CA2263500C - Malonate derivatives useful as intermediates for producing isoxazolidinadione hypoglycemic agents - Google Patents

Abstract

Disclosed are novel malonate derivatives of the formula (XIV):

(see fig. I ) (wherein R is an optionally substituted aromatic hydrocarbon, an optionally substituted alicyclic hydrocarbon, an optionally substituted heterocyclic group, an optionally substituted condensed heterocyclic group or a group of the formula:

R1 is a cyclic group, R2 and R3 are hydrogen or lower alkyl, X
is O, S or NH, R4 is hydrogen, lower alkyl or hydroxyl; R5 is lower alkyl; and R7 is lower alkyl), useful as intermediates for producing isoxazolidinedione derivatives which have superior hypoglycemic and hypolipidemic actions and are useful for the treatment of diabetes and the complications thereof.

Description

MALONATE DRIVATIVBS AND THEIR PRODUCTION
This is a divisional application of Canadian Patent Application Ser. No. 2,157,032 filed December 26, 1994.
Technical Field The subject matter of the parent application has been restricted to novel isoxazolidlnedione derivatives which have hypoglycemic action and hypolipidemic action, and are useful as therapeutic agents for diabets and the complications thereof, and as therapeutic agents for the related diseases such as hyperlipidemia.
The subject matter of this divisional application is restricted to malonate derivatives of formula (XIV) described hereinunder and their production processes.
However, it should be understood that the expression "the present invention" or the like includes the subject matter of bath the parent and divisional applications.
Background Art In general, the treatment of non-insulin-dependent diabetes mellitus (NIDDM) involves a combination of alimentotherapy, kinesitherapy, and administration of insulin or oral hypoglycemic agents. As the oral hypoglycemic agents, there are currently known sulfonylureas such as tolbutamide, chlorpropamide, acetohexamide, glibenclamide and tolazamide and biguanides such as phenformin, buformin and metformin.
While the sulfonylureas have strong hypoglycemic action, they sometimes induce severe and prolonged hypo-glycemia, and chronic use thereof may impair their effective-ness. In addition, the biguanides frequently induce severe lactic acidosis. For these reasons, the use of these medications has required considerable attention.
Japanese Patent Unexamined Publication No.
85372/1986 teaches that thiazolidinedione derivatives such as ~5_ C4_ L2_ ~5_ - la -methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4-thiazolidinedione]
have hypoglycemic action, and Japanese Patent Unexamined Publication No. 51189/1985 teaches that thiazolidinedione derivatives such as [(~ )-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]-2,4-thiazolidinedione]
have hypoglycemic action. It has been also taught that oxazolidinedione derivatives such as [5-[4-[2-(2-phenyl-5-methyloxazol-4-yl)ethoxy]benzyl]-2,4-oxazolidinedione]
described in Japanese Patent Unexamined Publication No.
170478/1991 and [5-[4-[2-[N-(2-benzoxazolyl)-N-methyl]amino-ethoxy]benzyl]-2,4-oxazolidinedione] described in W092/02520 possess hypoglycemic action and cholesterol lowering action.
However, these compounds are not necessarily satisfactory in terms of activity, and the use thereof rather causes anxiety when their side effects (e. g. toxicity) are taken into consideration. These publications do not include a description suggesting an isoxazolidinedione derivative such as the compounds of the present Invention.
Disclosure of the Invention The present inventors have conducted intensive studies in an effort to provide a compound effective as a therapeutic drug for diabetes, the complications thereof and hyperlipidemia, and found novel low toxic isoxazolidinedione derivatives having superior hypoglycemic action and hypolipidemic action, which resulted in the completion of the invention.
Accordingly, the present invention relates to novel isoxazolidinedione derivatives of the formula (I) n R --wherein R is an optionally substituted aromatic hydrocarbon, an optionally substituted alicyclic hydrocarbon, an optionally substituted heterocyclic group, an optionally substituted condensed heterocyclic group or a group of the formula wherein R1 is an optionally substituted aromatic hydro-carbon, an optionally substituted alicyclic hydrocarbon, an optionally substituted heterocyclic group or an optionally substituted condensed heterocyclic group, R2 and R3 are the same or different and each is a hydrogen atom or a lower alkyl, and X is an oxygen atom, a sulfur atom or a secondary amino;
R4 is a hydrogen atom, a lower alkyl or a hydroxy;
R5 is a lower alkyl optionally substituted by hydroxy; and P and Q are each a hydrogen atom or P and Q together form a bond, and pharmaceutically acceptable salts thereof.
The present invention also provides malonate derivatives of the formula (XIV): a malonate derivative of the formula (XIV):
O RS COOR ~
R ~ ~ ~ ~ c~
O / COORS

(wherein R is optionally substituted aromatic hydrocarbon, an optionally substituted alicyclic hydrocarbon, an optionally substituted heterocyclic group, an optionally substituted condensed heterocyclic group or a group of the formula R2-~-wherein R1 is an optionally substituted aromatic hydrocarbon, an optionally substituted alicyclic hydrocarbon, an optionally substituted heterocyclic group or an optionally substituted condensed heterocyclic group, R2 and R3 are the same or different and each is a hydrogen atom or a lower alkyl, and X is an oxygen atom, ' ' 27103-138D
a sulfur atom or a secondary amino;
R4 is a hydrogen atom or a lower alkyl;
R5 is a lower alkyl; and R~ is a lower alkyl), The present invention further provides processes for producing the malonite derivatives of the formula (XIV), which comprise: [A] reacting compounds of the formula (XIII):
O Rs \
I I Y cx~
N O /

(wherein R, R4 and R5 are as defined above with respect to the formula (XIV) and Y is a halogen atom) with malonic di-lower alkyl esters, in organic solvents in the presence of bases under cooling to.under heating, or [B] treating compounds of the formula (XXZ):
O Rs \ \ COORS
R I I / COORS
N O

(wherein R, R4, R5 and R~ are as defined above) with hydrogenation catalysts in organic solvents under hydrogen atmosphere at normal temperature to under heating.

As used here in the present specification, "aromatic hydrocarbon" means phenyl, biphenyl, naphthyl and the like.
It may be aralkyl such as benzyl, with preference given to phenyl.
"Alicyclic hydrocarbon" means that having 3 to 7 carbon atoms, and is exemplified by cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclobutadienyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl and cycloheptadienyl. Preferred is alicyclic hydrocarbon having 5 to 7 carbon atoms, such as cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl and cycloheptadienyl, with preference given to cyclopentyl and cyclohexyl.
"Heterocyclic group" is a 5- or 6-membered heterocyclic group, preferably aromatic heterocyclic group having, as an atom constituting the ring besides carbon atom, 1 to 3, preferably 1 or 2, hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom. Specific examples include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimldinyl, pyridazinyl, triazinyl, dithiazolyl, dioxolanyl, dithiolyl, pyrrolidinyl, dithiadiazinyl, thiadiazinyl, morpholinyl, oxazinyl, thiazinyl, piperazinyl, pyperidinyl, pyranyl and thiopyranyl, with preference given to thienyl, furyl, pyrrolyl, imidazolyl, pyridyl and pyrimidinyl, and particular preference given to pyridyl, pyrimidinyl and imidazolyl.
"Condensed heterocyclic group" means a ring wherein 5- or 6-membered heterocyclic groups, preferably aromatic heterocyclic groups having, as an atom constituting the ring besides carbon atom, 1 to 3, preferably 1 or 2, hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom have been condensed, or a ring wherein such heterocyclic group, preferably aromatic heterocyclic group and a 4- to 6-membered aromatic hydrocarbon ring, preferably phenyl, have been condensed. Specific examples include furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, thienothiazolyl, imidazopyrazolyl, cyclopentapyrazolyl, pyrrolopyrrolyl, cyclopentathienyl,.thienothienyl, oxadiazolopyrazinyl, benzofurazanyl, thiadiazolopyridinyl, triazolothiazinyl, triazolopyrimidinyl, triazolopyridinyl, benzotriazolyl, oxazolopyrimidinyl, oxazolopyridinyl, benzoxazolyl, thiazolopyridazinyl, thiazolopyrimidinyl, benzoisothiazolyl, benzothiazolyl, pyrazolotriazinyl, pyrazolothiazinyl, imidazopyrazinyl, purinyl, pyrazolo-pyridazinyl, pyrazolopyriminidyl, imidazopyridinyl, pyrano-pyrazolyl, benzimidazolyl, indazolyl, benzoxathiolyl, benzo-dioxalyl, dithioropyrimidinyl, benzodithiolyl, indolidinyl, indolyl, isoindolyl, furopyrimidinyl, furopyridinyl, benzo-furanyl, isobenzofuranyl, thienopyrazinyl, thlenopyrlmidinyl, thienodioxynyl, thienopyridinyl, benzothienyl, isobenzothienyl, cyclopentaoxazinyl, cyclopentafuranyl, benzothiadiazinyl, benzotriazinyl, pyridoxazinyl, benzoxazinyl, pyrimidothiazinyl, benzothiazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridazinyl, pyridopyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxathiinyl, benzodioxynyl, benzodithiinyl, naphthylidinyl, isoquinolinyl, quinolinyl, benzopyranyl, benzo-s thiopyranyl, chromanyl, isochromanyl and indolinyl, with preference given to benzoxazolyl, benzoisothiazolyl, benzo-thiazolyl, benzimidazolyl, indazolyl, benzoxathiolyl, benzo-dioxalyl, benzodithiolyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothia-diazinyl, benzotriazinyl, benzoxazinyl, benzothiazinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxathiinyl, benzo-dioxynyl, benzodithiinyl, isoquinolinyl, quinolinyl, benzo-pyranyl, benzothiopyranyl, chromanyl, isochromanyl and indolinyl, and particular preference given to indolyl, isoindolyl, benzo-furanyl, isobenzofuranyl, benzothienyl, isobenzothienyl, isoquinolinyl and quinolinyl.
"Lower" means that the number of the carbon atoms constituting the group is 1 to 6, preferably 1 to 4.
"Lower alkyl" means alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and neohexyl. Preferred is alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, with particular preference given to methyl.
"Optionally substituted" means that the group may be substituted by 1 to 3 same or different substituents. Examples of the substituent include lower alkyl such as methyl, ethyl, propyl, butyl and tert-butyl; lower alkoxy such as methoxy, ethoxy, propoxy, butoxy and tert-butoxy; halogen atom; nitro;
s cyano~ hydroxyls acyl including lower alkanoyl (such as formyl, acetyl, propionyl, butyryl, and isobutyryl), benzoyl and naphthoyli acyloxy including lower alkanoyloxy (such as formyloxy, acetyloxy, propionyloxy, butyryloxy and isobutyryloxy) and benzoyloxyr aralkyloxy such as benzyloxy, phenethyloxy and phenylpropyloxyl mercapto~ lower alkylthio such as methylthio, ethylthio, propylthio, butylthio, isobutylthio and tart-butylthio~ amino lower alkylamino such as methylamino, ethylamino, propylamino, isopropylamino and butylaminot di-lower alkylamino such as dimethylamino, diethylamino, dipropylamino, diisopropylamino and dibutylamino~ carboxyl lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and tart-butoxycarbonyl~
carbamoyll trifluoromethyl~ phosphoryl~ sulfo~ sulfamoylt lower alkylphosphonamido such as methylphosphonamido, ethylphosphonamido, propylphosphonamido and isopropylphosphonamido~ methylenedioxy~ lower alkoxyphosphoryl such as methoxyphosphoryl, ethoxyphosphoryl, propoxyphosphoryl and isopropoxyphosphoryl~ lower alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and tart-butylsulfonyl~ and lower alkylsulfonylamino such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino and tart-butylsulfonylamino. Preferred are hydroxyl, lower alkyl, lower alkoxy, aralkyloxy, mercapto, lower alkylthio, vitro, halogen atom, trifluoromethyl, amino, di-lower alkylamino, lower alkylamino, acyl, cyano, carbamoyl, acyloxy, sulfo, carboxyl and lower alkoxycarbonyl, with particular preference given to hydroxyl, lower alkyl and lower alkoxy.
10a "Pharmaceutically acceptable salt" may be any as long as it forms a non-toxic salt with a novel isoxazolidinedione deriva-tive of the above-mentioned formula (I). Examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic base salts such as tri-methylamine salt, triethylamine salt, pyridine salt, pycoline salt, dicyclohexylamine salt and N,N'-dibenzylethylenediamine salt; and amino acid salts such as lysine salt and arginine salt.
The compound of the present invention has superior hypoglycemic action and hypolipidemic action, and is not only useful as an agent for the prevention and treatment of diabetes and hyperlipidemia, but also expected to be useful as an agent for preventing arteriosclerosis. When the compound of the formula (I), which is the compound of the present invention, or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is generally admixed with a pharmacologically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, aromatic, coloring, sweetener, thickener, flavor, solubilizer, and other additives known her se, such as water, vegetable oil, alcohol such as ethanol and benzyl alcohol, carbohydrate such as polyethylene glycol, glycerol triacetate, gelatin, lactose and starch, magnesium stearate, talc, lanolin, petrolatum and the like, and formulated into tablet, pill, powder, granule, suppository, injection, eye drop, liquid, capsule, troche, aerosol, elixir, suspension, emulsion, syrup and the like which may be administered orally or parenterally.
While the dose varies depending on the kind and severity of the disease, the compound to be administered, administration route, age, sex and body weight of patient and the like, the compound (I) is preferably administered orally at a dose of, in general, 0.01-1,000 mg, particularly 0.05-100 mg per day to an adult.
The compound of the formula (I) has one or more asymmetric carbons. When it has one asymmetric carbon, a pure optically active compound, a mixture thereof at an optional proportion or a racemate exists; and when it has two or more asymmetric carbons, optically pure diastereomers, racemates thereof, a combination of these or a mixture thereof at an optional proportion exist(s). These are all encompassed in the present invention. Depending on the case, they may be hydrates. As is evident from the structure, the above-mentioned compound (I) can exist as a keto-enol type tautomer, which is also within the scope of the present invention.
The compound of the present invention can be synthesized, for example, by the following methods. It is needless to say that the production method of the compound of the present invention is not limited to them.

Ra COOR61 (II) (Step 1) ORa COORgi ~ R5 (III) R51' ' N
H I
O
(Step 2) O Ra COORe O
(Step 17 ) R_ 'Y H2N R5 (IV) y y (V) O R2 R3 (XV) oRa cooRg (Step 3) (Step 12) oRa cooRg Ri-XH II
R N R5 ,~ (XIX) ~ y~N R5 (XVI) H ~ R2 Ra H O
o (Step 16) (vi) (Step 13) R2 R3 O R5 (XVII) I COORg (Step 4) y N
Ra (Step 14) R Ra O R5 R--<~ ~ 5 (VII) RZ~~ I (XVIII) N COORg Ri-XH Y N OH
Ra (XIX) Ra (Step 5). o R5 (Step 15) R----y I
N ~ OOH
(VIII) Ra (Step 6 ) R \ I (Ix) N Z

CHO
(Step 7) (x>
O Rs ~ CHO
OOR~ R I
N / (XI) COORS O
(XX) Rs (Step 18) (Step 8) O Rs ~ ~ COORS R5 I O ~ OH
N O / COORS R~ I I / (XII) N ~~O
(XXI) R4 (Step 9) O Rs ~ Y
R I I / (XIII ) N ~ w0 (Step 10) O Rs ~ COORS
R (XIV) N I Q I / ' COORS
(Step 20) O Rs ~ COY
(Step 11) R~N I I / COY
-O

(XXII) o (Step 21) O Rs ~
R I ~ ,NH (I) N O / O O
Rs Step 1 The compound (III) wherein Rs~ is a carboxy-protecting group such as benzyl, R5, is a lower alkyl, an optionally substituted aromatic hydrocarbon, an optionally substituted alicyclic hydrocarbon, an optionally substituted heterocyclic group, an optionally substituted condensed heterocyclic group or a group of the formula Rs R
R~ X
wherein R~, RZ and R3 are as defined above, and R4 and Rs are as defined above, can be synthesized by reacting compound (II) wherein R4 and Rsl are as deffined above, which is an aspartate derivative, in the presence of pyridine or a base such as triethylamine, in acid anhydride such as acetic anhydride and propionic anhydride, at room temperature to heating, and treating the resulting compound with water. In this reaction, addition of 4-dimethylaminopyridine sometimes affords better results.
Step 2 The compound (IY) wherein Rs is an alkyl, and R, and R5 are as defined above, is obtained by removing N-acyl such as N-acetyl of the formula R51-CO- by heating compound (III) wherein R4, Rs, Rsl and Rs, are as defined above, in an acidic solvent such as hydrochloric acid. Since Rs is eliminated at the same time, the resulting compound is esterified by reacting same in an alcohol solvent such as methanol, ethanol and propanol, in the presence of an acid such as hydrogen chloride, whereby compound (IV) is obtained.
Step 3 The compound (YI) wherein R, R~, Rs and Rs are as defined above, can be synthesized by reacting compound (IY) wherein R4, Rs and Rs are as defined above, and compound (Y) wherein Y is a halogen atom and R is as defined above, in an organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethoxyethane, pyridine and acetone or a mixed solvent thereof, in the presence of a base such as triethylamine, pyridine and N-methylmorpholine under cooling to room temperature.
Step 4 The compound (VII) wherein R, R4, R5 and Rs are as defined above, can be synthesized by reacting compound (YI) wherein R, R4, Rs and Rs are as defined above, in an organic solvent such as benzene, toluene, acetonitrile, chloroform and tetrahydrofuran, or without solvent, in the presence of an acid catalyst such as sulfuric acid and p-toluenesulfonic acid and a dehydrating agent such as acetic anhydride, at room temperature to under heating, preferably under heating.
Step 5 The compound (VIII) wherein R, R4 and R5 are as defined above, can be synthesized by reducing compound (YII) wherein R, R,, Rs and Rs are as defined above, by a conventional method, using a 'reducing agent such as diisobutyl aluminum hydride, in 1 s an organic solvent such as benzene, toluene, ether, dioxane and tetrahydrofuran.
Step 6 The compound (IX) wherein Z is p-toluenesulfonyloxy, benzenesulfonyloxy, methanesulfonyloxy or a leaving group such as halogen atom and the like, and R, R4 and R5 are as defined above, can be synthesized by reacting compound (VIII) wherein R, R4 and Rs are as defined above, and sulfonyl chloride such as p-toluenesulfonyl chloride, benzenesulfonyl chloride and methanesulfonyl chloride, or a halogenating agent such as phosphorus tribromide and thionyl chloride, in an organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethyl-formamide, dimethylsulfoxide, acetone and ethyl acetate, or a mixed solvent thereof, or without solvent, in the presence of a base such as triethylamine, 4-dimethylaminopyridine and pyridine, under cooling to under heating.
Step 7 The compound (XI) wherein R, R4 and R5 are as defined above, can be synthesized by reacting compound (IX) wherein R, R~, Rs and Z are as defined above, and 4-hydroxybenzaldehyde (X) in an organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, sulforan and dimethoxyethane, in the presence of a base such as sodium hydride, potassium hydride, sodium amide, sodium alkoxide, potassium alkoxide, triethylamine and sodium hydroxide, under cooling to under heating.
Step 8 The compound (XII) wherein R, R~ and R5 are as defined above can be synthesized by reducing compound (XI) wherein R, R4 and R5 are as defined above, using a catalyst such as sodium borohydride, lithium aluminum hydride, lithium borohydride and dibutyl aluminum hydride, in a solvent such as ethanol and isopropanol.
Step 9 The compound (XIII) wherein R, R4, R5 and Y are as defined above, can be synthesized by reacting compound (XII) wherein R, R4 and R5 are as defined above, in a solvent such as pyridine and dioxane in the presence or absence of a catalyst such as zinc chloride, adding a halogenating agent such as hydrogen bromide, phosphorus trichloride, phosphorus tribromide and thionyl chloride, at room temperature to under heating. It can be also synthesized by reacting compound (XII) wherein R, R4 and Rs are as defined above, in a solvent such as anhydrous carbon tetrachloride, adding triphenylphosphine, at room temperature to under heating.
Step 10 The compound (XIV) wherein R, is a lower alkyl, and R, R~
and Rs are as defined above, can be synthesized by reacting compound (XIII) wherein R, R4, R5 and Y are as defined above, with malonic diester, in an organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, sulforan and dimethoxyethane, in the presence of a base such as sodium hydride, potassium hydride, sodium amide, sodium alkoxide, potassium alkoxide, triethylamine and sodium hydroxide, under cooling to under heating.
Step 11 The compound (I) wherein R, R, and R5 are as defined above, can be synthesized by reacting compound (XIV) wherein R, R4, Rs and R, are as defined above, with hydroxyamine in an anhydrous alcohol solution, under cooling to under heating.
When the compound has hydroxy as the substituent for R, a compound having methoxy and the like as the substituent is synthesized and hydrolyzed under acidic conditions.
The compound (VIII) can be synthesized by introducing substituent R~ after ring closure, as mentioned below.
Step 12 The compound (XYI) wherein R2, R3, R,, R5, Rs and Y are as defined above, can be synthesized by reacting compound (IY) wherein R4, Rs and Rs are as defined above, with compound (XV) wherein Ra, R3 and Y are as defined above, in an organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethoxyethane, pyridine and acetone, or a mixed solvent thereof, in the presence of a base such as triethylamine, pyridine and N-methylmorpholine, under cooling to room temperature.

Step 13 The compound (XYII) wherein RZ, Ra, R4, R5, Rs and Y are as defined above, can be synthesized by reacting compound (XYI) wherein R2, R3, R4, Rs, Rs and Y are as defined above, in an organic solvent such as benzene, toluene, acetonitrile, chloroform and tetrahydrofuran or without solvent, in the presence of an acid catalyst such as sulfuric acid and p-toluenesulfonic acid and a dehydrating agent such as acetic anhydride, at room temperature to under heating, preferably under heating.
Step 14 The compound (XYIII) wherein Rz, R3, Rs, R5 and Y are as defined above, can be synthesized by reducing compound (XVII) wherein Ra, R3, R4, Rs and Y are as defined above, in an organic solvent such as benzene, toluene, ether, dioxane and tetrahydrofuran, using a reducing agent such as diisobutyl aluminum hydride, by a conventional method.
Step 15 The compound (YIII) wherein R, R4 and R5 are as defined above, can be synthesized by reacting compound (XYIII) wherein R2, R3, R4, R5 and Y are as defined above, and compound (XIX) wherein R, and X are as defined above, in an organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide and dimethylsulfoxide, water or a mixed solvent thereof, in the presence of a base such as sodium hydride, potassium hydride, sodium amide, sodium alkoxide, potassium alkoxide, triethylamine and sodium hydroxide, under cooling to under heating.
The compound (VI) can be also synthesized by the following steps.
Step 16 The compound (VI) wherein R, R4, R5 and Rs are as defined above, can be synthesized by reacting compound (XYI) wherein Rz, R3, R4, Rs, Rs and Y are as defined above, and compound (XIX) wherein R1 and X are as defined above, in an organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide and dimethylsulfoxide, water or a mixed solvent thereof, in the presence of a base such as sodium hydride, potassium hydride, sodium amide, sodium alkoxide, potassium alkoxide, triethylamine and sodium hydroxide, under cooling to under heating.
Step 17 The compound (YII) wherein R, R4, Rs and Rs are as defined above, can be synthesized by reacting compound (III) wherein R4, R5, R51 and Rs~ are as defined above, in an organic solvent such as benzene, toliene, acetonitrile, chloroform and tetrahydrofuran or without solvent, in the presence of an acid catalyst such as sulfuric acid and p-toluenesulfonic acid and a dehydrating agent such as acetic anhydride, at room temperature to under heating, preferably under heating.

Step 18 The compound (XXI) wherein R, R4, Rs and R~ are as defined above, can be synthesized by refluxing under heating compound (XI) wherein R, R, and R5 are as defined above, and compound (XX) wherein R, is as defined above, in an organic solvent such as toluene and benzene, using a catalyst such as piperidinium acetate, ethylene diammonium acetate and ammonium acetate, which has been formed from acetic acid and piperidine in the system, while removing water out from the system.
Step 19 The compound (XIY) wherein R, R~, R5 and R~ are as defined above can be synthesized by reacting compound (XXI) wherein R, R~, R5 and R~ are as defined above, in an organic solvent such as methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane and acetic acid or a mixed solvent thereof, using a catalyst such as palladium carbon and palladium black under a hydrogen atmosphere at normal temperature to under heating.
Step 20 The compound (XXII) wherein R, R4, Rs and Y are as defined above, can be synthesized by hydrolyzing compound (XIV) wherein R, R,, Rs and R, are as defined above, to give a dicarboxylic acid and treating same with a halogenating reagent such as thionyl chloride and oxalyl chloride.
Step 21 The compound (I') wherein R, R4 and Rs are as defined above can be synthesized by reacting compound (XXII) wherein R, R,, Rs and Y are as defined above, with hydroxyl amine, in the presence of a base such as pyridine and triethylamine.
The above-mentioned methods are particularly advantageous when P and Q are hydrogen atoms.
The compound (I) thus obtained can be isolated and purified by known separation-purification means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization and chromatography.
Of the compounds (I), a compound wherein P and Q are combined, which is represented by the formula (I') 0 Rs R I ( ~ NH (I' ~N 0 ~ 0 0/

wherein R, R4 and R5 are as defined above, can be synthesized by, for example, the following method.
COOR, I , ,1' 0 Rs HO ~ COORS
R ~ ~ (XXIII) N Z
(IX) R, (Step 22) 0 RS ~ ~ COORS
R ~ I
N 0 ~ COOR, (Step 23) R, (XXIY) 0 Rs R ~ I ~ \ \ ~H (I') R~
Step 22 The compound (~) wherein R, R,, Rs and R, are as defined above, can be synthesized by reacting compound (IX) wherein R, R,, Rs and Z are as defined above, with compound (XXIT3) wherein R7 is as defined above, in an organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, sulforan and dimethoxyethane, in the presence of a base such as sodium hydride, potassium hydride, sodium amide, sodium alkoxide, potassium alkoxide, triethylamine and sodium hydroxide, under cooling to under heating.
Step 23 The compound (I') wherein R, R4 and Rs are as defined above, can be synthesized by reacting compound~~r) wherein R, R4, Rs and R~ are as defined above, with hydroxyamine using sodium methoxide in an anhydrous methanol solution, under cooling to under heating.
The present invention is explained in more detail by way of Examples in the following, to which the present invention is not limited.

Example 1 Step 1 : Synthesis of benzyl 3-acetamido-4-oxopentanoate B-Benzyl L-aspartate (400 g, 1.79 mol) was suspended in triethylamine (748 ml, 5.37 mol) and acetic anhydride (676 ml, 7.16 mol) was dropwise added at 0°C with stirring. After stirring for 30 minutes, 4-dimethylaminopyridine (20.0 g, 0.16 mol) was portionwise added under ice-cooling. The mixture was stirred overnight at room temperature, and ice was added under ice-cooling. At the end of the exothermic process, water (700 ml) was added. A 7.5N aqueous solution of potassium hydroxide was portionwise added to make its pH 9. The mixture was extracted three times with ethyl acetate (1,000 ml), and the organic layer was washed twice with 1N hydrochloric acid (1,000 ml), twice with a saturated aqueous solution of sodium hydrogencarbonate (500 ml) and with saturated brine (500 ml) in order. The layer was dried over magnesium sulfate and concentrated to dryness to give 390 g of the title compound.
Step 2 : Synthesis of methyl 3-amino-4-oxopentanoate hydrochloride 6N Hydrochloric acid (700 ml) was added to the compound (390 g, 1.50 mol) synthesized in the above Step 1, and the mixture was stirred under reflux for 2 hours. The mixture was cooled to room temperature and the reaction mixture was washed twice with dichloromethane (500 ml). The aqueous layer was concentrated to dryness. A solution of hydrogen chloride in methanol (1,500 ml) was added under ice-cooling and the mixture was stirred. The mixture was gradually warmed and the mixture was stirred overnight at room temperature. Concentration to dryness gave 247 g of a crude product. The crude product (60 g) was recrystallized from isopropanol to give 30 g of the title compound as a white solid.
Step 3 : Synthesis of methyl 3-(benzene-2-carboxamide)-4-oxopentanoate The compound (9.40 g, 51.3 mmol) synthesized in the above Step 2 was suspended in dichloromethane (200 ml) at 0°C.
Benzoyl chloride was added thereto, and N-methylmorpholine (20.8 g, 0.2 mol) was dropwise added gradually with stirring.
The mixture was stirred for 3.5 hours, and water (100 ml) was added to separate an organic layer. Further, an organic layer was extracted from the aqueous layer with dichloromethane (100 ml). The extracted organic layers were combined, washed with 1N aqueous hydrochloric acid (100 ml) and water (100 ml) in order, and dried over magnesium sulfate. Concentration to dryness gave 12.75 g of the title compound (yield 1000 .
Step 4 : Synthesis of methyl [2-(2-phenyl)-5-methyl-4-oxazolyl]acetate Anhydrous acetate (70 ml) was added to the compound (12.75 g, 51.2 mmol) synthesized in the above Step 3 and the compound was dissolved. Con. sulfuric acid (1.0 ml) was dropwise added with stirring. The mixture was stirred at 90°C for 3 hours and cooled to room temperature. Water (100 ml) was added to the reaction mixture, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane (100 ml). The extract was dried over magnesium sulfate, and concentrated to dryness to give 8.75 g of the title compound (yield 74~).
Step 5 : Synthesis of 2-[2-(2-phenyl)-5-methyl-4-oxazolyl]-ethanol A solution of the compound (8.75 g, 37.88 mmol) synthesized in the above Step 4 in toluene (200 ml) was dropwise added to a solution (133 ml, 133.20 mmol) of diisobutyl aluminum hydride in toluene at 0°C under a nitrogen stream. Two hours later, methanol (100 ml) was dropwise added. Then; 2N hydrochloric acid (700 ml) was added to this gel reaction mixture to dissolve same, and the mixture was extracted 4 times with ethyl acetate (500 ml). The extracted organic layers were combined, washed with saturated brine (200 ml) and dried over magnesium sulfate. Concentration to dryness gave 7.69 g of the title compound (yield 1000 .
Step 6 : Synthesis of 2-[2-(2-phenyl)-5-methyl-4-oxazolyl]-1-ethyltosylate Pyridine (30 ml) was added to a solution (15 ml) of the compound (7.69 g, 37.88 mmol) synthesized in the above Step 5 in dichloromethane, and p-toluenesulfonyl chloride (7.58 g, 39.77 mmol) was gradually added at 0°C. After stirring for 6 hours, dichloromethane (100 ml) was added to dilute same, and dilute hydrochloric acid (100 ml) was added. The mixture was partitioned, and the organic layer was sequentially washed with water (100 ml), a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and saturated brine (100 ml).
Drying over magnesium sulfate and concentration to dryness gave 11.63 g of the title compound (yield 86~).
Step 7 : Synthesis of 4-[2-[2-(2-phenyl)-5-methyl-4-oxazolyl]-ethoxy]benzaldehyde A 60~ oil of sodium hydride (3.14 g, 78.4 mmol) was washed twice with n-hexane (20 ml) under a nitrogen stream and added with dimethylformamide (20 ml), and the mixture was cooled to 0°C. A solution (20 ml) of 4-hydroxyaldehyde (9.57 g, 78.4 mmol) in dimethylformamide was added with stirring. After stirring for 10 minutes, a solution (30 ml) of the compound (28 g, 78.4 mmol) synthesized in the above Step 6 in dimethylformamide was dropwise added. The mixture was warmed to room temperature and stirred for 60 hours. The mixture was neutralized with 1N hydrochloric acid and extracted twice with ethyl acetate (100 ml). The extracted organic layer was washed twice with water (100 ml) and dried over magnesium sulfate.
The solvent was distilled away to give 24.1 g of the title compound as a colorless solid (yield 1000 .
Step 8 . Synthesis of 4-[2-[2-(2-phenyl)-5-methyl-4-oxazolyl]-ethoxy]benzyl alcohol Sodium borohydride (2.46 g, 65.1 mmol) was gradually added to a solution (300 ml) of the compound (20 g, 65.1 mmol) synthesized in the above Step 7 in ethanol, and the mixture was stirred for 1 hour. Ethanol was distilled away and water (200 ml) was added. Filtration of the resulting precipitates gave 19.5 g of the title compound as a yellow solid (yield 97%).
Step 9 . Synthesis of 4-[2-[2-(2-phenyl)-5-methyl-4-oxazolyl]-ethoxy]benzyl chloride Thionyl chloride (8.9 ml, 124.2 mmol) was gradually added to a solution (300 ml) of the compound (19.18 g, 62.1 mmol) synthesized in the above Step 8 and zinc chloride (1.74 g, 12.78 mmol) in dioxane at room temperature, and the mixture was stirred for 1 hour. After stirring, dioxane and thionyl chloride were distilled away under reduced pressure and water (200 ml) was added. The mixture was extracted twice with dichloromethane (100 ml) and dried over magnesium sulfate.
After drying, the solvent was distilled away to give 19.69 g of the title compound as a yellow solid (yield 94%).
Step 10 . Synthesis of diethyl 4-[2-[2-(2-phenyl)-5-methyl-4-oxazolyl]ethoxy]benzyl malonate A 60% oil of sodium hydride (488 mg, 12.2 mmol) was washed twice with n-hexane (5 ml) under a nitrogen stream and added with tetrahydrofuran (20 ml), and the mixture was cooled to 0°C. Diethyl malonate (1.95 g, 12.2 mmol) was added with stirring. After stirring for 30 minutes, the compound (4 g, 12.2 mmol) synthesized in the above Step 9 was added and the mixture was heated at 70°C for 2 hours. The mixture was warmed to room temperature and the mixture was neutralized with 1N hydrochloric acid. The mixture was extracted twice with dichloromethane (100 ml) and dried over magnesium sulfate. The solution was purified by fast flow liquid chromatography (developing solvent; hexane:ethyl acetate=2:1) to give 3.13 g of the title compound as a colorless solid (yield 57~).
Step 11 . Synthesis of 4-[4-[2-(2-phenyl-5-methyl-4-oxazolyl)-ethoxy]benzyl]-3,5-isoxazolidinedione A solution (4 ml) of hydroxyamine ~ hydrochloride (348 mg, 5.00 mmol) in anhydrous methanol was added to a solution (4 ml) of sodium methoxide (540 mg, 9.99 mmol) in anhydrous methanol at 0°C. The resulting sodium chloride was filtered off and a solution (4 ml) of the compound (1.5 g, 3.33 mol) synthesized in the above Step 10 in anhydrous methanol was added. The mixture was stirred overnight at room temperature: After stirring, the solvent was distilled away, and the residue was dissolved in an aqueous solution of sodium hydroxide and washed twice with ether (20 ml). 1N Hydrochloric acid was added to the aqueous layer to make same acidic. The mixture was extracted twice with ether (50 ml), dried over magnesium sulfate. The obtained solid was dissolved in ether and an insoluble material was removed. Evaporation of ether under reduced pressure gave 412 mg of the title compound as a colorless solid (yield 32~).
Example 1' : Synthesis of dimethyl 4-[2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy]benzilidene malonate (Step 18) Dimethyl malonate (1.39 g, 0.01 mol), acetic acid (0.3 ml) and piperidine (0.3 ml) were added to a solution of the compound (2.94 g, 0.01 mol) synthesized in Example 1, Step 7 in toluene (30 ml), and the mixture was refluxed under heating using a Dean Stark trap while removing water to outside the system. Four hours later, toluene was distilled away and the obtained residue was recrystallized from methanol to give a colorless solid (2.5 g, yield 6090.
Synthesis of dlmethyl 4-(2-(2-phenyl-5-3nethyl-4-oxazolyl)-ethoxy]benzyl malonate (Step 19) The above-mentioned compound (2.5 g, 0.06 mol) was dissolved in a mixed solvent of methanol-dioxane (1:5, 20 ml), and 59~ Pd-C (150 mg) was added. The mixture was vigorously stirred under an HZ atmosphere at normal temperature and under atmospheric pressure. Two hours later, the catalyst was filtered off and the solvent was distilled away to give a solid. Recrystallization from methanol gave a colorless solid (2.15 g, yield 8590.
Synthesis of 4-[4-[2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy]-benzyl]-3,5-isoxazolidinedione (Step 11) A solution (4 ml) of sodium methoxide (574 mg, 10.6 mmol) in anhydrous methanol was gradually added to hydroxyamine~
hydrochloride (360 mg, 5.3 mmol) in anhydrous methanol solvent (4 ml). The precipitated sodium chloride was filtered off, and a solution (4 ml) of the above-mentioned compound (1.5 g, 3.5 mmol) in anhydrous methanol was added. The mixture was stirred at 60°C for 3 hours.
The solvent was distilled away, and 1N aqueous HC1 (50 ml) was added to the residue to make same assume acidity. The residue was extracted twice with ether (50 ml) and dried over magnesium sulfate. The solvent was distilled away and the obtained solid was recrystallized twice from methanol to give 650 mg of a colorless solid (yield 47~).
mp . 154.6-155.4°C
The signals at 400 MHz NMR: 2.35 (s,3H), 2.92 (t,J=6.5Hz,2H), 3.23-3.27 (m,2H), 3.50 (t,J=4.9Hz,lH), 4.11 (t,J=6.7Hz,2H), 6.77-7.95 (m,9H) Reference Example 1 . Synthesis of diethyl 4-hydroxybenzilidene malonate 4-Hydroxybenzaldehyde (24.4 g, 0.20 mol), diethyl malonate (30.4 ml, 0.2 mol), benzoic acid (3.0 g) and piperidine (3.0 ml) were dissolved in toluene (200 ml), and the mixture was refluxed for 6 hours with dehydration using a Dean Stark trap.
After cooling the mixture to room temperature, the resulting solid was filtrated and washed with toluene, a 0.5N aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and ether in order. The obtained solid was dried under reduced pressure to quantitatively give the title compound as a white solid.
Example 2 Step 22 : Synthesis of diethyl 4-[2-(2-phenyl-5-methyl-4 oxazolyl)ethoxy]benzilidene malonate A 60~ oil of sodium hydride (616 mg, 15.4 mmol) was washed twice with n-hexane (2 ml) under a nitrogen stream and added with dimethylformamide (20 ml). The mixture was cooled to 0°C. Diethyl 4-hydroxybenzilidene malonate (4.07 g, 15.4 mmol) synthesized in the above Reference Example 1 was added to this solution. After stirring for 10 minutes, the compound (5.00 g, 14.0 mmol) synthesized in Example 1, Step 6 was added and the mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. After the washing, the organic layer was dried over magnesium sulfate and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol=98:2) to give 5.44 g of the title compound as a white solid.
Step 23 : Synthesis of 4-[4-[2-(2-phenyl-5-methyl-4-oxazolyl)-ethoxy]benzilidene]-3,5-isoxazolidinedione A solution (10 ml) of hydroxyamine ~ hydrochloride (977 mg, 14.1 mmol) in anhydrous methanol was added to a solution (10 ml) of sodium methoxide (956 mg, 14.1 mmol) in anhydrous methanol at 0°C. The resulting sodium chloride was filtered off and a solution (10 ml) of the compound (4.21 g, 9.37 mol) synthesized in the above Step 17 in anhydrous methanol was added. An equivalent of sodium methoxide was added, and the mixture was stirred for 3 hours. After stirring, the solvent was distilled away, and the residue was extracted with ethyl acetate, washed with dilute hydrochloric acid and saturated brine, and dried over magnesium sulfate. The solvent was distilled away. The obtained solid was dissolved in ether and an insoluble material was removed. Ether was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; chloroform:
methanol=95:5) to give 1.45 g of the title compound as a white solid (yield 32~).
Examples 3 and 4 In the same manner as in Example 1, the compounds of Table 1 were obtained.

II II "O vi p ~ ~p' N
N "': ~_ ~ ~ ~ r ~~ N
o x .-. v c'? ~ ~n N
..r ~ W 00 ~ ~ N pj ~
> et M x x dr x r. N x r. b x x N N ~~ N N N
M N Ov ,~N, ~ M x E ~ ~ ~ ~ ~ ~ ~O ~b ~D
M
t~ N ~ ~ n 11 1" w ~ In ~ V r1 V r_i M ~ ; '. x M b .~.r o t~, M~ o~ ~_,~ ~ o .. x O N
U M M ~C d ,~p ~ej f~ N n N E
x xx x~ xx ~ x x x~ xx x~ xx V ~ a x ~1 t~ 00 N ~' ~ N h b ~O ~ ~p ~p ~p op I) ~~~hii~_~~~ir:rOV~..
x a x N ~n N w.. " ~: 'y-' ~ ~ M et Oy~ Ow-. O C = ~ ~ ~'~ N M ~ r N vp fV ~' M rx~ N ~fj N . x x r: ~: ~ ~ '~ N x .'T,' ~ t~ N .~~N' cx~1 N M x cx~7 N M N N
N H x ~ ~ N
h x Vr7 x n r. I~ x ~-:
M t~ M Ov M ~ x M ~ x N ~O CV ~ fV .-~ cV v0 N
."~ , v, v ~n o .-~ ~'1"'., E ! a ! ~ ! ~ ! '° ! o O O ~ 'o N o - o .~
O ~ +-~ °' ~ ~ v o .D '~
cfl z z O
O z Z O z O 'O 'O
'O O 'O 'O
-O O
\O ~ \O
O
'd O O
O O O
O
t~.
H
O
U
._ - p ~z p ~z o ~z O ~z O ~z / ~cn cn i z z .-, N M

As mentioned above, the present invention is not limited to the above-mentioned Examples. For example, the compounds shown in the following Tables 2 to 17 are also encompassed in the present invention.

Table 2 O

NH
O O
R R4 Rs R R4 Rs R R4 Rs HO ' I H Me ~ H Me ~ I H Me N

Ms ~ I o it Me ~ r, ,, HOOC ' ~. r, r, N

i i Et0 ~ r, ~~ Et0 ~ 'r o NC ' / o Et Et0 N

HS ' I '~ o HS ~ o r, Et ' ( r, N

y I '~ Et HO ~ '~ '~ HZN ' I ~r Me w N

Met OzN ~ ~ O 4 OpN-~ Et it Me '~ o O
N

HOOC ' I '~ '~ H3COOC ~ '~ Et Et0 ' ( Me N

NC ' ( '' '' MeS ~ H Me Br ' I H o N

CI ' I '~ '~ H2N ~ % ~, HO ' I . % o N

HzN ~ I~ Me 'r Br ~ r, ,, H2N ' ~ ~. o N

Tabl a 3 O
NH
o ~ 0 0 N
H Me Et '~ H M >
C

e N H Me N S

Me ~N ~ ~ Et0 rN
au ' J ,, ,, Eto ~ ,, ,, ' '~ ,, ,, N S

N
Me0 ~j ~~ Et EtS-',', ~~ ,, HO ' '> ,, Et ~ , ' N S H

N
HS JN o Me HO-',', o ,, HS-',L~, , , ~ '~ , , ' N S H

N
HO ~~ it 4 O2N '~ o ~, H2N ' 'J ~i Me N S N

H

N
02N ~J ~~ r~ H3COC '~ Et ,, O2N ' '~ o N S N

H

N
HOOC ~J O ~, NC-',', it Et HOOC ' '> Me ~
' N S N

H

N
NC ~J ~. o H2N-',', H Me NC ' '~ H
~
' N S H

N
fir' N '/ ,, Ct Br ' '>
' ' /' ,, ~NJ LS N

H

~,,N Et0 ~N
H2N ' Me '~ Et0 '~ % ,, HS ' J >

N N

S Et Table 4 O
R H
N
R R4 RS R R4 RS R R4 Rs H Me ' I S H Me ~ Me \ H

HO 'N r, 4 HO ' I r, ,, HO ' ( \ ,, ,, N \
S

Et 'N p Et HS ~ ( it it Et0-/ I ~~ Ef H \ \
~ S

EtS '\ rr Me Et0 / I r, ,, HO / \
\ ~i HO

\ \
HOOC 'N r, O MeOC ( ~r ~~ HOOC \ I r Me \
~ S

H O

H2N LH ~~ O HOOC ' Et it OZN ~ I ~i o I S \

O

02N L \ ~~ o Me0 '~ % Et NC \ I \ Me H I S

Me0 CI 'N ii O H2N '~ H Me H2N \ I H b I S \

H CI

Et2N 'N ,, ,, CI I \ rr p CI \ I \ ~~ it H ~ S , O

.\ / \
BuOC 'H Me ~~ t-Bu ' r, r, Me \ ( O r, r, ( S

Table 5 H

H Me 1 I j H Me ~ I H Me N N O

/ ~N /
HS ' I ~ ~~ ,, HS ~ I ~ ., ,, HO \ I o O
N NJ O

/ ~ ' suo ~ I o Et suo ~ I , ~. ~, Meo ' I ~. Et ~ . N O
N

H2N ~ I ~i Me H2N ~ I J i. ., HZN \ I . .
, N O
N

/ ~ / ~N /
OZN ' I '. ~, OZN ' I ~ .' O2N ' I ~. Me ~ N O
N

HOOC-/ I
., ., HOOC ~ I Et ~i Br ~ I n O
N J O
N

~N
CI ' I N O ~~ CI ' I N~ % Et Me l~_ I Me ~i O
CI

CI ~/ I o o CI '/ I J H Me MeS ~ I H ,, ~ CI~ N MeS~ O
CI~ N

w N M f\.~
Me0 '/ I ., ,, Me0 ~/ I ., ,~ MeS '/''r ~, o N N J i1 0J
Me0 Me0 NC J~

/ / ~N HO
CI '/ I Me ., CI '~, I ., ., ~ ~ O ., .
N N J i T I
HzN H2N

Table 6 O
R2 ~..
~N H
R1- ~ O O
RI X. R2 R3 R4 Rs RI X R2 R3 Ra Rs S H Me H Me HzN ~ I S H Me H Me HO ~ I MeOC ~
.. .. .. .. I .. .. .. ..
W

Me \ I . ~ . . . Et2HN-' ., . H . Et ( i Et0 ~ I . . H Me . t_gu ~/, ., ,, . Et .
I
t-Bu i i HS I . ~ . . Et Me0 ~ I ., ., ., ., Me Me0 ,, ., ,.
w H Me ~I ~ I . , . , , O ~
CI~

i 02N w I .~ .. .~ .. ~. H2N l%: .. .. .. H ..
I
CI

t-Bu HOOC I . . Me . . HO I . . Me .
%~
t-Bu NC ' I . , , . H2N ~~ ., ., ., ., ., I
HO

i CI ~ . . . . , Me ~ . . . . .
CI~

Table 7 Ra O Rs R2w ~ /
R~.-X N, ~ wOi ~ O
R1 X R2 R3 R4 RS R, X. R2 R3 R4 RS

H2N-~ S H Me H Me H2N:l J S H Me H Me N

HO ~ , , , , . HO ~ J ., ., ., ,, ,, N

i Me ~ , , , . . Me ' J ,, ,, H , Et N

i N
Et0 ~ , , H Me ~ Et0 ~J , , . Et N

HS ~ ~ ~, , , Et HS ~j ~, ., ,, , Me N

I
, , . H Me MeOC ~J . . . , ., ~N ~

N

i 0 . , , , N ~ .

2 , , . . .. 2 , ,. ,. H ., ~ J
N

HOOC ~ , , Me , , HOOC ~~ , . Me ,, N

NC ~ , , . . , NC ~ j , ,, ., ., ., N

c1 ~ ., , , , , c1 ~J ~. ~, , ,, ,, N

Table 8 O

NH
R1- O ~ O O
R1 X R2 R3 R4 RS R, X 'R2 R3 R4 RS

N
H2N ~ S H Me H Me CN~ S H Me H Me I

~N
HO ~ . . ., ., ,, HO ' ~~ ,, N

H

~N
Me ~ . . . . ~. H2N ' ~~ . . H

, , . Et N

H

N
Et0 ~ , ~. H Me . Et ~ ~~ , . . , L . , , t N , H

~N -HS ~ . , , . Et Et0 ' ~~ ,, ,, ,, ., Me N

H

r.N
HZNOC ~ . ~. ~. H Me HS LN . . ~. . .

H

rN
OZN ~ ,, ,, ,, ,, ,, NC ' ~~ ., ., ., H

N

H

r.N
HOOC ~ . . Me ~. 02N ' ~ . M . .
N

. , . . e , , H

N
NC ~ ., ., ., ,, ,, HOOC-~',~ ,, , . .
>

'N , , . o H

~N
CI . . . . . CI ' ~~ , , , , , , , , , ,, ,, N

H

Table 9 O
R Rs O Rs \
NH
R1-X N O ~ O O
Ra R i X- R2 R3 R4 Rs R 1 X R2 R3 R4 Rs ~

Ho ~ I S H Me H Me I ~ S H Me H Me . S
N

Me0 ' 1 ~. . . . . HO '~ . . . . .
, N S

1 , ~ . . . . H2N '~ ., ., H . Et N S

~, H Me . Et '~ ,, ,, . Et .

S

C~ ~, I ., ., ., . Et Et0 ; ~ ., ,, ., ., , Me ' ~ N

/
Me \ I ~. . . H Me HS '~ , ., ,, ., ., ~

O S

/
e~ ' I . , . . . NC '~ , , ., H ., ~

S

H2N ~ I , Me , . OZN '~ ~ Me ~ , ~

o S

NC \ I ., ., ,, ., ., EtOC '~ ., ., ., ., ,, o S

HO ~ I ~ , ~ , ~ CI '~ , . , , ~ ~
O

S

Table 10 O
R2 ' NH
R~- / O O
RI X R2 R3 Ra Rs RI X R2 R3 Ra Rs I O H Me H Me H2N ' I O H Me H Me HO \ I . . . . o MeOC \ ., ., ., ., I

i Me ' I . . . . . Et2HN ' ., . H . Et I

i i Et0 ~ . . H Me ~ t-Bu ( . . , Et , ~y.
t-Bu MeO ~ ( Me HS I ~ ~ ~ Et ,, ,, ,, ., MeO~

O ' I . . . H Me CI ~~, ., .. . . ., I
CI

02N ~ I ~ . . . ., HZN ~ I ., ., ., H , CI/

t-Bu , HOOC ' . , Me . . HO ~'~ ~, . Me I t-Bu i NC ' I ~ o . , ., H2N ~~ ., ., ., ., ., HO

i CI- I . . . . . Me ~ o .
CI

Table 11 O
R R3 ~ R5 NH
R~-X N O ~ O O
Ra RI X R2 R3 R4 RS R, X R2 R3 R4 RS

H2N ~ O H Me H Me H2N ' J O H Me H Me N

HO ~ ~ ~ ~ HO

~ . . . . . N

Me ~ , , , . ~, Me ' J ,, ., H ,, Et N

~N
Et0 H

,~N , , Me Et0 ' J . , . Et , N

HS ~ ~ ~ ~ ~ Et HS ~J , .. .. ,, Me N

"
~

LO , . . H Me MeOC ~J , , , .
~N N

02N ~N ., ., ., ,, . 02N ~J ~ , , H .
N.

HOOC ~ . . Me . , HOOC ~J , , Me N

i ~ Nc ~~

Nc , ,, , , ,, ' ,, , , , , N

c~ ~ , ,, ., ., ., ci ~J . , , ,, N

__~..N.:_ . _. _._ __.. _._:_._..__.~..a Table 12 O
NH
/. 0 O
R1 X R2 R3 R4 RS R, X R2 R3 R4 RS

N __ H2N- O H Me H Me ~N~ O H Me H Me I

,\ . , O . , . . , rN , , , HO L
~

N , .

H

rN
Me ~ . , . . . H2N L ., ., H Et N .

H

N
Et0 ~ , , H Me , Et L ~~ , , , Et , , , .

N , H

rN
HS , . , ., Et Et0 ' ~~ ,, ,, ,, ., Me N
H

~N
H2NOC . . , H Me HS L ~~ . , , . .

N
H

N
02N ~ , , NC , , , H
N

L .

H

rN
HOOC ~ . . Me , , 02N L N~ , , Me .

.

H

N
NC ~ HOOC ~ ~
J

, , , , , , 'N , o , , , H

rN
CI ~ . , , , . CI ' ~) . , ., ~. ,.

N

H

Table 13 O

NH
R1- O ~ O O
R1 X R2 R3 R4 RS R, X R2 R3 R4 RS

Ho ' I O H Me H Me I ~ O H Me H Me , S
N

Me0 ~ I ~ , % ~. ,. HO ; ~ ,. ,, ,. o , ~

N "S

w CI ' I ~. ~. ,. ~. ,, H2N , ~ ,, ,, H ~. Et N L'S

i Ho ~ I ,, ,, H Me ,. Et-', ~ ,, ,, ,, Et ,.
, ' ~

HO S
N

c1 j I ., ., ., ~. Et Et0 '~ ., ,, ,, ., , Me N

CI S

Me ' I ~ . ,, H Me HS '~ ~. ,. ,, ~

S

Br ~ I ~, ,. ,. ,. ,, NC '~ ~, ,, ,. H .
~

o S

H2N \ I % Me ~. , OZN '~ , , Me , ,, ~

o S

NC ' ( ,, ,, ,, ., ., EtOC '~ ., ,, ., ., ,.
~

O S

HO ~ I , o ,, ,~ , CI '~ , , , , ,, ~
O

S

Table 14 O
R R3 O RS \
NH
Ry-X N O ~ O O
Ra R1 X R2 R3 R4 RS R, X R2 R3 R4 RS

I NH H Me H Me H2N ~ ( NH H Me H Me i HO I . . . . .,, MeOC ~ . . . . .

Me ~ I . . o ~ ~ EtyHN ' ., ., H . Et I

Et0 ~ I ' H Me ' t-Bu ~/~ . . Et , I
t-Bu i i HS- ( '. . . Et Me0 ~ I ., ., ., ,, Me Me0 (~ i . . . H Me CI ~~ ' ' ' ' ' , CI

i 02N ~ I .. .~ .~ .~ .~ H2N ~ .. .. .~ H
~

CI

t-Bu I f~~
HOOC . . e . . HO-~ I . . e . .
'-u t-B

i NC ~ I . . . '. H2N l~ ' ' '' ' ' HO

CI ~ I . . . . . Me ~ I . . ~ .
CI~

Table 15 O
R2 \
NH
R~- ~ p O
R1 X R2 R3 R4 RS R, X R2 R3 R4 RS

HZN ~ NH H Me H Me H2N ' j NH H Me H Me N

HO ~ . . . , .. HO ' J . ~, . . .
N

i Me ~ ~. ~. . . ~. Me ' j ., ,, H ~. Et N

~i N
Et0 ~ . , H Me . Et0 ' J . , , Et , N

HS ~ ~ . . . Et HS ~J ., ., ., ., Me N

. . , H Me MeOC ~J . . . . , N

N . , . . . N ~ .

2 , . , . , 2 , .. .. H ..
~ J
N

HOOC ~ . ~. Me , . HOOC ~J . ~. Me N

NC ~ . . , ~. . NC ~J . . . . ,, N

ci ~ , , ., ., , ci ~j , , , , N

Table 16 NH
O O

N
H2N- NH H Me H Me CN NH H Me H Me I

~N
HO , ~, o ~, ~, HO 'N , .

H

N
Me ~ , '~ ' '~ '~ H2N LN , ~, H ~, Et ~

H

N
Et0 ~ '~ '~ H Me '~ Et L N , ~, ~, Et , H

N
Et0 r ~
S ~ t L ~ , , . e N
H

~N
_ H HS-',', .. ,, ,, .. ,, H , , , e ~~
NOC L

H

N
0 ,~ ,~ ,~ ,~ ,~ NC ; N ,, ., ,, H ., N ~

H

~N
HOOC ~ , Me ~, . OzN L ~~ . , Me , , N
H

N
HOOC ~ ~
C , , , , . LN . , .

H

~N
CI ~ . . ~. ., ,, CI ' ~~ ., ,, ,, .~ ., N
H

Table 17 Q
R Ra. O Rs \
NH
R1-X . N O / O O
Ra R1 X R2 R3 R4 Rs RI X R2 R3 R4 Rs Ho ' I NH H Me H Me I ~ NH H Me H Me , S
N

i Me0 ~ I o ~. . ~. . HO , ~ . . ~. ~. .
' N S

ct ~ I . ~. ~. ~. . HZN-',', ,, . H ~, Et , ~
' N S

Ho ~ I ., ,, H Me ~. Et ~ ~. , . Et S
HO N

i ct ~ I . . ~. . Et Et0-',', ,, ., ,, .
, ~ e ~ N ~' CI S

nne \ I ~ . . H Me HS '~ . , , .
~

o S

Br \ I ~, ~. ~, . ~, NC '~ ~ ~, . H
~
O

S

H2N \ I . ~. Me ~, ~. OxN '~ ~ ~ Me .
~

o S

NC ' I ., ., ., ., ., EtOC '~ ,, ., ., ., ,, o S

HO \ I , ~, ~. , ~. CI '~ , , , ~ S
O

Experimental Example 1 Genetically obese, hyperglycemic and hyperlipidemic diabetic mice (C57BL/Ksj-db/db, male, Jackson Laboratories/Clea Japan, Inc., 13 weeks of age and KK-Ay, male, Clea Japan, Inc., 13 weeks of age) were used for the pharmacological tests. As a reference compound, a hypoglycemic agent CS-045 [(~ )-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]-2,4-thiazolidinedione] [see Diabetes, vol. 37, p. 1549.(1988)] was used.
The mice were weighed and blood samples were taken immediately before the initiation of administration on day 1.
Serum glucose and serum triglyceride were measured, based on which the mice were grouped (6-8 per group) in such a manner that there existed no difference in terms of average body weight, average serum glucose and average serum triglyceride.
The test drugs were all suspended in a solution of 0.5~
sodium carboxymethylcellulose and administered orally twice a day (the second administration was 6 hours after the first administration) on day 1, day 2, day 3 and day 4. To a vehicle control group, a solution of 0.5~ sodium carboxymethylcellulose was orally administered.
At day 5, blood samples were taken again and measured for serum glucose and serum triglyceride. The blood sample was taken from orbital cavity plexus by 400 u1 under anesthetization with ether and kept at ice temperature. After separation into serum (12000 rpm, 5 min.), serum glucose was measured by hexokinase method (glucose-HK-test "BMY";
Bohelinger Mannheim Yamanouchi) and serum triglyceride was measured by enzyme method (triglycolor III "BMY"; Bohelinger Mannheim Yamanouchi) using an automatic analyzer COBAS FARA
(manufactured by Roche).
Change in percent of serum glucose and serum triglyceride in each group was calculated using serum glucose and serum triglyceride, respectively, of vehicle control group at day 5 as follows:
Change in percent of serum glucose (3~) -serum glucose of each serum glucose of vehicle group at day 5 ~ - ~ control group at day 5 serum glucose of vehicle control group at day 5 Change in percent of serum triglyceride value (9~) -serum triglyceride of serum triglyceride of vehicle ~~ each group at day 5 ~ -~ control group at day 5 serum triglyceride of vehicle control group at day 5 The results are shown in Table 18.
Table 18 x 100 x 100 dose serum glucose serum triglyceride (m (9~) (9~) /

g KK-A' mouse db/db mouse KK-Ar mouse db/db mouse kg) Ex. 10 -38.3 -19.8 -50.3 -29.1 CS-045 100 -29.4 -21.5 -22.9 -55.5 As shown in Table 18, the compound of the present invention lowered serum glucose and serum triglyceride of both kinds of diabetic mice more significantly than did the control compound.
From the foregoing, it is evident that the compound of the present invention has superior hypoglycemic and hypolipidemic actions and is useful for the treatment of diabetes and hyperlipidemia. In addition, the compound of the invention is expected to be efficacious for the prevention and treatment of the complications of diabetes.
Industrial Applicability The~oxazolidine derivative compound (I) and a salt thereof of the present invention are novel compounds having extremely potent and low toxic hypoglycemic action as compared with known oxazolidine derivatives and other therapeutic agents of diabetes, and are very useful as therapeutic agents for diabetes and hyperlipidemia. In addition, the compounds of the present invention are expected to be useful for the prevention of the complications of diabetes, especially for the prevention of arteriosclerosis.

Claims (18)

CLAIMS:

1. A malonate derivative of the formula (XIV) (wherein:
R is (A) an aromatic hydrocarbon selected from the class consisting of phenyl, biphenyl and naphthyl, which is optionally substituted by 1 to 3 substituents;
(B) an alicyclic hydrocarbon having 3 to 7 carbon atoms, which is optionally substituted by 1 to 3 subsituents;
(C) a 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which is optionally substituted by 1 to 3 substitutents;
(D) a 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which is condensed with a 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or condensed with a 4- to 6-membered aromatic hydrocarbon, which is optionally substituted by 1 to 3 substituents; or (E) a group of the formula:

wherein:
R1 is (A) an aromatic hydrocarbon selected from the class consisting of phenyl, biphenyl and naphthyl, which is optionally substituted by 1 to 3 substituents;
(B) an alicyclic hydrocarbon having 3 to 7 carbon atoms, which is optionally substituted by 1 to 3 subsituents;
(C) a 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which is optionally substituted by 1 to 3 substitutents; or (D) a 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which is condensed with a 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or condensed with a 4- to 6-membered aromatic hydrocarbon, which is optionally substituted by 1 to 3 substituents;
R2 and R3 are the same or different and each is a hydrogen atom or a lower alkyl, and X is an oxygen atom, a sulfur atom or a secondary amino group;
R4 is a hydrogen atom or a lower alkyl group;

R5 is a lower alkyl group; and R7 is a lower alkyl group);
the substituents are each selected from the group consisting of hydroxyl, lower alkyl and lower alkoxy.

2. The malonate derivative of claim 1, wherein R4 is a hydrogen atom and R5 is a lower alkyl group.

3. The malonate derivative of claim 2, wherein:
R is phenyl which is optionally substituted by 1 to 3 substituents, a 5- or 6-membered aromatic heterocycle group having 1 or 2 hetero atoms selected from sulfur atom, oxygen atom and nitrogen atom, which is optionally substituted by 1 to 3 substituents, or a 5- or 6-membered aromatic heterocyclic group having 1 or 2 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom, which is condensed with a benzene ring and which is optionally substituted by 1 to 3 substituents.

4. The malonate derivative of claim 3, wherein R is phenyl, a 5- or 6-membered aromatic heterocyclic group having one or two hetero atoms selected from sulfur atom, oxygen atom and nitrogen atom, or a 5- or 6-membered aromatic heterocyclic group having 1 or 2 hetero atoms selected from sulfur atom, oxygen atom and nitrogen atom, which is condensed with a benzene ring.

5. The malonate derivative of claim 3, wherein R is phenyl, or a 5- or 6-membered aromatic heterocyclic group having sulfur atom, which is condensed with a benzene ring.

6. The malonate derivative of claim 2, wherein R is phenyl, benzothienyl or 1-methyl-1-(2-pyridylthio)methyl.

7. The malonate derivative of claim 2, wherein R is phenyl.

8. The malonate derivative of claim 2, wherein R is a group of the formula:
wherein R1, R2 and R3 are as defined in claim 1.

9. The malonate derivative of claim 8, wherein R1 is phenyl which is optionally substituted by 1 to 3 substituents, or a 5- or 6-membered aromatic heterocyclic group having one or two hetero atoms selected from sulfur atom, oxygen atom and nitrogen atom, which is optionally substituted by 1 to 3 substituents.

10. The malonate derivative of claim 8, wherein R1 is a 5- or 6-membered aromatic heterocyclic group having one or two hetero atoms selected from sulfur atom, oxygen atom and nitrogen atom.

11. The malonate derivative of claim 8, wherein R1 is a 5- or 6-membered aromatic heterocyclic group having nitrogen atom.

12. The malonate derivative of claim 8, wherein R1 is pyridyl.

13. The malonate derivative of claim 1, which is a member selected from the group consisting of dimethyl 4-[2-[2-(2-phenyl)-5-methyl-4-oxazolyl)ethoxy]-benzyl malonate, diethyl 4- [2- [2- (2-phenyl) -5-methyl-4-oxazolyl) ethoxy] -benzyl malonate, and diisopropyl 4-[2-[2-(2-phenyl)-5-methyl-4-oxazolyl)ethoxy]-benzyl malonate.

14. The malonate derivative of claim 1, wherein:
R is (i) an aromatic hydrocarbon selected from the class consisting of phenyl, biphenyl, and naphthyl, (ii) an alicyclic hydrocarbon selected from the class consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclobutadienyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl and cycloheptadienyl, (iii) a heterocyclic group selected from the class consisting of thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazinyl, dithiazolyl, dioxolanyl, dithiolyl, pyrrolidinyl, dithiadiazinyl, thiadiazinyl, morpholinyl, oxazinyl, thiazinyl, piperazinyl, piperidinyl, pyranyl and thiopyranyl, (iv) a condensed heterocyclic group selected from the class consisting of furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl, cyclopentapyrazolyl, pyrrolopyrrolyl, cyclopentathienyl, thienothienyl, oxadiazolopyrazinyl, benzofurazanyl, thiadiazolopyridinyl, triazolothiazinyl, triazolopyrimidinyl, triazolopyridinyl, benzotriazolyl, oxazolopyrimidinyl, oxazolopyridinyl, benzoxazolyl, thiazolopyridazinyl, thiazolopyrimidinyl, benzoisothiazolyl, benzothiazolyl, pyrazolotriazinyl, pyrazolothiazinyl, imidazopyrazinyl, purinyl, pyrazolo-pyridazinyl, pyrazolopyrimidinyl, imidazopyridinyl, pyrano-pyrazolyl, benzimidazolyl, indazolyl, benzoxathiolyl, benzo-dioxalyl, dithioropyrimidinyl, benzodithiolyl, indolidinyl, indolyl, isoindolyl, furopyrimidinyl, furopyridinyl, benzo-furanyl, isobenzofuranyl, thienopyrazinyl, thienopyrimidinyl, thienodioxynyl, thienopyridinyl, benzothienyl, isobenzothienyl, cyclopentaoxazinyl, cyclopentafuranyl, benzothiadiazinyl, benzotriazinyl, pyridoxazinyl, benzoxazinyl, pyrimidothiazinyl, benzothiazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridazinyl, pyridopyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoathinyl, benzodioxynyl, benzodithinyl, naphthylidinyl, isoquinolinyl, quinolinyl, benzopyranyl, benzothiopyranyl, chromanyl, isochromanyl and indolinyl, or (v) a group of the formula:

[wherein R1 is an aromatic hydrocarbon, an alicyclic hydrocarbon, a heterocyclic group or a condensed heterocyclic group, each having the same meanings as defined above for R independently from R;
R2 and R3 are the same or different and are each a hydrogen atom or a C1-C6alkyl ; and X is O, S or NH];
R4 is a hydrogen atom or a C1-C6alkyl;
R5 is a C1-C6alkyl; and R7 is a C1-C6alkyl, wherein the aromatic hydrocarbon, the alicyclic hydrocarbon, the heterocyclic group and the condensed heterocyclic group defined above for R and R1 may have 1 to 3 same or different substituents each independently selected from the class consisting of C1-C6alkyl, C1-C6alkoxy and hydroxyl.

15. A process for producing the malonate derivative of the formula (XIV) as defined in claim 1, which comprises:
[A] reacting a compound of the formula (XIII):

(wherein R, R4 and R5 are as defined in claim 1, and Y is a halogen atom) with a malonic di-lower alkyl ester, in an organic solvent in the presence of a base, under cooling to or while heating, or [B] treating a compound of the formula (XXI):

(wherein R, R4, R5 and R7, are as defined in claim 1) with a hydrogenation catalyst in an organic solvent under a hydrogen atmosphere at normal temperature or while heating.

16. The process of claim 15, wherein process variant [A] is chosen; and the compound of the formula (XIII) is prepared by reacting a compound of the formula:

(wherein R, R4 and R5 are as defined in claim 1) with a halogenating agent in a solvent at room temperature or while heating.

17. The process of claim 15, wherein process variant [B] is chosen; and the compound of the formula (XXI) is prepared by refluxing while heating a compound of the formula:

(wherein R, R4 and RS are as defined in claim 1) and a compound of the formula:

(wherein R7 is as defined in claim 1) in an organic solvent using a catalyst selected from the group consisting of piperidinium acetate, ethylene diammonium acetate and ammonium acetate, while removing water out of a reaction system.

18. The compound dimethyl 4-[2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy]benzyl malonate according to claim 1.