8.0 Hz), 7.18 (d, 1H , J = 8.0 Hz), 8.00 (s, 1H), 8.63 (s, 1H).

Example 40 3-Acetylamino-8-hydroxy-7- (3-morpholinopropyl) -2H-1-benzopyran-2-one [Compound 40]
3-acetylamino-8- (methoxymethoxy) -7- (3-morpholinopropyl) -2H-1-benzopyran-2-one (230 mg, 0.6 mmol) of Reference Example 10-7 in methylene chloride (10 mL) 4 mol / L-HCl / dioxane (1.5 mL, 6.0 mmol) was added to the solution, and the mixture was stirred at room temperature for 24 hours. The precipitated hydrochloride was treated in the same manner as in Example 34 to obtain 100 mg (49%) of compound 40 as crystals.
. Mp 199-200 over C. MS (EI) m / z :. 346 (M +) IR (KBr):. 1700, 1680, 1524, 1363 cm -1 1 H-NMR (CDCl 3) ··: 1.91 -1.97 (m, 2H), 2.23 (s, 3H), 2.33 (t, 2H, J = 6.0 Hz), 2.52-2.59 (m, 4H), 2.78 (t, 2H, J = 6.5 Hz), 3.84- 3.92 (m, 4H), 6.95 (d, 1H, J = 8.0 Hz), 6.99 (d, 1H, J = 8.0 Hz), 8.05 (s, 1H), 8.61 (s, 1H).

Example 41 3-Acetylamino-5,7-bis [(4-methyl-1-piperazinyl) methyl] -8-hydroxy-2H-1-benzopyran-2-one [Compound 41]
3-acetylamino-8-hydroxy-2H-1-benzopyran-2-one of Example 8 [Compound 8] (3.0 g, 13.7 mmol), 37% formalin (6.0 mL, 68.5 mmol) and 1-methylpiperazine ( 7.5 mL, 68.5 mmol) was added to a mixed solvent of ethanol (40 mL) -DMF (40 mL), and the mixture was heated to reflux for 18 hours. After allowing to cool, ether and petroleum ether were added, and the precipitated crystals were collected by filtration and washed with ethanol to obtain 4.7 g (78%) of Compound 41.
. Mp 184-185 over C. MS (EI) m / z :. 443 (M +) IR (KBr):. 1713, 1691, 1516, 1134 cm -1 1 H-NMR (DMSO-d 6) ·· : 2.12 (s, 3H), 2.16 (s, 3H), 2.17 (s, 3H), 2.27-2.37 (m, 16H), 3.48 (s, 2H), 3.76 (s, 2H), 6.94 (s, 1H ), 8.97 (s, 1H), 9.66 (s, 1H).

Reference Example 11 N '-(tert-butoxycarbonyl) -8- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxyhydrazide Succinimide of Reference Example 4- (methoxymethoxy) -2- Oxo-2H-1-benzopyran-3-carboxylate (5.0 g, 14.4 mmol) and tert-butylcarbazate (3.8 g, 28.8 mmol) were added to methylene chloride (50 mL), and the mixture was stirred at room temperature for 3.5 hours. After washing with water and saturated brine and drying, the solvent was distilled off. Petroleum ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 3.2 g (60%) of a compound.
¹ H-NMR (CDCl ₃ ): 1.44 (s, 9H), 3.46 (s, 3H), 5.37 (s, 2H), 7.38 (dd, 1H, J = 8.0, 8.0 Hz), 7.53 (d, 1H, J = 8.0 Hz), 7.16 (d, 1H, J = 8.0 Hz), 8.80 (s, 1H), 9.17 (s, 1H), 9.46 (s, 1H).

Example 42 8-Hydroxy-2-oxo-2H-1-benzopyran-3-carboxyhydrazide [Compound 42]
N '-(tert-butoxycarbonyl) -8- (methoxymethoxy) -2-oxo-2H-1-benzopyran-3-carboxyhydrazide (3.0 g, 8.2 mmol) of Reference Example 11 in methylene chloride (20 mL) 4 mol / L-HCl / dioxane (20 mL, 82.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 19 hours. The precipitated crystals were collected by filtration and washed with ether to give the hydrochloride of the title compound. This was dissolved in water and neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the precipitated crystals were collected by filtration and washed with water to obtain 1.6 g (91%) of Compound 42.
Mp. 257-258 ー C. (dec.). MS (EI) m / z: 220 (M ⁺ ). IR (KBr): 3206, 1723, 1572, 1506, 1471, 1290 cm ^-1 . ¹ H- NMR (DMSO-d ₆ ): 4.74 (s, 2H), 7.22-7.24 (m, 2H), 7.38-7.39 (m, 1H), 8.75 (s, 1H), 9.63 (s, 1H), 10.42 (s, 1H).

Example 43 3-Acetylamino-5- (N, N-diethylamino) methyl-8-hydroxy-7- (3-piperidinopropyl) -2H-1-benzopyran-2-one [Compound 43]
3-Acetylamino-8-hydroxy-7- (3-piperidinopropyl) -2H-1-benzopyran-2-one (35) (500 mg, 1.5 mmol) of Example 35, 37% formalin (0.5 mL , 4.5 mmol) and N, N-diethylamine (0.5 mL, 4.5 mmol) were added to a mixed solvent of ethanol (15 mL) -DMF (10 mL) and heated under reflux for 24 hours. After allowing to cool, chloroform was added to the reaction solution, and the mixture was washed with water and saturated brine. The solvent was dried and evaporated to give 180 mg (30%) of Compound 43 as an oil.
MS (EI) m / z: 429 (M ⁺ ). ¹ H-NMR (DMSO-d ₆ ) ・ ・: 0.99 (t, 6H), 1.40-1.61 (m, 6H), 1.78-1.80 (m, 2H ), 2.16 (s, 3H), 2.20-2.22 (m, 2H), 2.38-2.45 (m, 8H), 2.62-2.65 (m, 2H), 5.54 (s, 2H), 6.97 (s, 1H), 9.03 (s, 1H), 9.59 (s, 1H).

Reference Example 12 3-Acetylamino-7-allyl-8-allyloxy-2H-1-benzopyran-2-one 3-acetylamino-7-allyl-8-hydroxy-2H-1-benzopyran- of Example 33 2-one [compound 33] (19.5 g, 75.2 mmol), allyl bromide (9.2 mL, 13.7 mmol) and anhydrous potassium carbonate (15.6 g, 112.8 mmol) were added to DMF (250 mL) and stirred at room temperature for 4 hours. did. The reaction solution was diluted with water, and the precipitated crystals were collected by filtration, washed with water, and dried to give 15.4 g (68%) of the title compound as crystals.
¹ H-NMR (DMSO-d ₆ ): 2.15 (s, 3H), 3.42-3.44 (m, 2H), 4.58-4.59 (m, 2H), 5.04-5.07 (m, 2H), 5.24-5.26 (m, 1H), 5.38-5.42 (m, 1H), 5.80-6.00 (m, 1H), 6.00-6.02 (m, 1H), 7.12 (d, 1H, J = 8.0 Hz), 7.35 (d, 1H , J = 8.0 Hz), 8.55 (s, 1H), 9.74 (s, 1H).

Example 44 3-Acetylamino-5,7-diallyl-8-hydroxy-2H-1-benzopyran-2-one [Compound 44]
Add 3-acetylamino-7-allyl-8-allyloxy-2H-1-benzopyran-2-one (15.4 g, 51.4 mmol) from Reference Example 12 to N, N-dimethylaniline (150 mL) and heat to reflux for 5 hours. did. After allowing to cool, the reaction solution was added to dilute hydrochloric acid, and the precipitated crystals were collected by filtration, washed with dilute hydrochloric acid and water, and dried to obtain 15.0 g (97%) of Compound 44 as crystals.
¹ H-NMR (DMSO-d ₆ ): 2.16 (s, 3H), 3.38-3.40 (m, 2H), 3.44-3.46 (m, 2H), 4.50-5.07 (m, 4H), 5.91-5.95 (m, 2H), 6.91 (s, 1H), 8.76 (s, 1H), 9.55 (s, 1H), 9.73 (s, 1H).

Reference Example 13 3-Acetylamino-5,7-diallyl-8- (methoxymethoxy) -2H-1-benzopyran-2-one 3-acetylamino-5,7-diallyl-8-hydroxy of Example 44 -2H-1-benzopyran-2-one [compound 44] (15.0 g, 50.1 mmol) and N, N-diisopropyl-N-ethylamine (17.5 mL, 100.2 mmol) were dissolved in methylene chloride (200 mL) and iced. Methoxymethyl chloride (7.6 mL, 100.2 mmol) was added under cooling. After removing the ice bath and stirring at room temperature for 15 hours, the reaction solution was washed with water and saturated brine. The solvent was dried. The residue crystals obtained by distilling off the solvent were recrystallized from ethanol and dried to obtain 7.6 g (44%) of the title compound.
¹ H-NMR (DMSO-d ₆ ): 2.16 (s, 3H), 3.47-3.51 (m, 4H), 3.56 (s, 3H), 5.06-5.12 (m, 4H), 5.15 (s, 2H ), 5.09-6.12 (m, 2H), 7.02 (s, 1H), 8.77 (s, 1H), 9.78 (s, 1H).

Reference Example 14 3-acetylamino-5,7-bis (3-hydroxypropyl) -8- (methoxymethoxy) -2H-1-benzopyran-2-one 3-acetylamino-5,7 in Reference Example 13 -Diallyl-8- (methoxymethoxy) -2H-1-benzopyran-2-one (8.0 g, 23.3 mmol) in anhydrous THF (100 mL) was added to a 1 mol / L BH ₃ -THF solution under ice-cooling ( 93 mL, 93.2 mmol) was added, and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. Subsequently, 3 mol / L aqueous sodium hydroxide solution (23 mL) and 30% aqueous hydrogen peroxide (25 mL) were sequentially added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried, and the solvent was evaporated to give the title compound as crystals (6.8 g (77%)).
¹ H-NMR (DMSO-d ₆ ): 1.69-1.72 (m, 4H), 2.16 (s, 3H), 2.69-2.76 (m, 4H), 3.43-3.46 (m, 4H), 3.56 (s , 3H), 4.40-4.50 (m, 2H), 5.14 (s, 2H), 7.05 (s, 1H), 8.75 (s, 1H), 9.76 (s, 1H).

Reference Example 15 3-acetylamino-5,7-bis [3- (methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one 3-acetylamino of Reference Example 14 -5,7-bis (3-hydroxypropyl) -8- (methoxymethoxy) -2H-1-benzopyran-2-one (5.7 g, 15.0 mmol) in methylene chloride (100 mL) under ice-cooling Triethylamine (8.4 mL, 60.1 mmol) and methanesulfonyl chloride (3.5 mL, 40.1 mmol) were sequentially added, followed by stirring at 0 ° C. for 1 hour. Methylene chloride was added to the reaction solution, washed with water and saturated brine, and dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 70: 1) to obtain 3.5 g (44%) of the title compound as crystals.
¹ H-NMR (DMSO-d ₆ ): 1.98-1.99 (m, 4H), 2.17 (s, 3H), 2.70-2.80 (m, 4H), 3.18 (s, 3H), 3.31 (s, 3H ), 3.56 (s, 3H), 4.23-4.25 (m, 4H), 5.16 (s, 2H), 7.12 (s, 1H), 8.74 (s, 1H), 9.90 (s, 1H).

Reference Example 16 3-acetylamino-5,7-bis (3-piperidinopropyl) -8- (methoxymethoxy) -2H-1-benzopyran-2-one 3-acetylamino-5 of Reference Example 15 , 7-bis [3- (methanesulfonyloxy) propyl] -8- (methoxymethoxy) -2H-1-benzopyran-2-one (70 mg, 13 mmol) and piperidine (0.8 mL, 7.8 mmol) in anhydrous toluene (15 mL) Added to the solution and heated to reflux for 24 hours. The residue obtained by concentrating the reaction solution was dissolved in chloroform and washed with water and saturated brine. Ether and petroleum ether were added to the residue obtained by evaporating the solvent, and the precipitated crystals were collected by filtration to obtain 400 mg (66%) of the title compound as crystals.
¹ H-NMR (DMSO-d ₆ ): 1.30-1.32 (m, 4H), 1.34-1.37 (m, 8H), 1.47-1.49 (m, 4H), 2.16 (s, 3H), 2.22-2.28 (m, 12H), 2.65-2.74 (m, 4H), 3.56 (s, 3H), 5.13 (s, 2H), 7.07 (s, 1H), 8.76 (s, 1H), 9.78 (s, 1H).

Example 45 3-Acetylamino-5,7-bis (3-piperidinopropyl) -8-hydroxy-2H-1-benzopyran-2-one [Compound 45]
3-acetylamino-5,7-bis (3-piperidinopropyl) -8- (methoxymethoxy) -2H-1-benzopyran-2-one (300 mg, 0.6 mmol) of Reference Example 16 in methylene chloride ( 15 mL) To the solution was added 4 mol / L-HCl / dioxane (1.5 mL, 5.8 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with methylene chloride, and then washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The solvent was dried and evaporated to obtain 150 mg (55%) of Compound 45 as crystals.
. Mp 159-160 over C. MS (EI) m / z :. 469 (M +) IR (KBr):. 2933, 1714, 1668, 1538 cm -1 1 H-NMR (DMSO-d 6) ··・: 1.30-1.40 (m, 2H), 1.48-1.50 (m, 6H), 1.59-1.61 (m, 4H), 1.69-1.79 (m, 2H), 1.80-1.89 (m, 2H), (s, 3H), 2.22-2.40 (m, 12H), 2.61-2.68 (m, 4H), 6.93 (s, 1H), 8.75 (s, 1H), 9.72 (s, 1H).

  The Maillard reaction inhibitory action of the compound of the present invention was confirmed by a screening system using various proteins and sugars. An example of the results is given below.

<Example 46> Measurement of Maillard reaction inhibitory action Lysozyme and glucose were dissolved in 250 mM sodium phosphate buffer (pH = 7.4) to a concentration of 10 mg / mL and 200 mM, respectively, at 45 ° C. for 3 days. After incubation, a certain amount was taken out and subjected to electrophoresis using SDS-PAGE. After electrophoresis, the product was stained with 0.2% Coomassie Brilliant Blue R-250, and the amount of dimer produced was quantified with an image scanner. The compound of the present invention was added at the time of incubation to a concentration of 0.1 mM, and the inhibitory effect on protein dimer formation caused by glycation cross-linking of the protein by Maillard reaction was examined. An example of the evaluation results is shown in Table 1.

  The compound of the present invention has a Maillard reaction inhibitory action and is useful for the prevention or treatment of diseases and functional disorders caused by glycation cross-linking of proteins by Maillard reaction. That is, diseases involving the Maillard reaction, such as coronary heart disease, peripheral circulation disorder, cerebrovascular disorder, neuropathy, nephropathy, arteriosclerosis, joint sclerosis, cataract, retinopathy, diabetic osteopenia, etc. Diabetes complications, dialysis complications such as dialysis amyloidosis, or diseases caused by aging, such as atherosclerosis, glomerulonephritis, senile cataract, osteoarthritis, periarticular stiffness, joint sclerosis, senile osteoporosis It is useful for prevention or treatment of the above. In addition, it suppresses the formation of collagen cross-linking, which causes skin hardening, wrinkle formation, loss of elasticity and gloss, and coloring that causes dullness and itching of skin, and is intended to prevent skin aging and improve skin It can also be used as a fee. Furthermore, the compounds of the present invention can prevent the generation and coloring of aromatic components, mutagens and active oxygen due to the progress of the Maillard reaction even in cosmetics and foods containing proteins and amino acids. It is also useful as a discoloration / deterioration inhibitor to be added.

Claims (7)

A coumarin derivative represented by the general formula (I ′) and a pharmaceutically acceptable salt thereof.

[Wherein R ₁ ′ is —NH—X or CO—Y; X is hydrogen, acetyl group or benzyl group; Y is substituted with an alkyl group, phenyl group, hydroxyl group, alkoxy group, amino group or alkyl group; R ₂ ′ is hydrogen; R ₃ ′ is a hydroxyl group or acetoxy group; R ₅ ′ is hydrogen; R ₄ ′ and R ₆ ′ are the same or different and each represents hydrogen, an allyl group, (N, N-dialkyl An amino) alkyl group, a piperidinoalkyl group, a morpholinoalkyl group, an imidazolylalkyl group, or a (unsubstituted or substituted piperazino) alkyl group; However, when X is hydrogen or an acetyl group or Y is an alkoxy group, R ₄ ′ or R ₆ ′ represents a group other than hydrogen. ] A Maillard reaction inhibitor containing at least one of a coumarin derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof.

[Wherein R ₁ is —NH—X, —CO—Y or a hydroxyl group; X is hydrogen, acetyl group or benzyl group; Y is an alkyl group, phenyl group, hydroxyl group, alkoxy group, amino group or alkyl group; R ₂ is hydrogen; R ₃ is a hydroxyl group, a methoxy group or an acetoxy group; R ₅ is hydrogen; R ₄ and R ₆ are the same or different and each represents hydrogen, an allyl group, (N, N-dialkyl) An amino) alkyl group, a piperidinoalkyl group, a morpholinoalkyl group, an imidazolylalkyl group, or a (unsubstituted or substituted piperazino) alkyl group; ]   A prophylactic / therapeutic agent for diabetic complications comprising the Maillard reaction inhibitor according to claim 2.   A prophylactic / therapeutic agent for dialysis complications comprising the Maillard reaction inhibitor according to claim 2.   A skin aging inhibitor containing the Maillard reaction inhibitor according to claim 2.   Cosmetics containing the Maillard reaction inhibitor of Claim 2.   A discoloration / deterioration inhibitor containing the Maillard reaction inhibitor according to claim 2.