JPS60178879A - Furanone derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is OH, alkoxyl or (substituted) arlower alkoxyl; R<2> is aryl, heterocyclic group or lower alkenyl which may be substituted; R<3> is H, COOH, thiocarboxy or (substituted)aryl; R<4> is H or lower alkyl; A is lower alkylene; n is 0 or 1, provided that n is 0 when R<1> is OH or 1-5C alkoxyl; R<2> is aryl or substituted aryl; R<3> is COOH; R<4> is H] or a salt thereof. EXAMPLE:Ethyl 3-[4-hydroxy-3-(2-naphthyl)-5-oxo-2,5-dihydro-2-furyl]propionate. USE:A remedy for diabetic complications, e.g. neurosis, cataract, renopathy, etc. having inhibitory activity against aldose reductase. PREPARATION:For example, a compound expressed by formula II, a derivative or salt thereof is reacted with a compound expressed by formula III or a salt thereof to afford the aimed compound expressed by formula IV.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides a! This invention relates to novel furanone derivatives that have redose reductase inhibitory activity, etc., and are used in the medical field.

[Conventional technology]

As furanone derivatives having aldose reductase inhibitory activity, for example, those described in JP-A-59-16884 are known.

Structure of the Invention] The furanone derivative which is the object compound of the present invention is represented by the following general formula.

(In the formula, R1 is a hydroxy group, an alkoxy group, or a/i/(lower) alkoxy group, and the aryl part in the alkoxy group is a lower alkyl group, a lower alkoxy group. or may be substituted with a halogen atom; R2 is an aryl group, a heterocyclic group, or a lower alkenyl group, and each of these groups is a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group,
Al (lower) alkoxy group, halo (lower) alkyl group,
It may be substituted with a lower alkylthio group, a nitro group, an amino group, or an aryl group; R3 may be substituted with a hydrogen atom, a carboxy group or a thiocarboxy group, or a derivative thereof, or a carboxy group or a derivative thereof. A good IJ-al group, R4 is a hydrogen atom or
Lower alkyl group and A each mean a lower alkylene group, and n each means an integer of 0 or "."

However, R1 is a hydroxy group or C□~C5apv:
roxy group iR" is monosubstituted with an aryl group, a halogen atom, or a halo (low i) alkyl group, and the fc7 group 1R is a carboxy group or a derivative thereof; and R
When 4 is a hydrogen atom, n is 0) In addition, in the compound where R1 is a hydroxy group in the above formula (1), the tautomer r-=][1
)) (wherein, R2, R3, R4, A and n each have the same meanings as before) and the compound has these tautomers (a) or (
11) J or as an equilibrium mixture thereof, both of which are within the scope of this invention. In this specification, for convenience, the compound [
1] is expressed by the above formula (a).

The object compound [1] of the present invention and its salt are produced by the method shown by the following formula.

Production method 1 Production method 6 Or its fortune or ya's worth Production method 5 Production method 6 Production method 7 Production method 8 Production method 9 Production method 10 Production method 11 (In the formula, R^ is an afrecoxy group or an alkoxy group The aryl part of the alkoxy group may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; R is an esterified carboxy group, an esterified carboxy group aryl group or mono(or di)lower alkyl group substituted with jVl<moyl group or mono(or di)lower moyl group,
This lower alkyl moiety is substituted with an esterified carboxy group; the lower alkyl moiety is substituted with an esterified carboxy group; is a mono(or di)lower alkylthiocarbamoy J' group, and these lower alkyl moieties are substituted with a carboxy group. R5 is an alkyl group or an al(lower) alkyl group, and the aryl part of the al(lower) alkoxy group may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; Rλ and R8 are each a hydrogen atom, Lower anoleki t4 optionally substituted with a carbamoyl group, a carboxy group or a derivative thereof; R'
is a lower alkanoyl group or a tahal(lower) alkyl group; R8 is a lower alkyl group; R9 is a lower alkyl group;
and Xid mean a leaving group, R, R, R,
R, A and n each have the same meaning as before. ) Each definition in this ab will be explained in detail below.

Unless otherwise specified, "lower" in <ILLA7LEKIL/ group, lower alkoxy group, lower alkylene group, etc. means a group having 1 to 6 carbon atoms.

Examples of the alkoxy group in R1 and the bow include methoxy, ethoxy, propoxy, isopropoxy, butoxy, imbutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, Examples include dodecyloxy.

Al(low i)alkoxy groups in R1 and R include, for example, benzyloxy, benzhydrofleoxy, trityloxy, phenethyloxy! Examples include rheoxy, 5-phenylpropoquine, naphthylmethoxy, and the like.

Examples of the "aryl" moiety in the alkoxy group of R1 and R^ and the alkyl group of R5 and R and the aryl group in R2, R3, Rλ, and R8 include phenyl, naphthyl, I
For example, 6゜R1 and R': In the alkoxy group of L and the alkyl group of P, the aryl moiety is a lower alkyl group, a lower alkoxy group, or a halogen atom. may be replaced with .

Suitable examples of the lower alkyl group in the substituent of this "IJ/S" moiety include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl and the like. Suitable examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoquine, butoxy, tertiary butoxy, pentyloxy, hexyloxy, and the like. Suitable examples of halogen atoms include chlorine, bromine, iodine and fluorine.

The aryl group for R2 is a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, an al(lower) alkoxy group, a halo(lower) aJV kyl group, a lower alkylthio group, a nitro group, an amino group or an aryl group. It may be substituted with one or more selected substituents.

Suitable examples of the halo (lower) alkyl group in the substituent of the aryl group of R2 include chloromethyl, promononal, iodomethyl, fluoromethyl, dichloromethyl, 2
, 2.2-) dichloromethyl, trifleocomethyl, and the like. Suitable examples of the lower alkylthio group include methifrethio, ethyl-rethio, propyfretio, isopropylthio, buty)Vthio, tertiary-butylthio, hexylthio, and the like. Examples of the lower alkyl group, lower alkoxy group and halogen atom include those similar to those exemplified as the substituent in the "aryl" moiety of R1 and Rλ above, and also lower alkoxy groups and examples of aryl groups include
Those similar to those exemplified for R1 and R^ can be mentioned.

The heterocyclic group in R2 includes a monocyclic heterocyclic group and a polycyclic heterocyclic group, and these heterocyclic groups contain at least one heteroatom consisting of an oxygen atom, a sulfur atom, or a nitrogen atom. do. Suitable examples of these heterocyclic groups include 5- to 6-membered monocyclic heterocyclic groups (e.g., furinone, 1-thienyl, pyrrolyl, imidazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridinio, piperidyl, pyrrolidinyl, etc.); Fused heterocyclic groups (e.g. Bensif IJ
/, benzochenyl, indolyl, quinoli, etc.)
One example is Nato. These heterocyclic groups are only 7j
It may be substituted with the same substituents as those exemplified as substituents for the l 7+/ group.

The lower alkenyl group in R2 includes vinyl, isopropenyl, 1-ethylvinyl, 1-probenyl,
Allyl, 1--y" tenyl, 2--y" tenyl, 3-phthynyl, 4-pentenyl, 5-hexenyl, and the like. These lower alkenyl groups may be substituted with the same substituents as those exemplified as the substituents for the aryl group of R2.

Derivatives of the levoxy group or thiocarboxy group in R3 include esters, thioesters, amides, thioamides, diazomethylcafflebonyl and the like. Suitable examples of the ester residue in the ester or thioester include lower alkyl (e.g. evamethyl, ethyl, propyl, isopropyl, butyl, tertiary butyl,
hexyl, etc.), aryl (phenyl, naphthyl, etc.),
Alkyl (lower alkyl) benzyl, phenethyl, benzhydryl, etc.) and the like. Preferable examples of the amides or thioamides include carbamoyl and thiocarbamoyl, which include, for example, the aforementioned lower alkyl groups, carbamoyl groups, lower alkoxycarbonyl (lower) alkyl groups (e.g., methoxycarbonylmethyl, ethoxycarbamoyl, etc.). It may be substituted with carbonylmethyl, tertiary-butoxycarbonylmethyl, -methoxycarbonylethyl, etc.).

Examples of the derivative of the carboxy group which is a substituent of the aryl group of R include the same ones as mentioned above.

Esterified carboxy group of Rλ or aryl
Examples of ester residues in the 1 levoxy group, mono(or di) lower alkylthiocarbamoyl group or mono(or di) lower alkylthiocarbamoyl group include R3 Examples of the carboxyl group derivatives include the same ester residues of the esters exemplified.

Examples of mono(or di)lower alkylthiocarbamoyl and mono(or di)lower alkylthiocarbamoyl in Rλ and R3 include, for example, N-methylcarbamoyl, N,N-dimethyl! Lebamoyl, N-ethylcaflevamoyl, N,N-diethylcarbamoyl,
N-ethyl-N-methyl force! Revamoi l, N, -7'
Lopylcarbamoyl, N-methyl-N-propylenecarbamoyl
Lebamoyl, N-ethyl-N-isoterobylcarbamoyl, N-j'f-ruthiocarbamoyl, N-dimethylthiocarbamoyl, N-ethylthiocarbamoyl, N,N-dienalylthiocarbamoyl , N-Ethyl-N-/Tilthioyl Lebamoyl, N-Propylthioca! Examples include lebamoyl, N-methifurean N-propylthiocarbamoyl, and ethylenic isopropylthiocarbamoyl.

R4, R:, Lower Al'f in R valley R8 and R9
J'71if)tJHM Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

Suitable examples of the alkyl group for R include, in addition to the above-mentioned lower alkyl group, heptyl, offal, nonyl, decyl, randecyl, dodecyl, and the like.

Suitable examples of the lower (lower) ivkyl group in R and R7 include benzyl, phenethyl, benzhydryl, trityl, and the like.

The lower alkyl group in R3 and R8 may be substituted with a carboxy group or a derivative thereof, and examples of the derivative of the carboxy group include the same ones as exemplified for R.

Suitable examples of lower alecanoyl for R include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, and the like.

The lower alkylene group in AK includes both linear and branched alkylene groups, such as methylene, ethylene,
Trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, ethyl ethylene, propyl ethylene, isopropyl ethylene, methylpentamethylene, etc.-1) Preferred examples of the removing #l group of ff lale X include chloride, Halides such as bromide and iodide,
Examples include sulfonates such as benzenesulfonate, tosylate, and mesylate.

Suitable pharmaceutically acceptable bridges for the target compound [1] are conventional non-toxic salts, such as alkaline metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). metal salts, such as
Ammonium salts, organic bases and +7) fi () rimes 7 rare amine salts, triethyl v amine salts, pyridine salts, picoline salts, dicyclohexyl 7 rare amine fi, N, N-dibenzylethylene diamine salts, etc.), and organic acids ( formate,
Acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, tonorenine sulfonate, etc.), Asahi with inorganic acids (hydrochloride, hydrobromide, sulfate, phosphorus) Examples include salts with amino acids (arginine salts, orninane salts, etc.).

Compounds C1a) to lr) are included within the definition of compound (1), and therefore, as suitable salts of these compounds, mention may be made of the same ones as exemplified for compound (IJ).

The target compound CIJ and its production method will be explained in detail below.

Production method 1 Compound CI&) and its salt can be prepared by reacting a compound (-11J or a derivative at its carboxy group or a salt thereof with compound J) or a salt thereof,
can be manufactured.

Suitable salts of compound (Il) and its derivative at the carboxy group include the same salts as exemplified for compound [1].

As a derivative at the carboxy group of compound CI),
Includes esters, activated amides, etc. Suitable examples of such derivatives include lower alkyl esters (e.g., esters, methyl esters, ethyl esters, fluoryl esters, hexyl esters, etc.), aryl esters (e.g., phenyl ethyl, tril ethyl, etc.). ) or esters such as N-hydroxynuccinimide, N-hydroxyphthalimide and active enzymes with L<1-hydroxy-6-chloropenzotriazo IV, etc.;
Suitable salts of imidazole, triazole or dimethylpyrazole compound CII) include the same salts as exemplified for compound [1].

This reaction is usually carried out using water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, benzene, toluene, xylene, ethyl acetate, N,
Although the reaction is carried out in a conventional solvent such as N-dimethylformamide or pyridine, any organic solvent that does not adversely affect the reaction can be used. Among these solvents, hydrophilic solvents may be used in combination with water.

This reaction is usually carried out in the presence of a base or an acid, preferably in the presence of a base. Preferred bases include, for example, alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.), alkaline earth gold hydroxides IX (y
K oxidizing power! lithium, magnesium hydroxide, etc.), alkali metal carbonate (sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonate (sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), sodium hydride, lithium isopropylamide, tertiary m (low m> Alkylamine (trimethylamine, triethylamine, etc.), pyridine or its MJ
(picoline, lutidine, 4-dimethyll-reaminopyridine, etc.), 1,5-diazabicyclo[4,3,0)-nonene-5, 1,4-diazabicyclo[2.2.2]octane, 1.8 -DiazabicycloC5.4.0) Inorganic or organic bases such as undecene-7.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

Manufacturing method 2 Ash can be manufactured.

This reaction is usually carried out in a solvent, and examples of the reaction solvent include commonly used solvents such as methanol, ethanol, propano-IV, tetrahydrofuran, dioxane, methylene chloride, N,N-dinotylformamide, and dimethyl sulfoxide. In addition, any solvent can be used as long as it does not adversely affect the reaction. When the compound l'/) is a liquid, it can also be used as a solvent.

This reaction is preferably carried out in the presence of a base.

The base used may be the same as those exemplified in Production Method 1, or the reaction may be carried out under heating.

Production method Compound [1e] and its salt can be produced by subjecting compound [d] or its salt to a deenaturation reaction.

This reaction can be carried out by conventional methods such as hydrolysis and reduction.

Hydrolysis is preferably carried out in the presence of an acid or a base.

Suitable examples of acids used include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), organic acids (e.g.,
Formic acid, acetic acid, trifluoroacetic acid, benzene-7 lephonic acid, toluene-nulfonic acid, etc.), acidic ion exchange resins, etc.

Suitable examples of the base used include those similar to those exemplified in Production Method 1.

River water splitting is usually carried out in a solvent, such as
In addition to water, methanol, ethanol, propatool, tetrahydrofuran, dioxane, N,N-dinotylformamide, dimethyl sulfoxide, etc., any solvent can be used as long as it does not adversely affect the reaction. may be used in combination of two or more types. When the above acid is a hedron, it can also be used as a solvent.

Reduction methods used in this production method include chemical reduction methods and catalytic reduction methods, and these can be carried out by conventional methods.

Suitable examples of reducing agents used in the chemical reduction method include metals (e.g., iron, zinc, iron, etc.) or metal compounds (e.g., chromium chloride, chromium acetate, etc.) and organic or inorganic acids ( For example, phosphoric acid, acetic acid, propionic acid,
trifluoroacetic acid, p-toluene-nulphonic acid, hydrochloric acid, sulfuric acid, etc.).

Suitable examples of catalysts used in the catalytic reduction method include platinum catalysts (e.g., platinum plate, platinum sponge, platinum black, platinum colloid, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., palladium colloid, palladium black, etc.). , palladium oxide, palladium carbon, palladium colloid, palladium-barium sulfate, palladium-barium acetate, etc.), nickel catalyst (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (e.g. reduced cobalt, Raney cobalt, etc.), Iron catalysts (e.g. reduced iron,
Raney iron, etc.), copper catalysts (for example, reduced copper, Raney copper, Ullmann copper, etc.), and the like.

The reduction can be carried out using commonly used solvents such as water, methanol,
In addition to ethanol, propatool, tetrahydrofuran, dioxane, acetic acid, propionic acid, and the like, any solvent may be used as long as it does not adversely affect the reaction.

Although the reaction temperature JX is not particularly limited, the reaction is usually carried out at room temperature or under heating.

It can be produced by reacting a reactive derivative at the carboxyl group or a salt thereof with a compound CD or a reactive derivative at the amino group or a salt thereof.

Suitable reactive derivatives at the carboxy group of compound [lf) include acid halides, intoxicants, and
It also includes active amides, active esters, etc.

Suitable examples of such reactive derivatives include, for example, low i alkyl esters (methifle ester, ethyl ester, clobyl ester, hexylnis rJ4>”!
Emetetv@ such as active esters with dN-hydroxynuccinimide, N-hydroxyphthalimide or ui-human axy-6-chlorobenzotriazole, etc.
; acid chloride, acid bromide, phosphoric acid, substituted phosphoric acid (
mixed acid anhydrides with acids such as dialkyl phosphoric acid, phenyl phosphoric acid, etc.), aliphatic carboxylic acids (pivalic acid, acetic acid, trichloroacetic acid, etc.); symmetrical acid anhydrides; with imidazole, triazole, or dimethylpyrazole, etc. Examples include activated amides.

Suitable materials for compound [V] can include the same compounds as those exemplified for compound [1].

Suitable reactive derivatives at the amino groups of the compound include the conventional derivatives used for amidation, such as the Schiff base type imino or its enamine formed by the reaction of the compound [■] with the Pony IV compound. By the reaction of type tautomer, compound [silyl derivative, compound V, produced by the reaction of silyl compound with trimethylsiliferacetamide, bis(trimethylsilyl)acetamide, etc.] and phosphorus trichloride or phosgene. Examples include derivatives generated.

Reactive derivatives of compounds 1fJ and CD are compound L
ID and CV) are selected as appropriate.

If the compound [lf) is used in the form of free levonic acid or its salts, customary condensing agents such as UN, N-
Dicyclohexylcarbodiimide, N-cyclohexyl
N-morpholinoethylcarbodiimide, N-ethyl-N-(3-dimenalaminopropyl)levodiimide, thionyl chloride, oxalyl chloride, lower alkoxylic acid (e.g. ethyl chloroformate, isobutyl chloroformate) / etc.), 1-(p'lolobenzenemelphonyloxy)-6-chloro-1H-benzotriacyN, etc.), and the reaction is preferably carried out in the presence of N, etc.

This reaction usually involves water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, benzene, toluene, xylene, ethyl acetate tv,
Any organic solvent that does not adversely affect the reaction can be used, although it is carried out in a conventional solvent such as NIN-dimethylformamide, pyridine. Furthermore, among these solvents, hydrophilic solvents may be used in combination with water.

This reaction is carried out, for example, by alkali metal hydroxide (hydroxide 1-
aluminum, potassium hydroxide, etc.), alkali metal carbonates (sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (aqueous sodium carbonate, potassium hydrogen carbonate, etc.), tertiary (lower) alkyl) V amines (trimenalamine, The reaction is preferably carried out in the presence of an inorganic or organic base such as trimethylamine, etc.), pyridine or its derivatives (picoline, l-retidine, 4-dimethyl-l-reaminopyridine, etc.).

Incidentally, when the above-mentioned group or condensing agent is liquid, it can also be used as a solvent.

The reaction temperature is not particularly limited, and the reaction can be carried out under cooling or heating.

Production method 5 Compound [11] and its fortune are made by reacting compound [1h] or its salt with compound 0D or its salt! t) can be manufactured.

Suitable salts of compound [-VD include the same salts exemplified for compound [l].

The reaction medium is usually carried out in a solvent, such as methanol, ethanol-1, propano-1, tetrahydrofuran, dioxane, methylene chloride, N,N-dimethylformamide, dimethyl Examples include commonly used solvents such as sulfoxide;
Any solvent can be used as long as it does not adversely affect the reaction.

This reaction is preferably carried out in the presence of a base.

Bases used include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.); alkali metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride, etc.); lithium diisopropylamide; sodium Amide; organic base (e.g., trimethylamine, trimethylamine, pyridine, 1,8-diazabicyclo[5,4,CI J-undecene-7,1,5-
Diazabicyclo 4.3. O)-Nonene-5,1,4-
diazabicyclo(2,2,2)octane, etc.).

The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under heating.

Production method 6 Compound 1k] and its derivatives can be produced by subjecting compound C, Ij] or a salt thereof to a reduction reaction.

This reduction reaction (can be carried out in the same manner as the reduction in Production Method 6. Therefore, the reaction conditions etc.
The example given in can be applied as is.

Production Method 7 Compound Lll) and its derivatives can be produced by subjecting compound Lll) or its functional compound to an elimination reaction of the hydroxy protecting group.

This elimination reaction is carried out in 7J1 as explained in the production method B above.
1. It is carried out using conventional methods such as ice decomposition and reduction. Therefore, the reaction conditions etc. exemplified in Production Method B can be applied as they are.

Production method 8 Compound 10) and its derivatives can be produced by reacting compound [-11 or a salt thereof with compound CVID.

This reaction can be carried out in the same manner as Production Method 2,
Therefore, the reaction conditions etc. exemplified in Production Method 2 can be applied as they are.

Production method 9 Compound Ip) and its salt can be produced by subjecting a reactive derivative at the carboxyne group of compound Ip) or a salt thereof to an esterification reaction.

As the reactive derivative at the carboxy group of compound [1f) used in this reaction, conventional derivatives such as acid chlorides (eg, acid chloride, acid bromide, etc.) can be mentioned.

Examples of the esterifying agent used in this reaction include alcohols or reactively equivalent compounds thereof (eg alcohols, halides, sulfonic acids, diazotized compounds, etc.).

This reaction may be preferably carried out in the presence of a base or an acid depending on the form of the caffleboxy group of the compound lfJ and the type of esterifying agent. Suitable bases include those exemplified in Production Method 1, and suitable acids include sulfuric acid, hydrochloric acid, p-toluene sulfonic acid, and the like.

This reaction is usually carried out in a solvent, such as acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, tetrahydrofuran, ethyl acetate/l/, NIN-dimethylformamide, dimethyl llenulfoxide, etc. In addition to these commonly used solvents, any solvent can be used as long as it does not adversely affect the reaction. Furthermore, when the esterifying agent is liquid, it can also be used as a solvent.

The reaction temperature is not particularly limited, and is usually under cooling or 7J1
The reaction is carried out under 1 heat.

Production method 1U Compound C1q) and its derivatives can be produced by reacting compound (1f) or a reactive derivative thereof at the carboxy group or a salt thereof with diazomethane.

The power of compound [1f]! Suitable examples of reactive derivatives for the mboxy group include those similar to those exemplified in Production Method 4.

When compound [1f] is used in the form of a free carboxylic acid or a salt thereof, for example, thionyl chloride, oxalyl chloride, lower alkoxyl chloride (e.g., ethyl chloroformate, isobutyl chloroformate, etc.), etc. This is carried out by activating the carboxy group and then reacting it with diazomethane.

This reaction is usually carried out in a solvent such as dioxane, chloroform, methylene chloride, tetrahydrofuran, benzene, tonolenine, etc., but any solvent can be used as long as it does not adversely affect the reaction. If the above-mentioned condensing agent is a liquid, it can also be used as a solvent.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature.

Production method 11 Compound Llr) and its salt can be produced by reacting 1 g of the compound Llr) or its salt with a thiocarbonyl or other agent.

Examples of suitable woodcutter for compound [1r] include those similar to compound [1g].

Suitable examples of thiocarbonyl and other agents include phosphorus penta-etc, trivalent carbon phosphorus, 0IO-diethyldithiophonufate, boron sulfide, silicon disulfide, 2,4-binu(4-
Examples include methoxyphenyl)-1,6,2,4-dithiadiphonufethane, 2,4-disulfide, and the like.

This reaction is usually carried out in a solvent, such as acetonitrile, tetrahydrofuran,
Commonly used 'f4Ks such as diglyme, l/renine, xylene, and pyridine can be used, and any other solvent can be used as long as it does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under heating.

Compounds obtained by each of the above production methods Ia), [IC],
[le], [16], [11], C1k), clm),
CXO], C,lp), C1q) and (1r) can be isolated and purified by conventional methods such as recrystallization, column chromatography, and reprecipitation.

Compounds CI), CI), [River], LID, [V] and CVD contain stereoisomers due to one or more asymmetric carbon atoms in the molecule, but such isomers and All mixtures thereof are within the scope of this invention.

The furanone derivatives [Ia] of this invention and their pharmaceutically acceptable salts can be used, for example, as pharmaceutical compositions for the treatment of diabetic cataracts. This pharmaceutical composition can be provided as various pharmaceutical preparations, such as solid preparations, semi-solid preparations, and liquid preparations, which can be prepared using organic or inorganic carriers or excipients suitable for external use, internal use, or topical application. active substances,
That is, it contains a furanone derivative [1] or a pharmaceutically acceptable salt thereof. The active ingredient may be combined with innocuous and pharmaceutically acceptable auxiliary ingredients to form tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, or other suitable forms. be done. Such auxiliary ingredients include ingredients effectively used in the production of solid preparations, semi-solid preparations, or liquid preparations, such as water, glucose, lactose, gelatin, mannitol, defunfun, tri-glue, X-magnesium silicate, cornstarch, keratin,
Colloidal IV silica, botetoscouch, urea, etc. are exemplified, and stabilizers, dispersants, colorants, fragrances, etc. may also be added as supplements. The pharmaceutical composition of this invention also includes:
Anti-deception agents and fungicides can also be added to maintain the activity of the active ingredients.

The amount of the active ingredient in the composition should be such that the active ingredient is sufficient to exert the desired therapeutic effect on the progress and current state of the disease.

When applying this pharmaceutical acid to the human body, intravenous administration, intramuscular administration, oral administration, etc. are desirable. The effective dose of this active substance varies depending on the age and symptoms of the patient, but it is usually 0.1 kg/kg of body weight → take a rabbit's eye,
Collect the crystals from there.

The lens was homogenized with 3 volumes of distilled water at 4°C (all subsequent operations were also performed at 4”C), then 10, [][l
[The supernatant was obtained by centrifugation at 1 g for 60 minutes. This supernatant was dialyzed against two portions of 0.05M saline. The dialyzed fluid thus obtained was used as an enzyme solution.

11) Method 0.51 phosphate buffer (pH 6,2), 0.1 m12
．． 0M lithium sulfate 0.2#+1 Compound of this invention (dissolved in physiological saline aK) uai
l Enzyme solution (aldose reductase solution, prepared with 1) above) 0.5 tgl (NADPEI) NA when the above reaction solution was reacted at 65'C for 2 minutes
The degree of decrease in D P H
A, B, manufactured by LKB Producer A, B,
)'s Automata Thousand Tsuk Reaction Rate Anonymizer Ellekeybee-86QQ (Aut, oma
t, 1cReaetiOn Rat;eAnalyZ
er LKB-8600). The enzyme activity when the change in absorbance was 0 or 0 for 1 minute was determined to be 1 unit.

The results are as shown in Table 1 below.
l) indicates the concentration of the compound of the invention at which total aldose reductase activity is inhibited by 50%.

Test B (Sorbitol accumulation TmN in sciatic nerve): Group of 5 Sprague-Dawli
After fasting male rats (6 weeks old) for 24 hours,
Streptocytosine f 2m M citrate MHtrH
(pH 4,5) and administered intraperitoneally at a dose of 2 ml/kg (streptocytosine 75~/kg). One week later, blood was collected from the tail vein and the blood sugar level was measured.
Rats with blood sugar levels of d1 or higher were used in the test as streptocytosine diabetic rats. A test drug suspended in a 0.5% methylcellulone solution was given to these diabetic rats in a predetermined manner at 8 days after administration of streptocytosine.
The mice were orally administered once a day for 5 days starting from Sun and Moon (these were referred to as the streptocytosine-treated drug administration group). Six hours after the final drug administration, the rats were sacrificed and the sciatic nerve (~ruby)-
The content of 1.1 was measured.

The content of sorbitol in the sciatic nerve was also measured from the control group, a streptocytosine-untreated drug-treated group and a streptocytosine-treated drug-administered group, and from these results, the inhibitory effect of the test drug on sorbitol accumulation in the sciatic nerve was determined. It is shown as the inhibition rate value calculated from the following formula. Table 2 shows the inhibition rates for representative examples.

Formula [Effect of the Invention] As shown in the above test results, the furanone derivative (1), which is the target compound of the present invention, exhibits remarkable aldose reductase inhibitory activity and is effective against diabetic complications such as diabetic neuropathy and diabetes mellitus. sexual cataract, diabetic nephropathy, diabetic f
It is used as a medicine for treating diseases such as iI membrane disease.

〔Example〕

Next, the present invention will be explained with reference to examples.

Example 1 (69) was dissolved in N,N-dimethylformamide (80m/)
1,8-diazabicyclo(5,4,0)undecene-7 (3.5 ml) was added dropwise while stirring at 0°C. After stirring the mixture at O'C for 2 hours, the solvent was removed under reduced pressure. Pour the residue into dilute hydrochloric acid and extract with ethyl acetate.

The extract is washed with water, dried, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography,
Purify by eluting with chloroform and ethyl 3-[4-hydroxy-3-(2-naphthyl)-5-oxo-2,5-dihydro-2-furyl]propionate (4.8 g).

IR (chloroform): 2980, 1740, 1400
゜160i1 N M R(CDCj?3, δC1,28(3H,t
, J=7Hz).

1.60-2.03 (IH, m), 2.10-2.87
(31(, m).

4.23 (2H, q, J=7Hz), 5.67 (IH,
dd.

J=2.8H2), 7.40-8.22 (7H, m).

Hereinafter, the compounds of Examples 2 to 16 are obtained in the same manner as in Example 1.

Example 2 Ethyl 3-[4-hydroxy-3-(1-naphthyl)-5-oxo-2,5-dihydro-2-furyl]propionate IR (chloroform) + 1750.1730CIRN
M R (CDCI!3.δ): 1.08-1.50 (3
H, m).

1.55-2.68 (4H, m), 3.92-4.38
(2H, m).

5.60 (IH, dd, J=2.8Hz),
7.25-8.05 (7H, m) Example 3 3-[4-hydroxy-3-(6-medoxy-2-naphthyl)-5-oxo-2,5-dihydro-2-furyl]
Ethyl propionate IR (chloroform): 1740, 1625.1605
i1 Example 4 3-[4-hydroxy-3-(5-methoxy-2-naphthyl)-5-oxo-2,5-dihydro-2-furyl]
Ethyl propionate IR (rioo form): 1740, 1600.1580
0j'' Example 5 Ethyl 3-[4-hydroxy-3-(4-methylthiophenyl)-5-oxo-2,5-dihydro-2-furyl]propionate Melting point: 104-106°C IR' /shi)+3280.1725,167
0,15901: WNMR (CD30D, δ): 1.3
0 (3H, t, J=7Hz).

1.67-2.10 (IH, m), 2.10-3.60
(3H, m).

2.50(3t(,s), 4.18(2H,q, J=7
Hz).

5.52 (IH, dd, J=2.8Hz), 7.33 (
2H.

cl, J=9Hz), 7.70(2H,d, J=9Hz
) Mass: 322 (M+) Example 6 3-[:3-(4-biphenylyl)-4-hydroxy-
Ethyl 5-oxo-2,5-dihydro-2-furyl]propionate IR: 3500, 3300, 3000
゜1740.1390.1160dl Example 7 3-(3-(3-chloro-4-methoxyphenyl)-4
-Hydroxy-5-oxo-2,5-dihydro-2-furyl]ethyl propionate IR
, 1740, 1730 #"N M R (CDCj'3.
δ): 1.30 (3H, t, J=7Hz).

1.7-2.1 (IH, m), 2.2-2.9 (3H,
m).

3.97 (3H, s), 4.20 (2H, q, J=7H
z).

5.43 (IH, dd, J=2.9Hz), 6.67 (
IH.

s), 6.99 (LH, d, J=8Hz), 7.60 (
IH.

dd, J=2,8I(z), 7.80(1)1. d, J
= 2Hz) Example 8 Ethyl 3-[4-hydroxy-3-(4-methoxy-3-trifluoromethylphenyl)-5-oxo-2,5-dihydro-2-furyl]propionate IR (nudia/ C3300, 1740, 1735ai
1N M R (DMSO-d6.δ) = 1.17 (3H
, t, J=7Hz).

1.6(,8(LH,m), 2.2-2.6(3H,m
).

3.93 (3H, s), 4.00 (214, q, J=7
Hz).

5.58 (IH, dd, J=2.8Hz), 7.33 (
IH.

dj=8Hz), 7.88(IH, dd, J=2.8H
z).

8.97 (IH, d, J=2Hz), 10.73 (IH
,s) Example 9 4-(4-hydroxy-5-oxo-3-phenyl-2
, 5-dihydro-2-furyl) methyl benzoate NMR (DMSO-d6.δ): 3.85 (3H,
s), 6.67 (LH, s), 7.3-7.8 (5B,
m), 7.57 (2H.

d, J=8Hz),? , 97 (2H, d, J=8) (z
) Example 10 3-(4-hydroxy-5-oxo-3-fe, =, /
-2,5-dihydro-2-furyl) methyl benzoate Melting point: 156-157°C IR (chloroform): 3400, 1750, 1720
dlN M R (CDCJ3.δ): 3.90 (3H,
s), 6.27 (IH.

s), 7.2-7.7 (7H, m), 7.9-8.2 (
2H,m) Example 11 2-(4-hydroxy-5-oxo-3-phenyl-2
,5-dihydro-2-furyl)methylbenzoate IR (Mefl/,'): 3480,1755.17
20#”NMR(DMSO-d6.δ):4.95
(3H, 8).

7.2-8.0 (IOH, m) Example 12 Ethyl 3-[4-hydroxy-5-oxo-3-(2-chenyl)-2,5-dihydro-2-furyl]propionate IR oo form): 3500, 1730, 1680
゜640m1 NMR (CDCI!3, δ): 1.27 (3H,
t, J=7Hz).

1.70-2.30 (IH, m), 2.27-2
．． 90 (3H, m).

4.17 (2H, q, J=7Hz), 5.37 (lH,
dd.

J=2.8Hz), 7.03-7.60(3H, m)M
ass: 282 (M+) Example 13 4-hydroxy-5-oxy-3-phenyl-2,5-
n-butyl dihydro-2-furancarboxylate NMR (CDCJ3.δC0,83(3H,t,J
=7Hz).

0.7-1.8 (4H, m), 4.15 (2H, t, door Hz).

5.77 (IH, s), 7.10 (IH, s), 7.3
-7.9 (5H, m) Example 14 4.5-diphenyl-3-hydroxy-2(5H)-furano/NMR (DMSO-d6.δ): 6.53 (IH,
s), 7.3-7.8 (5H, m), 7.33 (5H
,s) Example 15 5-ethyl-3-hydroxy-4-phenyl-2 (5H
)-furanone NMR(CD(J?3., δ): 0.91(3H,
t, J=8H2).

1.2-2.5 (3H, m), 5.45 (IH, dd
, J=3゜6Hz), 7.2-7.81:5H,m)
Example 16 3-hydroxy-5-methyl-4-phenyl-2(5H
,)-Furanone Melting point: 139-x4oC IR (nuji v-/shi): 3300, 1720ai"N
M R (CDCj'3.δ): 1.57 (3H, d, J
=7Hz).

5.47 (IH, q, J=7Hz), 7.2-7.8
(5H, m).

Example 17 Methyl 2-dimethoxy-3-(p-tolyl)propionate (4.22 g) was dissolved in formic acid (20 gJ) and heated at 65 to 70° C. for 1 hour and 50 minutes with stirring. After cooling the reaction mixture, it is extracted with methylene chloride. After washing the extract with water and drying, the solvent was distilled off under reduced pressure to obtain 2-oxo-3-(
Methyl p-)lyl)propionate (2.95 g) is obtained. This compound and ethyl 3-formylpropionate (
2,5:2t/) was dissolved in N,N-dimethylformamide, and while stirring at 0°C, 1,8-diazabicyclo(
5,4,0) undecene-7 (2,45txl) to 1
．． Drip over 5 minutes. After stirring the mixture at the same temperature for 2.5 hours, the solvent was distilled off under reduced pressure, and IN hydrochloric acid was added to the residue. After extraction with ethyl acetate and washing the extract with water and drying, the solvent was distilled off under reduced pressure. The residue was recrystallized from diimpropyl ether to give 3-[4-hydroxy-5-oxo-
3-(p-tolyl)-2,5-dihydro-2-furyl]
Ethyl propionate (2.71 g) is obtained.

IR (nuji y-/shi): 3300, 1760 (shoulder), 1
745°1710', 1675α Compounds of Examples 18 to 23 were obtained in the same manner as in Example 17.

Example 18 3-(3-(4-benzyloxyphenyl)-4-hydroxy-5-oxo-2,5-dihydro-2-furyl)
Ethyl propionate IR (nuji w-/shi): 3300, 1730, 1675
．． 1605ai' Example 19 3-[4-hydroxy-3-(4-methoxyphenyl)
-5-oxo-2,5-dihydro-2-furyl]ethyl propionate IR (Nujotare) +3325.1725.1670
．． 1605i1 Example 20 3-[4-hydroxy-3-(4-impropoxyphenyl)-5-oxo-2,5-dihydro-2-furyl]
Ethyl propionate IR (Nujotsure) = 3300.1730,1675
．． 1605i' Example 21 3-[4-hydroxy-5-oxo-3-(α-su f'
)-2,5-dihydro-2-furyl]ethyl propionate IR(nujo-)shi): 3310.1720.4660
ff1N M R (CDCj?3.δ): 1.27 (
3H,t, J==7Hz).

1.57-2.20 (IH, m), 2.30-2.8
0 (3H, m).

4.18 (2H, q, J=7Hz), 5.23 (
IH, dd.

J=2.8Hz), 6.98(IH,d, J=17Hz
).

7.05 (1B, d, J = 17Hz), 7.20 (IH
,brs).

7.27-7.67 (5H, m) Example 22 3-[4-hydroxy-3-(4-nitrophenyl)-
Ethyl 5-oxo-2,5-dihydro-2-furyl]propionate IR (Fuji 319 3225, 1745, 1690, 1
595C1i1 Example 23 Ethyl 3-[3-(3,4-dichlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-2-furyl)propionate IR (nuzi-a/shi): 3280, 1750,170
5.1680ai” Example 24 Ethyl 3-[4-hydroxy-3-(2-naphthyl)=5-oxo-2,5-dihydro-2-furyl]propionate (3.0 g), potassium carbonate (1, Methyl iodide (0.69 g?) was added dropwise to a mixture of N,N-dimethylformamide (30 ml) and N,N-dimethylformamide (52 g) at room temperature while stirring, and the mixture was further stirred at the same temperature for 2.5 hours.N,N-dimethyl Formamide is distilled off under reduced pressure, and the residue is poured into dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and brine in turn, and then dried. The solvent is distilled off under reduced pressure, and the 3-[4-
Methoxy-3-(2-naphthyl)-5-oxo-2,5
-dihydro-2-furyl]ethyl propionate (3,3
g) is obtained.

IR (RI00 form): 1750, 1640, 160
0c1i' and below, Example 25 was prepared in the same manner as in Example 24.
~42 compounds are obtained.

Example 25 3-(3-(4-biphenylyl)-4-methoxy-5-
Oxo-2,5-dihydro-2-furyl]ethyl propionate IR (rioo form): 1750, 1640,
1600ai1 Example 26 Ethyl 3-[4-methoxy-3-(6-medoxy-2-naphthyl)-5-oxo-2,5-dihydro-2-furyl]propionate Melting point = 79-80°C IR (Nujozure): 1740, 1720, 1710
, 1600c1i1N M R (DMSO-d6.δ)
: 1.13 (3H, t, J=7Hz).

1.45-2.05 (IH, m), 2.05-2.6
7 (3H, m).

衾吾Kitaminai also 3.90 (3H, s), 4.0 (3H,
s).

403 (2H, q, J=7Hz), 5.73 (I
H, dd.

J=2.8Hz), 7.08-8.27 (6H, m) Example 27 3-[4-methoxy-3-(5-methoxy-2-naphthyl)-5-oxo-2,5-dihydro -2-Furyl]ethyl propionate I R (Roo*/l, mu): 1750,1640,1
590,1570C1ir1N M R (CDCj'3
, δ): 1.23 (3H, t, J=7Hz).

1.47-2.03 (IH, m), 2.03-2.70
(3H, m).

3.97 (3H, s), 4.10 (3H, s,), 4.
13 (2H.

q, J=7Hz), 5.53(IH, dd, J=2.8
Hz).

6.70-8.37 (6H, m) Example 28 3-[4-methonasyl 5-oxo-3-(p-tolyl)
-2,5-dihydro-2-furyl propion? Ethyl IR (Nujozure): 1755, 1735 (74),
1645°1610oi1 N M R<CDCl! 3. δ): 1.25 (3H,
t, J=7Hz).

1.48-1.97 (lH, m), p, 20-2.
73 (3H, m).

2.38 (3H, s), 4.08 (3H, s), 4.1
5 (2H.

Q, J=7Hz), 5.42 (IH, dd, J=2.8
Hz).

7.28 (2H, d, J = 8 days z), 7.60 (2H,
d.

J=8Hz) Example 29 Ethyl 3-(3-(4-benzyloxyphenyl)-4-methoxy-5-oxo-2,5-dihydro-2-furyl)propionate IR (Nudigil C1750, 1735 (shoulder), 164
0゜1605,1570cfI NMR(CDCj?3.δ):1.24(3H,t
, J=7Hz).

1.43-1.97 (IH, m), 2.20-2.74
(3H, m).

4.05 (3H, s), 4.12 (2H, q, J=7H
z).

5.08 (2H, s), 5.37 (IH, dd, J=2
．． 8Hz).

7.04 (2H, d, J=9Hz), 7.23-7.5
7 (5H, m).

7.63 (2H, d, J = 9Hz) Example 30 3-[4-methoxy-3-(4-methoxyphenyl)-
Ethyl 5-oxy-2,5-dihydro-2-furyl propionate IR (Finonimu): 1750.1650.1610.
1570i1N M R (CDCj'3.δ): 1.2
7 (3H, t, J=7Hz).

1.47-2.00 (IH, m), 2.23-2
．． 80 (3H, m).

3.87 (3H, s), 4.08 (3H, s), 4.1
7 (2H.

q, J=7Hz), 5.42 (IH, dd, J=2.8
Summer) 2).

7.02 (2H, d, J=8H2), 7.70 (2H,
d.

J=8Hz) Ethyl 3-(3-(3,4-dichlorophenyl)-4-medoxy-5-oxo-2,5-dihydro-2-furyl]propionate IR (film): 1750, 1730 (shoulder), [ 4O
aN M R (CDCJ3.δ): 1.27 (3H, t
, J=7Hz).

1.47-2.00 (IH, m), 2.17-2.90
(3H, m).

4.18 (3H, s), 4.18 (2H, q, J=7H
z).

5.42 (IH, dd, J=2.8Hz), 7.55 (
2H.

s), 7.90 (IH, s) Example 32 3-[4-methoxy-3-(4-nitrophenyl)-5
-oxo-2,5-dihydro-2-furyl]ethyl propionate IR (rioo form): 1750, 1720, 1640
゜1595, 1345c1++ NMR (CDCJ3.δ): 1.27 (3H, t,
J=7Hz).

1.48-1.82 (IH, m), 2.08-2.67
(3H, m).

4.20 (3H, s), 4.15 (2H, q, J=7H
z).

5.48 (IH, dd, J=2.8Hz), 7.8'5
(2H.

d, J=9Hz), 8.27 (2H, d, J=9Hz)
Example 33 3-(3-(3-chloro-4-methoxyphenyl)-4
-Methoxy-5-oxo-2,5-dihydro-2-furyl]ethyl propionate Melting point: 100-102°C IR (Nujo Sole): 1740.1730GN M
R(CDCJ3.δC1,27(3H,t,J=7Hz
).

1.6-1.9 (IH, m), 2.1-2.7' (3H
, m).

3.90 (3H, s), 4.12 (3H, s), 4.1
3 (2H.

q, J=7Hz), 5.30(IH, dd, J=2.8
Hz).

6.93 (IH, d, J=8Hz), 7.53 (IH,
dd.

J = 2.8Hz), 7.78 (IH, d, J = 2Hz)
Example 34 4-(4-methoxy-5-oxo-3-phenyl-2,
Methyl 5-dihydro-2-furyl)benzoate NMR (CDCj'3.δ): 3.95 (3H,s
), 4.25 (3H.

s), 6.22 (IH, s), 7.2-7.7 (5H,
m).

7.40 (2H, d, J-8Hz), 8.00 (2H,
d.

J=8Hz) Example 35 3-(4-methoxy-5-oxo-3-phenyl-2,
Methyl 5-dihydro-2-furyl)benzoate Melting point -87~89℃ IR (chloroform): 1750, 1720αN MR
(cDcJ3.δ); 3.90 (3H, s), 4.25
(3H.

s), 6.23 (IH, s), 7.2-7.7 (7H,
m).

7.8-8.2 (2H, m) Example 36 2-(4-methoxy-5-oxo-3-phenyl-2,
Methyl 5-dihydro-2-furyl)benzoate IR (RI00 form): 1750o++ Example 37 n-Butyl 4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furancarboxylate N M R(CDCJ3.δC0,8-1,8(7H,
m), 4.10 (2H, t, J=6Hz), 4.13 (
3H, s), 5.67 (IH, s), 7.3-7.8 (
5H, m) Example 38 Ethyl 3-(4-hebutyloxy-5-oxo-3-phenyl-2,s-dihydro-2-furyl)propionate IR (film): 1755,1740.1645ai
1N M R (CDCj?3, δ) = 0.73-2.
00 (17H, m).

2.20-2.77 (3H, m), 4.17 (2H,
q.

J=7Hz), 4.30-4.67 (2H, m
), 5.48 (IH, dd, J=2.8Hz), 7
．． 37-7.90 (5H, m) Example 39 Ethyl 3-(4-benzyloxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate I R (74#!,) :2970.1745.1150
．． 11004'NMR (CDCI!31δC1,22(
3H, t, J=7Hz).

1.43-2.00 (LH, m), 2.10-2.6
0 (3H, m).

4.12 (2H, q, J-7Hz), 5.33 (IH,
d.

J=13Hz), 5.60(IH,d, J=13Hz
).

5.37 (IH, dd, J=2.8Hz), 7.33-
7.830 (4H, m) Example 40 Ethyl 3-(4-(47meth)oxybenzyloxy)-5-oxo-3-phenyl-2,5-dihydro-2-furyl]propionate IR (Nujotsure C1750 ,1640,1610,
1510CfNMR (CDCI!3, δ):1.
27 (3H, t, J=7Hz).

1.48-1.92 (IH, m), 2.20-2
．． 62 (3H, m).

3.80 (3H, S), 4.18 (2H, q, J=7H
2).

5.33 (tH, dj=8Hz), 5.45 (IH,
dd.

J=2.8Hz), 5.53(riH,d, J=8Hz
).

6.90 (2H, d, J=9Hz), 7.37 (
2H,d.

J=9)12), 7.37-7.87 (5H,
m) Example 41 Ethyl 3-(4-(4-methylbenzyloxy)-5-oxo-3-phenyl-2,5-dihydro-2-furyl]propionate IR (Nuji-/lz): 1740 .1640.161
0ai'N M R(CDCJ3, δC1,27(3
H, t, J = 7Hz).

1.47-2.0 (IH, m), 2.33 (3H, s)
.

2.13-2.63 (3H, m), 4.18 (2H, q
.

J = 8Hz), 7.17 (2H, d, J = 9Hz), 7
．． 33 (2H, d, J=9Hz), 7.27-7.80
(5H, m) Example 42 Ethyl 3-(4-(4-chlorobenzyloxy)-5-oxo-3-phenyl-2,5-dihydro-2-furyl]propionate Melting point = 65°C IR w-/shi):1750,1?30,1645
．． 1600GN MR (CDCI!3, δ): 1
．． 25 (3H, t, J=7Hz).

1.53-1.92 (IH, m), 2.08-2.6
8 (3H, m).

4.17 (2H,q, J=7Hz), 5.28-5
．． 62 (3H.

m), 7.25-7.58 (9H, m) Example 43 3-hydroxy-5-methyl-4-phenyl-2 (5H
)-furanone (39) is dissolved in ethanol (10 ml) and a solution of diazomethane in diethyl ether is added. The reaction mixture was concentrated to give 3-methoxy.

C5-methyl-4-phenyl-2(5H)-furanone (3.22 g) is obtained as an oil.

IR (Mediyosure C1 F55,1 F10ai1 Example 44 3-[4-methoxy-3-(
4-methoxy-3-trifluoromethylphenyl)-5
-ethyl oxy-2,5-dihydro-2-furyl]propionate is obtained.

IR (nujozure): 1760, 1730.1615
#”N M R (CDCj?3.δ): 1.27 (3H
, t, J=7Hz).

dd, J=2.9Hz), 7.10(IH, d, J=8
Hz).

7.83 (IH, dd, J=2.5.8Hz), 7.9
5 (IH.

d, J=2.5Hz) Example 45 3-(4-hydroxy-5-oxo-3-phenyl-2
, 5-dihydro-2-furyl) methyl propionate (2
62,3 da), benzyl chloride (154 cape), potassium carbonate (165,9 W) and N,N-dimethylformamide (2,5 s+t) are stirred at room temperature for 5 hours. Add ethyl acetate and 6N hydrochloric acid to the reaction mixture. The organic layer is separated, washed successively with IN hydrochloric acid, water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography eluting with benzene to give 3-(4-benzyloxy-5-oxo-3-phenyl-2,5-dihydro-2-
Furyl) methyl propionate (z1o*y) is obtained.

Melting point: 268-70°C IR (chloroform): 1755d1 Mass spectrometry: 352 (M+) Compounds of Examples 46-50 are obtained in the same manner as in Example 45.

Example 46 3-[4-(4-methylbenzyloxy)-5-oxo-3-phenyl-2,5-dihydro-2-furyl]
Methyl propionate Melting point: 262-65°C IR (chloroform): 17ssi1 Mass spectrometry: 366 (M+) Example 47 3-(4-(4-methoxybenzyloxy)-5-oxo-3-phenyl-2,5- Methyl dihydro-2-furyl propionate IR()4lum): 1750cm-'Mass spectrometry: 38
2(M+) Example 48 3-(4,-(4-chlorobenzyloxy)-5-oxo-3-phenyl-2,5-dihydro-2-furyl)
Methyl propionate melting point near 0-73℃ IR (chloroform): 1750off1 Trade volume analysis: 3
86(M+) Example 49 3-(4-(3,4-dichlorobenzyloxy)-5-
Methyl oxo-3-phenyl-2,5-dihydro-2-furyl]propionate Melting point: 287-90°C IR (Riooho/'A): 1745ai' Mass spectrometry: 4
21(Flr+) Example 50 3-(4-decyloxy-5-oxo-3-phenyl-
Methyl 2,5-dihydro-2-furyl)propionate IR (film): 1755i” Mass spectrometry: 402 (M+) Example 51 3-[4-methoxy-3-(2-naphthyl)-5-oxo-2 ,5-dihydro-2-furyl]ethyl propionate (3.3 g), 3N hydrochloric acid (33 liters) and acetic acid (4
3+$) mixture was heated at 100° C. for 2 hours with stirring. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed successively with water and saline and then dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to give 3-[4-methoxy-3-(2-naphthyl)-5-oxo-2,5-
Dihydro-2-furyl]propionic acid (154 g) is obtained.

Melting point: 137-138℃ IR (Nujozure Cl750, 1690, 1640,
1590ai1N M R (CDCj?3.δ):1.
53-2.05 (IH, m).

2', 18-2.83 (3H, m), 4.12 (3H,
s).

5.58 (IH, dd, J=2.8Hz), 7.23-
8.20 (7H, m), 8.58 (IH, m) Compounds of Examples 52 to 89 were obtained in the same manner as in Example 51.

Example 52 3-[4-hydroxy-3-(2-naphthyl)-5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point: 185°C NMR (CD30D, δ): 1.40 -2.17
(IH, m).

2.20-3.00 (3H, m), 5.65 (
IH, dd.

J=2.8Hz), 7.40-8.28 (7H, m) Example 53 3-(3-(4-biphenylyl)-4-methoxy5-
Oxo-2,5-dihydro-2-furyl]propionic acid Melting point: 135-136.5°C IR (nujo 7): 1750.1710.169
0.1640c1i”NMR(CDCJ?3.δ)
:1.43-2.07 (IH, m).

2.07-2.77 (3H, m), 4.03 (3H, s
).

5.37 (IH, dd, J=2.8Hz), 7.12
-7.77 (4H, m), 7.57 (5H, s) Example 54 3-(3-(4-biphenylyl)-4-hydroxy-5
-Oxo-2,5-dihydro-2-furyl]propionic acid I R (nuji, r-zure): 3150, 1730, 17
QQi1 Example 55 3-[4-methoxy-3-(6-medoxy-2-naphthyl)-5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point: 164-165°C IR (Nujig- /shi): 1750, 1700, 1640
, 1620° 1600cIi1 4.0 (3H, s), 5.68 (IH, dd, J=2.
'8Hz).

7.05-8.17 (6H, m) Example 56 3-[4-hydroxy-3-(6-medoxy-2-naphthyl)-5-oxo-2,5-dihydro-2-furyl]
Propionic acid melting point: 202-204℃ IR (Nujopre): 3280.1740.1700
．． 1620.

1600CIil NMR (DMSO-d6.δ): 1.48-2
．． 03 (IH, m).

2.03-2.70° (3H, m), 3.90 (3H,
s).

5.67 ('IH, dd, J=2, 8Hz)
, 7.08-8.23 (6H, m) Example 57 3-[4-methoxy-3-(5-methoxy-2-naphthyl)-5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point: 149-150°C IR (, (shirozure): 1755.1690,16
50.1590゜1570ai1 N M R, (DMSO-d6.δC1,50-2,0
3 (LH, m).

2.10-2.60 (3H, m), 3.98 (3H, s
).

4.02 (3H, s), 5.73 (IH, dd', J=
2.8Hz)+7.0-8.35(6H,m) Example 58 3-[4-hydroxy-3-(5-methoxy-2-naphthyl)-5-oxo-2,5-dihydro-2-furyl ]
Propionic acid melting point 7215-216''C I R (nud = + 1): 3200.1730,17
00.1590i' mackerel-2,47 (3H, m), 3.9
8 (3H, s).

5.70 (LH, dd, J=2.8Hz), 6.90-
8.33 (6H, m) Example 59 3-[4-methoxy-3-(4-methylthiophenyl)
-5-Oxo-2,5-dihydro-2-furyl]propionic acid Melting point °140-141°C IR (nujia-zure): 1740, 1690. ．． 16
40.1590011NMR (CD30D, δ)
:1.50-1.98 (IH, m).

2.10-2.57 (3H, m), 2.50 (3H, s
).

4.02 (3H, s), 5.53 (IH, dd, J=2
．． 8Hz).

7.33 (2H, d, J=9Hz), 7.67 (2H,
d.

J=9Hz) Mass spectrometry: 308 (M+) Example 60 3-[4-hydroxy-3-(4-methylthiophenyl)-5-oxo-2,5-dihydro-2-furyl]propionic acid melting point = 185-186 ℃ IR (nujiq #): 3125, 1725, 16901
JNMR (CD30D, δ): 1.57-2.10 (I
H, m).

2.10-2.60 (3H, m), 2.47 (3H, s
).

5.50 (1B, dd, J=2.8Hz), 7.37 (
2H.

d, J=9Hz), 7.73 (2H, d, J=9Hz)
+ Mass spectrometry: 294 (M) Example 61 3-[4-methoxy-5-oxo-3-(p-tolyl)
-2,5-dihydro-2-furyl]propionic acid Melting point: 146.5-1475°C IR (nuji m-/shi); 3125, 1745, 171
0. -1640゜610i1 NMR (CDCj?3.δ): 1.53-2.0
0(IH,'m).

2.37 (3H, s), 2.20-2.73 (3H, m
).

4.07 (3H, s), 5.43 (IH, dd,
J=2.8Hz).

7.28 (2H, d, J=8Hz), 7.55 (2H,
d.

J=8Hz), 8.40 (IH, brs) Example 62 3-[4-hydroxy-5-oxo-3-(p-tolyl)-2,5-dihydro-2-furyl]propionic acid Melting point: 167 .5-168.5℃ IR (Nujol): 3200, 1750 (shoulder), 17
35°1695.1610m” NMR (DMSO-d6.δ): 1.37-2.00 (
LH, m).

2.07-2.47 (3H, m), 2.33 (3H, s
).

5.57 (IH, dd, J=2.'8H2), 7.33
(2H.

d, J=8Hz), 7.67 (2H, d, J=8Hz)
.

10.63 (IH, brs), 11.80 (IH, br
s) Example 63 3-[:3-(4-benzyloxyphenyl)-4-methoxy-5-oxo-2,5-dihydro-2-furyl]
Propionic acid melting point: 114-115°C IR (Nujol)-1745, 1735 (shoulder), 17
05.

1635.1600α NMR (cDcr3.δ): 1.47-2.04 (
IH, m).

2.20-2.83 (3H, m), 4.07 (3H, s
).

5.10 (2H, s), 5.39 (IH, dd, J=2
．． 8Hz).

7.04 (2H, d, J=9Hz), 7.23-7.5
7 (5H.

m), 7.62 (:2H, d, J=9Hz), 8.67
(IH.

brs ) Example 64 3-[3-(4-benzyloxyphenyl)-4-hydroxy-5-oxo-2,5-dihydro-2-furyl]
Propionic acid melting point: 198-199°C
．． 1695.1605c71r'NMR(DMSO
-d6. δ): 1.40-2.00 (IH, m).

2.00-2.50 (3H, m), 3.40 (IH, b
rs).

5.20 (2H, s), 5.57 (IH, dd, J=2
．． 8Hz).

7.20 (2H, d, J+”9Hz), 7.37-7.
67 (5H.

m), 7.73 (2H, d, J=9Hz), 10.80
(IH.

brs ) Example 65 3-(3-(4-hydroxyphenyl)-4-methoxy-5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point = 176-177°C I R /shi):3285.1740,171
0,1635.

1605α NMR (DMSO-d6.δ): 1.40-1
．． 97 (IH, m).

2.00-2.50 (3H, m), 3.33 (IH, b
rs).

3.92 (3H, s), 5.53 (IH, dd, J=2
．． 8Hz).

6.90 (2H, d, J=9Hz), 7.57 (2H,
d.

J=9Hz), 10.87 (IH, brs)
Example 66 3-[4-methoxy-3-(4-methoxyphenyl)-
5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point, 129-130°C IR (Nujol): 1760, 1710, 1645.
1600ai1N M R (CD(J?3.δ);1.
57-1.93 (IH, m).

2.20-2.83 (34 (, m), 3.84 (3H,
s).

4.07 (3H, s), 5.40 (IH.

dd, J = 2.8Hz), 6.98 (2H, d, J = 9
Hz).

7.64 (2H, d, J=9Hz), 8.13 (IH,
brs) Example 67 3-[4-hydroxy-3-(4-methoxyphenyl)
-5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point: 172.5-174.5°C IR (Nuji-+-#): 3125.17'15,166
0', 1605m1NMR (DMSO-d6.δ): 1
．． ．． 40-1.90 (114, m).

2.03-2.50 (3) (, m), 3.80 (3H,
s).

5.53 (LH, dd, J=2.8Hz), 7.07 (
2H.

d, J=9Hz), 7.73 (2H, d, J=9Hz>
.

10.37 (IH, brs), 12.12 (LH, b
rs) Example 68 3-(3-(3,4-dichlorophenyl)-4-methoxy-5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point: 136-137°C I R -zshi): 1765, 1700.164
0ai”NMR (CDCJ3.δ): 1.47-1.9
0(IH, m).

2.20-2.80 (3H, m), 4.17 (3H, s
).

5.40 (IH, dd, J=2.8Hz), 7.52 (
2H.

s), 7.70 (IH, brs), 7', 85 (IH,
s) Example 69 3-(3-(3,4-dichlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point: 178.5-179.5°C J R (, (a-/su:3100.1730.169
5i'NMR (DMSO-d6.δ): 1.40-1.
97 (LH, m).

2.00-2.50 (3H, m), 3.33 (IH, b
rs).

5.60 (IH, dd, J=2.8Hz), 7.77
(2H.

s), 8.03 (LH, s), 11.67 (LH, br
s) Example 70 3-[4-methoxy-5-oxo-3-(α-styryl)-2,5-dihydro-2-furyl]propionic acid Melting point: 103-105°C I R<5<dig- /shi): 1750, 1695, 16
40,161531NMR(CDCI!3.δ):
1.60-2.10 (IH, m).

2.30-2.83 (3H, m), 4.10 (3H, s
).

5.18CIH, dd, J=2.8Hz>, 6.93C
2H.

s), 7.23-7.67 (5H, m), 8.70 (I
H, brs) Example 71 3-[4-hydroxy-5-oxy-3-(α-styryl)-2,5-dihydro-2-furyl]propionic acid 1' contact point: 141-143°C I R<nujo /lz);3140,1735.16
900f1NMR (DMSO-d6+, δ) = 1.60
−2.10 (IH, m).

2.10-2.50 (3H, m), 3.35 (IH, b
rs).

5.26 (LH, dd, J=2.8Hz), 6.98 (
IH.

d, J=17Hz), 7.13(IH, d, J=17H
'z).

7.26-7.70 (5H, m), 11.30 (IH,
brs) Example 72 3-[4-methoxy-3-(4-nitrophenyl)-5
-Oxo-2,5-dihydro-2-furyl] 10 pionic acid Melting point: 168-169.5℃ IR (nujozure) +1760.1700,1640
, 1590°510i1 NMR (DMSO-d6.δ): 1.45-1.90 (
IH, m).

1.9:3-2.40 (3H, m), 4.03 (3H,
s).

5.70 (IH, dd, J=2,8H2), 7.90 (
2H.

d, J=9Hz), 8.27 (2H, d, J=9Hz)
Example 73 3-[4-hydroxy-3-(4-nitrophenyl)-
5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point: 198-200°C IR (Nujosol C3310, 1750, 1710
, 1670°x6ooi' NMR (DMSO-d6.δ): 1.47-2
．． 00 (IH, m).

2.00-2.50 (3B, m), 5.67 (H4, d
d.

J=2. lz), 7.97 (28, d, J=9Hz).

8.32 (2H, d, J = 9Hz), 11.83 (2H
, brs) Example 74 3-[3-(3I'rollo-4-methoxyphenyl)-4
-Methoxy-5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point, 120-1205°C IR (nujosure): 1760,1700ci”N
M R(CD(J'3.δ)-1,4-2,0(IH,
m), 2.1-2.7 (3H, m), 3.97 (3H,
s), 4.13 (3B, s).

5.38 (IH1dd+J=2+8[(z), 6.97
(IHld, J=8Hz), 7.53 (IH, dd, J
=2.8Hz).

7.77 (IH, d, J = 2Hz> Example 75 3-(3-(3-chloro-4-methoxyphenyl)-4
-Hydroxy-5-oxy-2.5-dihydro-2-furyl]propionic acid Melting point: 208-211°C IR (nujis-/I/C3300, 1740, 1710
0ffN M R (DMSO-d6.δC1,5-2,
6 (4H, m).

3.90 (3H, s), 5.51 (IH, dd, J=2
．． 8Hz).

7.22 (IH, d, J=9Hz), 7.63 (IH,
dd.

J=2.9Hz), 7.82(IH, d, J=2Hz)
Example 76 3-[4-Methoxy-3-(4-methoxy-3-trifluoromethylphenyl)-5-oxo-2,5-dihydro-2-furyl]propionic acid IR )
:1755,1700,1615cIi1N M R(
DMSO-d6. δ): 1.2-1.8 (IH, m).

2.0-2.6 (3H, m), 3.9'7 (3H, s)
, 3.99 (3H, s ), 5.65 (IH, dd
, J=2.5.8Hz).

7.35 (LH, d, J = 10Hz), 7.87 (IH
, dd.

J=2.5.10Hz), 7.93(IH, d, J=2
．． 5Hz) Example 77 3-[4-Hydroxy-3-(4-methoxy-3-trifluoromethylphenyl)-5-oxo-2,5-dihydro-2-furyl]propionic acid I R(nudi=+ -Zure): 3300.1735.1700, 16ooc1
i”NMR(DMSO-d6.δ): 1.2-1.
8 (IH, m).

2.0-2.6 (3H, m), 3.92 (3H, s),
5.55 (IH, dd, J=2,7H2), 7.32 (
IH, d.

J=9Hz), 7.90(IH, dd, J=2.9Hz
).

8.00 (IH, d, J=2Hz) Example 78 3-(3-(4-impropoxyphenyl)-4-methoxy-5-oxo-2,5-dihydro-2-furyl]propionic acid melting point ° 90-92°C IR: 1750, 1715, 164
0.16002-'N M R(CDCj?3.δC1
, 34 (6H, d, J=6H2).

1.50-1.90 (IH, m), 2.20-2
．． 74 (3H, m).

4.07 (3H, s), 4.62 (IH, q, J=6H
z).

5.40 (IH, dd, J=2.8Hz), 6.97 (
2H.

d, J=9Hz), 7.63(2H, dJ=9Hz)'
.

8.05 (IH, brs) Example 79 3-[4-hydroxy-3-(4-impropoxyphenyl)-5-oxo-2,5-dihydro-2-furyl]
Propionic acid melting point = 178-179°C IR (Nujol): 3400 (shoulder), 3175.17
35°1690.1605G NMR(DMSO-d6.δ)=1.27(6H,
d, J=6Hz).

1.40-1.90 (IH, m), 2.10-2
．． 50 (3H, m).

4.68 (IH, q, J=6Hz), 5.50 (IH,
dd.

J=2.8Hz), 7.02 (2H, d, J-9Hz)
.

7.67 (2H, d, J=9Hz), 10.57 (IH
,brs).

11.67 (IH, brs) Example 80 3-[4-hydroxy-3-(1-naphthyl)-5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point: 168-170°C IR ( Nuzi V pre C3125, 1735CIi'NMR
(DMSO-d6.δ): 1.50-2.70 (4H,
m).

5.60 (IH, dd, J-2, 8Hz), 7.33-
8.17 (7H, m), 10.0-10.80 (IH,
m) Example 81 3-[3-(4-aminophenyl)-4-hydroxy-
5-oxo-2,5-dihydro-2-furyl]propionic acid Melting point = 212-213°C IR: 3370, 3290, 1735
, 1710°1665.1605α NMR (DMSO-d6.δ): 1.30-1.8
7 (IH, m).

1.90-2.50 (3H, m), 3.33 (IH, b
rs).

5.37 (IH, dd, J=2.8Hz), 5.47 (
1)(.

brs), 6.60 (2B, d, J-9Hz), 7.4
0 (2H, d, J=9Hz), 10.00 (2H, br
s) Example 82 4-(4-methoxy-5-oxo-3-phenyl-2,
5-dihydro-2-furyl)benzoic acid melting point -178~1
79℃ IR (Nujopre): 1760, 1690Q Stomach N M
R(DMSO-d, , δ): 4.10 (3H, s)
, 6.73 (IH, s), 7.2-7.8 (5H, m)
, 7.57 (2H.

d, J=8Hz), 7.97 (2H, d, J=8Hz)
Example 83 3-(4-methoxy-5-oxo-3-phenyl-2,
5-dihydro-2-furyl)benzoic acid melting point 164-1
66°C IR distillation (0 roform): 1750, 1690an'N
M R (DMSO-d6.δ): 4.10 (3H, s)
, 6.60 (IH, s), 7.3-8.1 (9H, m)
Example 84 2-(4-methoxy-5-oxo-3-phenyl-2,
5-dihydro-2-furyl)benzoic acid melting point °190-1
91℃ IR (nujo/shi): 1760.16900i”N
M, R (DMSO-d6.δ): 4.10 (3H, s)
, 7.2-8.0(10)(,m) Example 85 3-[4-hydroxy-5-oxy-3-(2-chenyl)-2,5-dihydro-2-furyl]propionic acid Melting point: 187-19CI I R (nuji v-/su: 3270, 1720.1665
0ff”NMR(DMSO-d6.δ):1.50
-2.08 (IH, m).

2.10-2.70 (3H, m), 5.47 (IH, d
d.

J=2.8Hz), 7.0-7.93 (3H, m) Mass spectrometry: 254 (M+) Example 86 3-(4-methoxy-2-methyl-5-oxo-3-phenyl-2, 5-dihydro-2-furyl) propionic acid Melting point -115 to 117°C IR (Nujo Pre): t7so, 169s46ssi
'NMR (DMSO-d6.δ): 1.58 (3H, s
), 2.15 (4H, s), 3.8 (3H, s), 7.
4-7.6 (5H.

m) Example 87 3-(4-hebutyloxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)10pionic acid wJ1 point: 85-86'C I R (Nujo, 7shi) :2650.1750.171
0.1655m'N M R (CDC/3.δ): 0.
70-2.10 (14H, m).

2.20-2.90 (3H, m), 4.20-4.67
(2H, m).

5.48 (IH, dd, J=2.8Hz), 7.37-
7.90 (5H, m), 9.98 (IH, brs) Example 88 N-(4-methoxy-5-oxo-3-phenyl-2,
5-dihydro-2-furancarbonyl)-N-methylglycine Melting point: 172-173°C IR (nud*-#): 1760, 1620osN M
R (DMSO-d6.δ): 2.88 (s), 3.30
(s).

4.00(s), 6.47(s), 6.60(s)
, 7.4-7.8(m) Example 89 N-(4-methoxy-5-oxy-3-phenyl-2,
5-dihydro-2-furanthiocarbonyl)-N-methylglycine NMR (DMSO-d6.δ): 3.37 (s),
3.60(s).

3.98 (s), 4.70 (a), 4
．． 83 (s), 6.70 (s), 6.83 (s)
), 7.3-7.7(m) Example 90 n-gutyl 4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furancarboxylate (400#)
IN sodium hydroxide aqueous solution (2,8*/) is added to a tetrahydrofuran (4*/) solution at 0°C, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with water and then washed with diethyl ether.

The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The bolting liquid is sequentially washed with water and saline and then dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from diimpropyl ether to give 4-methoxy-5-oxy-3-phenyl-2,5-dihydro-2-furancarboxylic acid (26
8■) is obtained.

Melting point: 128-132℃ IR (nujivzushi): 1770, 1735.1655f
fNMR(DMSO-da, δC4,04(3H
, s), 6.10 (IH, S), 7.4-7.9 (5H
, m) Example 91 IN hydroxylation of methyl 3-(4-benzyloxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate (201 Cape) in dioxane (2+w/ml solution) Add aqueous sodium solution (0.68 ml) dropwise and stir at room temperature for 3 hours. Pour the reaction mixture into water and wash with diethyl ether. Adjust the aqueous layer to pH 1.0 with 10% hydrochloric acid, then extract with ethyl acetate. The extract is washed successively with water and brine, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure and the residue was crystallized from n-hexane to give 3-(4-benzyloxy-5-oxy-3-phenyl-2,5-dihydro-2-furyl)propionic acid (9).
8~) is obtained.

Melting point: 105-108°C IR (chloroform): 2700-2400.1940
゜1915, 1690 cIn'' Mass spectrometry: 338 (M+) Compounds of Examples 92 to 96 were obtained in the same manner as in Example 91.

Example 92 3-(4-(4-methyl-benzyloxy)-5-oxo-3-phenyl-2,5-dihydro-2-furyl]propionic acid Melting point: 117-120°C IR (chloroform): 2700- 2400,1740
゜700d1 Mass spectrometry: 352 (M+) Example 93 3-C4=(4-methoxybenzyloxy)-5-oxo-3-phenyl-2,5-dihydro-2-furyl]propionic acid Melting point: 105-110°C IR (chloroform): 2700-2400.1755
゜1715o++-” Mass spectrometry: 368 (M+) So-3-phenyl-2,5-dihydro-2-furyl]
Propionic acid melting point: 125-128°C tR (chloroform): 2700-2400.1?55
.

1710cWr1 Mass spectrometry: 372 (M+) Example 95 3-(4-(3,4-dichlorobenzyloxy)-5-
Oxo-3-phenyl-2,5-dihydro-2-furyl]propionic acid Melting point -148~150℃ IR (chloroform): 2700~2400, 1755
゜1710CIi1 Mass spectrometry: 407 (M+) Example 96 3-(4-decyloxy-5-oxo-3-phenyl-
2,5-dihydro-2-furyl]propionic acid Melting point: 82-84°C IR (chloroform): 2700-2400, 1750
゜171Oα Mass spectrometry: 388 (M+) Example 97 3-(4-methoxy-5-oxo-3-phenyl-2,
5-dihydro-2-furyl)propionic acid (6,599
), triethylamine (39 scraps), and methylene chloride (330 m/) while cooling to -23°C, isobutyl chloroformate (3.6 m7) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Add 28% ammonia water (6%
6 m/) was added dropwise, and the mixture was further stirred at the same temperature for 20 minutes. The reaction mixture is poured into water, and the organic layer is separated, washed successively with an aqueous sodium carbonate solution and brine, and then dried.

The solvent was distilled off under reduced pressure to obtain 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propanamide (4.37 g).

16ssi'NMR(CDCJ'3, δ)=1.4-2.1
(IH, m).

2.2-2.8 (3H, m), 4.08 (3H, s)
, 5.45 (IH, dd, J=2.8Hz), 5.8 (
2H, brs).

7.3-7.8 (5H, m) Example 98 3-(4-methoxy-5-oxo-3-phenyl-2,
5-dihydro-2-furyl)propionic acid (4, (1)
was suspended in thionyl chloride (2 (Igf) and refluxed with stirring for 2 hours. Excess thionyl chloride was distilled off under reduced pressure to give 3
-(4-methoxy-5-oxo-3-phenyl-2,5
-dihydro-2-furyl) 10pionic acid chloride is obtained as an oil. This compound is dissolved in benzene (10 m/) and added dropwise to a hot benzene (4'O shoulder/) suspension of urea (16 g), followed by refluxing for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, and dried. 6 The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol to obtain -oxo-3-phenyl-2,5-dihydro-2-furyl)ph.

Robionil]urea (1.80 g) was obtained.

Melting point = 163-165°C IR (Nuji g-7): 3450, 3400, 330
0,3150°1750.1740,1720.169
0i”NMR(DMSO-d6.δ):1.20-
2.60 (4H, m).

3.95 (3H, s), 5.50-5.80 (18, m
).

7.20-7.80 (5H, m), 10.10 (IH,
s) Elemental analysis: Calculated value as C15H16N205:
C59,20,II 5.30. N9. z.

Measured value: C59,47, H5,43, N 8.79 Example 99 4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furancarboxylic acid (666 mg) and thionyl chloride (7 m/ ) is stirred at reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methylene chloride (6 t). This solution was mixed with N-methylgly7 dimethyl ester hydrochloride (4591&), triethylamine (0,951ytt) and methylene chloride (13
Add to the mixture of (1) while keeping the temperature below 10℃,
Stir for 30 minutes at 0°C. The reaction mixture was poured into a mixed solvent of diethyl ether (100ml) and 0.5N hydrochloric acid (100ml). The organic layer is separated, sequentially washed with water, an aqueous solution of sodium hydrogen oxide, water, and brine, and then dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from diimpropyl ether to give N-(4-methoxy-5-oxo-
3-phenyl-2,5-dihydro-2-furancarbonyl)-N-methylglycine methyl ester (71O■)
get.

IR (methylene chloride): 1765,1680αN M
R(DMSO-d6.δC2,90(s), 3.32(
s).

3.63(s), 3.78(s), 403(s), 4.
15(s).

tss(s), 6.55 (s > , 6.68C8)
, 7.4-7.8 (5H, m) Example 100 3-(4-benzyloxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)furopion 9 (20
0■) and triethylamine (o, o9g/) are dissolved in methylene chloride (Low/), and -2c;, -r: ethyl chloroformate (0,084ml) is added dropwise while stirring. After stirring at the same temperature for 40 minutes, 28% aqueous ammonia (1.5 g/) was added dropwise, and the mixture was further stirred at the same temperature for 20 minutes. The reaction mixture is poured into water, and the organic layer is separated and washed successively with an aqueous sodium bicarbonate solution and water. The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to give 3-
(4-benzyloxy-5-oxo-3-phenyl-2
,5-dihydro-2-furyl)propanamide (140
■) Crane.

Melting point: 136-137℃ 11 (Chloroform C3520, 3400, 3000
Example 101 In the same manner as in Example 100, N-butyl-3-(4-
Benzyloxy-5-oxo-3-phenyl-2,5-
dihydro-2-furyl)propanamide is obtained.

Rin (point: 67-68℃ IR (chloroporum): 3450, 1750, 1705
゜1660α Example 102 Diisopropylamine (2,66 g/) and n-butyllithium (1
, 5M hexane solution, 127IIt) and prepared lithium diisopropylamide from 3-methoxy-5-methy/
L/-4-phenyl-2(5H)-fufuran (3,22
g) in tetrahydrofuran (60 ml)
Add over 15 minutes at ℃.

This mixture was stirred at the same temperature for 1 hour and then at -20°C for 15 minutes or more, then cooled to -70°C and methyl 3-bromopropionate (1,90+/) was added. , oic for 1 hour, acetic acid (2,18+++/) was added, and the solvent was distilled off. The residue was dissolved in diethyl ether, 0, IN hydrochloric acid,
Wash sequentially with water, aqueous sodium bicarbonate solution, water and brine, and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. A mixed solvent of n-hexane and ethyl acetate (2
0:1/J to 4:1%), the fractions containing the target product were combined, the solvent was distilled off, and 3-(4-methoxy-2-methyl-5-oxo-3-phenyl- 2,5
-dihydro-2-furyl) methyl propionate (273
g) is obtained as an oil.

IR (film): 17500i" NMR (CDCJ3, δC1,62 (3H, s)
, 2.2-2.6 (4H, m), 3.63 (3H, s)
, 3.90 (3H, s).

7.3-7.6 (5H, m) Example 103 3-[4-hydroxy-3-
Ethyl (4-nitrophenyl)-5-oxy-2,5-dihydro-2-furyl]propionate (0.32 g),
Stannous chloride (0,96 g) and ethanol (2+/
) is heated at 75-85°C for 30 minutes. After cooling, the mixture is poured into cold water, adjusted to pH 7-8 with a 5% aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed with water and dried, the solvent was distilled off under reduced pressure, and 3-[
Ethyl 3-(4-aminophenyl)-4-hydroxy-5-oxo-2,5-dihydro-2-furyl]propionate (0.17 g) is dissolved.

IR (, itji, -ru): 3475 (shoulder), 3375
．． 3250 (shoulder).

1725.1710 (shoulder), 1660°1630, 1
600#' Example 104 Ethyl 3-(3-(4-benzyloxyphenyl)-4-methoxy-5-oxo-2,5-dihydro-2-furyl)propionate (1,839) was dissolved in ethanol (45 g
/) and add 10% palladium on carbon (069) to this.
and stirred at room temperature for 2 hours under a hydrogen stream. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-〇-hexane to give 3-(3-(,4-hydroxyphenyl)-4-methoxy-5- Oxo-2,
Ethyl 5-dihydro-2-furyl]propionate (12
5g).

IR (nuji v → shi) = 3400.1720, 1630,
1605°1580ff' NMR(CDCI!3.δ):1.25(3H,t
, J=7Hz).

1.50-2.00 (IH, m), 2.20-2.8
0 (3H, m).

4.06 (3H, s), 4.15 (2H, q, J
=7Hz).

5.38 (IH, dd, J=2.8Hz), 6.00
(IH.

s), 6.93 (2H, d, J=9Hz), 7.60 (
2H.

d, J=9Hz) Example 105 3-[3-(4-benzyloxyphenyl)-4-hydroxy-5-oxo-2,5-dihydro-2-furyl]
Propionic acid (0,149) and 3N hydrochloric acid (1,4m
) was dissolved in acetic acid (1.4 g/') and heated at 100°C for 25 minutes.
Heat with stirring at 130° C. for 1.75 hours.

After cooling, the reaction mixture is poured into water and extracted with ethyl acetate.

Wash the extract with brine and dry. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 3-[4-hydroxy-3-(4-hydroxyphenyl)-5-oxo-2,5-dihydro- 2
-Furyl]propionic acid (57 mg) was obtained.

Melting point °251-253'C IR (nujozure): 3200, 1735, 1700
, 1660°1600i1 NMR (DMSO-d6.δ): 1.40-2.00(
IH, m) +2.00-2.50 (3H, m), 3.4
0 (IH, brs).

5.48 (IH, dd, J=2.8Hz), 6.90 (
2H.

d, J=9Hz), 7.60 (2H, d, J=9Hz)
.

10.33 (2H, brs) Example 106 Ethyl 3-(3-(4-hydroxyphenyl)-4-methoxy-5-oxo-2,5-dihydro-2-furyl]propionate (0.16 g), carbonic acid Potassium (87#)
and N,N-dimethylformamide (1,5 liters) at room temperature with stirring.
, 1 ml) and further stirred at the same temperature for 24 hours.

Pour the mixture into water and extract with ethyl acetate. Extract I
After sequentially washing with N-hydrochloric acid and brine, drying is performed, and the solvent is distilled off under reduced pressure.

The residue was purified by silica gel column chromatography and eluted with chloroform to give 3-(3-(4-isopropoxyphenyl)-4-meth)oxy-5-oxo-2,
5-dihydro-2-furyl]ethyl propionate (o,
1 gg) as an oil.

IR (film C1750, 1730 (shoulder), 1640
゜600i1 NMR(cDcz3.δ): 1.24(3i(,t
, J=7Hz).

1.33 (6H, d, J=6Hz), 1.40-2
．． 00(LH.

m), 2.20-2.77 (3H, m), 4.06 (3
H,s).

4.13 (2H, q, J=7H2), 4.60 (1,
H, 7-fold line.

J=6Hz), 5.38(IH, dd, J=2.8Hz
).

6.93 (2H, dj=9Hz), 7.63 (2H, d
.

J=9Hz) Example 107 3-[4-methoxy-5-oxo-3-(α-styryl)-2,5-dihydro-2-furyl]propionic acid (0
, 3g) was dissolved in ethanol (12ml), concentrated sulfuric acid (0.6g/) was added dropwise thereto over 30 minutes, and then the solution was dissolved at room temperature for 2 hours.
．． Stir for 5 hours. Ethanol was distilled off under reduced pressure, and the residue was poured into cold water and extracted with chloroform. The extract is sequentially washed with water and brine, dried, and then the solvent is distilled off.

The residue was recrystallized from diimpropyl ether to give 3-[4
-mer-cy-5-oxo-3-(α-styryl)-2,
5-dihydro-2-furyl]ethyl propionate (03
g).

IR (Film Cl750, 1640.1610zN
M R (CDCJ3, δ): 1.27 (3H, t, J
=7Hz).

1.60-2.10 (IH, m), 2.30-2.80
(3H, m); 4.12 (3H, s), 4.17 (:2
H, q, J = 7Hz).

5.20 (IH, dd, J=218H2), 6.97 (
2H.

s), 7.23-7.67 (5H, m) Example 108 3-[4-methoxy-3-
Ethyl (4-methylthiophenyl)-5-oxo-2,5-dihydro-2-furyl]propionate is obtained.

Melting point: 66-67℃ ■ R: 1750.1720.164
'0.1590GIN MR(CD(J?3),
δ)', 1.22 (3H, t, J=7Hz).

1.5 (1-1,97 (IH, m), 2.03-2.
57 (3H, m).

2.50 (3H, 8), 4.0 (3H, S), 4.13
(2H.

q, J=7Hz), 5.50(IH, dd, J=2.8
Hz).

7.33 (2H, d, J=9Hz), 7.63 (
2I(,d.

J=9Hz).

Mass spectrometry: 336 (M) Example 109 3-(4-methoxy-5-oxo-3-phenyl-2,
5-dihydro-2-furyl)propionic acid (500#)
and thionyl chloride (2 m/) is heated at 70° C. for 1 hour with stirring. After cooling, excess thionyl chloride is distilled off under reduced pressure, and methylene chloride is added to the residue. The solution is added dropwise to an ethereal solution of hesiazomethane. The solvent was distilled off under reduced pressure, and the residue was recrystallized from diisopropyl ether to give 5-(4-diazo-3-oxobutyl)-3-methoxy-4-phenyl-2(5H)-furanone (4651
v).

Melting point near 0℃ (decomposition) IR (chloroform); 3100, 2100, 1750
゜i 64 oi' N M R(CD(J?3.δ)-1,4-2,0(I
H, m).

2.3-2.8 (3H, m), 4.08 (3H, s)
, 5.27 (IH, s), 5.42 (IH, dd, J=
2.8Hz).

7.3-7.8 (5H, m) Example 11O N-(4-methoxy-5-oxo-3-phenyl-2,
5-dihydro-2-furancarbonyl)-N-methylglycine methyl ester (468#W), 2,4-bis(
A mixture of 2,4-disulfide (59117) and toluene (9,4m+/) is refluxed for 3.5 hours. After cooling, the reaction mixture was subjected to silica gel column chromatography using a mixed solvent of benzene and acetone (
50:IV/V~20-furanthiocarbonyl)-N-
Methylglycine methyl ester (357■) is obtained.

IR (methylene chloride): 1760i1 NMR (CDCj'3.δ): 3.45 (s), 3.5
8(s), 3.70(s), 3.88(s), 4.12
(s), 4.48(s).

4.95(s), 6.05(s), 6.22(s), 7
．． 3-7.8 (m) Applicant Fujisawa Pharmaceutical Co., Ltd. Continued from page 1 ■ Int, CI,' Identification code Office serial number 4333:
・Procedural amendment voluntarily) March 7, 1985 1. Indication of the case 1985 Patent Application No. 6508 2. Name of the invention Furanone derivative 3. Person making the amendment Relationship with the case Patent applicant Osaka 4-3 Doshomachi, Higashi-ku, Ichi (5,24) Fujisawa Pharmaceutical Co., Ltd. Representative Tomoyoshibe Fujisawa 4゜ Agent ■ 532 2-1-6 Kashima, Yodoyo-ku, Osaka Fujisawa Pharmaceutical Co., Ltd. Osaka Factory Details In the "Detailed Description of the Invention" column (1) of the specification, page 37, lines 2 to 5, r60mM----(NAAlI3) has been corrected as follows.

r 60mM D,L-glyceraldehyde 0.05ml (3) rlcz (μg/ml) on page 38, line 2
rlcg J. (μM)”.

April 1, 1985; Indication of the case; 1985 Patent Application No. 6508; 2; Name of the invention: furanone derivatives; 3; Person making the amendment; Relationship to the case; Patent applicant: Higashi-ku, Osaka City 4-3 Doshomachi (524) Fujisawa Pharmaceutical Co., Ltd. Representative Tomoyoshibe Fujisawa 4, Agent■ 532 2-1-6 Kashima, Yodoyo-ku, Osaka City Fujisawa Pharmaceutical Co., Ltd. Osaka Factory 6, amendments to be made (1) The following example is added to the second line from the bottom of page 103 of the specification, "Applicant."

1 to 5 - 111 The following compound is obtained in the same manner as in Example 1.

(1) 3-[3-(2,3-dichlorophenyl)-
4-hydroxy-5-dihydro-2,5-dihydro-2-
[Frill] Ethyl propionate IR (Riooform): 1760.1730cm
-'NMR(CDC18,ε): 1.23(3H
, t, J=7Hz).

1.47-2.83 (4H, rn).

4.10 (21', q, , C7Hz>.

5.67 (11(, dd, J=4.8Hz).

7.23-7.80 (3H, m) (3-43-(2,4-dichlorophenyl)-4-
Hydroxy-5-year-old xo-2,5-dihydro-2-furyl]ethyl propionate IR (chloroform): 1750.1730 Country-1
HMR (CDCI, δ): 1.23 (3H,t,
J=7Hz).

1.50 = 2.23 (28, m).

2.33-2.60 (2H, m).

4.10 (2H, q, J=7Hz).

5.70 (IH, dd, J=4.8Hz>.

7.17-7.57 (3H, m> (3) 3-[3-(3,5-dichlorophenyl)-4
-Ethyl-hydroxy-5-oxo-2,5-dihydro-2-furylcobropionate IR (chloroform): 1750cm -1HMR
(CDCI, δ): 1.30 (3H, t, J=
7Hz).

■, 50-2.10 (LH, m).

2.17-2.73 (3H, m).

4.12 (2H, q, J=7Hz>.

5.41 (IH, dd, J=2.8Hz).

7.17-7.67 (31, m> (6) 3-[3-(2,5-dichlorophenyl)-4
-Hydroxy-5-oxo-2,5-dihydro-2-furyl]ethyl propionate IR (chloroform): 3475.1750.172
5cm-'NMR (CDC1,, δ): 1.23 (3
H, t, J=7Hz).

1.5(1-2,23(IH,,m).

2.33-2.80 (3H, m>.

4.17 (2H, q, J=7Hz>.

5.73 <1) 1. dd, J=4.8Hz).

7.17=7.63 (3H, m) (5) 3-[3-(2,8-dichlorophenyl)-4
Ethyl -hydroxy-5-dihydro-2,5-dihydro-2-furyl]propionate IR: 3300.1750 (Shoulder).

1740, 1725 (shoulder) am-' 衷輿輿-111 In the same manner as in Example 24, 3-[3-(3,5-dichlorophenyl)-4-methoxy-5-year-old xo-2,5-dihydro- 2-furyl]ethyl propionate is obtained.

IR (chloroform): 1760.1730 cm-
'Base layer W: The following compound is obtained in the same manner as in Example 51.

(1) 3-[3-(2,3-dichlorophenyl)-
4-hydroxy-5-dihydro-2,5-dihydro-2-
Furylcobrobionic acid m p: 186-187°C IR (Nujol): 1740.1705 cm-'
NMR (CD+OD, δ): 1.27-2.10
(2H, m).

2.2 (1-2.57 (2H, m).

5.47 (IH, dd, J=4.8Hz).

7.23-7.60 (3H,m> (ri 3-[3-(2,4-dichlorophenyl)-4-
Hydroxy-5-year-old xo-2,5-dihydro-2-furylcopropionic acid (ml): 168°C IR (Nujol): 3200.1750.1710
cm-'NMR (CD5OD, δ): 1.47~
2.17 (2H, m>.

2.23-2.60 (2H, m).

5.58 (LH, dd, J=4.8Hz>.

7.37-7.63 (3H, m> (3) 3-[3-(3,5-dichlorophenyl)-4
-Hydroxy-5=oxo-2,5-dihydro-2-furyl]propionic acid mp: 212-213°C IR (Nujol): 3150. L730.170
0cm-'NMR(cosop, δ): 1.50
~2.07 (IH, m).

2.10-2.67 (3H, m).

5.45 (IH, dd, J=2.8Hz>.

7.33 (IH, d, J-2Hz).

7.71 (2H, d, J=2Hz>(phrase 3-[3
-(3,5-dichlorophenyl)-4-methoxy-5-
2,5-dihydro-2-furylcobrobionic acid m p: 150°C IR (nujol): 1760.1700 cm-'
NMR (CD5OD, δ): 1.50-2.67
(4H, m).

4.10 (3H, s).

5.48 (LH, dd, J=2.8Hz>.

7.40-7.73 (31, m) (5) 3-[3-(2,5-dichlorophenyl)-4
-Hydroxy-5-year-old xo-2,5-dihydro-2-furylcopropionic acid mp: 174-176°C IR (Nujol>: 3175.1735.1710
cm-'NMR(CD$OD, δ): 1.47
~2.13 (LH, m).

2.2 (1-2.57 (3H, m).

5.57 (IH, dd, J=4.8Hz).

7.2 (1-7.63 (3B, m) (6) 3-[
3-(2,6-dic0071 = L)-4-hydroxy-5-year-old xo2',5-dihydro-2-furyl]
Propionic acid mp: 192-193℃ IR (Nujol>:3tso, 1745.1710
cm-'NMR(DlISO-d, , δ): 1
．． 47-2.13 (2H, m>.

2, 20-2.50 (2H, m).

5.36 (LH, dd, J= 4,8Hz), 7.34-7.73 (3H.

m), 10.83 (IH, br s).

11.93 (LH, br 8) J that's all

Claims (1)

[Scope of Claims] Formula (wherein R'' is a hydroxy group, an alkoxy group is an alkoxy group (lower), and the aryl moiety in the AW (lower) afrecoxy group is a lower alkyl group, a lower It may be substituted with an alkoxy group or a halogen atom; R2 is an aryl group, a convex cyclic group, or a lower Alreganino V group, and each of these groups is a halogen atom, a hydroxy group, a lower alkyl group, or a lower alkoxy group. ,
7/lower) alkoxy group, halo(lower) alkyl group, lower alkylnao group, nitro group, amino group, and u7
May be substituted with U-74; R3u hydrogen atom,
Power! Levoxy group or thiocarbo: ¥-7 or a derivative thereof, or an aryl group optionally substituted with a carboxy group or a derivative thereof, R4 is a hydrogen atom or a lower alkylene group; and A means a lower alkylene group, respectively. , and n means an integer of D or 1, respectively. However, R1 is a hydroxy group or a C□-C5 alkoxy group; R is an aryl group or an aryl group monosubstituted with a halogen atom or a halo (lower) alkyl group; R
is a carboxyl group or a derivative thereof; and when R4 is a hydrogen atom, n is 0) and pharmaceutically acceptable salts thereof.