JPH04139177A - Furalbenzoquinone derivative, its production and carcinostatic agent - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is H, 1-6C alkyl or 1-6C hydroxyalkyl; R<2> to R<5> are H, OH or any two of them are OH, or R<2>, R<3>, R<4> and R<5> are H when R<3> is OH or R<2>, R<3> and R<5> are H when R<4> is OH. EXAMPLE:2-(1-Hydroxyethyl)-5,8-dihydroxynaphtho[2,3,b]furan-4,9-dione. USE:A carcinostatic agent. PREPARATION:For example, a compound shown by formula II (X is H or halogen) is subjected to Diels-Alder reaction with butadiene derivative shown by formula III (R<2> is H or protected OH), then isomerized, deprotected, isolated and purified by column chromatography to give compounds shown by formula IV and formula V (R<3> is H or OH).

Description

[Detailed description of the invention]

[0001]

[Industrial application field]

The present invention relates to a novel furalbenzoquinone derivative, a method for producing the same, and an anticancer agent containing a furalbenzoquinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient. [0002]

[Conventional technology]

Several quinone derivatives have been known to have anticancer effects, and among these, mitomycin C, aclacinomycin A, daunorubicin hydrochloride, doxorubicin hydrochloride, and the like are widely used in clinical treatment. However, among the quinone derivatives, furalbenzoquinone derivatives are known as kigerinone (Kige 11n) named by Bengami et al.
Only a few compounds are known, including one (Kenichi Bengami et al., Phytochemistry, 2).
0 (9), 2271 (1981)) [0003
In addition, the pharmacological effects of these furalbenzoquinone derivatives have not been studied much, but Kingston et al. , measuring the cytotoxic effect on KB cells (D, G, 1.K
ingston et al., Jof Nat.
Ural Products, 45 (5), 600
(1982)). [0004]

[Chemical formula 16] ○ [0005]

[Chemical formula 17] [0006]

[0007] However, in the report by Kingston et al., the separation and purification of Quigerinone (Compound A) and Compound B were not performed, and the activity was measured using a mixture of Compound A and Compound B.
The true pharmacological activity of each was unknown. Prior to filing this application, the present inventors filed an application for a furalbenzoquinone derivative, an anticancer agent containing this derivative as an active ingredient, and a method for producing the same (Japanese Patent Application Laid-Open No. 196576/1983). [0008] However, this patent application by the present inventors
6, it was necessary to further clarify the true pharmacological activity of each compound obtained by extraction and purification. [0009]

[Means to solve the problem]

In view of the above-mentioned problems, the present inventors have conducted extensive research with the aim of developing a new and useful anticancer agent through chemical synthesis rather than extraction and purification from natural products as in the previous application. The present invention has been achieved by being able to produce a novel method for producing rubenzoquinone derivatives, a novel furalbenzoquinone derivative, a medically acceptable salt thereof, and an anticancer agent containing them as an active ingredient. [00101] That is, as a result of intensive research for the purpose of freely introducing substituents at each position of naphtho[2,3-b]furan-4,9-dione, the present inventors found that benzo[2,3-b]furan-4,9-dione b] Furan-4,7-dione or a novel benzo[2,
3-b] A chain or cyclic diene compound is added to the furan-4,7-dione derivative by Diels-Ander (D i
We have developed a synthetic method that involves a reaction (el 5-Al der) reaction, synthesized various new furalbenzoquinone derivatives, isolated and purified these optically active forms from racemic forms, and further developed their anticancer properties. The present invention was completed by examining the activity. [0011] The furalbenzoquinone derivative of the present invention is represented by the general formula (I) shown in Chemical Formula 1. [0012]

[0013] In this general formula (I), R1 is hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched alkyl group having 1 to 6 carbon atoms. R2 to R5 are hydrogen or hydroxyl groups, and any two of them are hydroxyl groups. [0014] In the general formula (I), R1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms,
Those in which R2 to R5 are hydrogen or hydroxyl groups, and any two of them are hydroxyl groups, are also included in the furalbenzoquinone derivatives of the present invention. [0015] In the general formula (I), R1 is a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms,
Those in which R2 to R5 are hydrogen or hydroxyl groups, and any two of them are hydroxyl groups, are also included in the furalbenzoquinone derivatives of the present invention. [0016] In the general formula (I), R1 is hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched hydroxy group having 1 to 6 carbon atoms. When it is an alkyl group, R2 to R5 are hydrogen or a hydroxyl group, and R3 is a hydroxyl group, R2
R4R5 is hydrogen, and R4 is included in hydroquinone derivatives. [00173 In the general formula (I), R1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms,
When R2 to R5 are hydrogen or a hydroxyl group, and R3 is a hydroxyl group, R2R4R5 is hydrogen, and when R4 is a hydroxyl group, R2R3R
Those in which 5 is hydrogen are also included in the furalbenzoquinone derivatives of the present invention. [0018] In the general formula (I), R1 is hydrogen or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms, R2 to R5 are hydrogen or a hydroxyl group, and
When R3 is a hydroxyl group, R2R4R5 is hydrogen, and when R4 is a hydroxyl group, R2
Those in which R3R5 is hydrogen are also included in the furalbenzoquinone derivatives of the present invention. [0019] Further, the furalbenzoquinone derivative of the present invention has the general formula (
II). [0020]

[0021] In this general formula (II), R1 is hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched alkyl group having 1 to 6 carbon atoms. It is a hydroxyalkyl group consisting of [0022] In the general formula (II), those in which R1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms are also included in the furalbenzoquinone derivatives of the present invention. [0023] In the general formula (II), those in which R1 is a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms are also included in the furalbenzoquinone derivatives of the present invention. [0024] Further, the furalbenzoquinone derivative of the present invention is represented by general formula (III). [0025]

[0026] In this general formula (III), R1 is hydrogen, or a chain or branched alkyl group having 1 to 6 carbon atoms,
or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. [0027] In the general formula (III), those in which R1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms are also included in the furalbenzoquinone derivatives of the present invention. [0028] In the general formula (III), those in which R1 is a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms are also included in the furalbenzoquinone derivatives of the present invention. [0029] Further, the furalbenzoquinone derivative of the present invention has the general formula (
IV). [0030]

[0031] In this general formula (IV), R1 is hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched alkyl group having 1 to 6 carbon atoms. It is a hydroxyalkyl group consisting of [0032] Also included in the furalbenzoquinone derivatives of the present invention are those having an alkyl group consisting of: [0033] In the general formula (IV), those in which R1 is a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms are also included in the furalbenzoquinone derivatives of the present invention. [0034] Further, the furalbenzoquinone derivative of the present invention has the general formula (V)
[0035]

[0036] In this general formula (V), R1 is hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched alkyl group having 1 to 6 carbon atoms. It is a hydroxyalkyl group consisting of [0037] In the general formula (V), those in which R1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms are also included in the furalbenzoquinone derivatives of the present invention. [0038] In the general formula (V), those in which R1 is hydrogen or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms are also included in the furalbenzoquinone derivatives of the present invention. [0039] Further, the furalbenzoquinone derivative of the present invention has the general formula (V
I). [0040]

[0041] In this general formula (VI), R1 is hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched alkyl group having 1 to 6 carbon atoms. It is a hydroxyalkyl group consisting of [0042] In the general formula (VI), those in which R1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms are also included in the furalbenzoquinone derivatives of the present invention. [0043] In the general formula (VI), those in which R1 is hydrogen or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms are also included in the furalbenzoquinone derivatives of the present invention. [0044] Furthermore, the anticancer agent of the present invention contains any of the above furalbenzoquinone derivatives or a pharmaceutically acceptable salt of the furalbenzoquinone derivative as an active ingredient. [0045] Compounds contained in the furalbenzoquinone derivative and anticancer agent of the present invention include, for example, 5-hydroxynaphtho[2,3-b)furan-4,9-dione, 6-hydroxynaphtho[2,3- b] Furan-4,9-dione, 7
-Hydroxynaphtho[2,3-b)furan-4,9-dione, 8-hydroxynaphthoC2,3-b)furan-4
, 9-dione, 6-t-butyldimethylsilokinaphtho [
2,3-b) Furan-4,9-dione, 7-t-butyldimethylsilokinaphtho[::2,3-b]furan-4,
9-dione, 5,6-hydroxynaphthoC2,3-b
Furan-4,9-dione, 5,7-dihydroxynaphtho(2,3-b, furan-4゜9-dione, 5,8-
dihydroxynaphtho[2,3-t)furan--4,9-
Dione, 6,7-dihydroxynaphtho(2,3-b)furan-4,9-dione, 6°8-dihydroxynaphtho[
2,3-b) Furan-4,9-dione, 7,8-dihydroxynaphtho[2,3-b, furan-4,9-dione, 2-(1-hydroxyethyl)-5-hydroxynaphtho[ 2,3-b]furan-4,9-dione, 2-(1-
hydroxyethyl)-6-hydroxynaphtho[2,3-
b, Furan-4゜9-dione, 2-(1-hydroxyethyl)-7-hydroxynaphthoC2,3-b) Furan-4,9-dione, 2-(1-hydroxyethyl)-8
-Hydroxynaphtho[2,3-b]furan-4,9-dione, 2-(1-hydroxyethyl)-6-t-butyldimethylsilokinaphtho[2,3-b]furan-4,9-
Dione 2-(1-hydroxyethyl)-7-t-butyldimethylsilokinaphtho[2°3-b]furan-4.9
-dione, 2-(1-hydroxyethyl)-5,6-dihydroxynaphtho[2,3-b]furan-4,9-dione, 2-(1-hydroxyethyl)-5,7dihydroxynaphtho[2, 3-b] Furan-4,9-dione 2-(
1-hydroxyethyl)-5,8-dihydroxynaphtho[2,3-bfuran-4,9-dione, 2-(1-hydroxyethyl)-6,7-dihydroxynaphtho[2,
3-b) Furan-4,9-dione, 2-(1-hydroxyethyl)-6,8-dihydroxynaphtho[:'2.3
-b) Furan-4,9-dione, 2-(1-hydroxyethyl)-7,8-dihydroxynaphtho [2,3-b)
Furan-4,9-dione, 2-(1-hydroxy-4-
methylpentyl)-5-hydroxynaphtho[2,3-b
1-furan-4,9-dione, 2-(1-hydroxy-
4-methylpentyl)-6-hydroxynaphtho(2,3
-b) Furan-4,9-dione, 2-(1-hydroxy-4-methylpentyl)-7-hydroxynaphtho[2,
3-b) Furan-4,9-dione, 2-(1-hydroxy-4-methylpentyl)-8-hydroxynaphtho(2
,3-b) Furan-4,9-dione, 2-(1-hydroxy-4-methylpentyl)-6-t-butyldimethylsiloxinaf)(2,3-b) Furan-4,9-dione, 2-(1-hydroxy-4-methylpentyl)-7-
t-Butyldimethylsilokinaphtho[2,3-b, furan-4゜9-dione, 2-(1-hydroxy-4-methylpentyl)-5,6-dihydroxynaphtho[2,3-
b) Furan-4,9-dione, 2-(1-hydroxy-
4-methylpentyl)5,7-dihydroxynaphtho[2
,3-b,furan-4,9-dione,2-(1-hydroxy-4-methylpentyl)-5,8-dihydroxynaphtho(2,3-bfuran-4,9-dione,2- (
1-hydroxy-4-methylpentyl)-6,7-dihydroxynaphtho[2,3-b)furan-4,9-dione, 2-(1-hydroxy-4-methylpentyl)-6
,8-dihydroxynaphtho[2,3-b)furan-4,
9-dione, 2-(1-hydroxy-4-methylpentyl)-7,8-dihydroxynaphtho[2,3-b, furan-4,9-dione, 2-methyl-5-hydroxynaphtho[2, 3-b,]]Furan-4,9-dione 2-methyl-6-hydroxynaphtho[2,3-bfuran--4
, 9-dione, 2-methyl-7-hydroxynaphtho[2
,3-bfuran-4,9-dione,2-methyl-8-
hydroxynaphtho[2,3-b]furan-4,9-dione 2-methyl-6-t-butyldimethylsilokinaphtho[
2,3-bfuran-49-dione, 2-methyl-7-
t-Butyldimethylsilokinaphtho[2,3-b]furan-4,9-dione, 2-methyl-5,6-dihydroxynaphtho[2,3-b)furan-4,9-dione, 2-methyl- 5,7-dihydroxynaphtho[23-b, furan-4,9-dione, 2-methyl-5,8-dihydroxynaphtho[2,3-b, furan-4,9-dione, 2
-Methyl-6,7-dihydroxynaphtho(2,3-b)
Furan-4,9-dione, 2-methyl-6,8-dihydroxynaphtho[2,3-b]furan-4,9-dione,
2-Methyl-7,8-dihydroxynaphtho[2,3-b
] Furan-4,9-dione, 2-butyl-5-hydroxynaphtho(2,3-b) Furan-4,9-dione, 2-
Butyl-6-hydroxynaphtho[2,3-b, furan-
-4,9-dione, 2-butyl-7-hydroxynaphtho[2,3-b)furan-4,9-dione, 2-butyl-
8-Hydroxynaphtho[2,3-b)furan-4,9-
dione, 2-butyl-6-t-butyldimethylsilokinaphtho[2,3-b]furan-4,9-dione, 2-butyl-7-butyldimethylsilokinaphtho[2,3-b]
) Furan-4,9-dione, 2-butyl-5,6-dihydroxynaphtho[:'2.3-b) Furan-4,9-dione, 2-butyl-5,7-dihydroxynaphtho[2,
3-b] Furan-4,9-dione 2-butyl-5,8-
dihydroxynaphtho[2,3-bfuran-4,9-dione, 2-butyl-6,7-dihydroxynaphtho[2,
3-b) Furan-4,9-dione, 2-butyl-6,8
-dihydroxynaphtho[2,3-b)furan-49-dione, 2-butyl-7,8-dihydroxynaphtho[2,
3-b:) Furan-4,9-dione, 2-(2-methylpropyl)-5-hydroxynaphtho[2°3-b]furan-4,9-dione, 2-(2-methylpropyl)- 6
-hydroxynaphtho[2,3-bfuran--4,9-dione, 2-(2-methylpropyl)-7-hydroxynaphtho[2,3-t)]]furan-4,9-dione 2-(
2-methylpropyl)6-t-butyldimethylsilokinaphtho[2,3-b]furan-49-dione, 2-(2-
methylpropyl) 7-t-butyldimethylsilokinaf)
[2,3-b+furan-4,9-dione, 2-(2-methylpropyl)-8-hydroxynaphtho(2,3-b)
Furan-4,9-dione, 2-(2-methylpropyl)
-5,6-dihydroxynaphtho[2,3-b]furan-
4,9-dione 2-(2-methylpropyl)-5,7-
Dihydroxynaphtho[2,3-b]furan-4,9-dione, 2-(2-methylpropyl)-5,8-dihydroxynaphtho[2,3-t)furan-4,9-dione,
2-(2-methylpropyl)-6fudihydroxynaphtho[:'2.3-b)furan-4,9-dione, 2-(
2-methylpropyl)-6,8-dihydroxynaphtho [
2,3-b]furan-4,9-dione, 2-(2-methylpropyl)-7,8-dihydroxynaphtho(2,3
-b") furan-4,9-dione, etc. [0046] The methylbenzoquinone derivative of the present invention can be produced by two new production methods shown below (hereinafter referred to as method A and method B). ). [0047] Method A is shown in chemical formula 7. [0048]

[0049] In this chemical formula 7, R1 represents hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. , R2 represents hydrogen or a protected hydroxyl group, R3 represents hydrogen or a hydroxyl group, X
represents a hydrogen or halogen atom. [0050] Here, the protected hydroxyl group means, upon reaction,
When a hydroxyl group is protected by a conventional hydroxyl-protecting group, such as a trialkylsilyl group, a tetrahydropyranyl group, an acetoxy group, a methoxymethyl group, or a benzyl group. [0051] Method A involves subjecting a methylbenzoquinone derivative represented by general formula (VII) to a Diels-Alder reaction with a butadiene derivative represented by general formula (VIII), followed by isomerization, oxidation, and deprotection. By performing isolation and purification, the general formula (I
This is a method for producing methylbenzoquinone derivatives represented by X) and (X). [0052] The Diels-Alder reaction of the above general formula (VII) and general formula (VIII) is carried out in an inert gas atmosphere without a solvent or in an organic solvent, and when an organic solvent is used, the organic Alcohols, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, and halogenated hydrocarbons can be used as the solvent, preferably aromatic hydrocarbons and halogenated hydrocarbons, and more preferably benzene, toluene, and methylene chloride. can be used. [0053] Regarding the reaction temperature and reaction time, the general formula (VI
Although it varies depending on the types of I) and (VIII) and the reaction solvent used, for example, in general formula (VII), X=
In the case of hydrogen, the reaction is carried out for about 1 hour to 24 hours at a reaction temperature ranging from water cooling to room temperature. If the reaction progresses slowly, heating may be carried out under reflux in order to speed up the reaction rate.
[0054] After the reaction, the reaction solvent is distilled off under reduced pressure, and the residue is dissolved in an organic solvent that is easily miscible with water, such as alcohols, ethers, preferably THF or dioxane, and an acid such as hydrochloric acid is added to the residue. In addition, at a reaction temperature ranging from water cooling to room temperature, 1
By reacting for 3 hours to 3 hours, the general formula (engineering v)
and a methylbenzoquinone derivative represented by (X). [0055] In general formula (VII), when X = halogen atom, bases such as carbonates, acetates, amines, sodium hydroxide, By adding potassium hydroxide, preferably carbonate or acetate, more preferably potassium carbonate or sodium acetate, and reacting under heating reflux conditions from room temperature for about 1 to 8 hours, the formulas (IX) and (X) are expressed. methylbenzoquinone is produced. The produced methylbenzoquinone derivatives are isolated and purified by silica gel column chromatography to obtain methylbenzoquinone derivatives represented by general formulas (IX) and (X), respectively. [0056] Next, method B will be explained. [0057] As shown in Chemical Formula 8, the methyl benzoquinone derivative represented by the general formula (XI) is isomerized using a base, and then oxidized and deethylenized to produce the methyl benzoquinone derivative represented by the general formula (XII). A benzoquinone derivative is produced. [0058]

[0059] In this chemical formula 8, R represents hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. and RR represents hydrogen, a hydroxyl group, or a protected hydroxyl group. [0060] The above isomerization reaction is carried out using a base in an organic solvent, and alcohols, dimethylformamide, dimethyl sulfoxide, ethers, aromatic hydrocarbons, halogenated hydrocarbons, etc. are used as the reaction solvent. Preferably, THF is used. As the base, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium t-butoxy, etc. can be used. The reaction temperature and reaction time vary depending on the methylbenzoquinone derivative represented by general formula (XI), the reaction solvent used, and the type of base; for example, when THF and sodium hydride are used,
The reaction is allowed to proceed for about 30 minutes to 8 hours at a reaction temperature of about -10°C to room temperature. [00611 The oxidation reaction is carried out using an oxidizing agent in an organic solvent, and the reaction solvent is alcohols, ethers, etc.
Aromatic hydrocarbons and halogenated hydrocarbons can be used, preferably ethers and halogenated hydrocarbons, more preferably THF or methylene chloride. As an oxidizing agent,
Commonly used oxidizing agents such as metal oxides can be used, but
Preferably, copper oxide, lead oxide, chromium oxide, silver oxide, silver carbonate, and more preferably silver oxide are used. Furthermore, in order to remove the generated water, a commonly used dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, etc. can be added as necessary. The reaction temperature and reaction time vary depending on the methylbenzoquinone derivative represented by the general formula (XI), the reaction solvent used, and the oxidizing agent, but for example, when THF and silver oxide are used, the reaction temperature is 0°C to 50°C. Allow to react for about 1 to 8 hours. [0062] Depending on the type of methylbenzoquinone derivative represented by general formula (XI), the deethylene reaction may be carried out together with the oxidation reaction. For example, in general formula (XI),
In the case of a methylbenzoquinone derivative with R, R=)limethylsiloxy group, R3, R4=H, deethylenization is performed along with the oxidation reaction, and the corresponding general formula (X■■) R2, R5=OH
, R3, R4=H, a methylbenzoquinone derivative is produced. In addition, if it is difficult to remove ethylene with oxidation, it can be removed by heating in the absence of a solvent. The reaction temperature and reaction time vary depending on the type of methylbenzoquinone derivative represented by general formula (XI).
to 150°C for about 30 minutes to 8 hours. [0063] Methylbenzoquinone derivatives represented by general formulas (I) to (VI) can be produced by the above methods A and B. [0064] Furthermore, the methylbenzoquinone derivative represented by general formula (XI) is a novel methylbenzoquinone derivative and is useful as a raw material for pharmaceuticals. [0065]

[0066] Alkyl group, or chain or branched carbon number 1
Represents a hydroxyalkyl group consisting of ~6 members, R2~R
5 represents hydrogen, a hydroxyl group, or a protected hydroxyl group. [0067] Compounds included in general formula (XI) include 5,8.4
a,8a-tetrahydro-5,8-ethano-5-trimethylsiloxynaphtho[2,3-b]furan-4°9-dione, 5,8.4a,8a-tetrahydro-5,8-ethano-8- Trimethylsiloxynaphtho [2,3-b,l
Furan-4,9-dione, 5,8.4a,8a-tetrahydro-5,8-ethano-5-t-butyldimethylsilokinaphtho[23-b)-yran-4,9-dione, 5
,8.4a,8a-tetrahydro-5°8-ethano-8
-t-Butyldimethylsilokinaphtho(2,3-b)furan-4°9-dione, 5,8.4a,8a-tetrahydro-5,8-ethano-5,8-ditrimethylsilokinaphtho[2,3 -b) -y:/-4,9-dione, 5,8
．． 4a8a-tetrahydro-5,8-ethano-5,8-
di-t-butyldimethylsilonaphtho[2,3-b]7
7:/-4,9-dione, 5,8.4a,8a-tetrahydro-5,8-ethano-6-trimethylsiloxynaphtho[2,3-b)furan-4,9-dione, 5,8. 4
a,8a-tetrahydro-5,8-ethano-7-trimethylsiloxynaphtho[2,3-bfuran-4,9-dione, 5,8.4a,8a-tetrahydro-5,8-ethano-6- t-Butyldimethylsilokinaphtho[2,3-
b, l-7u:/-4.9-dione, 5,8.4a, 8
a-Tetrahydro-5,8-ethano-7-t-butyldimethylsilokinaphtho (2,3-b,furan-4,9-
dione, 2-butyl-5,8,4a,8a-tetrahydro-5,8-ethano-5-trimethylsiloxynaphtho[
2,3-b) Furan-4,9-dione 2-butyl-5,
8,4a,8a-tetrahydro-5,8-ethano-8-
trimethylsiloxynaphthoC2,3-b)furan-4,
9-dione, 2-butyl-58,4a,8a-tetrahydro-5,8-ethano-5-t-butyldimethylsilokinaphtho[2,3-b17ran-4,9-dione,2-buty)'v- 5,8,4a8a Tetrahydro-5,8-ethano-8-t-butyldimethylsilokinaphtho[2,3-
b, 17ran-4,9-dione, 2-butyl-5,8,
4a,8a-te) Rhydro-5,8-ethano-5,8-
Ditrimethylsiloxynaphtho['2.3-b]2.3-
bfuran-4,9-dione-5,8,4a,8a-tetrahydro-5,8-ethano-5,8-di-t-butyldimethylsilonaphtho[2,3-b]furan-4, 9-
dione, 2-butyl-5,8,4a,8a-tetrahydro-58-ethano-6-trimethylsiloxynaphtho(2
, 3-b) Furan-4,9-dione, 2-butyl-5,
8,4a,8a-tetrahydro-5,8-ethano-7-
Trimethylsiloxynaphtho[2,3-b)furan-4,
9-dione, 2-butyl-5,8,4a,8a-tetrahydro-5,8-ethano-6-t-butyldimethylsilokinaphtho(2,3-b)furan-4,9-dione, 2-
Butyl-5,84a,8a-tetrahydro-5,8-ethano-7-t-butyldimethylsilokinaphtho(2,3-
b) Furan-4,9-dione, 2-(1-hydroxyethyl)-5,8,4a,8a-tetrahydro-5,8-
Ethano-5-trimethylsiloxynaphtho [2,3-b]
Furan-4,9-dione, 2-(1-hydroxyethyl)-5,8,4a,8a-tetrahydro-5,8-ethano-8-trimethylsiloxynaphtho['2.3-b]furan-4.9 -dione, 2-(1-hydroxyethyl)
-5,8,4a,8a-tetrahydro-5,8-ethano-5-t-butyldimethylsilokinaphtho[2,3-bfuran--4,9-dione, 2-(1-hydroxyethyl)-5 ,8,4a,8a-tetrahydro-5,8-ethano-8-butyldimethylsilokinaphtho[2,3-b
] Furan-4,9-dione, 2-(1-hydroxyethyl)-5,8,4a,8a-tetrahydro-5,8-
Ethano-5,8-ditrimethylsiloxynaphtho[2,3
-b) Furan-4,9-dione, 2-(1-hydroxyethyl)-5,8,4a,8a-tetrahydro-5,
8-Ethano-5,8-di-t-butyldimethylsilonaphtho(2,3-b)furan-4,9-dione, 2-(1
-hydroxyethyl)-5,8,4a,8a-tetrahydro-5,8-ethano-6-trimethylsiloxynaphtho[2,3-b]furan-4,9-dione, 2-(1-hydroxyethyl)- 5,8,4a,8a-tetrahydro-5,8-ethano-7-trimethylsiloxynaphtho (
2,3-b) Furan-4,9-dione, 2-(1-hydroxyethyl)-5,8,4a,8a-tetrahydro-
5,8-Ethano-6-t-butyldimethylsilokifth(2,3-b)7ran-4,9-dione, 2-(1-hydroxyethyl)-5,8',4a. 8a-tetrahydro-5,8-ethano-7-t-butyldimethylsilokinaphtho[2,3-b)]furan-4,
Examples include 9-dione. [0068]

[0069] In this chemical formula 10, R1 is hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. R2 to R5 represent hydrogen, a hydroxyl group, or a protected hydroxyl group. [0070] Chemical formula 10 is a compound represented by general formula (XI) obtained by subjecting a methylbenzoquinone derivative represented by general formula (XIII) and a cyclohexadiene derivative represented by general formula (XVI) to a Diels-Alder reaction. This is a method for producing methylbenzoquinone derivatives. The above reaction is carried out in an inert gas atmosphere without a solvent or in an organic solvent. When an organic solvent is used as the reaction solvent, the organic solvent can be alcohols, ethers, esters, aromatic hydrocarbons, aliphatic Hydrocarbons and halogenated hydrocarbons can be used, preferably aromatic hydrocarbons and halogenated hydrocarbons, more preferably,
Use benzene, toluene, and methylene chloride. Regarding the reaction temperature and reaction time, the methylbenzoquinone derivative represented by the general formula (XIII) used and the general formula (XVI)
Although it varies depending on the type of cyclohexadiene derivative represented by and the reaction solvent used, it is usually about 1
Allow to react for about 24 hours. If the reaction progresses slowly, heating may be carried out under reflux in order to speed up the reaction rate. [0071] Example Eva, general formula (XIII, R1 = 1-hydroxyethyl group) and general formula (XVI, R2R =) limethylsiloxy group, R3, R4 = hydrogen) in methylene chloride for 20 to 30
By reacting at ℃ for 1 to 3 hours, the corresponding general formula (
XI) is produced. [0072] Furthermore, the methylbenzoquinone derivative represented by general formula (XIII) is a novel furalbenzoquinone derivative and is useful as a raw material for pharmaceuticals. This is shown in Chemical Formula 11. [0073] [0074] In this formula 11, R1 represents a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. [0075] Compounds included in general formula (XIII) include 2
-(1-hydroxyethyl)-benzo[2,3-b]furan-4,7-dione, 2-(2-hydroxyethyl)
-benzo[2,3-b]furan-4,7-dione, 2-
(1-hydroxybutyl)-benzo[2,3-b]furan-4,7-dione, 2-(2-hydroxybutyl)-
Benzo[2,3-b]furan-4,7-dione, 2-(
1-hydroxyhexyl)-benzo[2,3-b]furan-47-dione, 2-(3-hydroxyhexyl)-
Benzo[2,3-b]furan-4,7-dione, 2-(
4-hydroxyhexyl)-benzo[2,3-b]furan-4,7-dione, 2-(1-hydroxy-3-methylbutyl)-benzo[2,3-b]furan-4,7-dione, 2-(1-hydroxy-4-methylpentyl)-
Examples include benzo[2,3-b]furan-4,7-dione. [0076] A method for producing the methylbenzoquinone derivative represented by the general formula (XIII) will be explained. [0077]

embedded image [0078] In this chemical formula 12, R1 represents a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. [0079] A methylbenzoquinone derivative represented by general formula (XIII) is produced by oxidizing a benzofuran derivative represented by general formula (XIV). This reaction is carried out using an oxidizing agent in an organic solvent. As the reaction solvent, organic solvents such as aromatic hydrocarbons, aliphatic hydrocarbons, ethers, and halogenated hydrocarbons can be used, and as the oxidizing agent, ordinary metal oxides can be used, and silver oxide is preferably used. The reaction temperature and reaction time vary depending on the benzofuran derivative represented by the general formula (XIV) and the reaction solvent and oxidizing agent used, but for example, when THF and silver oxide are used, the reaction temperature is 0 to 50°C. Allow to react for about 30 minutes to 1 hour. The reaction product was post-treated by a conventional method to give the general formula (XIII)
A methylbenzoquinone derivative represented by is produced. [0080] Furthermore, a methylbenzoquinone derivative represented by general formula (VII) is produced by adding a halogen atom to the methylbenzoquinone derivative represented by general formula (XIII). This is shown in Chemical formula 14. [0081]

[0082] In this chemical formula 14, R1 is hydrogen, a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched hydroxy group having 1 to 6 carbon atoms. It represents an alkyl group, and X represents hydrogen or a halogen atom. [0083] Hydrogen halide, for example, 30% HBr-
The halogen is added by adding an acetic acid solution at a reaction temperature of room temperature while cooling with ice and allowing the reaction to occur for about 30 minutes to 2 hours. At this time, since the methylbenzoquinone body is reduced to a hydroquinone body, the general formula (XIV) shown in Chemical Formula 12 above is obtained.
An oxidation reaction similar to that of oxidizing the benzofuran derivative represented by the general formula (XIII) to the general formula (V
A methylbenzoquinone derivative represented by II) is produced. [0084] Furthermore, the benzofuran derivative represented by the general formula (XV) shown in Chemical Formula 13 is a new benzofuran derivative and is useful as a pharmaceutical raw material. [0085]

[0086] In this formula 13, R1 represents a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms, and X represents hydrogen or a tetrahydropyranyl group. [0087] Compounds included in the above general formula (XV) include 2-(
1-hydroxyethyl)-4,7-cyhydroxybenzo[2,3-b]furan-2-(2-hydroxyethyl)-4,7-cyhydroxybenzo[23-b]furan-2-( 1-Hydroxybutyl)-4,7-cyhydroxybenzo[2,3-b]furan-2-(2-hydroxybutyl)-4,7-cyhydroxybenzo[2,3-
b] Furan-2-(1-hydroxyhexyl)-4,7
-cyhydroxybenzo[2,3-bfuran-,2-(
3-hydroxyhexyl)-4,7-cyhydroxybenzo[2,3-bfuran-,2-(4-hydroxyhexyl)-4,7-cyhydroxybenzo[2,3-bfuran-,2 -(1-hydroxy-3-methylbutyl)-
4,7-cyhydroxybenzo[2,3-b]furan-
2-(1-hydroxy-4-methylpentyl)-4,7
-cyhydroxybenzo[2,3-b]furan-2-(
1-hydroxyethyl)-4,7-ditetrahydropyranyloxy-benzo[2,3-b]furan-2-(2-
hydroxyethyl)-4,7-ditetrahydrobilanyloxy-benzo[2,3-b] fuyn, 2- (1
-hydroxybutyl)-4,7-ditetrahydrobylanyloxy-benzo[2,3-b]furan-2-(2-hydroxybutyl)-4,7-ditetrahydropyranyloxy-benzo[2,3-b] Furan-2-(1-hydroxyhexyl)-4,7-ditetrahydropyranyloxy-benzo” [2,3-b]furan, 2-(3-hydroxyhexyl)-4,7-ditetrahydropyranyloxy-benzo 2,3-b]furan, 2-(4-hydroxyhexyl)-47-ditetrahydropyranyloxy-benzo[2,3-b]furan, 2-(1-hydroxy-
3-Methylbutyl)-4,7-ditetrahydrobylanyloxy-benzo[2,3-b]furan, 2-(1-hydroxy-4-methylpentyl)4,7-ditetrahydropyranyloxy-benzo[2,3 -b]furan, etc. [0088] A method for producing the methylbenzoquinone derivative represented by the above general formula (XV) will be explained. The outline of the manufacturing method is shown below.
5. [0089]

[Chemical Formula 15] O Compound Compound ε Compound Compound ox H Compound Compound ■ ○ [0090] In this Chemical Formula 15, R1 is a chain or branched alkyl group having 1 to 6 carbon atoms, or a chain or branched alkyl group having 1 to 6 carbon atoms. It represents a hydroxyalkyl group consisting of 1 to 6 separated carbon atoms, and X represents hydrogen or a tetrahydropyranyl group. [0091] 7-Hydroxybenzofuran (compound D) is oxidized with potassium nitrosodisulfonate to form a methylbenzoquinone form (compound E), and then reduced with a reducing agent such as hydrosulfide that is commonly used for reducing benzoquinone to form a hydroquinone form (compound E). F) is obtained. Compound F is converted into THP (tetrahydropyranyl) using dihydropyran to obtain compound G. [0092] Next, a method for producing Compound H and Compound (I) from Compound G will be described. [0093] As a reaction solvent, ethers or halogenated hydrocarbons,
Preferably using THF, n-butyllithium is added at -80°C to 0°C to chloride the carbon at the 2-position with lithium, and then aldehydes or alkyl halides are added and the mixture is heated at -80°C to 0°C.
The reaction is carried out at a temperature of 0.degree. C. to 0.degree. C. for about 30 minutes to 3 hours, and the intended side chain R1 is introduced into the 2-position to produce compound H. [0094] Compound H was further deprotected (de-T
Compound ■ can be produced by converting into HP),
Compound J can be obtained by oxidizing this compound (1). [0095] Further, in general formula (I), the compound having an asymmetric carbon atom in R1 has optical isomers, but the pharmacological activity of the compound in living organisms often differs greatly between its optically active forms. It is desirable to produce each of these individually to obtain an optically active substance with superior pharmacological activity. However, it is well known that it is generally extremely difficult to separate and purify an optically active compound from a racemic compound, which is a mixture of optically active compounds. Pharmacological activity has not previously been measured. [0096] The present inventors have investigated various methods for isolating and purifying the optical isomer of a compound having an asymmetric carbon atom in R1 in general formula (I) from a racemate. , these isolation and purification are difficult;
Furthermore, as a column packing material for optical isomer separation, among commercially available packing materials, cellulose derivative-coated silica gel packing material (CHIRALCEL OJ (manufactured by Daicel Chemical Industries, Ltd., R=-COPhCH3 (however, Ph
is a benzene ring)) is suitable for the separation and purification of the optically active substance of the present invention, and furthermore, by using a hexane:ethanol mixed solvent and changing the mixing ratio depending on the target compound, these optical isomers can be obtained for the first time. , e.g. optically active (+)- and (-)-2-(1-hydroxyethyl)
-5-hydroxynaphtho[2,3-b]furan-4,9
-dione, (+)- and (-)-2-(1-hydroxyethyl)-8-hydroxynaphtho[2,3-b]furan-4,9-dione, (+)- and (-)-2 −(
It was discovered that 1-hydroxyethyl)-5,8-dihydroxynaphtho[2,3-b]furan-4,9-dione, etc. can be isolated and purified well, and that these optically active forms are more effective than racemic forms. It was found that it has high anticancer activity. [0097] The alkali addition salts of methylbenzoquinone derivatives represented by any of the general formulas (I) to (VI) can be produced by methods known per se, and among these, pharmaceutically acceptable salts Examples include sodium salts, potassium salts, magnesium salts, calcium salts, and non-toxic amine salts such as ammonium salts. [0098] The drug for cancer treatment of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, rectally, etc.), and when administered, the dosage form is adjusted to suit each administration method. can do. Such drugs are available in tablets, tablets, etc. depending on their use.
Can be prepared into any of the following formulations: capsules, granules, powders, fine granules, gunpowder, troches, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, etc. . [0099] In preparing these preparations, for example, non-toxic excipients, binders, disintegrants, lubricants,
By known methods using additives such as preservatives, antioxidants, tonicity agents, buffers, coating agents, flavoring agents, solubilizing agents, bases, dispersants, stabilizers, coloring agents, etc. It can be formulated into a formulation. [0100] Specific examples of the non-toxic additives that can be used are as follows. [0101] First, excipients include starch and its derivatives (dextrin, carboxymethyl starch, etc.), cellulose and its derivatives (methyl cellulose, hydroxypropyl cellulose, etc.), sugars (lactose, sucrose, glucose, etc.),
Silicic acid and silicates (natural aluminum silicate, magnesium silicate, magnesium aluminate metasilicate, etc.) Carbonates (calcium carbonate, magnesium carbonate, sodium hydrogen carbonate, etc.) Aluminum/magnesium hydroxide, synthetic hydrotalcite, polyoxy Examples include ethylene derivatives, glyceryl monostearate, sorbitan monooleate, and the like. [0102] As a binder, starch and its derivatives (gelatinized starch, dextrin, etc.), cellulose and its derivatives (ethyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose, etc.)
Examples include gum arabic tragacanth, gelatin, sugars (glucose, white sugar, etc.) ethanol, polyvinylpyrrolidone, polyvinyl alcohol, and the like. [0103] Examples of disintegrants include starch and its derivatives (carboxymethyl starch, sodium carboxymethyl cellulose, crystalline cellulose, hydroxypropyl methyl cellulose, etc.), carbonates (calcium carbonate, sodium hydrogen carbonate, etc.), tragacanth, gelatin, agar, etc. . [0104] As the lubricant, stearic acid, calcium stearate, magnesium stearate, talc, silicic acid and its salts (light silicic anhydride, natural aluminum silicate, etc.),
Examples include titanium oxide, calcium hydrogen phosphate, dry aluminum hydroxide gel, macrogol, and the like. [0105] Preservatives include paraoxybenzoic acid esters, sulfites (sodium sulfite = 612-rum, sodium pyrosulfite, etc.), phosphates (sodium phosphate, calcium polyphosphate, sodium polyphosphate, sodium metaphosphate, etc.), alcohol. (chlorobutanol, benzyl alcohol, etc.), benzalkonium chloride, benzethonium chloride, phenol, cresol, chlorocresol, dehydroacetic acid, sodium dehydroacetate, glyceryl sorbate, sugars, and the like. [0106] As the antioxidant, sulfites (sodium sulfite,
(sodium bisulfite, etc.) Rongalite, erythorbic acid, L-ascorbic acid, cysteine, acetylcysteine, thioglycerol, butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, ascorbate palmitate, dl-α-tocopherol, nordihydroguaiaretic acids, etc. [0107] Isotonic agents include sodium chloride, potassium nitrate, sodium nitrate, dextran, glycerin, glucose,
etc. [0108] Examples of the buffer include sodium carbonate, hydrochloric acid, boric acid, phosphates (sodium hydrogen phosphate, etc.), and the like. [0109] Coating agents include cellulose derivatives (hydroxypropyl cellulose cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, etc.) shellac, polyvinylpyrrolidone, polyvinylpyridines (
(poly-2-vinylpyridine, poly-2-vinyl-5-ethylpyridine, etc.), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol phthalate, methacrylate/methacrylic acid copolymer, and the like. [01101 As a flavoring agent, sugars (lactose, sucrose, glucose, etc.)
Examples include saccharin sodium, sugar alcohols, and the like. [0111] Examples of solubilizing agents include ethylenediamine, nicotinamide, sodium saccharin, citric acid, citrates, sodium benzoate, soaps, polyvinylpyrrolidone, polysorbates, sorbitan fatty acid esters,
Examples include glycerin, propylene glycol, benzyl alcohol, diethylline, sugar ester, and the like. [01!2] Bases include fats (pork intestines, etc.), vegetable oils (olive oil, sesame oil, etc.), animal oils, lanolin, petrolatum, paraffin, wax, resins, bentonite, glycerin, glycols, higher alcohols ( stearyl alcohol,
cetanol, etc.) cellulose derivatives, etc. [0113] Examples of dispersants include gum arabic, tragacanth, cellulose derivatives (methyl cellulose, etc.), polyoxyl stearates, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, sorbitan fatty acid esters, and the like. . [0114] Examples of the stabilizer include sulfites (sodium hydrogen sulfite, etc.), nitrogen, carbon dioxide, and the like. [0115] The active ingredients of the invention in such formulations also include:
The content of the methylbenzoquinone derivative varies depending on its dosage form, but it is generally desirable to contain it at a concentration of 0.1 to 100% by weight. [0116] The dosage of the preparation according to the present invention can be varied widely depending on the type of warm-blooded animal including humans, the severity of the symptoms, the doctor's diagnosis, etc. Generally, the active ingredient is administered orally. 0.01 per kg of body weight per day
~100mg/kg, preferably 0.01-30mg/
Preferably, the dose is 1 kg, body weight in case of parenteral administration.
It is preferred to administer 0.01 to 50 mg/kg, preferably 0.01 to 10 mg/kg per kg per day. However, it is also possible to change the dosage range depending on the severity of the patient's symptoms and the doctor's diagnosis. Furthermore, the above dosage can be administered once a day or in several divided doses. [0117]

【Example】

Next, the present invention will be explained in more detail with reference to Examples. [0118] (Example 1) 8-hydroxynaphtho[2,3-b]furan-4,9-
Synthesis of dione (compound 1). [0119] Under nitrogen atmosphere, Benz ears 2,3-b]Furan-4,7
-100 mg (0,676 mmol) of dione and 1. ml of 1-methoxy-1-trimethylsiloxy-butane-1°3-diene (128 mg (0,74
4 mmol) was added dropwise and stirred for 1 hour. After evaporating the solvent under reduced pressure, 1 ml of THF and 0.2 ml of 35% hydrochloric acid were added to the residue.
was added and stirred at room temperature for 1 hour. Next, the mixture was extracted with methylene chloride, washed with water, dried, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 26 mg (yield: 17%) of the title compound. 1HNMR (CDC13, δ-TMS): 5.21
(S, LH), 7.0 (S, LH) 7.27 (d
, LH, J=8.4Hz) 7.61 (dd, LH,
J=8.4Hz, 8.4Hz) 7.73 (d, LH
, J=8.4Hz), 12.02 (S, LH) [01
201 (Example 2) 5-hydroxynaphtho[2,3-b]furan-4,9-
Synthesis of dione (compound 2).

In December, 5- or 6-bromobenzo[2,3-
b] Furan-4,7-thio: /226mg (1,0m
2.2 ml of methylene chloride was added to the solution (2.2 ml of methylene chloride), cooled on ice immediately after melting, and 414 mg of potassium carbonate (3.0 ml
mol) was added and stirred. Next, methylene chloride 0.
190 mg of 1-methoxy-1-trimethylsiloxy-buta:/-1,3-diene (1,1
After stirring for 2 hours while gradually heating up to room temperature, 410 mg of sodium acetate (5 m mol) was added dropwise.
mol) was added thereto, and the mixture was heated under reflux for 50 minutes. After removing salts by filtration, acidifying with a small amount of acetic acid, extraction with methylene chloride, washing with water and drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (45 mg, yield). 21%). IHNMR (CDC13, δ-TMS); 5.2
1 (S, LH), 7.0 (S, LH) 7.27
(d, LH, J=8.4Hz) 7.61 (dd,
LH, J=8.4Hz, 8.4Hz) 7.73 (d
, LH, J=8.4Hz) 12.17 (S, LH) [0122] (Example 3) 2-(1-hydroxyethyl)-8-hydroxynaphtho[2,3-bfuran--4,9 -dione (compound 3)
synthesis of. [0123] Under a nitrogen atmosphere, 4,8.9-)lyacetoxynaphtho[
2,3-b] Furan 51 mg (0,149 m mo
3 ml of THF was added to 1) and cooled to -70°C. A hexane solution of 1.44 mmol of n-butyllithium was slowly added dropwise, and after the addition was completed, the temperature was raised to -10°C and stirred for 1 hour. Next, cool it again to -70℃,
Acetaldehyde 80mg (1.82m mol)
A solution prepared by dissolving the above in 1 ml of THF was added dropwise, and after the dropwise addition was completed, the temperature was raised to room temperature and stirred for 1 hour. Next, after acidifying with dilute hydrochloric acid, extraction with ethyl acetate, washing with water, and drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. 19 mg of the title compound (yield 49%)
I got it. 1.66 (d, 3H, J=6.8Hz), 2.22
(S, LH) 5.05 (m, LH), 6.86 (S
, LH) 7.28 (d, LH, J=8.4Hz)7.
61 (dd, LH, J=8.4Hz, 8.4Hz)7
, 73 (d, LH, J=8.4Hz) , 1
2.03 (S, LH) IR (KBr, cm'): 3400 (○H), 1672 (C=0), 1640
(C=○) UV (methanol): 235 nm, 295 nm, 420 nm Melting point: 160°C [0124] (Example 4) 2-(1-hydroxyethyl)-5,8,4a, 8a-
Tetrahydro-5,8-ethano-5-trimethylsiloxynaphtho[2,3-b]furan-4,9-dione and 2-
Synthesis of (1-hydroxyethyl)-5,8,4a,8a-tetrahydro-5°8-ethano-8-trimethylsiloxynaphtho[2,3-b]furan-4,9-dione. [0125] 2-(1-hydroxyethyl)-benzo[2,3-b]furan-4,7-thio:/3.0 g (
15.6 mmol) was added with 20 rnl of methylene chloride and dissolved, and the mixture was dissolved in 20 ml of methylene chloride at room temperature. 1-trimethylsiloxycyclohexane-1,3
3.9 g (23.4 mmol) of -diene was added dropwise and the mixture was stirred for 1 day. The solvent was distilled off under reduced pressure to obtain 5.2 g (yield: 89%) of a mixture of the two title compounds. [0126] (Example 5) 2-(1-hydroxyethyl)-8-hydroxynaphtho[2,3-b]furan-4,9-dione (Compound 3)
and 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione (compound 4)
synthesis of. [0127] Under nitrogen atmosphere, 2.5 g of sodium hydride (62,4
Add 20 ml of THF to 1.0 m mol) and suspend at -5°C.
After cooling to 2-(1-hydroxyethyl)-5,84a
, 8a-tetrahydro-5,8-ethano-5-trimethylsiloxynaphtho[2,3-b]furan-4,9-dione and 2-(1-hydroxyethyl)-5°8.4a,8
Add 5.2 g (14,4 mm. l) of a-tetrahydro-5,8-ethano-8-trimethylsiloxynaphtho[2,3-b]77:/-4,9-dione (7) mixture, and cool with water. The mixture was stirred for 30 minutes. After neutralizing with a saturated aqueous ammonium chloride solution, the mixture was made acidic with dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off under reduced pressure. Next, THF was added to the residue to dissolve it, yielding 3.62 g of silver oxide (
After stirring at room temperature for 1 hour, the solid matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure to give 2.0 g of a mixture of title compounds 3 and 4 (
A yield of 73%) was obtained. [0128] (Example 6) 2-(1-tetradecanoyloxyethyl)-8-tetrazokayloxynaphtho[2,3-b]furan-4,
9-dione (compound 5) and 2-(1-tetradecanoyloxyethyl)-5-tetrazokayloxynaphtho[
Synthesis of 2,3-b]furan-4,9-dione (compound 6). [0129] To 2.0 g of the mixture of Compound 3 and Compound 4 obtained in Example 5, 24 ml of pyridine was added and dissolved, and under a nitrogen atmosphere,
4. Tetradecanoyl chloride at room temperature. 6g (18,
7 mmol) was added dropwise and stirred for 30 minutes. Water was added, extracted with ethyl acetate, washed with water, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.95 mg of the title compound 5 and 063 g of the title compound 6. [01301 2-(1-tetradecanoyloxyethyl)-8-tetradecanoyloxynaphthoc2,3-b]furan-4,
1HNMR (CDC) for 9-dione (compound 5)
13, δ-TMS): 0.86 to 0.89 (m, 6
H), 1.2-1.9 (m, 44H) 1.65 (d
, 3H, J=6.0Hz) 2.34 (t, 2H, J=
7.5Hz). 2.75 (t, 2H, J=7.5Hz)6, 0(q,
LH, J=6.0Hz), 6.84 (s, L
H) 7.38 (d, LH, J=9.0Hz) 7.75
(dd, J=9.0Hz, 9.0Hz)8.14 (
d, LH, J=9.0Hz) [0131] 2-(1-tetradecanoyloxyethyl)-5-tetrazokayloxynaphtho[2,3=b]furan-4,
Regarding 9-dione (compound 6), IHNMR (CDC
13, δ-TMS): 0.86 to 0.89 (m, 6
H), 1.2-1.9 (m, 44H) 1.65 (d
, 3H, J=7.5Hz) 2.34 (t, 2H, J=
7.5Hz). 2.75 (t, 2H, J=7.5Hz). 6.02 (q, LH, J=7.5Hz), 6.81
(s, LH) 7.35 (d, LH, J=9.0Hz
)7.75 (dd, LH, J=9.0Hz, 9.0H
z) 8.19 (d, LH, J=9.0Hz) [013
2] (Example 7) 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione (compound 4
) composition. To 0.63 g of compound 6 obtained in Example 6 was added THFloml.
was added to dissolve, and 20 ml of O,IN NaOH aqueous solution was slowly added dropwise under ice cooling. After the dropwise addition was completed, the temperature was raised to room temperature and stirred for 4 hours. After neutralization with dilute hydrochloric acid, extraction with ethyl acetate, washing with water, and drying, the solvent was distilled off under reduced pressure to obtain 0.20 g (yield: 76%) of the title compound 4. 'HNMR (CDC13, δ-TMS): 1.66
(d, 3H, J=6.8Hz), 2.23 (S,
LH) 5.04 (m, LH), 6.85 (S,
LH) 7.28 (d, IH, J=8.4Hz) 7.6
2 (dd, LH, J=8.4Hz, 8.4Hz)7
．． 76 (d, LH, J=8.4Hz), 12.18
(S, LH) IR (KBr, cm 1): 3400 (OH), 1660 (C=0), 1630
(C=O)UV (methanol); 247 nm, 295 nm, 400 nm Melting point: 161-162°C [0133] (Example 8) 2-(1-hydroxyethyl)-8-hydroxynaphtho[2,3-b]furan Synthesis of -4,9-dione (compound 3). [0134] 1.95 g of Compound 5 obtained in Example 6 was treated in the same manner as in Example 7 to obtain 0.48 g of the title compound 3 (62% yield).
)Obtained. IHNMR (CDC13, δ-TMS); 1.66
(d, 3H, J=6.8Hz), 2.2'2 (S, L
H) 5.05 (m, LH), 6.86 (S, LH)
7.28 (d, LH, J=8.4Hz) 7.61
(dd, LH, J=8.4Hz, 8.4Hz) 7.73
(d, LH, J=8.4Hz), 12.03 (S,
IH) IR (KBr, cm'): 3400 (OH), 1672 (C=○), 1640
(C=○) UV (methanol); 235 nm, 295 nm, 420 nm Melting point: 160-162°C [0135] (Example 9) 6.8-dihydroxynaphtho[2,3-b]furan-4
．． 9-dione (compound 7) and 5,7-dihydroxynaphtho[2,3-b]furan-4,9-dione (compound 8).
) composition. [0136] Benzo[2,3-bfuran--4,7
- 3 methylene chloride to 50 mg (034 mmol) of dione
131 mg of 1-methoxy-1,3-ditrimethylsiloxybutane-13-diene (0,51 m m
After stirring for 1 hour, the solvent was distilled off under reduced pressure. 3 ml of THF was added to the obtained residue under a nitrogen atmosphere, diluted hydrochloric acid was added under water cooling, and the mixture was stirred for 5 minutes. After extraction with ethyl acetate, washing with water and drying, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography.
11 mg (yield: 13%) of the title compound 7 and 10 mg (yield: 12%) of the title compound 8 were obtained. [0137] 6.8-dihydroxynaphtho[2,3-b]furan-4
,9-dione (compound 7), 1HNMR (DMSO-d6.δ-TMS): 6.5
4 (S, LH), 6.86 (s, LH), 7.06
(s, LH) 8.4 (s, LH), 11.28 (
S, LH), 12.09 (s, LH) [0138] 5,7-dihydroxynaphtho[2,3-b]furan-4
,9-dione (compound 8), IHNMR (DMS O-d6.δ-TMS): 6.
54 (S, LH), 6.86 (s, LH), 7.0
6 (s, LH) 8.4 (s, IH), 11.28
(S, LH), 12.26 (s, LH) [0139] (Example 10) 2-(1-hydroxyethyl)-5,7-dihydroxynaphtho[2,lb]furan-4,9-dione ( Compound 9
) and 2-(1-hydroxyethyl)-6°8-dihydroxynaphtho[2,3-b]furan-4,9-dione (
Synthesis of compound 10). [01401 Under nitrogen atmosphere, 2-(1-hydroxyethyl)benzo[2,3-b]furan-4,7-dione 6, Og (3
1,2m mol) was added and dissolved in 40ml of methylene chloride, and 1-methoxy-1,3-ditrimethylsiloxybutane was dissolved in 40ml of methylene chloride at room temperature.
1,3-diene 12. Og (46.8 m m. l) was added dropwise, and after stirring for 1 hour, the solvent was distilled off under reduced pressure. The subsequent treatment operations were carried out in the same manner as in Example 5 to obtain 1.6 g of a mixture of the title compound 9 and the title compound 10. Then, in the same manner as in Example 6, 20 ml of pyridine was added and dissolved in 1.6 g of this mixture, and 4.2 g of tetradecanoic acid chloride was added dropwise at room temperature under a nitrogen atmosphere, stirred for 30 minutes, water was added, and extracted with ethyl acetate. did. After washing with water and drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-(1-tetradecanoyloxyethyl)-5
,7-ditetradecanoyloxynaphtho[2,3-b]
2.0 g of furan-4,9-dione (compound 11) and 2
-(1-tetradecanoyloxyethyl)-6,8-ditetradecanoyloxynaphtho[2,3-b]furan-
0.8 g of 4,9-dione (compound 12) was obtained. Compound 11 and Compound 12 were then each treated in the same manner as in Example 7 to obtain 0.7 g of the title compound 9 and 0.3 g of the title compound 10. [0141] IHNMR (DMSO-d6.δ-TM
S): 1.45 (d, 3H, J=6.4Hz), 4
．． 85 (m, IH) 5.78 (s, LH), 6.5
4 (S, LH), 6.86 (s, LH) 7.06
(s, LH), 11.28 (s, LH), 12.09
(S, LH) 3000 (○H), 1672 (C=
○), 1640 (C=O)[0142] IHNMR ( DMSO-d6.δ-T
MS): 1.45 (d, 3H, J=6.4Hz),
4.85 (m, LH) 5.78 (s, LH), 6.
54 (S, LH), 6.86 (s, LH) 7.06
(s, LH), 11.28 (s, LH), 12.26
(S, LH) IR (KBr, cm 1); 3000 (○H), 1660 (C=0), 1630
(C=O)[0143] (Example 11) 2-(1-hydroxyethyl)-6-t-butyldimethylsiloxynaphtho[23-b]furan-4,9-dione (compound 13) and 2- (1-hydroxyethyl)-7
Synthesis of -t-butyldimethylsiloxynaphtho[2,3-b]furan-4,9-dione (compound 14). [0144] Under nitrogen atmosphere, 6.8 g of 2-(1-hydroxyethyl)-benzo[2,3-b]fura:/-4,7-dione
(17.7 mmol) was added and dissolved in 100 ml of methylene chloride, and at room temperature, 5.8 g of 2-t-butyldimethylsiloxy-cyclohexane-1,3-diene (2
After stirring for 25 hours, the solvent was distilled off under reduced pressure. To 4.48 g of the obtained residue, add THF3
The resulting solution was added dropwise under nitrogen atmosphere to a suspension of 2.23 g (55.6 mm) of sodium hydride and 60 ml of THF under water cooling, and the mixture was stirred for 30 minutes. After neutralizing with a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off under reduced pressure. Next, 60 ml of THF was added to the residue to dissolve it, 2.57 g (11.1 mmol) of silver oxide and anhydrous magnesium sulfate were added, and after stirring for 2 hours, the solid matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure. did. The residue was heated at 130° C. for 4 hours under a nitrogen atmosphere, and then separated and purified by silica gel column chromatography to obtain 2.17 g of the title compound 13 and 2.0 g of the title compound 14. [0145] IHNMR (DMSO-d6
．． δ-TMS); 0.15 (s, 6H), 0.88
(s, 9H) 1.40 (d, 3H, J=4.0Hz
) 4.57 (d, LH, J=3.5Hz) 4.65~
4.95 (m, LH) 6.65 (s, LH), 7.37 (m, LH), 7.0
5 (m, LH) 7.72 (m, LH) IR (KBr, cm'): 3420 (OH), 1670 (C=0), 1590
, 1290.1240[0146] IHNMR (DMSO-d
6. δ-TMS): 0.15 (s, 6H), 0.8
8 (s, 9H) 1.40 (d, 3H, J=4.0H
z) 4.57 (d, LH, J=3.5Hz) 4.65
~4.95 (m, IH) 6.65 (s, LH), 7.37 (m, LH), 7.
15 (m, LH) 7.82 (m, LH) IR (KBr, cm-1); 3420 (OH), 1670 (C=○), 1590
, 1290.1240[0147] (Example 12) 2-(1-hydroxyethyl)-6-hydroxynaphtho[2,3-b]furan-4,9-dione (Compound 15)
synthesis of. [0148] Compound 13 obtained in Example 11; 2-(1-hydroxyethyl)-6-t-butyldimethylsiloxynaphtho[2,
3-b] THF2 to 2.17 g of furan-4,9-dione
Add 50ml and dissolve, add 100ml of 0.1M acidic sodium fluoride (NaF, HF) aqueous solution at room temperature,
Stirred for 10 minutes. Next, it was extracted with ethyl acetate, washed with water, dried, and then the solvent was distilled off under reduced pressure to obtain the title compound 15 in 1.2
8g of obtained 1HNMR (acetone-d6.δ-TM
S): 1.53 (d, 3H, J=6.0Hz), 4
．． 70 (S, LH)4.97 (q, LH, J=6.
0Hz), 6.77 (S, LH) 7.12 (m, L
H), 7.48 (m, LH) 7.92 (d, LH,
J=2.0Hz), 9.7 (S, LH)IR (KBr
, cm-1): 3420 (OH), 1670 (C=0), 1590
,1530°1360.1320,1250.740[
[0149] (Example 13) 2-(1-hydroxyethyl)-7-hydroxynaphtho[2,3-b]furan-4,9-dione (Compound 16)
synthesis of. [01501 Compound 14 obtained in Example 11: 2-(1-hydroxyethyl)-7-t-butyldimethylsiloxynaphtho[2,
3-b] 2.0 g of furan-4,9-dione in Example 12
The title 2-(1-hydroxyethyl)-7-hydroxynaphtho[2,3-b]furan-4,
IHNMR (acetone-d 6. δ-TMS) obtained 1.0 g of 9-dione (compound 16); 1,53 (d,
3H, J=6.0Hz), 4.70 (S,
LH) 4.97 (q, LH, J=6.0Hz), 6.
77 (S, IH) 7.22 (m, LH), 7.48
(m, LH) 8.05 (d, IH, J=2.0H
z), 9.7 (S, LH) IR (KBr, cm'): 3420 (OH), 1670 (C=O), 1590
,1530°1360.1320,1250.740[
[0151] (Example 14) 5.8.4a,8a-tetrahydro-5,8-ethano-
Synthesis of 5,8-ditrimethylsiloxynaphtho[2,3-b]furan-4,9-dione (Compound 17). [0152] Under nitrogen atmosphere, benzo[2,3-b]furan-4,7
-dione Ig (3,76 mmol) in methylene chloride 10
1,4-ditrimethylsiloxycyclohexane dissolved in 5 ml of methylene chloride at room temperature.
333 g (13.0 mmol) of 1,3-diene was added dropwise. - After stirring overnight, the solvent was distilled off under reduced pressure and the title compound 5,8.4a,8a-tetrahydro-5,8-ethano-
Obtain 2.0 g (yield 73%) of 5,8-ditrimethylsiloxynaphtho[2,3-b]furan-4,9-dione (compound 17). 1HNMR (CDC13, δ-TMS): 0.23
(s, 18H), 1.65 (m, 2H), 1.95
(m, 2H) 3.17 (m, 2H), 5.95 (s
, 2H) 6.72 (d, LH, J=1.7Hz)7.
58 (d, IH, J=1.0Hz) [0153] (Example 15) 5.8-dihydroxy-naphtho[2,3-b]furan-
Synthesis of 4,9-dione (compound 18). [0154] 960 mg of sodium hydroxide was suspended in THFroom, and under ice cooling, 5, 8.4a, 8a obtained in Example 14 was added.
-tetrahydro-5,8-ethano-5,8-ditrimethylsiloxynaphtho[2,3-b]furan-4,9-dione (compound 17) 2.0 g (3,83 m mol
) and stirred for 30 minutes. Acidified with dilute hydrochloric acid,
After extraction with methylene chloride, washing with water, and drying, the solvent was distilled off under reduced pressure to obtain 0.9 g (yield: 75%) of the title compound 18. IHNMR (CDC13, δ-TMS) Near, 01
(s, 2H), 7.77 (S, 2H), 12.53
(s, LH) 12.70 (S, LH) [0155] (Example 16) 2-(1-hydroxyethyl) -5,8,4a, 8a
Synthesis of -tetrahydro-5,8-nitano-5-ditrimethylsiloxynaphtho[2,3-b]furan-4,9-dione. [0156] 3.0 g of 2-(1-hydroxyethyl)-benzo[2,3-b]77-4,7-sion (1
Add 20 ml of methylene chloride to 5.6 mmol) and dissolve, and add 4.1 g of 1,4-ditrimethylsiloxycyclohexane-1,3-diene to 20 ml of methylene chloride at room temperature.
1 was added dropwise, and after stirring day and night, the solvent was distilled off under reduced pressure to obtain 6.5 g (yield: 93%) of the title compound. IHNMR (CDC13, δ-TMS) 0.12 (S
, 18H), 1.24 (d, 3H, J=4.0Hz)
1.67 (m, 2H), 1.95 (m, 2H), '2.
31 (S, LH) 3.18 (m, 2H), 5.2
1 (bs, LH), 6.61 (S, LH) 6.7
4 (d, LH, J=1.7Hz) 7.58 (d, L
H, J=1.0Hz) IR (KBr, cm') 3200 (○H), 1670 (C=○), 1580
．． 1490[0157] Example 17 Synthesis of 2-(1-hydroxyethyl)-5,8-dihydroxynaphtho[2,3-b]furan-4,9-dione (Compound 19). [0158] Under nitrogen atmosphere, 2.5 g of sodium hydride was dissolved in THF20
ml of 2-(1-hydroxyethyl)-5,8,4a,8a-tetrahydro-58-ethano-5,8-ditrimethylsiloxynaphtho[2,3-b] under ice cooling.
] A solution of 6.5 g of furan-49-dione dissolved in 20 ml of THF was added dropwise and stirred for 30 minutes. After neutralizing with a saturated aqueous ammonium chloride solution, the mixture was made acidic with dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off under reduced pressure. Add THF to the obtained residue and dissolve it to obtain 4.0 g of silver oxide.
and 4.0 g of anhydrous magnesium sulfate were added thereto, and after stirring at room temperature for 1 hour, the solid matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.3 g of the title compound (compound 19) (yield 54
%)Obtained. IHNMR (acetone-d6. δ-TMS)1.
60 (d, 3H), 4.95 (d, LH, J=2.
0Hz) 5.05 (m, LH), 6.90 (S, L
H) 7.35 (S, 2H), 12.54 (S, IH),
12.66 (S, LH) IR (KBr, cm 1) 3400 (OH), 1618 (C=○), 1524
, 1440° 1318.1244.1164 Melting point: 172°C (dec) [0159] (Example 18) 2-Butyl-5,8,4a,8a-tetrahydro-5,
8-Ethano-5,8-ditrimethylsiloxynaphtho[2
, 3-bfuran--4,9-dione synthesis. [01601 Under nitrogen atmosphere, 4.0 g of 2-butyl-benzo[2,3-b]furan-4,7-dione (19,6 m mo
Add 25 ml of methylene chloride to 1) and dissolve, and add 1 ml of methylene chloride at room temperature.
,4-ditrimethylsiloxycyclohexane-1,3-
A solution of 5.1 g of diene in 25 ml of methylene chloride was added dropwise, and after stirring day and night, the solvent was distilled off under reduced pressure to obtain 8.2 g (yield: 91%) of the title compound. IHNMR (CDC13, δ-TMS) 0.11 (
S, 18H), 0.35 (t, 3H, J=6.0Hz
) 1.00-1.68 (m, 4H), 1.95 (
m, 2H) 3.18 (m, 2H), 3.39 (t,
2H, J=1.0Hz) 6.63 (S, LH), 6.
73 (d, LH, J=1.7Hz) 7.59 (d,
LH, J=1.0Hz) IR (KBr, cm') 1660 (C=0), 1590.1500 [0161
] (Example 19) 2-butyl-5,8-dihydroxynaphtho[2,3-b
] Synthesis of furan-4,9-dione. [0162] THF25 in 3.2 g of sodium hydride under nitrogen atmosphere
ml of 2-butyl-5,8,
4a,8a-tetrahydro-5,8-ethano-5,8-
Ditrimethylsiloxynaphtho[2,3-b]furan-4
,9-dione 82g (17,9m mo 1) in T
A solution dissolved in 25 ml of HF was added dropwise and stirred for 30 minutes. After neutralizing with a saturated aqueous ammonium chloride solution, the mixture was made acidic with dilute hydrochloric acid and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off under reduced pressure. THF was added to the resulting residue to dissolve it, 5.0 g of silver oxide and 5.0 g of anhydrous magnesium sulfate were added, and after stirring at room temperature for 1 hour, the solid matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.97 g (yield 58%) of the title compound. IHNMR (acetone-d6.δ-TMS) 0.68
(t, 3H, J=6.0Hz), 1.00-1.68
(m, 4H) 3.40 (t, 2H, J=7.0Hz)
6.90 (S, LH), 7.36 (S, 2H) 1
2.55 (bs, LH), 12.63 (bs, L
H) 3400 (OH), 1620 (C=○), 15
20,1430.1320[0163] (Example 20) 4,7-ditetrahydropyranyloxy-benzo[2,
3-b] Synthesis of furan [0164] Potassium nitrosodisulfonate 49.2 under nitrogen atmosphere
21 of a 1715 M potassium dihydrogen phosphate aqueous solution and 31 of cold water were added to the solution (0.1 mm. 1) and stirred. It was dissolved in acetone 11 at 0°C to 5°C. 7-Hydroxybenzofuran 6°7g (0.05m mol
) was added dropwise. After stirring for 3 hours at 0°C to 10°C, the mixture was extracted with ethyl acetate, and a saturated aqueous hydrosulfide solution was added to the organic layer, followed by vigorous shaking. Next, wash the organic layer with water,
After drying, the solvent was distilled off under reduced pressure, 100 ml of dihydropyran was added to the residue under a nitrogen atmosphere, and 1.25 g of pyridinium paratoluenesulfonate (5 m m
A solution of 50 ml of methylene chloride was added to the mixture, and the mixture was stirred all day and night. After neutralization by adding a 5% aqueous sodium carbonate solution, extraction with methylene chloride, washing with water, and drying, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 10.2 g of the title compound. (yield: 64%). IHNMR (CDC13, δ-TMS) 1.5-2.3
(m, 12H), 3.5-3.6 (m, 2H)3.
8-4.1 (m, 2H), 5.45 (S, LH) 5
．． 55 (S, IH), 6.8-6.7 (m, 3H)
7.5 (S, LH) IR (KBr, cm') 3100.1500, 1450.1200 [0165] (Example 21) 2-(1-Hydroxyethyl)-4,7-ditetrahydrobyranyloxy-benzo[ Synthesis of 2,3-b]furan. [0166] 15.9 g (0.05 m
mol) was added to 70 ml of THF and dissolved. -78℃
Cooled to
mol) dropwise and the temperature was raised to -60°C over 1 hour. The mixture was cooled again to -78°C, a THF solution of excess acetaldehyde was added, and the mixture was stirred for 2 hours. Next, after neutralizing by adding ammonium chloride aqueous solution, extraction with methylene chloride,
After washing with water and drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 16.0 g of the title compound.
(yield 89%). IHNMR (CDC13, δ-TMS) 1.62 (
d, 3H, J=6.5Hz), 1.5-2.3 (m
, 12H) 2.70 (m, LH), 3.5-3.6
(m, 2H) 3.8-4.1 (m, 2H), 4.
96 (m, LH) 5.46 (S, LH), 5.
54 (S, LH) 6.80~7.00 (m, 3H
) IR (KBr, cm 1) 3500.3200, 1550.1490 [0167] (Example 22) Synthesis of 2-(1-hydroxyethyl)-4,7-cyhydroxybenzo[2,3-b]furan . [0168] 2-(1-Hydroxyethyl)-4,7-ditetrahydropyranyloxy-benzo[2,3-b]-y Ran I
O, Og (21.6 mmol) with methanol 10
Add 0ml of oxalic acid, dissolve it, cool on ice, and add 0.24g of oxalic acid (2
, 7m mol 1) was added thereto, the temperature was gradually raised, and the mixture was stirred at room temperature overnight. After adding water and extracting with ethyl acetate, washing with water and drying, the solvent was distilled off to obtain 5.10 g (yield 95%) of the title compound. IHNMR (CDCl δ-TMS) 3' 1.63 (d, 3H, J = 6.5Hz) 2゜73 (
d, LH, J=4.5Hz) 4.96 (dg, LH,
J=6.5Hz, J=4.5Hz)6.69 (S, 3
H), 8.19 (S, 2H)IR (KBr, cm-
1) 3400.3200, 1580.1570 [0169] (Example 23) 2-(1-hydroxyethyl)-benzo[2,3-b]
Synthesis of furan-4,7-dione. [0170] 2-(1-hydroxyethyl)-4,7 under nitrogen atmosphere
-cyhydroxybenzo[2,3-b]furan 5.10
g (26.3m mol) was dissolved in 30ml of THF, and then 12.8g (55.2m mol) of silver oxide was dissolved under ice-cooling.
mol) and 12.8 g of anhydrous magnesium sulfate,
Stirred for 0 minutes. Next, the solid matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain 4.80 g (yield: 95%) of the title compound. IHNMR (CDCl2.δ-TMS) 1.60 (d
, 3H, J=6.5Hz) 2.73 (d, LH, J=
4.5Hz) 4.95 (dg, LH, J=6.5H
z, J=4.5Hz) 6.66 (S, 3H) IR (KBr, cm') 3500.3150, 1670, 1590.1570 Melting point: 87-88°C [0171] (Example 24) 2-Butyl- Synthesis of 4,7-ditetrahydrobyranyloxy-benzo[2,3-b]furan. [0172] In Example 21, using butyl bromide in place of acetaldehyde, 4,7-ditetrahydrobyranyloxy-benzo[
2,3-b]furan 10.0g (31.4mmol)
7.0 g (yield 70%) of the title compound was obtained. [0173] (Example 25) 2-Butyl-4,7-cyhydroxybenzo[2,3-
b] Furan-synthesis. [0174] In Example 22, 2-(1-hydroxyethyl)-
4,7-ditetrahydrobylanyloxybenzo[2,
3-b]furan - Instead, 7.0 g (187 mmol) of 2-butyl-4,7-ditetrahydropyranyloxy-benzo[2,3-b]furan was used to prepare the title compound 3.
5 g (yield 90%) was obtained. [0175] Example 26 Synthesis of 2-butyl-benzo[2,3-b]furan-4,7-dione. [0176] In Example 23, 2-(1-hydroxyethyl)-
4,7-cyhydroxybenzo[2,3-bfuran-instead of 2-butyl-4,7-cyhydroxybenzo[2
,3-b] Fan 3.5g (16.9m mo
1), 3.2 g (yield 92%) of the title compound was obtained. [0178] (Example 27) Optically active (+)-2-(1-hydroxyethyl)-8-
Synthesis of hydroxynaphtho[23-b]furan-4,9-dione (compound 20). [0179] A UV detector for HLC UVIDEC-100II (manufactured by JASCO Corporation) was connected to a high-pressure pump model 572P (manufactured by Gascro Industries Co., Ltd.) for HLC (high performance liquid chromatography), and a cellulose derivative-coated silica gel was connected to this. φ5 x 50 cm filled with filler CHIRALCEL OJ (manufactured by Daicel Chemical Industries, Ltd.)
2-(1-hydroxyethyl)-8- obtained in the same manner as in Example 3 was added to an HLC apparatus connected to an HLC column.
A solution of 40 mg of hydroxynaphtho[2,3-b]furan-4°9-dione (compound 3) dissolved in 1 ml of THF was injected, and a mixed solvent of hexane:ethanol = 5:1 was flowed at a flow rate of 60 ml/min. Chromatography was performed and UV absorption at 240 nm was measured. In the resulting chromatography, UV absorption peaks were observed at Rt (retention time) of 56 minutes and 70 minutes. The UV absorption peak portion at Rt 56 minutes was fractionated, and the solvent was distilled off under reduced pressure to obtain 18 mg of the optically active title compound (Compound 20). IHNMR (CDC13, δ-TMS); 1.66
(d, 3H, J=6.8Hz), 2.22 (S, LH
)5.05 (m, LH), 6.86 (S, LH)7
．． 28 (d, LH, J=8.4Hz)7.61 (
dd, LH, J=8.4Hz, 8.4Hz) 7.73
(d, IH, J=8.4Hz), 12.03 (S
, LH) IR (KBr, cm-1): 3400 (OH), 1672 (C=O), 1640
(C=O)UV (methanol); 235 nm, 295 nm, 420 nm Melting point: 184-186°C Specific optical rotation: [α] + 11, 4 (c
=0. 18. CHCI3)-[0180] (Example 28) Optically active (-)-2-(1-hydroxyethyl)-8-
Synthesis of hydroxynaphtho[23-b]furan-4,9-dione (compound 21). [0181] The UV absorption peak portion at Rt 70 minutes obtained in the chromatogram of Example 27 was fractionated in the same manner as in Example 27, and the solvent was concentrated and distilled off under reduced pressure to obtain the optically active title compound (Compound 2
1) 13 mg was obtained. 1HNMR (CDC13, δ-TMS): 1, 66
(d, 3H, J=6.8Hz), 2.22 (S
, LH) 5.05 (m, LH), 6.86 (S,
IH) 7.28 (d, LH, J=8.4Hz) 7.6
1 (dd, IH, J=8.4Hz, 8.4Hz)7
．． 73 (d, LH, J=8.4Hz), 12.03
(S, LH)IR (KBr, cm 1); 3400 (OH), 1672 (C=O), 1640
(C=0) UV (methanol); 235 nm, 295 nm, 420 nm Melting point; 178-180°C Specific optical rotation; [a] D11, 3 (c =
0, 13, CHCI3) [0182] (Example 29) Optical activity (+)-2-(1-hydroxyethyl)-5-
Synthesis of hydroxynaphtho[23-b]furan-4,9-dione (compound 22). [0183] $ 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9- obtained by processing in the HLC apparatus described in Example 27 in the same manner as in Example 7 50 mg of dione (compound 4) was dissolved in 1 ml of THF and injected, and a mixed solvent of hexane:ethanol = 5:1 was added at a flow rate of 60 m.
Chromatography was performed by running at 17 min, and UV absorption was measured at 240 nm. In the obtained chromatogram, UV was applied at Rt (retention time) of 64 minutes and 76 minutes.
Although an absorption peak was obtained, the separation of the two peaks was not good, so recycle chromatography was performed two more times, the UV absorption peak at Rt 64 was fractionated, and the solvent was distilled off under reduced pressure. , the optically active title compound (
20 mg of compound 22) was obtained. IHNMR (CDC13, δ-TMS); 1.66
(d, 3H, J=6.8Hz), 2.23 (S, LH
)5.04 (m, LH), 6.85 (S, LH)7
．． 28 (d, LH, J=8.4Hz)7.62 (d
d, LH, J=8.4Hz, 8.4Hz) 7.76 (
d, LH, J=8.4Hz), 12.18 (S, LH
)3400 (OH), 1660 (C=0), 163
0 (C=○) UV (methanol); 247 nm, 295 nm, 400 nm Melting point; 171-173°C Specific optical rotation; [α]25=+16.9 (c=0.12
．． CHCl ) [0184] (Example 30) Optically active (-)-2-(1-hydroxyethyl)-5-
Synthesis of hydroxynaphtho[23-b]furan-4,9-dione (compound 23). [0185] The Rt76 minute absorption peak obtained in the chromatogram of Example 29 was fractionated in the same manner as in Example 29, and the solvent was concentrated and distilled off under reduced pressure to obtain the optically active title compound (Compound 23) 25
mg was obtained. IHNMR (CDC13, δ-TMS): 1.66
(d, 3H, J=6.8Hz), 2.23 (S, LH
)5.04 (m, IH), 6.85 (S, LH
)7.28 (d, LH, J=8.4Hz)7.62
(dd, LH, J=8.4Hz, 8.4Hz) 7.76
(d, LH, J=8.4Hz), 12.18 (S,
LH) IR (KBr, cm'): 3400 (OH), 1660 (C=○), 1630
(C=0) UV (methanol); 247 nm, 295 nm 400 nm melting point; 169 ~
170°C Specific rotation; [α] 16, 5 (c = 0
．． 16, CHC13)-[0186] (Example 31) Optically active (+)-2-(1-hydroxyethyl)-5,
8-dihydroxynaf)[2,3-b]furan-4,9
-Synthesis of dione (compound 24). [0187] 2-(1-hydroxyethyl)-5,8- obtained by processing in the HLC apparatus described in Example 27 in the same manner as in Example 17.
200 mg of dihydroxynaphtho[2,3-b]furan-49-dione (compound 19) was dissolved in 4 ml of THF and injected, and chromatography was performed by flowing a mixed solvent of hexane:ethanol = 3:1 at a flow rate of 60 ml/min. The UV absorption at 240 nm was measured. In the obtained chromatogram, UV absorption peaks were obtained at Rt (retention time) of 44 and 52 minutes, but since the separation of the two peaks was not good, recycling chromatography was performed two more times. The UV absorption peak portion was separated, and the solvent was distilled off under reduced pressure to obtain 90 mg of the optically active title compound (Compound 24). IHNMR (acetone-d6, δ-TMS); 1.60
(d, 3H), 4.95 (d, LH, J=2.0H
z) 5.05 (m, LH), 6.90 (S, LH),
7.35 (s, 2H) 12.54 (s, LH), 1
2.66 (s, LH) IR (KBr, cm'): 3420 (OH), 1618 (C=○), 1524
, 1440° 1318.1244.1164 Melting point: 169-170°C Specific optical rotation: [α] , = +19.7 (c = 0.10.
CHCl3)[0188] (Example 32) Optical activity (-) -2-(1-hydroxyethyl)-5
,8-dihydroxynaf)[2,3-bfuran--4,
Synthesis of 9-dione (compound 25). [0189] U at Rt52 obtained in the chromatogram of Example 31
The V absorption peak portion was collected in the same manner as in Example 20, and the solvent was concentrated and distilled off under reduced pressure to obtain the optically active title compound (compound 2
5) 90 mg was obtained. IHNMR (acetone-d6, δ-TMS); 1.60
(d, 3H), 4.95 (d, LH, J=2.0
Hz) 5.05 (m, LH), 6.90 (S, LH)
, 7.35 (s, 2H) 12.54 (s, IH),
12.66 (s, LH)IR (KBr, cm'); 3420 (OH), 1618 (C=O), 1524
, 1440° 1318.1244.1164 Melting point; 168-170°C Specific rotation: [α] D--19,7 (c=0.1
0. CHCl3) [0190] Next, the anticancer activity of the compounds of the present invention was measured. [0191] (Example 33) Measurement of anticancer activity using mice transplanted with murine leukemia P388 cells. [0192] 1 x 10 murine leukemia P388 cells were intraperitoneally transplanted into 5-week-old female BDFI mice, 6 mice per group, and 24 hours later, the test substance containing 0.5% carboxymethylcellulose was implanted. Suspend a specified amount in physiological saline,
It was administered intraperitoneally to the mouse. The anticancer activity was evaluated based on the survival rate (ILS). The results are shown in Table 1. [0193] [Table 1] [0194] In Table 1, the dosage unit is (mg/kg),
Also, life extension rate (, ILS) = (TC)/CXl00
(%). Here, T is the number of days of survival in the treated group, and C is the number of days of survival in the untreated group. [0195] All of these exhibit good anticancer activity and are useful as anticancer agents. In addition, the acute toxicity (L
D5o) was administered intraperitoneally to mice (male) at 20
It was 0 mg/kg or more. [0196] Next, in the examples shown below, formulation examples using the compound of the present invention and specifically specifying the dosage form and composition are shown. Note that the present invention is not limited to the following examples. [0197] Example 34 Tables 2 and 3 show formulation examples of tablets containing 5 mg and 25 mg of active ingredient per tablet (200 mg). [0198]

[Table 2]

[Table 3] [0200] Further, details of the manufacturing method of these tablets are as follows. First, crystals of Compound 19 are crushed, and lactose and starch are added thereto and mixed. Then 10% starch paste is added to the above mixture and stirred to produce granules. After drying, the particles were sized to a particle size of approximately 850 microns, talc and magnesium stearate were mixed therein, and the mixture was compressed into tablets. [0201] (Example 35) Table 4 shows a formulation example of a capsule containing 20 mg of active ingredient per capsule (100 mg). [0202]

[Table 4] This capsule was manufactured as follows. Compound 19
was thoroughly ground, starch, lactose and magnesium stearate were added, and after thorough mixing, the mixture was filled into capsules. [0204]

【Effect of the invention】

As explained above, the present invention has revealed a new and useful methylbenzoquinone derivative and its true pharmacological activity through chemical synthesis that does not involve extraction and purification from natural products. To provide a novel methylbenzoquinone derivative useful as a pharmaceutical raw material, a method for producing the same, a novel methylbenzoquinone derivative having excellent anticancer effects, a medically acceptable salt thereof, and an anticancer agent containing these as an active ingredient. I can do it.

Claims (35)

[Claims] [Claim 1] A furalbenzoquinone derivative represented by the general formula (I). [Chemical 1] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is hydrogen, a chain or branched alkyl group consisting of 1 to 6 carbon atoms, or a chain or Represents a branched hydroxyalkyl group consisting of 1 to 6 carbon atoms, R^2 to R^5 are hydrogen or hydroxyl groups,
And any two of them are hydroxyl groups. ) [Claim 2] In the general formula (I), R^1 is hydrogen;
or a chain or branched alkyl group having 1 to 6 carbon atoms, and R^2 to R^5 are hydrogen or hydroxyl groups, and any two of them are hydroxyl groups, according to claim 1. furalbenzoquinone derivative. [Claim 3] In the general formula (I), R^1 is a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms, and R^2 to R^5 are hydrogen or a hydroxyl group. The furalbenzoquinone derivative according to claim 1, wherein any two of these groups are hydroxyl groups. [Claim 4] In the general formula (I), R^1 is hydrogen;
or a chain or branched alkyl group having 1 to 6 carbon atoms or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms, and R^2 to R^5 are hydrogen or When it is a hydroxyl group and R^3 is a hydroxyl group, R^2, R^4, R^5 are hydrogen, and when R^4 is a hydroxyl group, R^2,
Furalbenzoquinone derivative where R^3 and R^5 are hydrogen. [Claim 5] In the general formula (I), R^1 is hydrogen;
or a chain or branched alkyl group having 1 to 6 carbon atoms, and when R^2 to R^5 are hydrogen or a hydroxyl group, and R^3 is a hydroxyl group, R
The fural according to claim 4, wherein ^2, R^4, and R^5 are hydrogen, and when R^4 is a hydroxyl group, R^2, R^3, and R^5 are hydrogen. Benzoquinone derivative. 6. In the general formula (I), R^1 is hydrogen or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms, and R^2 to R^5 are hydrogen or hydroxyl. group, and when R^3 is a hydroxyl group, R^2, R^4, R^5 are hydrogen, and
When R^4 is a hydroxyl group, R^2, R^3,
The furalbenzoquinone derivative according to claim 4, wherein R^5 is hydrogen. 7. A furalbenzoquinone derivative represented by general formula (II). [Chemical formula 2] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 is hydrogen, a chain or branched alkyl group consisting of 1 to 6 carbon atoms, or a chain or It is a branched hydroxyalkyl group consisting of 1 to 6 carbon atoms.) 8. The furalbenzoquinone derivative according to claim 7, wherein in the general formula (II), R^1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms. 9. The furalbenzoquinone derivative according to claim 7, wherein in the general formula (II), R^1 is a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. 10. A furalbenzoquinone derivative represented by general formula (III). [Chemical formula 3] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R^1 is hydrogen, a chain or branched alkyl group consisting of 1 to 6 carbon atoms, or a chain or It is a branched hydroxyalkyl group consisting of 1 to 6 carbon atoms.) 11. The furalbenzoquinone derivative according to claim 10, wherein in the general formula (III), R^1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms. 12. The furalbenzoquinone derivative according to claim 10, wherein in the general formula (III), R^1 is a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. 13. A furalbenzoquinone derivative represented by general formula (IV). [Chemical formula 4] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R^1 is hydrogen, a chain or branched alkyl group consisting of 1 to 6 carbon atoms, or a chain or It is a branched hydroxyalkyl group consisting of 1 to 6 carbon atoms.) 14. The furalbenzoquinone derivative according to claim 13, wherein in the general formula (IV), R^1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms. 15. The furalbenzoquinone derivative according to claim 13, wherein in the general formula (IV), R^1 is a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. 16. A furalbenzoquinone derivative represented by general formula (V). [Chemical formula 5] ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (V) (In the formula, R^1 is hydrogen, a chain or branched alkyl group consisting of 1 to 6 carbon atoms, or a chain or branched alkyl group consisting of 1 to 6 carbon atoms. It is a hydroxyalkyl group consisting of separated carbon atoms of 1 to 6.) 17. The furalbenzoquinone derivative according to claim 16, wherein in the general formula (V), R^1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms. 18. The furalbenzoquinone derivative according to claim 16, wherein in the general formula (V), R^1 is hydrogen or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. 19. A furalbenzoquinone derivative represented by general formula (VI). [Chemical 6] ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (VI) (In the formula, R^1 is hydrogen, a chain or branched alkyl group consisting of 1 to 6 carbon atoms, or a chain or branched alkyl group consisting of 1 to 6 carbon atoms. It is a hydroxyalkyl group consisting of separated carbon atoms of 1 to 6.) 20. The furalbenzoquinone derivative according to claim 19, wherein in the general formula (VI), R^1 is hydrogen or a chain or branched alkyl group having 1 to 6 carbon atoms. 21. The furalbenzoquinone derivative according to claim 19, wherein in the general formula (VI), R^1 is hydrogen or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms. 22. A furalbenzoquinone derivative which is optically active (+)-2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione. 23. A furalbenzoquinone derivative which is optically active (-)-2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione. 24. A furalbenzoquinone derivative which is optically active (+)-2-(1-hydroxyethyl)-8-hydroxynaphtho[2,3-b]furan-4,9-dione. 25. A furalbenzoquinone derivative which is optically active (-)-2-(1-hydroxyethyl)-8-hydroxynaphtho[2,3-b]furan-4,9-dione. Claim 26: Optically active (+)-2-(1-hydroxyethyl)-5,8-dihydroxynaphtho[2,3-b]
The furalbenzoquinone derivative according to claim 1, which is furan-4,9-dione. Claim 27: Optically active (-)-2-(1-hydroxyethyl)-5,8-dihydroxynaphtho[2,3-b]
The furalbenzoquinone derivative according to claim 1, which is furan-4,9-dione. [Claim 28] [Claim 7] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIII) → ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IX) ▲ There are mathematical formulas, chemical formulas, tables, etc.▼(X) (In the formula, R^1 is hydrogen, a chain or branched alkyl group consisting of 1 to 6 carbon atoms, or a chain or branched carbon number Represents a hydroxyalkyl group consisting of 1 to 6 members, R^2 represents hydrogen or a protected hydroxyl group, R^3 represents hydrogen or a hydroxyl group, and X is
Represents a hydrogen or halogen atom. ) A furalbenzoquinone derivative represented by general formula (VII) is subjected to a Diels-Alder reaction with a butadiene derivative represented by general formula (VIII), followed by isomerization and deprotection, followed by column chromatography. A method for producing furalbenzoquinone derivatives represented by general formulas (IX) and (X) by isolating and purifying furalbenzoquinone derivatives represented by formulas (IX) and (X). [Claim 29] [Claim 8] ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (X I ) → (XII) (In the formula, R^1 is a hydrogen atom or a chain or branched carbon number of 1 to 6 (R^2 to R^5 represent hydrogen, a hydroxyl group, or a protected hydroxyl group.) A method for producing a furalbenzoquinone derivative represented by the general formula (XII) by isomerizing the furalbenzoquinone derivative represented by the general formula (XI) using a base, followed by oxidation and deethylenization. 30. A furalbenzoquinone derivative represented by the general formula (X I ). [Chemical Formula 9] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(X I) (In the formula, R^1 is hydrogen, a chain or branched alkyl group consisting of 1 to 6 carbon atoms, or a chain or It represents a branched hydroxyalkyl group having 1 to 6 carbon atoms, and R^2 to R^5 represent hydrogen, a hydroxyl group, or a protected hydroxyl group.) [Claim 31] [Chemical formula 10] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XIII) ▲ Mathematical formulas,
There are chemical formulas, tables, etc.▼(XVI) →▲There are mathematical formulas, chemical formulas, tables, etc.▼(X I) (In the formula, R^1 is hydrogen or a chain or branched carbon number of 1 to 6 Represents an alkyl group or a chain or branched hydroxyalkyl group having 1 to 6 carbon atoms, and R^2 to R^5 represent hydrogen, a hydroxyl group, or a protected hydroxyl group.) General formula ( The general formula (
A method for producing a furalbenzoquinone derivative represented by X I ). 32. A furalbenzoquinone derivative represented by general formula (XIII). [Chemical formula 11] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XIII) (In the formula, R^1 is a chain or branched carbon number of 1 to 6
represents a hydroxyalkyl group consisting of ) [Claim 33] [Chemical formula 12] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XIV) → ▲ Mathematical formulas,
There are chemical formulas, tables, etc. ▼ (XIII) (In the formula, R^1 is a chain or branched carbon number of 1 to 6
represents a hydroxyalkyl group consisting of ) A method for producing a furalbenzoquinone derivative represented by the general formula (XIII) by oxidizing a benzofuran derivative represented by the general formula (XIV). 34. A benzofuran derivative represented by general formula (XV). [Chemical formula 13] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XV) (In the formula, R^1 is a chain or branched carbon number of 1 to 6
a hydroxyalkyl group consisting of , X represents hydrogen or a tetrahydropyranyl group. ) 35. An anticancer agent containing the furalbenzoquinone derivative according to any one of claims 1 to 27 or a medically acceptable salt of the furalbenzoquinone derivative as an active ingredient.