Thiazolidine derivatives, their production and use

A thiazolidinedione derivative of the general formula: ##STR1## wherein X is an oxygen or sulfur atom, R.sup.1 and R.sup.2 each independently is hydrogen or a hydrocarbon residue which may optionally be substituted and R.sup.1 and R.sup.2 may jointly, together with the oxazole or thiazole ring, form a condensed ring and A is a lower alkylene group; or a salt thereof, are novel compounds, which exhibit in mammals blood sugar- and lipid-lowering activity, and are of value as a therapeutic agent for diabetes and/or therapeutic agent for hyperlipemia.

This invention relates to novel thiazolidinedione derivatives having blood 
sugar and lipid lowering activity, methods of producing the same and 
antidiabetic agents containing the same. 
Various biguanide type compounds and sulfonylurea type compounds have so 
far been used as antidiabetic agents. However, biguanides are rather 
obsolete nowadays because they induce lactic acidosis. Sulfonylureas, on 
the other hand, have potent blood sugar lowering activity but frequently 
cause severe hypoglycemia, so that much care is necessary in using them. 
Accordingly, the appearance of novel type antidiabetics free of these 
drawbacks has been waited for. Meanwhile, Japanese Patent Publications 
Kokai No. 22636/80 and Kokai No. 64586/80, Chemical & Pharmaceutical 
Bulletin, vol. 30, p. 3563 (1982), ibid., vol. 30, p. 3580 (1982) and 
ibid., vol. 32, p. 2267 (1984) describe that various thiazolidinedione 
derivatives exhibit blood sugar and lipid lowering activity. Antidiabetic 
activity of ciglitazone was also reported in Diabetes, 32, P. 804 (1983). 
None of them, however, has not come into practical use as an antidiabetic 
agent mainly because they are (1) weak in effect and/or (2) high in 
toxicity. 
The present inventors synthesized and evaluated various compounds not 
specifically described in the abovecited patent publications and, as a 
result, compounds having potent pharmacological activity with low toxicity 
were found. 
It is an object of the invention to provide those compounds which have a 
wide safety margin between the pharmacologically effective dose and the 
dose at which toxicity and/or adverse effects may appear and therefore can 
be put to practical use as antidiabetics. 
The present invention thus provides: 
(1) Thiazolidinedione derivatives of the general formula: 
##STR2## 
wherein X is an oxygen or sulfur atom, R.sup.1 and R.sup.2 each 
independently hydrogen or a hydrocarbon residue which may optionally be 
substituted and R.sup.1 and R.sup.2 may jointly, together with the oxazole 
or thiazole ring, form a condensed ring and A is a lower alkylene group, 
and salts thereof; 
(2) Pharmaceutical compositions suitable for the therapy of a mammal 
suffering from diabetes and/or hyperlipemia, which contain as the 
effective component a thiazolidinedione derivative of the general formula 
(I) or a pharmacologially acceptable salt thereof. 
(3) A method of producing thiazolidinedione derivatives of the general 
formula (I) and salts thereof which comprises hydrolyzing a compound of 
the general formula: 
##STR3## 
wherein the symbols are as defined above, or a salt thereof; and 
(4) A method of producing thiazolidinedione derivatives of the general 
formula: 
##STR4## 
wherein the symbols are as defined above, and salts thereof, which 
comprises reacting a compound of the general formula: 
##STR5## 
wherein R.sup.1, R.sup.2 and X are as defined above and Y is a halogen 
atom, with a compound of the formula: 
##STR6## 
The hydrocarbon residue represented by R.sup.1 and/or R.sup.2 in the above 
general formulas (I), (Ia), (II) and (III) may be an aliphatic hydrocarbon 
residue, an alicyclic hydrocarbon residue, an alicyclic-aliphatic 
hydrocarbon residue, an aromatic-aliphatic hydrocarbon residue or an 
aromatic hydrocarbon residue. Said aliphatic hydrocarbon residue includes 
saturated aliphatic hydrocarbon residues containing 1-8 carbon atoms, 
(e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 
t-butyl, pentyl, hexyl, heptyl and octyl), preferably 1-4 carbon atoms; 
said alicyclic hydrocarbon residue includes saturated alicyclic 
hydrocarbon residues containing 3-7 carbon atoms, such as cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and unsaturated 
alicyclic hydrocarbon residues containing 5-7 carbon atoms, such as 
1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 
2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl and 2-cycloheptenyl; said 
alicyclic-aliphatic hdyrocarbon residue includes groups resulting from 
bonding the abovementioned alicyclic hydrocarbon residues to the 
abovementioned aliphatic hydrocarbon residues and containing 4-9 carbon 
atoms, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, 
cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, 
cyclohexylmethyl, 2-cyclohexenylmethyl, cycloheptylmethyl and 
cycloheptylethyl; said aromatic-aliphatic hydrocarbon residue includes 
phenylalkyl groups containing 7-9 carbon atoms, such as benzyl, phenethyl, 
1-phenylethyl and phenylpropyl, and naphthylalkyl groups containing 11-13 
carbon atoms, such as .alpha.-naphthylmethyl, .alpha.-naphthylethyl and 
.beta.-naphthylethyl; and said aromatic hydrocarbon residue includes, 
among others, phenyl and naphthyl (.alpha.-naphthyl, .beta.-naphthyl). By 
saying that R.sup.1 and R.sup.2 jointly, together with the oxazole or 
thiazole ring, form a condensed ring, it is precisely meant that R.sup.1 
and R.sup.2, together with the thiazole or oxazole ring carbon atoms to 
which they are attaching, form a ring. Thus, it is meant that R.sup.1 and 
R.sup.2 are combined together to form a saturated or unsaturated divalent 
chain hydrocarbon residue containing 3-5 carbon atoms. Examples of said 
chain hydrocarbon residue are --CH.sub.2 CH.sub.2 CH.sub.2 --, --CH.sub.2 
CH.sub.2 CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 
CH.sub.2 --, --CH.dbd.CHCH.sub.2 --, --CH.dbd.CH--CH.dbd.CH--, 
--CH.dbd.CH--CH.dbd.CH--CH.sub.2 -- and --CH.dbd.CH--CH.sub.2 CH.sub.2 
CH.sub.2 --. 
The hydrocarbon residue represented by R.sup.1 and/or R.sup.2 may have at 
least one substituent in any position thereof. When R.sup.1 and/or R.sup.2 
contains an alicyclic group, R.sup.1 and/or R.sup.2 may have, on the ring 
thereof, 1-3 lower alkyl groups containing 1-3 carbon atoms (e.g. methyl, 
ethyl, propyl, isopropyl). When R.sup.1 and/or R.sup.2 contains an 
aromatic hydrocarbon residue or when R.sup.1 and R.sup.2 combinedly form a 
condensed ring, the ring may be substituted with 1-4 substituents, which 
may be the same or different. Said substituents include, among others, 
halogen (fluorine, chlorine, iodine), hydroxy, cyano, trifluoromethyl, 
lower alkoxy (e.g. one containing 1-4 carbon atoms, such as methoxy, 
ethoxy, propoxy or butoxy), lower alkyl (e.g. one containing 1-4 carbon 
atoms, such as methyl, ethyl, propyl, isopropyl or butyl) and lower 
alkylthio (e.g. one containing 1-3 carbon atoms, such as methylthio, 
ethylthio, porpylthio or isopropylthio). 
A lower alkylene groups represented by A is a straight or branched chain 
having 1 to 3 carbon atoms and includes methylene, ethylene, propylene and 
trimethylene. 
The halogen represented by Y in formula (III) includes chlorine, bromine 
and iodine. 
Compounds of the general formula (I) can form salts with bases since they 
have an acidic nitrogen atom in their thiazolidine ring. Such salts 
include, among others, pharmacologically acceptable salts such as sodium, 
potassium, magnesium and calcium salts. 
The compounds (I) and salts thereof according to the invention exhibit 
excellent blood sugar and blood lipid lowering activities in mammals (e.g 
mouse, rat, dog, cat, monkey, horse, human) and are low in acute toxicity 
as well as in sabacute toxicity. Therefore, the thiazolidinedione 
derivatives (I) and salts thereof are useful in the treatment of 
hyperlipidemia and/or diabetes and complications resulting therefrom. They 
are generally administered orally in the form of tablets, capsules, 
powders or granules, for instance. In some instances, they may be 
administered parenterally in the form of injections, suppositories or 
pellets, among others. In using them as therapeutic agents for diabetes or 
hyperlipidemia, they can be administered generally in an oral daily dose 
of 0.01-10 mg/kg or a parenteral daily dose of 0.005-10 mg/kg. Desirably, 
they are administered in such dose every day or intermittently 2-4 times a 
week. 
The compounds of general formula (I) or salts thereof can be produced by 
hydrolyzing the compounds of general formula (II) or salts thereof. This 
hydrolysis reaction is generally carried out in an appropriate solvent in 
the presence of water and a mineral acid. Examples of the solvent which 
are generally used are alkanols (e.g. methanol, ethanol, propanol, 
2-propanol, butanol, isobutanol, 2-methoxyethanol), dimethyl sulfoxide, 
sulfolane, dioxane and dimethoxyethane. The mineral acid is, for example, 
hydrochloric acid, hydrobromic acid or sulfuric acid and is used in an 
amount of 0.1-10 moles, preferably 0.2-3 moles, per mole of the compound 
of general formula (II). Water is used generally in large molar excess 
relative to the compound of general formula (II). This reaction is 
generally carried out with warming or heating and the reaction temperature 
is generally 60.degree.-150.degree. C. The heating time is generally 
several hours to ten and odd hours. 
Those compounds of general formula (I) wherein A is methylene and salts 
thereof, namely the compounds of general formula (Ia) and salts thereof 
[hereinafter collectively referred to as "compounds (Ia)"], can be 
obtained by reacting a compound of general formula (III) with a compound 
of general formula (IV) or a salt thereof [hereinafter collectively 
referred to as "compound (IV)"]. The reaction of the compound of general 
formula (III) and the compound (IV) is generally carried out in the 
presence of an appropriate solvent and an appropriate base and this 
reaction gives the compounds (Ia). 
Such solvent includes, among others, dimethylformamide, dimethyl sulfoxide, 
sulfolane, tetrahydrofuran and dimethoxyethane. Examples of said base are 
sodium hydride, potassium hydride, sodium amide, sodium alkoxide (e.g. 
sodium methoxide, sodium ethoxide), potassium alkoxide (e.g. potassium 
t-butoxide) and potassium carbonate. This reaction is preferably carried 
out by first allowing formation of a dianion by bringing such base into 
contact with the compound (IV) in a molar ratio of 2:1 and thereafter 
adding the compound of general formula (III) in an amount of 1 mole per 
mole of compound (IV). This condensation reaction is carried out generally 
at 0.degree.-120.degree. C., preferably 20.degree.-100.degree. C., and the 
reaction time is generally 0.5-5 hours. 
The thus-produced thiazolidinedione derivatives (I) and salts thereof can 
be isolated and purified by known separation/purification techniques such 
as, for example, concentration, concentration under reduced pressure, 
solvent extraction, crystallization, recrystallization, phase transfer and 
chromatography. 
The starting compounds (II) can be produced, for example, by the following 
methods: 
(1) The process illustrated below gives those compounds of general formula 
(I) wherein X is an oxygen atom, namely the compounds of general formula 
(IIa), and salts thereof [hereinafter collectively referred to as 
"compounds (IIa)]. 
##STR7## 
[In the above formulas, R.sup.1, R.sup.2 and A are as defined above and 
R.sup.3 is hydrogen or a lower alkyl group.] 
The reaction for deriving the compound (VII) from the compound (V) is 
carried out in the manner of condensation of the compound (V) with the 
compound (VI) in the presence of a deacidifying agent (e.g. potassium 
carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen 
carbonate, sodium hydroxide, potassium hydroxide, triethylamine). This 
reaction can be conducted in a solvent, such as dimethylformamide, 
dimethyl sulfoxide, tetrahydrofuran, ethyl ether, ethyl acetate, 
chloroform or dichloromethane, or a mixed solvent prepared by adding water 
to such solvent as necessary, at -10.degree. C. to 50.degree. C. 
The compound (VII) is then subjected to ring closure, whereby the compound 
(VIII) can be derived. This reaction is carried out generally in the 
presence of a dehydrating agent. Known dehydrating agents, such as 
phosphorus oxychloride, thionyl chloride, phosphorus pentoxide, 
polyphosphoric acid, polyphosphoric acid esters, acetic anhydride and 
sulfuric acid, and mixtures of these, may suitably be used. Although the 
reaction conditions may vary depending on the dehydrating agent employed, 
this reaction can be effected generally in an inert solvent (e.g. benzene, 
toluene, xylene, dichloromethane, chloroform) at about 
30.degree.-140.degree. C., or in an excess of the dehydrating agent, which 
serves also as a solvent, within said temperature range. The dehydrating 
agent is used in an amount of 1-30 moles per mole of compound (VII). 
The reaction for deriving the compound (IX) from the compound (VIII) can be 
readily carried out in the manner of a conventional catalytic reduction 
using palladium-on-carbon as catalyst or a conventional reduction using 
zinc or iron in combination with acetic acid. The compound (IX) may be 
isolated in pure form or may be subjected to the next reaction step 
without isolation or purification. 
The reaction for deriving the compound (XI) from the compound (IX) is 
carried out in the manner of the so-called Meerwein arylation. Thus, the 
compound (IX) is diazotized in the presence of a hydrohalogenic acid (HY) 
and then reacted with acrylic acid or an ester thereof (X) in the presence 
of a copper catalyst (e.g. cuprous oxide, cupric oxide, cuprous chloride, 
cupric chloride, cuprous bromide, cupric bromide). The compound (IX) may 
be purified, for example by chromatography or may be submitted to the next 
reaction step without isolation and purification. 
Reaction of the compound (XI) with thiourea then gives (IIa). This reaction 
is carried out generally in a solvent such as an alcohol (e.g. methanol, 
ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol), 
dimethylformamide, dimethyl sulfoxide or sulfolane. The reaction 
temperature is generally 20.degree.-180.degree. C., preferably 
60.degree.-150.degree. C. Thiourea is used in an amount of 1-2 moles per 
mole of compound (XI). In this reaction, a hydrogen halide is formed as a 
byproduct with the progress of the reaction, whereby the hydrohalogenic 
acid salt of compound (IIa) is formed. In this case, the reaction may be 
carried out in the presence of sodium acetate, potassium acetate or the 
like so that the hydrogen halide can be captured thereby and (IIa) can be 
produced in the free form. Such acid acceptor is used generally in an 
amount of 1-1.5 moles per mole of compound (XI). Such reaction gives the 
compound (IIa), which may be isolated as desired or may be submitted 
directly to the next hydrolysis step without isolation thereof. 
(2) The compounds (II) can also be produced by the following process: 
##STR8## 
In the formulas, the symbols are as defined above. 
In the above process, the compound (XII) is reacted with the compound 
(XIII) and thereafter, in the same manner as in the case of (VIII) in the 
process (1) described above, the resulting compound (XIV) is reduced, 
diazotized and subjected to the Meerwein arylation reaction. Further 
reaction of the arylation product with thiourea gives (II). The reaction 
of (XII) with (XIII) can be carried out in a solvent, such as 
dimethylformamide or tetrahydrofuran, in the presence of, for example, 
sodium hydride. 
Furthermore, the starting compound (IV) required in practicing the present 
invention can be synthesized by the method described in Chemical & 
Pharmaceutical Bulletin, vol. 30, p. 3563 (1982).

[EXAMPLES] 
Example 1 
A mixture of 
2-imino-5-{4-[2-(4-methyl-5-phenyl-2-oxazolyl)ethoxy]benzyl}-4-thiazolidin 
one (5,5 g), ethanol (100 ml) and 2N HCl (60 ml) was heated under reflux 
for 6 hours and then poured into water and extracted with chloroform. The 
chloroform layer was washed with water and dried (MgSO.sub.4). The solvent 
was distilled off to give 
5-{4-[2-(4-methyl-5-phenyl-2-oxazolyl)ethoxy}-2,4-thiazolidinedione (2.8 
g, 50.9%). Recrystallization from ethyl acetate gave colorless prisms. 
M.p. 168.degree.-169.degree. C. 
Elemental analysis: Calcd. for C.sub.22 H.sub.20 N.sub.2 O.sub.4 S: C, 
64.69; H, 4.93; N, 6.86; Found: C, 64.90; H, 5.05; N, 6.82. 
Examples 2-4 
In the same manner as Example 1, the compounds listed in Table 1 were 
obtained. 
TABLE 1 
______________________________________ 
##STR9## 
Ex- Recrystal- 
ample M.P. lization 
Yield 
No. R.sup.1 R.sup.2 
(.degree.C.) 
solvent (%) 
______________________________________ 
2 (CH.sub.3).sub.2 CHCH.sub.2 
CH.sub.3 
123-124 
Ethy- 88.0 
acetate- 
hexane 
3 H CH.sub.3 
156-157 
Ethanol 71.4 
##STR10## CH.sub.3 
175-176 
Ethanol- dichloro- methane 
48.2 
______________________________________ 
Example 5 
A mixture of 
2-imino-5-{4-[2-(5-methyl-4-phenyl-2-oxazolyl)ethoxy]benzyl}-4-thiazolidin 
one (7.6 g), 1N H.sub.2 SO.sub.4 (70 ml) and dioxane (70 ml) was stirred at 
80.degree. C. for 24 hours and then concentrated. The residue was 
neutralized with potassium carbonate and extracted with ethyl acetate. The 
ethyl acetate layer was washed with water and dried (MgSO.sub.4). The 
solvent was then distilled off and the oily residue was subjected to 
column chromatography using silica gel (120 g). 
Elution with chloroform-methanol 
(49:1, v/v) gave 
5-{4-[2-(5-methyl-4-phenyl-2-oxazolyl)ethoxy]benzyl}-2,4-thiazolidinedione 
as an oil (7.06 g, 92.7%). 
IR (Neat)cm.sup.-1 : 1755, 1700. 
NMR .delta.ppm in CDCl.sub.3 : 2.48(3H, s), 3.02(1H, d, d, J=14 and 9), 
3.21(2H, t, J=7), 3.41(1H, d, d, J=14 and 4), 4.35(2H, t, J=7), 4.41(1H, 
d, d, J=9 and 4), 6.84(2H, d, J=9), 7.11(2H, d, J=9), 7.2.about.7.75(5H, 
m), 9.30(1H, broad). 
The above-obtained oily substance (7.0 g) was dissolved in methanol (50 
ml), and 5N NaOMe (MeOH solution, 3.77 ml) was added to the solution. The 
mixture was stirred at room temperature for 10 minutes and concentrated 
and, then, the residue was treated with ether to give sodium salt of 
5-{4-[2-(5-methyl-4-phenyl-2-oxazolyl)ethoxy]benzyl}-2,4-thiazolidinedione 
(5.8 g, 78.6%). Recrystallization from methanol-ether gave colorless 
prisms. M.p. 261.degree.-262.degree. C. (decomposition). 
Elemental analysis: Calcd. for C.sub.22 H.sub.19 N.sub.2 O.sub.4 SNa: C, 
61.39; H, 4.45; N, 6.51; Found: C, 61.56; H, 4.56; N, 6.64. 
Example 6 
The procedure of Example 5 was followed to give sodium salt of 
5-{4-[2-(5-ethyl-4-phenyl-2-oxazolyl)ethoxy]benzyl}-2,4-thiazolidinedione 
in 76.9% yield. Recrystallization from ethanol gave colorless prisms. 
M.p. 248.degree.-250.degree. C. (decomposition). 
Elemental analysis: Calcd. for C.sub.23 H.sub.21 N.sub.2 O.sub.4 SNa: C, 
62.15; H, 4.76; N, 6.30; Found: C, 61.76; H, 4.66; N, 6.40. 
Example 7 
Sodium hydride (60% in oil, 1.2 g) was added to a solution of 
5-(4-hydroxybenzyl)-2,4-thiazolidinedione (3.4 g) in DMF (30 ml), and the 
mixture was stirred at room temperature for 30 minutes, followed by 
dropwise addition of a solution of 2-chloromethyl-4-phenylthiazole (4.4 g) 
in DMF (20 ml) at room temperature. The mixture was stirred at room 
temperature for 1 hour and at 60.degree. C. for 1 hour, poured into water, 
neutralized with acetic acid and extracted with ethyl acetate. The ethyl 
acetate layer was washed with water and dried (MgSO.sub.4). The solvent 
was then distilled off and the oily residue was subjected to column 
chromatography using silica gel (100 g). Elution with benzene-acetone 
(25:1, v/v) gave 
5-[4-(4-phenyl-2-thiazolylmethoxy)benzyl]-2,4-thiazolidinedione (2.9 g, 
49.2%). Recrystallization from ethanol gave light-yellow crystals. M.p. 
164.degree.-165.degree. C. 
Elemental analysis: Calcd. for C.sub.20 H.sub.16 N.sub.2 O.sub.3 S.sub.2 : 
C, 60.59; H, 4.07; N, 7.07; Found: C, 60.67; H, 4.03; N, 7.14. 
Examples 8-9 
The procedure of Example 7 was repeated to give the compounds listed in 
Table 2. 
TABLE 2 
______________________________________ 
##STR11## 
Example Yield 
No. X M.P. (.degree.C.) 
Recrystallization solvent 
(%) 
______________________________________ 
8 O 188-189 Dichloromethane-methanol 
32.5 
9 S 184-185 Dichloromethane-methanol 
35.3 
______________________________________ 
Example 10 
Production of tablets 
______________________________________ 
(a) (1) Sodium salt of 5-{4-[2-(5-methyl-4- 
30 g 
phenyl-2-oxazolyl)ethoxy]benzyl}-2,4- 
thiazolidinedione 
(2) Lactose 50 g 
(3) Corn starch 15 g 
(4) Carboxymethylcellulose calcium 
44 g 
(5) Magnesium stearate 1 g 
1,000 tablets 140 g 
______________________________________ 
A mixture of the indicated quantities of (1), (2) and (3), 30 g of (4) and 
an adequate quantity of water is kneaded, then dried under vacuum, and 
granulated. The granular composition obtained is mixed with 14 g of (4) 
and 1 g of (5) and the resulting mixture is tableted on a tableting 
machine to give 1,000 tablets each containing 30 mg of (1). 
Reference Example 1 
A mixture of 3-(4-nitrophenoxy)propionic acid (10.5 g), thionyl chloride 
(11.9 g), N,N-dimethylformamide (0.3 g) and toluene (100 ml) was stirred 
at 90.degree. C. for 1 hour, then concentrated under reduced pressure, and 
the oily residue was dissolved in ethyl acetate (30 ml). The solution was 
added dropwise to a mixture of 3-amino-5-methyl-2-hexanone hydrochloride 
(8.3 g), sodium carbonate (10.6 g), water (200 ml) and ethyl acetate (100 
ml) at room temperature. The mixture was stirred at room temperature for 1 
hour and the ethyl acetate layer was separated. The ethyl acetate layer 
was washed with water and dried (MgSO.sub.4). The solvent was distilled 
off to give 3-[3-(4-nitrophenoxy)propionylamino]-5-methyl-2-hexanone (11.5 
g, 71.4%). Recrystallization from ethyl acetate-hexane gave colorless 
prisms. M.p. 101.degree.-102.degree. C. 
Elemental analysis: Calcd. for C.sub.16 H.sub.22 N.sub.2 O.sub.5 : C, 
59.62; H, 6.88; N, 8.69; Found: C, 59.67; H, 6.79; N, 8.61. 
In the same manner as above, there were obtained the compounds listed in 
Table 3. 
TABLE 3 
______________________________________ 
##STR12## 
Re- 
crystallization 
Yield 
R.sup.1 R.sup.2 M.P. (.degree.C.) 
solvent (%) 
______________________________________ 
CH.sub.3 
##STR13## 134-135 Ethyl acetate- hexane 
75.5 
H CH.sub.3 147-148 Ethanol 52.6 
##STR14## 
CH.sub.3 131-132 Ethyl acetate 
79.6 
##STR15## 
CH.sub.3 143-144 Ethyl acetate- hexane 
63.2 
##STR16## 
C.sub.2 H.sub.5 
132-133 Ethyl acetate 
76.2 
______________________________________ 
Reference Example 2 
A mixture of 3-[3-(4-nitrophenoxy)propionylamino]-5-methyl-2-hexanone (11.0 
g), phosphorus oxychloride (6.3 g) and toluene (100 ml) was stirred under 
reflux for 1 hour. After cooling, the mixture was poured into ethyl 
acetate (200 ml), washed with saturated aqueous sodium hydrogen carbonate 
and water in that order and dried (MgSO.sub.4). The solvent was then 
distilled off and the oily residue was subjected to column chromatography 
using silica gel (150 g), whereby 
4-isobutyl-5-methyl-2-[2-(4-nitrophenoxy)ethyl]oxazole (8.1 g, 78.6%) was 
recovered from an ethyl acetate-hexane (1:4, v/v) eluate fraction. 
Recrystallization from ether-hexane gave colorless needles. M.p. 
45.degree.-46.degree. C. 
Elemental analysis: Calcd. for C.sub.16 H.sub.20 N.sub.2 O.sub.4 : C, 
63.14; H, 6.62; N, 9.20; Found: C, 63.14; H, 6.44; N, 9.27. 
In the same manner as above, there were obtained the following compounds 
listed in Table 4. 
TABLE 4 
______________________________________ 
##STR17## 
Re- 
crystallization 
Yield 
R.sup.1 R.sup.2 M.P. (.degree.C.) 
solvent (%) 
______________________________________ 
CH.sub.3 
##STR18## 117-118 Ethyl acetate- hexane 
89.0 
H CH.sub.3 89-90 Ethyl acetate- 
82.3 
hexane 
##STR19## 
C.sub.2 H.sub.5 
72-73 Ether-hexane 
89.5 
##STR20## 
CH.sub.3 91-92 Ether-hexane 
81.7 
##STR21## 
CH.sub.3 88-89 Ether-hexane 
86.3 
______________________________________ 
Reference Example 3 
A solution of 4-methyl-2-[2-(4-nitrophenoxy)ethyl]-5-phenyloxazole (12.5 g) 
in methanol (150 ml) was subjected to catalytic reduction in the presence 
of 5% Pd-C (wet, 3.0 g). The catalyst was then filtered off and the 
filtrate was concentrated to give 
2-[2-(4-aminophenoxy)ethyl]-4-methyl-5-phenyloxazole (11.0 g, 97.3%). 
Recrsytallization from ethanol gave colorless needles. M.p. 
106.degree.-107.degree. C. 
Elemental analysis: Calcd. for C.sub.18 H.sub.18 N.sub.2 O.sub.2 : C, 
73.45; H, 6.16; N, 9.52; Found: C, 73.53; H, 6.11; N, 9.44. 
The above procedure was followed to give 
2-[2-(4-aminophenoxy)ethyl]-5-ethyl-4-phenyloxazole in 98.7% yield. 
Recrsytallization from ether-hexane gave colorless prisms. M.p. 
89.degree.-90.degree. C. 
Elemental analysis: Calcd. for C.sub.19 H.sub.20 N.sub.2 O.sub.2 : C, 
74.00; H, 6.54; N, 9.08; Found: C, 74.05; H, 6.28; N, 9.25. 
Reference Example 4 
(1) 2-[2-(4-Aminophenoxy)ethyl]-4-methyl-5-phenyloxazole (10.5 g) was 
dissolved in acetone (100 ml)-methanol (30 ml), and 47% aqueous HBr (24.6 
g) was added to the solution, followed by dropwise addition of a solution 
of NaNO.sub.2 (2.7 g) in water (10 ml) at 5.degree. C. The mixture was 
stirred at 5.degree. C. for 15 minutes and methyl acrylate (18.4 g) was 
added thereto. The resulting mixture was then warmed to 38.degree. C. and, 
with stirring vigorously, cupurous oxide powder (1 g) was added 
portionwise to the mixture. The mixture was stirred until completion of 
nitrogen gas generation, then concentrated, and the residue was made basic 
with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate 
layer was washed with water and dried (MgSO.sub.4). The solvent was 
distilled off to give crude 
2-bromo-3-{4-[2-(4-methyl-5-phenyl-2-oxazolyl)ethoxy]phenyl}propionate as 
an oil (14.3 g, 89.9%). 
IR (Neat)cm.sup.-1 : 1740. 
NMR .delta.ppm in CDCl.sub.3 : 2.37(3H, s), 3.0.about.3.6(2H, m), 3.25(2H, 
t, J=7), 3.67(3H, s), 4.2.about.4.5(3H, m), 6.7.about.7.7(9H, m). 
(2) To a solution of the oily substance (14.0 g) obtained in the above 
procedure (1) in ethanol (150 ml) were added thiourea (2.4 g) and sodium 
acetate (2.6 g), and the mixture was stirred under reflux for 3 hours and 
then concentrated. The residue was neutralized with saturated aqueous 
sodium hydrogen carbonate, followed by addition of ether (50 ml)-hexane 
(50 ml). The mixture was stirred for 10 minutes and the resulting 
crystalline precipitate was collected by filtration to give 
2-imino-5-{4-[2-(4-methyl-5-phenyl-2-oxazolyl)ethoxy]benzyl}-4-thiazolidin 
one (6.0 g, 46.2%). Recrystallization from chloroform-methanol gave 
colorless prisms. M.p. 194.degree.-195.degree. C. 
Elemental analysis: Calcd. for C.sub.22 H.sub.21 N.sub.3 O.sub.3 S: C, 
64.85; H, 5.19; N, 10.31; Found: C, 64.67; H, 5.03; N, 10.02. 
In the same manner as above, there was obtained 
5-{4-[2-(5-ethyl-4-phenyl-2-oxazolyl)ethoxy]benzyl}-2-imino-4-thiazolidino 
ne. The overall yield from the corresponding amino compound was 39.2%. 
Recrystallization from methanol gave colorless prisms. M.p. 
164.degree.-165.degree. C. 
Elemental analysis: Calcd. for C.sub.23 H.sub.23 N.sub.3 O.sub.3 S: C, 
65.54; H, 5.50; N, 9.97; Found: C, 65.32; H, 5.42; N, 9.95. 
Reference Example 5 
A solution of 4-isobutyl-5-methyl-2-[2-(4-nitrophenoxy)ethyl]oxazole (7.8 
g) in methanol (100 ml) was subjected to catalytic reduction in the 
presence of 5% Pd-C (wet, 2.0 g). The catalyst was then filtered off and 
the filtrate was concentrated to give an amino compound as an oil. The 
amino compound was dissolved in acetone (50 ml)-methanol (20 ml), and 47% 
aqueous HBr (17.9 g) was added, followed by dropwise addition of a 
solution of NaNO.sub.2 (1.9 g) in water (6 ml) at 5.degree. C. or lower. 
The mixture was stirred at 5.degree. C. for 15 minutes. Methyl acrylate 
(15.7 g) was then added and the resulting mixture was warmed to 38.degree. 
C. and, with stirring vigorously, cupurous oxide powder (0.5 g) was added 
portionwise to the mixture. The mixture was stirred until completion of 
nitrogen gas generation and then concentrated. The residue was made basic 
with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate 
layer was washed with water and dried (MgSO.sub.4). The solvent was 
distilled off to give crude 
2-bromo-3-[4-[2-(4-isobutyl-5-methyl-2-oxazolyl)ethoxy]phenyl]propione as 
an oil (9.5 g, 86.4%). 
IR (Neat)cm.sup.-1 : 1740. 
NMR .delta.ppm in CDCl.sub.3 : 0.88(6H, d, J=7), 1.8-2.1(1H, m), 2.17(3H, 
s), 2.2.about.2.4(2H, m), 3.0.about.3.5(2H, m), 3.12(2H, t, J=7), 3.68(3H, 
s), 4.2-4.5(1H, m), 4.28(2H, t, J=7), 6.7-7.4(4H, m) 
(2) To a solution of the oily product (9.2 g) obtained in the above 
procedure (1) in ethanol (100 ml) were added thiourea (1.7 g) and sodium 
acetate (1.8 g), and the mixture was stirred under reflux for 3 hours and 
then concentrated. The residue was neutralized with saturated aqueous 
sodium hydrogen carbonate, followed by addition of ether (50 ml)-hexane 
(50 ml). The mixture was stirred for 10 minutes and the resulting 
crystalline precipitate was collected by filtration and recrystallized 
from ethyl acetate to give 
2-imino-5-{4-[2-(4-isobutyl-5-methyl-2-oxazolyl)ethoxy]benzyl}-4-thiazolid 
inone (3.0 g, 35.7%) as colorless prisms. M.p. 167.degree.-168.degree. C. 
Elemental analysis: Calcd. for C.sub.20 H.sub.25 N.sub.3 O.sub.3 S: C, 
61.99; H, 6.50; N, 10.84; Found: C, 61.96; H, 6.39; N, 10.70. 
In the same manner as above, there were obtained the compounds listed in 
Table 6. The yield is the overall yield from the corresponding starting 
amino compound. 
TABLE 6 
______________________________________ 
##STR22## 
Re- 
crystallization 
Yield 
R.sup.1 R.sup.2 M.P. (.degree.C.) 
solvent (%) 
______________________________________ 
H CH.sub.3 198-199 Methanol 38.6 
##STR23## 
CH.sub.3 152-154 Ethyl acetate 
50.1 
##STR24## 
CH.sub.3 178-180 Methanol 47.2 
______________________________________ 
Test Example 
Blood sugar and lipid lowering activities in mice 
The test compound was mixed with a powder diet (CE-2, Clea Japan) at an 
addition level of 0.005% and the diet was given to KKA.sup.y mice (male, 
8-10 weeks old; 5 mice per group) ad libitum for 4 days, during which the 
mice were freely accessible to water. Blood samples were collected from 
the orbital venous plexus and assayed for blood sugar level by the glucose 
oxidase method and for plasma triglyceride (TG) level by enzymaticlly 
determining glycerol formed using Cleantech TG-S kit (Iatron). Both the 
activity levels were calculated using the formula given below. The results 
thus obtained are shown in Table 7. For comparison, data for a known 
compound of a similar structure are also given. 
##EQU1## 
TABLE 7 
______________________________________ 
Blood sugar TG lowering 
lowering activity (%) 
activity (%) 
______________________________________ 
1 18* 7 
2 53**** 43*** 
4 54**** 51**** 
5 54**** 60**** 
6 46**** 51**** 
7 43**** 42*** 
8 35** 24 
9 43*** 43** 
control compound 
10 -13 
ciglitazone.sup.(1) 
______________________________________ 
t-Test 
*P &lt; 0.05, 
**P &lt; 0.02, 
***P &lt; 0.01, 
****P &lt; 0.001 
.sup.(1) 5[4(1-Methylcyclohexylmethoxy)]benzyl2,4-thiazolidinedione