THIAZOLIDINEDIONE DERIVATIVES, THEIR PRODUCTION AND USE

Description

TECHNICAL FIELD

[0001] The present invention relates to a novel thiazolidinedione derivative having hypoglycemic activity and blood lipid lowering activity, production thereof, and an antidiabetic agent containing it. The present invention is useful in the field of medicine.

BACKGROUND OF ART

[0002] As an agent for treating diabetes, various biguanide compounds and sulfonylurea compounds have been used. However, biguanide compounds are now hardly used because of their side effect of lactic acid acidosis. Although sulfonylurea compounds have potent hypoglycemic activity, they often cause serious hypoglycemia and must be used with care.

[0003] Thiazolidinedione derivatives having hypoglycemic activity and blood lipid lowering activity without the above disadvantages have been known. For example, JP-A 61-85372, JP-A 1-272573, JP-A 1-272574, JP-A3-2173, JP-A4-66579, JP-A4-69383, JP-A 6-157522, etc., disclose 2,4-thiazolidinedione derivatives having at the 5-position a substituent such as a benzyl group or an arylmethyl group substituted by a substituted aromatic ring, etc.

DISCLOSURE OF INVENTION

[0004] The present inventors have intensively studied 2,4-thiazolidinedione derivatives. As a result, it has been found that a novel 2,4-thiazolidinedione derivative has hypoglycemic activity and blood lipid lowering activity, said 2,4-thiazolidinedione derivative having at the 5-position a substituent such as a 2-(substituted phenyl or substituted pyridyl)ethyl group, a 3-(substituted phenyl or substituted pyridyl)propyl group, a 4-(substituted phenyl or substituted pyridyl)butyl group, a 5-(substituted phenyl or substituted pyridyl)pentyl group, etc., and having a bivalent straight or branched hydrocarbon chain containing a substituted phenyl or substituted pyridyl group at the terminal (in the case of a branched hydrocarbon chain, a part of it and a substituent on the substituted phenyl group may be linked together to form a ring). Thus, the present invention has been completed.

[0005] The present invention provides a 2,4-thiazolidinedione derivative of the formula (I):

wherein
   R is an aromatic heterocyclic group which may be attached through a straight or branched and saturated or unsaturated hydrocarbon chain having 8 carbon atoms, the aromatic heterocyclic group having the formula:

wherein B¹ is a sulfur atom, an oxygen atom or NR⁴ in which R⁴ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an aralkyl group selected from benzyl and phenethyl;
   B² is a nitrogen atom or C-R⁵ in which R⁵ is

(1) a hydrogen atom,

(2) a hydrocarbon group selected from

a) saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms

b) saturated or unsaturated alicyclic hydrocarbon group having 3 to 7 carbon atoms

c) saturated or unsaturated alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms

d) aromatic carbocycle-aliphatic hydrocarbon group selected from phenylalkyl having 7 to 9 carbon atoms and naphthylalkyl having 11 to 13 carbon atoms, and

e) aromatic hydrocarbon group selected from phenyl and naphthyl,

   when the hydrocarbon group contains an alicyclic group, the alicyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms, and
   when the hydrocarbon group contains an aromatic hydrocarbon group, the hydrocarbon group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylythio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms,

(3) 5- or 6-membered cyclic group which contains 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and which is attached through a ring-constituting carbon atom,
   when the cyclic group is saturated, the cyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms,
   when the cyclic group is unsaturated, the cyclic group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylthio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms, and
   when the cyclic group is substituted by at least 2 hydrocarbon groups at adjacent positions to each other on the cycle, these hydrocarbon groups may be linked together to form a condensed ring;

R³ is

(1) a hydrogen atom,

(2) a hydrocarbon group selected from

a) saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms

b) saturated or unsaturated hydrocarbon group having 3 to 7 carbon atoms

c) saturated or unsaturated alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms

d) aromatic carbocycle-aliphatic hydrocarbon group selected from phenylalkyl having 7 to 9 carbon atoms and naphthylalkyl having 11 to 13 carbon atoms, and

e) aromatic hydrocarbon group selected from phenyl and naphthyl,

   when the hydrocarbon group contains an alicyclic group, the alicyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms, and
   when the hydrocarbon group contains an aromatic hydrocarbon group, the hydrocarbon group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylythio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms,

(3) 5- or 6-membered cyclic group which contains 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and which is attached through a ring-constituting carbon atom,
   when the cyclic group is saturated, the cyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms,
   when the cyclic group is unsaturated, the cyclic group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylthio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms, and
   when the cyclicgroup is substituted by at least 2 hydrocarbon groups at adjacent positions to each other on the cycle, these hydrocarbon groups may be linked together to form a condensed ring;

R³ and R⁵ may be linked together to form a condensed ring when
R³ and R⁵ are attached to adjacent carbon atoms to each other;
n is 0 or 1;
X is CH;
Y is -CH₂CH₂-;
R¹ and R² are the same or different and are

(1) a hydrogen atom;

(2) a halogen atom;

(3) an optionally substituted hydroxyl group selected from a hydroxyl group and alkoxy groups having 1 to 4 carbon atoms;

(4) a hydrocarbon group selected from

a) saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms

b) saturated or unsaturated alicyclic hydrocarbon group having 3 to 7 carbon atoms

c) saturated or unsaturated alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms

d) aromatic carbocycle-aliphatic hydrocarbon group selected from phenylalkyl having 7 to 9 carbon atoms and naphthylalkyl having 11 to 13 carbon atoms, and

e) aromatic hydrocarbon group selected from phenyl and naphthyl,

   when the hydrocarbon group contains an alicyclic group, the alicyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms, and
   when the hydrocarbon group contains an aromatic hydrocarbon group, the hydrocarbon group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylythio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms,
and either R¹ or R² and a part of Y may be linked together to form a ring; and

   L and M are a hydrogen atom, or L and M are linked together to form a bond;
or a salt thereof.

[0006] The present invention also provides a pharmaceutical composition which comprises a 2,4-thiazolidinedione derivative of the above formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0007] The present invention also provides a process for producing a 2,4-thiazolidinedione derivative of the formula (I-B2) :

wherein each symbol is as defined above, which comprises hydrolyzing an iminothiazolidinone compound of the formula (III) :

wherein each symbol is as defined above.

[0008] The present invention also provides a process for producing a 2,4-thiazolidinedione derivative of the formula (I-B2a) :

wherein
   R' is the aromatic heterocyclic group as defined above, which may be attached through a saturated hydrocarbon chain having 1 to 8 carbon atoms;
   Y¹ is -CH₂CH₂-;
   either R¹ or R² and a part of Y¹ may be linked together to form a ring;
and the other symbols are as defined above; which comprises reducing a compound of the formula (I-B1) :

wherein each symbol is as defined above.

[0009] The present invention also provides a process for producing a 2,4-thiazolidinedione derivative of the formula (I-D1) :

wherein R'' is the aromatic heterocyclic group as defined above and the other symbols are as defined above, which comprises reacting a compound of the formula (V):

wherein each symbol is as defined above, with a compound of the formula (VI) :

        R''-CH₂-Q     (VI)

wherein Q is a leaving group and R'' is as defined above.

[0010] The above compound of the formula (I) includes the compounds represented by the following formulas.





wherein each symbol is as defined above.

[0011] In view of the efficacy, toxicity, etc., of the compounds, the compounds of the formulas (I-A1) and (I-A2) are preferred among the compounds of the formulas (I-A1), (I-A2) and (I-A3). In particular, the compound of the formula (I-A1) is preferred.

[0012] When L and M in the formula (I) are linked together to form a bond, the compound of the formula (I) means a compound of the formula (I-B1) :

wherein each symbol is as defined above. When L and M are each a hydrogen atom, the compound of the formula (I) means a compound of the formula (I-B2) :

wherein each symbol is as defined above.

[0013] The above compound of the formula (I-B1) has its (E)- and (Z) -isomers with respect to the double bond at the 5-position in the 2,4-thiazolidinedione ring.

[0014] The above compound of the formula (I-B2) has its (R)- and (S) -optically active substances with respect to the asymmetric carbon at the 5-position in the 2,4-thiazolidinedione ring, and includes these (R)- and (S)-optical isomers and racemic modifications.

[0015] Of the compounds of the formulas (I-B1) and (I-B2), the compound of the formula (I-B2) is preferred.

[0016] In the above formula (I), when any one or both of R¹ and R² are a hydrocarbon group, one of the hydrocarbon groups and a part of Y may be linked together to form a ring. Compounds in which R¹ and a part of Y are linked together to form a ring include the following compounds:



wherein the symbols are as defined above.

[0017] In the aromatic heterocyclic group which may be attached through a hydrocarbon chain represented by R in the formula (I), the heterocyclic group is attached to - (O)_n- directly or through a hydrocarbon chain. Preferably, it is attached through a hydrocarbon chain. The hydrocarbon chain may be straight or branched and saturated or unsaturated, and has 1 to 8 carbon atoms. Examples of the hydrocarbon chain include saturated bivalent hydrocarbon groups such as -CH₂-, -CH(CH₃)-, -(CH₂)₂-, -CH(C₂H₅)-, -(CH₂)₃-, -(CH₂)₄-, -(CH₂)₅-, -(CH₂)₆-, -(CH₂)₇-, etc.; unsaturated bivalent hydrocarbon groups such as -CH=CH-, -C(CH₃)=CH-, -CH=CH-CH₂-, -C(C₂H₅)=CH-, -CH₂-CH=CH-CH₂-, -CH₂-CH₂-CH=CH-CH₂-, -CH=CH-CH=CH-CH₂-, -CH=CH-CH=CH-CH=CH-CH₂-, etc. Preferably, the hydrocarbon chain is a ethylene group (-CH₂CH₂-) or a vinylene group (-CH=CH-).

[0018] Preferably, the heterocyclic group in R is represented by the formula:

wherein B¹ is a sulfur atom, an oxygen atom or NR⁴ [in which R⁴ is a hydrogen atom, a lower alkyl group (e.g., alkyl having 1 to 3 carbon atoms such as methyl, ethyl, etc.) or an aralkyl group (e.g., benzyl, phenethyl, etc.)]; B² is a nitrogen atom or C-R⁵ (in which R⁵ is a hydrogen atom, optionally substituted hydrocarbon group or optionally substituted heterocyclic group) ; R³ is a hydrogen atom, optionally substituted hydrocarbon group or optionally substituted heterocyclic group; R³ and R⁵ may be linked together to form a condensed ring when R³ and R⁵ are attached to adjacent carbon atoms to each other.

[0019] Examples of the heterocyclic groups include pyrrolyl (e.g., 2-pyrrolyl), pyrazolyl (e.g., 3-pyrazolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), triazolyl (e.g., 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), tetrazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl), etc.

[0020] The heterocyclic group may have at least one substituent at any possible position on the ring. The substituents include hydrocarbon groups, heterocyclic groups and an amino group. These substituents may have further substituents.

[0021] The hydrocarbon groups as the substituent of the heterocyclic group in R include aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, alicyclic-aliphatic hydrocarbon groups, (aromatic carbocycle)-aliphatic hydrocarbon groups, aromatic hydrocarbon groups, etc.

[0022] Examples of such aliphatic hydrocarbon groups include saturated aliphatic hydrocarbon groups (e.g., alkyl groups) having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; unsaturated aliphatic hydrocarbon groups (e.g., alkenyl groups, alkynyl groups) having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, etc.

[0023] Examples of such alicyclic hydrocarbon groups include saturated alicyclic hydrocarbon groups (e.g., cycloalkyl groups) having 3 to 7 carbon atoms, preferably 5 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; and unsaturated alicyclic hydrocarbon groups (e.g., cycloalkenyl groups) having 5 to 7 carbon atoms, preferably 5 to 6 carbon atoms, such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl, etc.

[0024] Examples of such alicyclic-aliphatic hydrocarbon groups include those having 4 to 9 carbon atoms each of which is composed of the above alicyclic hydrocarbon group and aliphatic hydrocarbon group, such as cycloalkyl-alkyl groups, cycloalkenyl-alkyl groups, etc. Specific examples of the alicyclic-aliphatic hydrocarbon groups include cyclopropyl-methyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl,cyclohexyl-methyl,2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, etc.

[0025] Examples of such (aromatic carbocycle)-aliphatic hydrocarbon groups include phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 3-phenyl-propyl, 2-phenylpropyl, 1-phenylpropyl, etc.; naphthyl-alkyl having 11 to 13 carbon atoms such as α-naphthylmethyl, α-naphtylethyl, β-naphthylmethyl, β-naphthylethyl, etc.

[0026] Examples of such aromatic hydrocarbon groups include phenyl, naphthyl (e.g., α-naphthyl, β-naphthyl), etc.

[0027] The heterocyclic group as the substituent represented by R³ and R⁵ is a 5- or 6-membered cyclic group which contains 1 to 3 ring-constituting heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and which is attached through a ring-constituting carbon atom. Examples thereof include unsaturated heterocyclic groups such as thienyl (e.g., 2-thienyl, 3-thienyl), furyl (e.g., 2-furyl, 3-furyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (e.g., 2-thazolyl, 4-thiazolyl, 5-thazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl), etc.; saturated heterocyclic groups such as piperidinyl (e.g., 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyl (e.g., 2-pyrrolidinyl, 3-pyrrolidinyl), morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl), tetrahydrofuryl (e.g., 2-tetrahydrofuryl, 3-tetrahydrofuryl), etc.

[0028] The amino group as the substituent of the heterocyclic group in R may be substituted. The substituted amino groups include N-monosubstituted amino groups and N,N-disubstituted amino groups.

[0029] Such N-monosubstituted amino group means an amino group having one substituent. Examples of the substituents include lower alkyl groups (e.g., alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl, i-butyl, t-butyl, etc.), cycloalkyl groups (e.g., cycloalkyl groups having 3 to 7 carbon atoms such as cyclopentyl, cyclohexyl, etc.), aryl groups (e.g., phenyl, naphthyl, etc.), aromatic heterocyclic groups (e.g., pyridyl, thienyl, furyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic groups (e.g., piperidinyl, pyrrolidinyl, morpholinyl, etc.), aralkyl groups (e.g., benzyl, phenethyl, etc.), acyl groups (e.g., acetyl, propionyl, etc.), a carbamoyl group, N-monosubstituted carbamoyl groups (e.g., N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, etc.), N,N-disubstituted carbamoyl groups (e.g., N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N,N-diethylcarbamoyl, etc.), lower alkoxycarbonyl groups (e.g., alkoxycarbonyl groups having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), a hydroxyl group, lower alkoxy groups (e.g., alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, etc.), aralkyloxygroups (e.g., benzyloxy, phenethyloxy, naphthylmethyloxy, etc.), etc.

[0030] Such N,N-disubstituted amino group means an amino group having two substituents. One of the substituents is similar to the substituents of the above N-monosubstituted amino groups. Examples of the other substituent include lower alkyl groups, cycloalkyl groups, aryl groups, aralkyl groups, etc. The two substituents may be linked together with the nitrogen atom to form a cyclic amino group. Examples of the cyclic amino groups include 1-azetidinyl, pyrrolidino, piperidino, morpholino, piperazino, and piperazino having at the 4-position a lower alkyl group (e.g., alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, etc.), an aralkyl group (e.g., benzyl, phenethyl, naphthylmethyl, etc.), an aryl group (e.g., phenyl, 4-methylphenyl, naphthyl, etc.), etc.

[0031] The hydrocarbon group and heterocyclic group as the substituent of the heterocyclic group in R may be substituted at any possible position. When the hydrocarbon group contains an alicyclic group or the heterocyclic group is saturated, the alicyclic or heterocyclic group may be substituted by 1 to 3 lower alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl) on the ring-constituting atoms which may be a nitrogen atom. When the hydrocarbon group contains an aromatic hydrocarbon group or the heterocyclic group is unsaturated, the hydrocarbon or heterocyclic group may have the same or different 1 to 4 substituents on the ring. Examples of the substituents include halogen (e.g., fluorine, chlorine, iodine), hydroxy, cyano, nitro, trifluoromethyl, lower alkoxy (e.g., alkoxy having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), lower alkyl (e.g., alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkoxycarbonyl (e.g., alkoxycarbonyl having 2 to 4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), lower alkylthio (e.g., alkylthio having 1 to 3 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, etc.), lower alkylamino (e.g., alkylamino having 1 to 4 carbon atoms such as methylamino, ethylamino, dimethylamino, etc.), etc.

[0032] When the heterocyclic group represented by R³ and R⁵ is substituted by at least 2 hydrocarbon groups at adjacent positions to each other on the heterocycle, these hydrocarbon groups may be linked together to form a condensed ring. In other words, the two hydrocarbon groups are linked together to form a saturated or unsaturated bivalent chain hydrocarbon group having 3 to 5 carbon groups. Examples of the chain hydrocarbon groups include -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂CH₂-, -CH=CHCH₂-, -CH=CH-CH=CH-, -CH=CH-CH=CH-CH₂-, -CH=CH-CH₂CH₂CH₂-, etc.

[0033] Examples of the hydrocarbon groups, heterocyclic groups represented by R³ or R⁵ and their substituents are similar to those described above for the substituents of the heterocyclic group in R.

[0034] The aromatic heterocyclic group is attached through any possible atom on the ring. Preferably, it is attached through a carbon atom adjacent to the nitrogen atom. For example, when B¹ is NR⁴ and B² is C-R⁵, it is particularly preferred that the heterocyclic group is attached through B².

[0035] Particularly preferred heterocyclic groups represented by the above formula are thiazolyl or oxazolyl represented by the formula:

wherein R⁵ is as defined above, R⁶, R⁷ and R⁸ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R⁷ and R⁸ may be linked together to form a condensed ring, B is an oxygen atom or sulfur atom.

[0036] Examples of the hydrocarbon group, heterocyclic group represented by R⁶, R⁷ and R⁸ and their substituents are similar to those described for the substituents represented by R³ and R⁵. R⁷ and R⁸ may be linked together to form a condensed ring. The condensed ring is similar to the above condensed rings which are formed by two hydrocarbon groups at adjacent positions to each other as the substituents of the heterocyclic group.

[0037] n is 0 or 1. When n is 0, R is directly attached to the benzene ring. When n is 1, R is attached to the benzene ring through one oxygen atom. n is preferably 1.

[0038] The halogen atom, optionally substituted hydroxyl group, and optionally substituted hydrocarbon group represented by R¹ or R² in the above formula (I) are similar to those described above for the substituents of the aromatic heterocyclic group in R.

[0039] Preferred examples of the compound of the formula (I) include:

5-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy) -phenyl]propyl]-2,4-thiazolidinedione (Example No. 9),

5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-phenyl]propyl]-2,4-thiazolidinedione (Example No. 10),

5-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-pr opyl]-2,4-thiazolidinedione (Example 18), and

5-[3-[4-(5-methyl-2-naphthyl-4-oxazolylmethoxy)phenyl)-propyl]-2,4-thiazolidinedione (Example 22).

[0040] The salt of the compound of the formula (I) of the present invention is preferably a pharmaceutically acceptable salt. Examples thereof include salts with inorganic bases, organic bases, inorganic acids, organic acids, basic or acidic amino acids, etc.

[0041] Preferred examples of the salts with inorganic bases include alkaline metal salts such as a sodium salt, potassium salt, etc., alkaline earth metal salts such as a calcium salt, magnesium salt, etc., an aluminium salt, an ammonium salt, etc.

[0042] Preferred examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.

[0043] Preferred examples of the salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

[0044] Preferred examples of the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0045] Preferred examples of the salts with basic amino acids include salts with arginine, lysine, ornithine, etc.

[0046] Preferred examples of the salts with acidic amino acids include aspartic acid, glutamic acid, etc.

[0047] In particular, a sodium salt or potassium salt is preferred.

[0048] The compound (I) (i.e., the compound of the formula (I); hereinafter compounds of other formulas sometimes be abbreviated likewise) or a pharmaceutically acceptable salt thereof of the present invention has low toxicity, and has hypoglycemic activity, blood lipid lowering activity, and insulin sensitivity enhancing activity. The compound (I) or a pharmaceutically acceptable salt thereof can be administered as such or as a mixture with a per se known pharmacologically acceptable carrier including excipient, bulking agent, etc., to mammals such as humans, mice, rats, cats, dogs, rabbits, bovines, swine, sheep and monkeys. Thus, it is useful as antidiabetic or hypotensive agent.

[0049] The compound (I) of the present invention has low toxicity. For example, when the compound prepared in Example 14 was orally administered to mice in a daily dose of 15 mg/kg for 4 days, there were no abnormal changes of the body weight and liver weight from those of a control.

[0050] Normally, the compound (I) or a salt thereof can orally be administered as tablets, capsules including soft capsules and microcapsules, powders, granules, etc. In some cases, it can parenterally be administered as injections, suppositories, pellets, etc. The oral dose for an adult (body weight: about 50 kg) is 0.05 to 10 mg/kg per day. Preferably, this dose is administered 1 to 3 times per day.

[0051] The compound (I) or a salt thereof of the present invention can be formulated with a pharmaceutically acceptable carrier and administered orally or parenterally as solid preparations such as tablets, capsules, granules, powders, etc; or liquid preparations such as syrups, injections, etc.

[0052] As the pharmaceutically acceptable carrier, various organic or inorganic carrier materials conventionally used for pharmaceutical preparations can be used, and formulated as excipients, lubricants, binders, disintegrators, etc., for solid preparations, or as solvents, solution adjuvants, suspending agents, tonicity agents, buffering agents, soothing agents, etc., for liquid preparations. If necessary, pharmaceutical additives such as antiseptics, antioxidants, colorants, sweetening agents, etc., can be used.

[0053] Preferred examples of the excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, etc.

[0054] Preferred examples of the lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, etc.

[0055] Preferred examples of the binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.

[0056] Preferred examples of the disintegrators include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, etc.

[0057] Preferred examples of the solvents include water for injection, alcohols, propylene glycol, macrogol, sesame oil, corn oil, etc.

[0058] Preferred examples of the solution adjuvants include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.

[0059] Preferred examples of the suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl-cellulose, etc.

[0060] Preferred examples of the tonicity agents include sodium chloride, glycerin, D-mannitol, etc.

[0061] Preferred examples of the buffering agents include buffers such as phosphates, acetates, carbonates, citrates, etc.

[0062] Preferred examples of the soothing agents include benzyl alcohol, etc.

[0063] Preferred examples of the antiseptics include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.

[0064] Preferred examples of the antioxidants include sulfites, ascorbic acid, etc.

[0065] The compound (I) can be prepared, for example, as follows.

Method A

[0066] 

wherein each symbol is as defined above.

[0067] The compound (I-B1) can be prepared by condensing the compound (II) with 2,4-thiazolidinedione in the presence of a base in a solvent.

[0068] The solvents include alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, etc.; N,N-dimethylformamide; dimethyl sulfoxide; and acetic acid.

[0069] The bases include sodium alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), potassium carbonate, sodium carbonate, sodium hydride, sodium acetate, secondary amines such aspiperidine, piperazine, pyrrolidine, morpholine, diethylamine, diisopropylamine, etc.

[0070] The amount of the 2,4-thiazolidinedione to be used is 1 to 10 mol, preferably 1 to 5 mol, per mol of the compound (II). The amount of the base to be used is 0.01 to 5 mol, preferably 0.05 to 2 mol, per mol of the compound (II).

[0071] The reaction temperature is 0 to 150°C, preferably 20 to 100°C, and the reaction time is 0.5 to 30 hours.

[0072] The compound (I-B1) thus obtained can be isolated and purified by conventional separation and purification techniques such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redistribution, chromatography, etc. The compound (I-B1) is sometimes obtained as a mixture of its (E) - and (Z) -isomers with respect to the double bond at the 5-position on the 2,4-thiazolidinedione ring.

Method B

[0073] 

wherein each symbol is as defined above.

[0074] The compound (I-B2) can be prepared by hydrolyzing the compound (III). This hydrolysis is normally carried out in an appropriate solvent in the presence of water and a mineral acid.

[0075] The solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, etc., dimethyl sulfoxide, sulfolane, etc., and mixtures thereof. The mineral acids include hydrochloric acid, hydrobromic acid, sulfuric acid, etc.

[0076] The amount of the mineral acid to be used is 0.1 to 20 mol, preferably 0.2 to 10 mol, per mol of the compound (III). The water is normally used in large excess based on the compound (III).

[0077] The reaction temperature is normally 20 to 150°C, preferably 50 to 120°C, and the reaction time is 0.5 to 50 hours.

[0078] The 2,4-thiazolidinedione derivative (I-B2) thus obtained can be isolated and purified by conventional separation and purification techniques such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redistribution, chromatography, etc.

Method C

[0079] 

wherein R' is an aromatic heterocyclic group which may be attached through a saturated hydrocarbon chain having 1 to 8 carbon atoms, Y¹ is -CH₂CH₂- and may be linked with R¹ or R² to form a ring, and the other symbols are as defined above.

[0080] The aromatic heterocyclic groups which may be attached through a saturated hydrocarbon chain having 1 to 8 carbon atoms and represented by R' can be selected from the above aromatic heterocyclic groups which may be attached through a hydrocarbon chain represented by R whose hydrocarbon chain is saturated.

[0081] The compound (I-B2a) can be prepared by subjecting the compound (1-B1) to reduction. This reduction can be carried out according to a conventional method in a solvent in the presence of a catalyst under an atmosphere of hydrogen at 1 to 150 atm.

[0082] The solvents include alcohols such as methanol, ethanol, propanol isopropanol, 2-methoxyethanol, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc,, ethers such as ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, etc, halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane, etc., ethyl acetate, acetic acid, and N,N-dimethylformamide, and mixture thereof. Preferred examples of the catalysts include metals such as nickel compounds, transition metal catalysts such as palladium, platinum, rhodium, etc.

[0083] The reaction temperature is 0 to 100°C, preferably 10 to 80°C, and the reaction time is 0.5 to 50 hours.

[0084] The 2,4-thiazolidinedione derivative (I-B2a) thus obtained can be isolated and purified by conventional separation and purification techniques such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redistribution, chromatography, etc.

Method D

[0085] 

wherein D is a lower alkoxy group, a lower alkylthio group or a lower acyloxy group, and the other symbols are as defined above.

[0086] The lower alkoxy groups represented by D include alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. The lower alkylthio groups include alkylthio groups having 1 to 4 carbon atoms, such as methylthio, ethylthio, propylthio isopropylthio, butylthio, etc. The lower acyloxy groups include acyloxy groups having 1 to 4 carbon atoms, such as acetyloxy, propionyloxy, etc. Two D groups may be linked together to form ethylenedioxy, propylenedioxy, dithiotrimethylene, etc. That is, -CH(D)₂ in the formula (IV) represents a protected aldehyde group.

[0087] The compound (IV) is condensed with 2,4-thiazolidinedione to give the compound (I-B1). This condensation reaction can be carried out according to the same manner as that described for the reaction of the compound (II) with 2,4-thiazolidinedione in Method A.

Method E

[0088] 

wherein Q is a leaving group, and the other symbols are as define above.

[0089] The leaving groups represented by Q include halogen atoms (e.g., chlorine, bromine, iodine), methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.

[0090] The compound (V) is condensed with the compound (VI) to prepare the compound (I-D1). This reaction is carried out in the presence of a base in an appropriate solvent according to conventional methods.

[0091] The solvents include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as dioxane, tetrahydrofuran, dimethoxyethane, etc., ketones such as acetone, 2-butanone, etc., N,N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., and mixed solvents thereof.

[0092] The bases include alkaline metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, etc., amines such as pyridine, triethylamine, N,N-dimethylaniline, etc., metal hydrides such as sodium hydride, potassium hydride, etc., alkoxides such as sodium ethoxide, sodium methoxide, potassium t-butoxide, etc. The amount of the base to be used is preferably about 1 to 5 mol per mol of the compound (V).

[0093] The reaction temperature is normally -50 to 150°C, preferably about -10 to 100°C, and the reaction time is 0.5 to 30 hours.

[0094] The compound (I-D1) thus obtained can be isolated and purified by conventional separation and purification techniques such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redistribution, chromatography, etc.

[0095] The starting compound (II) in Method A can be prepared, for example, by Method F below.

Method F

[0096] 

wherein R⁹ and R¹⁰ are the same or different and are a lower alkyl group, R¹¹ is a hydrogen atom or a lower alkyl group, q is 0, 1 or 2, and the other symbols are as defined above.

[0097] The lower alkyl groups represented by R⁹, R¹⁰ and R¹¹ include alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, etc.

[0098] In this method, firstly, the carbonyl derivative (VII) is reacted with a phosphonoacetic acid derivative or ω-phosphonocarboxylic acid derivative (VIII) to prepare the unsaturated ester derivative (IX). The reaction of the compound (VII) with the compound (VIII) can be carried out in the presence of a base in an appropriate solvent according to conventional methods.

[0099] The solvents include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as dioxane, tetrahydrofuran, dimethoxyethane, etc., alcohols such as methanol, ethanol, propanol, etc., N,N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., and mixed solvents thereof.

[0100] The bases include alkaline metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., amines such as pyridine, triethylamine, N,N-dimethylaniline, etc., metal hydrides such as sodium hydride, potassium hydride, etc., alkoxides such as sodium ethoxide, sodium methoxide, potassium t-butoxide, etc.

[0101] The amount of the base to be used is preferably about 1 to 5 mol per mol of the compound (VIII). The amount of the compound (VIII) is 1 to 5 mol, preferably about 1 to 3 mol, per mol of the compound (VII).

[0102] The reaction temperature is normally -50 to 150°C, preferably about -10 to 100°C, and the reaction time is 0.5 to 30 hours.

[0103] Then, the compound (IX) is subjected to reduction to prepare the alcohol derivative (X). This reduction can be carried out according to per se known methods such as reduction with a metal hydride, metal hydride complex compound, diborane or substituted borane. That is, this reaction can be carried out by reacting the compound (IX) with a reducing agent.

[0104] The reducing agents include alkaline metal borohydrides (e.g., sodium borohydride, lithium borohydride, etc.), metal hydride complex compounds (e.g., lithium aluminum hydride, diisobutyl aluminum hydride, etc.), and diborane. In particular, diisobutyl aluminum hydride is preferably used.

[0105] This reaction is carried out in an organic solvent which does not hinder the reaction. The solvent is appropriately selected depending on the kind of reducing agent from, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, etc, alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, etc., amides such as N,N-dimethylformamide, etc., and mixed solvents thereof.

[0106] The reaction temperature is -20 to 150°C, preferably about 0 to 100°C, and the reaction time is about 1 to 24 hours.

[0107] Then, the compound (X) is subjected to oxidation to prepare the unsaturated carbonyl derivative (II-1). This oxidation can be carried out according to per se known methods such as oxidation with manganese dioxide, chromic acid, dimethyl sulfoxide, etc. That is, this reaction can be carried out by treating the compound (X) with an oxidizing agent. The oxidizing agents include manganese dioxide, chromic anhydride, etc. In particular, manganese dioxide is preferably used.

[0108] This reaction is carried out in an organic solvent which does not hinder the reaction. The solvent is appropriately selected depending on the kind of oxidizing agent from, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, etc, dimethyl sulfoxide, etc., and mixed solvents thereof.

[0109] The reaction temperature is -20 to 150°C, preferably 0 to 100°C, and the reaction time is about 1 to 24 hours.

[0110] Then, the compound (II-1) is subjected to reduction to prepare the compound (II-2). This reduction can be carried out according to the same manner as that described in Method C.

[0111] The aldehyde derivatives (II-1) and (II-2) thus obtained can be isolated and purified by conventional separation and purification techniques such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redistribution, chromatography, etc.

[0112] The starting compound (VII) in Method F can be synthesized by the methods described in, for example, Chemical & Pharmaceutical Bulletin, vol. 39, p. 1440 (1990), JP-A 4-225978, JP-A 61-85372, JP-A 61-271287, JP-A 63-139182, JP-A 3-170478, WO9119496-A1, EP-428312-A, JP-A 1-299289, JP-A 63-230689, etc.

[0113] Some of the aldehyde derivatives (VII-1) can also be synthesized, for example, by Method G.

Method G

[0114] 

wherein Q' is a halogen atom, and the other symbols are as defined above.

[0115] The halogen atoms represented by Q' include, for example, chlorine, bromine, and iodine.

[0116] In this method, the compound (XI) is treated with butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, phenyllithium, phenylmagnesium bromide, etc., and then reacted with N,N-dimethylformamide to prepare the compound (VII-1).

[0117] The starting material (XI) in Method G can be prepared, for example, by Method H.

Method H

[0118] 

wherein W is a halogen atom, and the other symbols are as defined above.

[0119] The halogen atoms represented by W include, for example, chlorine, bromine, and iodine.

[0120] In this method, the phosphonium salt (XII) is condensed with the aldehyde derivative (XIII) to prepare the compound (XI-1). This condensation reaction can be carried out according to the same manner as that described for the reaction of the compound (VII) with the compound (VIII) in Method G.

[0121] Some of the intermediates of the formula (IX) in Method F can also be prepared, for example, by Method I.

Method I

[0122] 

wherein each symbol is as defined above.

[0123] This reaction can be carried out in the presence of a base in an appropriate solvent. The solvents include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as dioxane, tetrahydrofuran, dimethoxyethane, etc., alcohols such as methanol, ethanol, propanol, etc., ethyl acetate, acetonitrile, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone, etc., and mixed solvents thereof.

[0124] The bases include inorganic bases such as alkaline metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earthmetal hydroxides (e.g., magnesiumhydroxide, calcium hydroxide, etc.), alkaline metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, etc.), alkaline metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkaline metal acetates (e.g., sodiumacetate, potassium acetate, etc.), etc.; organic bases such as trialkylamines (e.g., trimethyl-amine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]non-5-ene, 1,8-diazabicyclo [5.4.0] -7-undecene, etc. The amount of the base to be used is preferably about 1 to 5 mol per mol of the compound (XV) .

[0125] The reaction temperature is normally -20°C to 150°C, preferably about -10°C to 100°C.

[0126] The synthesis of the starting compound (XIV) in Method I is described, for example, in Chemical & Pharmaceutical Bulletin, vol. 30, p. 3563 (1982), Chemical & Pharmaceutical Bulletin, vol. 30, p. 3580 (1982), Chemical & Pharmaceutical Bulletin, vol. 32, p. 2267 (1984), Arzneimittel Forschung/Drug Research, vol. 40, p. 37 (1990), Journal of Medicinal Chemistry, vol. 35, p. 2617 (1992), JP-A 61-267580, JP-A 61-286376, JP-A 61-85372, JP-A 2-31079, JP-A 62-5981, etc.

[0127] The compound (III) used in Method B can be prepared, for example, by Method J.

Method J

[0128] 

wherein each symbol is as defined above.

[0129] The compound (XV) is reacted with thiourea to prepare the compound (III). This reaction is normally carried out in a solvent such as an alcohol (e.g., methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol, etc.), dimethyl sulfoxide, N,N-dimethylformamide, sulfolane, etc. The reaction temperature is normally 20 to 180°C, preferably 50 to 150°C. The amount of the thiourea to be used is 1 to 2 mol per mol of the compound (XV).

[0130] As this reaction proceeds, a hydrogen halide is formed as a by-product. In order to trap this by-product, the reaction may be carried out in the presence of an acid-removing agent such as sodium acetate, potassium acetate, etc. The amount of the acid-removing agent to be used is normally 1 to 1.5 mol per mol of the compound (XV). The compound (III) thus formed can be isolated if necessary, but may directly be used in the acid hydrolysis step without isolation.

[0131] The starting compound (IV) in Method D and the starting compound (II) in Method A can be prepared, for example, by Method K.

Method K

[0132] 

wherein m is an integer of 1 to 6, and the other symbols are as defined above.

[0133] In this method, firstly the compound (VII) is condensed with the compound (XVI) to prepare the compound (IV-1). This condensation reaction can be carried out according to the same manner as that described for the reaction of the compound (VII) with the compound (VIII) in Method F.

[0134] Then, the compound (IV-1) is subjected to reduction to give the compound (IV-2). This reduction can be carried out according to the same manner as that described for the catalytic hydrogenation of the compound (I-B1) in Method C. The compound (IV-2) is de-protected by treatment with an acid in a water-containing solvent to give the aldehyde derivative (II-4). The solvents include mixed solvents of water with alcohols such as methanol, ethanol, propanol, etc., ethers such as tetrahydrofuran, dioxane, etc., acetonitrile, acetone, 2-butanone, acetic acid, etc. The acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, etc., organic acids such as p-toluenesulfonic acid, etc.

[0135] The starting compound (XV) in Method J can be prepared, for example, by Method L.

Method L

[0136] 

wherein each symbol is as defined above.

[0137] The compound (XVI) is reacted with a halogenating agent to prepare the compound (XV). As the halogenating agent, hydrochloric acid, thionyl chloride, phosphorous tribromide, etc., are preferably used. In these cases, the compound (XV) wherein Q' is chloride or bromide is formed. This reaction is carried out at -10 to 80°C in an appropriate inert solvent (e.g., benzene, toluene, xylene, chloroform, dichloromethane, etc.), or by using an excess halogenating agent as the solvent. The amount of the halogenating agent to be used is 1 to 20 mol per mol of the compound (XVI).

[0138] The resulting compound (XV) wherein Q' is chlorine or bromine may be reacted with 1 to 1.5 equivalent of sodium iodide or potassium iodide to give the compound (XV) wherein Q' is iodine. In this case, the reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, methanol, ethanol, etc., at 20 to 80°C.

[0139] The starting compound (XVI) in Method L can be prepared, for example, by Method M.

Method M

[0140] 

wherein Y² is -CH₂-, Y³ is -CH₂-, and the other symbols are as defined above.

[0141] In this method, the compound (II-4) is condensed with pyruvic acid to give the compound (XVII) in a water-containing alcohol in the presence of a base that is selected from the bases described for the reaction of the compound (II) with 2,4-thiazolidinedione in Method A. Then, the compound (XVII) is subjected to esterification to give the compound (XVIII). This esterification can be carried out by per se known methods. For example, the compound (XVII) is reacted with an alcohol (R¹⁰OH) in the presence of an acid to give the ester. Alternatively, a reactive derivative of the compound (XVII) such as an acid anhydride, acid halide (e.g., acid chloride, acid bromide), imidazolide or mixed acid anhydride (e.g., acid anhydrides with dimethyl carbonate, acid anhydrides with diethyl carbonate, anhydrides with diisobutyl carbonate, etc.) is reacted with an alcohol (R¹⁰OH) under suitable conditions.

[0142] Then, the compound (XVIII) is subjected to catalytic hydrogenation to give the compound (XIX). This catalytic hydrogenation can be carried out according to the same manner as that in Method C.

[0143] Then, the compound (XIX) is subjected to reduction to give the compound (XVI-1). This reduction can be carried out by per se known methods such as reduction with metal hydrides, reduction with metal hydride complex compounds, reduction with diborane or substituted borane, catalytic hydrogenation, etc. That is, this reaction can be carried out by treating the compound (XIX) with a reducing agent. The reducing agents include alkaline metal borohydrides (e.g., sodiumborohydride, lithiumborohydride, etc.), metal hydride complex compounds (e.g., lithium aluminum hydride, etc.), metal hydrides (e.g., sodium hydride, etc.), organic tin compounds (e.g., triphenyltin hydride, etc.), metals and metal salts such as nickel compounds, zinc compounds, etc., transition metal catalysts (e.g., palladium, platinum, rhodium, etc.) and hydrogen for catalytic hydrogenation, diborane, etc. In particular, alkaline metal borohydrides (e.g., sodium borohydride, lithium borohydride, etc.) are preferred.

[0144] This reaction is carried out in an organic solvent which does not hinder the reaction. The solvent is appropriately selected depending on the kind of reducing agent from, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, etc., amides such as N,N-dimethylformamide, etc., mixed solvents thereof.

[0145] The reaction temperature is -20 to 150°C, preferably 0 to 100°C, and the reaction time is about 1 to 24 hours.

[0146] As described above, the compound (I) of the present invention or a salt thereof has potent hypoglycemic and blood lipid lowering activity. The following experiment illustrates the activity of the compound (I).

Experiment

Hypoglycemic and lipid lowering activity in mice

[0147] A 0.005% mixture of the test compound with powdery feed (CE-2, Charles River Japan Inc.) was fed to KKA^y-mice (9 to 14 weeks old) for 4 days without any restriction. Blood was sampled from the orbital veniplex, and glucose and triglyceride in the plasma were quantitated by the enzymatic method using Iatrochem-GLU (A) kit (Yatron) and Iatro-MA701TG kit (Yatron). The results are shown in Table 1. The hypoglycemic activity and lipid lowering activity are indicated as a decrease ratio (%) of the glucose and triglyceride levels in the drug-administered group based on those in the control group, respectively.

Table 1

Compound (Example No.)	Hypoglycemic activity (% reduction)	Lipid-lowering activity (% reduction)
3	54	58
4	36	30
ref. ex. 80	58	61
7	48	37
8	53	66

[0148] The results show that the 2,4-thiazolidinedione derivative (I) of the present invention has potent hypoglycemic and lipid-lowering activity, and is useful as a medicament such as an antidiabetic, antilipemic, or hypotensive agent.

[0149] The following examples, preparations, and reference examples further illustrate the present invention in detail, but are not to be construed to limit the scope thereof.

Example 1

[0150] A mixture of 5- [3- (5-methyl-2-phenyl-4-oxazolyl-methoxy)cinnamilidene]-2, 4-thiazolidinedione (0.90 g), palladium-carbon (5%, 2.0 g) and chloroform (200 ml) - methanol (50 ml) was subjected to catalytic hydrogenation at 1 atm at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 5- [3- [3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidinedione (0.58 g, 64%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 123-124°C.

Elemental Analysis:
Calcd. for C23H22N2O4S	C, 65.38;	H, 5.25;	N, 6.63
Found	C, 65.49;	H, 5.26;	N, 6.74

Examples 2 to 4

[0151] According to the same manner as that described in Example 1, the compounds in Table 2 were obtained.

Example 5

[0152] According to the same manner as that described in Example 1, (E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]-cinnamilide ne]-2,4-thiazolidinedione was subjected to catalytic hydrogenation to give 5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]propyl ]-2,4-thiazolidinedione (yield: 22%). This product was recrystallized from ether-hexane. Colorless prisms, mp. 99-100°C.

Example 6

[0153] A mixture of 2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)cinnamaldehyde (2.00 g), 2,4-thiazolidinedione (1.10 g), piperidine (0.267 g) and acetic acid (15 ml) was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure. Crystals (1.64 g) of 5- [2-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamilidene]-2,4 -thiazolidinedione which was precipitated by addition of saturated aqueous sodium bicarbonate solution was collected by filtration and washed with ether. The crystals were dissolved in tetrahydrofuran (150 ml), and 5% palladium-carbon (1.64 g) was added. The mixture was subjected to catalytic hydrogenation at room temperature at a hydrogen pressure of 3.4 kgf/cm². The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give crystals. The crystals were recrystallized from dichloromethane-methanol to give 5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-propyl] -2,4-thiazolidinedione (0.742 g, 34%). White crystals, mp. 173-174°C.

Examples 7 to 8

[0154] According to the same manner as that described in Reference Example 83 as shown below, the compounds in Table 3 were obtained.

Example 9

[0155] According to the same manner as that described in Example 1, 5-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3,4-dihydro-2-nap hthylmethylidene]-2,4-thiazolidinedione was subjected to catalytic hydrogenation to give 5-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1,2,3,4-tetrahydr o-2-naphthyl-methyl]-2,4-thiazolidinedione (yield: 73%). This product was recrystallized from dichloromethane-methanol. Colorless prisms, mp: 194-195°C.

Example 10

[0156] According to the same manner as that described in Example 1, 5- [3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)-cinnamylidene]-2 ,4-thiazolidinedione was subjected to catalytic hydrogenation to give 5-[3-[3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)phenyl]propyl] -2,4-thiazolidinedione (yield: 71%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 131-132°C.

Example 11

[0157] According to the same manner as that described in Example 1, 5-[3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)-cinnamylidene]-2,4-thiazolidinedione was subjected to catalytic hydrogenation to give 5-[3-[3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)phenyl]propyl ]-2,4-thiazolidinedione (yield: 57%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 123-124°C.

Example 12

[0158] According to the same manner as that described in Example 6, 3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]cinnama ldehyde was condensed with 2,4-thiazolidinedione, and the resulting product was subjected to catalytic hydrogenation to give 5- [3- [3-methoxy-4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy]ph enyl]propyl]-2,4-thiazolidinedione (yield: 9%). This product was recrystallized from chloroform - diethyl ether. Colorless prisms, mp: 109-110°C.

Example 13

[0159] According to the same manner as that described in Reference Example - 83, 5-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-thiazolyl-methoxy)phe nyl]propyl]-2,4-thiazolidinedione was obtained (yield: 40%) and recrystallized from ethyl acetate - hexane. Pale yellow needles, mp: 149-150°C.

Example 14

[0160] A mixture of 5-[3-[3-methoxy-4-[2-[(E)-2-phenyl-ethenyl]-4-oxazolylmethox y]phenyl]propyl]-2,4-thiazolidine-dione (0.37 g), palladium-carbon (5%, 0.74 g) and tetrahydrofuran (20 ml) was subjected to catalytic hydrogenation at 1 atm and room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give crystals. The crystals were recrystallized from ethyl acetate - hexane to give 5- [3-[3 -methoxy-4-(2-phenethyl-4-oxazolylmethoxy)phenyl]prop yl]-2,4-thiazolidine-dione (0.20 g, 54%). Colorless prisms, mp: 126-127°C.

Example 15

[0161] According to the same manner as that described in Example 14, 5-[3-[3-methoxy-4-[2- [(E)-2-phenylethenyl]-4-thiazolylmethox y]phenyl]propyl]-2,4-thiazolidinedione was subjected to catalytic hydrogenation to give 5-[3-[3-methoxy-4-(2-phenethyl-4-thiazolylmethoxy)phenyl]pro pyl]-2,4-thiazolidinedione (yield: 59%). This product was recrystallized form ethyl acetate - hexane. Colorless prisms, mp: 104-105°C.

Preparation 1

[0162] 

Preparation of Tablets
(1)	5- [3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-2,4-thiazolidinedione	30 g
(2)	Lactose	50 g
(3)	Corn starch	15 g
(4)	Carboxymethylcellulose calcium	44 g
(5)	Magnesium stearate	1 g
	1000 tablets:	120 g

[0163] Total amounts of (1), (2) and (3) and 30 g of (4) were kneaded with water, dried in vacuo and granulated. The granule powder was mixed with 14 g of (4) and 1 g of (5), and the mixture was tabletted with a tabletting machine to give 1000 tablets each tablet containing 10 mg of (1).

Preparation 2

[0164] 

Preparation of tablets
(1)	5-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidinedione	10 g
(2)	Lactose	50 g
(3)	Corn starch	15 g
(4)	Carboxymethylcellulose calcium	44 g
(5)	Magnesium stearate	1 g
	1000 tablets:	140 g

[0165] Total amounts of (1), (2) and (3) and 30 g of (4) were kneaded with water, dried in vacuo and granulated. The granule powder was mixed with 14 g of (4) and 1 g of (5), and the mixture was tabletted with a tabletting machine to give 1000 tablets each tablet containing 30 mg of (1).

Reference Example 1

[0166] Sodium hydride (oily, 60%, 2.40 g) was added little by little to a solution of triethyl phosphonoacetate (12.3 g) in tetrahydrofuran (200 ml) at 0°C, and the mixture was stirred at 10 minutes. Then, 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (14.7 g) was added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - hexane (1:3, v/v) gave crystals of ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate (14.8 g, 81%). The crystals were recrystallized from ethanol. Colorless prisms, mp: 94-95°C.

Elemental Analysis:
Calcd. for C22H21NO4	C, 72.71;	H, 5.82;	N, 3.85
Found	C, 72.61;	H, 5.57;	N, 3.85

Reference Examples 2 to 6

[0167] According to the same manner as the described in Reference Example 1, the compounds in Table 4 were obtained.

Reference Example 7

[0168] According to the same manner as that described in Reference Example 1, 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-acetophenone was reacted with trimethyl phosphonoacetate to give methyl (E)-3- [4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-phenyl]-2-but enoate (yield: 54%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 125-126°C.

Reference Example 8

[0169] According to the same manner as that described in Reference Example 1, 4-isopropoxybenzaldehyde was reacted with triethyl phosphonoacetate to give ethyl 4-isopropoxycinnamate as an oil (yield: 93%).

[0170] NMR (δ ppm in CDCl₃) : 1.33(3H,t,J=7Hz), 1.35 (6H,d,J=6Hz), 4.25(2H,q,J=7Hz), 4.5-4.7(1H,m), 6.30 (1H,d,J=16Hz), 6.87(2H,d,J=9Hz), 7.46(2H,d,J=9Hz), 7.63(1H,d,J=16Hz).

Reference Example 9

[0171] According to the same manner as that described in Reference Example 1, 4-isopropoxybenzaldehyde was reacted with triethyl 4-phosphonocrotonate to give ethyl (E,E)-5-(4-isopropoxyphenyl)pentadienoate as crystals (yield: 58%). The crystals were recrystallized from ether-hexane. Colorless prisms, mp: 64-65°C.

Reference Example 10

[0172] A solution of diisobutyl aluminum hydride in toluene (1.5M, 51 ml) was added dropwise to a solution of ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate (14.0 g) in dichloromethane (200 ml) at 0°C. After stirring for 30 minutes, 2N hydrochloric acid (150 ml) was added at 0°C, and the mixture was stirred for 1 hour. The dichloromethane layer was separated, washed with saturated brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave crystals of (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-prop enol (11.5 g, 92%). The crystals were recrystallized from ethyl acetate. Colorless prisms, mp: 118-119°C.

Elemental Analysis:
Calcd. for C20H19NO3	C, 74.75;	H, 5.96;	N, 4.36
Found	C, 74.78;	H, 5.76;	N, 4.39

Reference Examples 11 to 16

[0173] According to the same manner as that described in Reference Example 10, the compounds in Table 5 were obtained.

Reference Example 17

[0174] According to the same manner as that described in Reference Example 10, methyl (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-bute noate was reduced with diisobutyl aluminum hydride to give (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-bute nol (yield: 63%). This product was recrystallized from ethyl acetate - ether. colorless crystals, mp: 126-127°C.

Reference Example 18

[0175] According to the same manner as that described in Reference Example 10, ethyl 4-isopropoxycinnamate was reduced with diisobutyl aluminum hydride to give (E) -3- (4-isopropoxy-phenyl) -2-propenol as an oil. This oil was purified by column chromatography on silica gel (eluent: ethyl acetate - hexane (1:4, v/v)) (yield: 83%).

[0176] NMR (δ ppm in CDCl₃) : 1.33(6H,d,J=6Hz), 1.38 (1H,t,J=6Hz), 4.30(2H,td,J=6&1.5Hz), 4.45-4.65(1H,m), 6.23(1H,dt,J=16&6Hz), 6.56 (1H,d,J=16Hz), 6.84(2H,d,J=8.5Hz), 7.31(2H,d,J=8.5Hz).

Reference Example 19

[0177] According to the same manner as that described in Reference Example 10, ethyl (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienoate was reduced with diisobutyl aluminum hydride to give crystals of (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienol (yield: 76%). The crystals were recrystallized from isopropyl ether. Colorless needles, mp: 91-92°C.

Reference Example 20

[0178] Activated manganese dioxide (25.0 g) was added to a solution of (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-phenyl]-2-pro penol (11.0 g) in dichloromethane (200 ml), and the mixture was stirred at room temperature for 2 hours. The insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure to give 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (10.5g, 96%). This product was recrystallized fromethyl acetate-hexane. Colorless columns, mp: 103-104°C.

Reference Examples 21 to 26

[0179] According to the same manner as that described in Reference example 20, the compounds in Table 6 were obtained.

Reference "Example 27

[0180] According to the same manner as that described in Reference Example 20, (E)-3-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)phenyl]-2-but enol was oxidized with activated manganese dioxide to give (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]crotona ldehyde (yield: 87%). This product was recrystallized from ethyl acetate - ether. Colorless crystals, mp: 94-95°C.

Reference Example 28

[0181] According to the same manner as that described in Reference Example 20, (E)-3-(4-isopropoxyphenyl)-2-propenol was oxidized with activated manganese dioxide to give 4-isopropoxycinnamaldehyde as an oil (yield: 89%).

[0182] NMR (δ ppm in CDCl₃) : 1.37(6H, d, J=6Hz), 4.5-4.7(1H,m), 6.61(1H, dd, J=16&8Hz), 6.92(2H, d, J=9Hz), 7.42(1H, d, J=16Hz), 7.51(2H,d,J=9Hz), 9.65(1H, d, J=8Hz).

Reference Example 29

[0183] According to the same manner as that described in Reference Example 20, (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienol was oxidized with activated manganese dioxide to give (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienal as an oil (yield: 99%).

[0184] NMR (δ ppm in CDCl₃) : 1.36(6H,d,J=6Hz), 4.5-4.7(1H,m), 6.22(1H,dd,J=15&8Hz), 6.8-7.05(4H,m), 7.26 (1H,dd,J=15&10Hz), 7.44(2H,d,J=9Hz), 9.59(1H,d,J=8Hz).

Reference Example 30

[0185] A solution of sodium carbonate (4.14 g) in water (80 ml) was added dropwise to a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (3.0g) and pyruvic acid (3.44 g) in methanol (80 ml). The mixture was stirred at 70 to 80°C for 24 hours, and then poured into water and washed with ethyl acetate. The aqueous layer was acidified with conc. hydrochloric acid to collect the precipitated crystals by filtration. The crystals were added to hydrogen chloride - containing ethanol (5%, 15 ml), and the mixture was heated under reflux for 30 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel. The fractions eluted with ethyl acetate - chloroform (1:9, v/v) gave ethyl (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidenepyr uvate (1.0 g, 25%). This product was recrystallized from dichloromethane-ethanol. Pale yellow needles, mp: 99-100°C.

Reference Example 31

[0186] A mixture of ethyl (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidenepyr uvate (0.85 g), palladium-carbon (10%, 0.1 g) and dioxane (80 ml) was subjected to catalytic hydrogenation at 1 atm at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (20 ml). Sodium borohydride (0.08 g) was added to the solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel. The fractions eluted with chloroform - ethyl acetate (1:9, v/v) gave ethyl 2-hydroxy-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]phen yl]acetate (0.55 g, 64%). This product was recrystallized from ethyl ether - hexane. Colorless needles, mp: 67-68°C.

Reference Example 32

[0187] According to the same manner as that described in Reference Example 30, 4-isopropoxybenzaldehyde was condensed with sodium pyruvate, and the resulting compound was esterified to give ethyl (E)-4-isopropoxybenzylidenepyruvate as an oil (yield: 36%).

[0188] NMR (δ ppm in CDCl₃) : 1.37(6H,d,J=6Hz), 1.41 (3H,t,J=7Hz), 4.39(2H,q,J=7Hz), 4.55-4.75(1H,m), 6.91 (2H,d,J=9Hz), 7.23(1H,d,J=16Hz), 7.58 (2H, d, J=9Hz), 7.83 (1H,d,J=16Hz).

Reference Example 33

[0189] A mixture of ethyl (E)-4-isopropoxybenzylidene-pyruvate (19.0 g), 5% palladium-carbon (3.00 g) and 20% (v/v) acetic acid - ethanol (500 ml) was subjected to catalytic hydrogenation at 1 atm at room temperature. The catalyst was filtered off, 5% palladium-carbon (3.00 g) was newly added to the filtrate, and catalytic hydrogenation was continued under the same conditions. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate -hexane (1:4, v/v) gave ethyl 2-hydroxy-4-(4-isopropoxyphenyl)acetate (11.2g, 58%) as an oil.

[0190] NMR (δ in CDCl₃) : 1.29(3H,t,J=7Hz), 1.32 (6H,d,J=6Hz), 1.8-2.2(2H,m), 2.65-2.75(2H,m), 2.80 (1H,d,J=5.5Hz), 4.1-4.25(1H,m), 4.21(2H,q,J=7Hz), 4.4-4.6(1H,m), 6.81(2H,d,J=8.5Hz), 7.10(2H,d,J=8.5Hz).

Reference Example 34

[0191] A mixture of ethyl 2-hydroxy-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pheny 1]butyrate (320 mg) and thionyl chloride (3 ml) was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - hexane (1:4, v/v) gave ethyl 2-chloro-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl ]butyrate (210 mg, 63%) as an oil.

[0192] NMR (δ in CDCl₃) : 1.29(3H,t,J=7Hz), 2.05-2.45(2H,m), 2.38(3H,m), 2.6-2.85(2H,m), 2.97(2H,t,J=6.5Hz), 4.15-4.3 (5H,m), 6.84(2H,d,J=8.5Hz), 7.09(2H,d,J=8.5Hz).

Reference Example 35

[0193] According to the same manner as that described in Reference Example 34, ethyl 2-hydroxy-4- (4-isopropoxyphenyl) -butyrate was chlorinated with thionyl chloride to give ethyl 2-chloro-4-(4-isopropoxypheyl)butyrate as an oil (yield: 27%).

[0194] NMR (δ ppm in CDCl₃) : 1.29 (3H,t, J=7Hz), 1.32 (6H,d,J=6Hz), 2.1-2.35 (2H,m), 2.6-2.9(2H,m), 4.15-4.3(3H,m), 4.4-4.6(1H,m), 6.82 (2H,d, J=8.5Hz), 7.09(2H,d,J=8.5Hz).

Reference Example 36

[0195] Sodium hydride (oily, 60%, 4.60 g) was added little by little to a solution of 2-(1,3-dioxolan-2-yl)ethyl-triphenylphosphonium bromide (51.0 g) in N,N-dimethylformamide (200 ml) at 0°C. After stirring for 15 minutes, 4-isopropoxybenzaldehyde (18.0 g) was added, and the mixture was stirred at 80 to 85°C for 5 hours. Water was added to the reaction mixture, acidified with 2N hydrochloric acid, and extracted with ether. The ether layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. An oil of the intermediate which was obtained from the fractions eluted with ethyl acetate - hexane (1:4, v/v) was dissolved in ethanol (250 ml), and 5% palladium-carbon (5.00 g) was added. The mixture was subjected to catalytic hydrogenation at 1 atm and room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - hexane (1:5, v/v) to give 2-[3-(4-isopropoxyphenyl)propyl]-1,3-dioxolane (6.70 g, 24%) as an oil.

[0196] NMR (δ ppm in CDCl₃) : 1.32(6H, d, J=6Hz), 1.6-1.8(4H,m), 2.5-2.65(2H,m), 3.8-4.0(4H,m), 4.4-4.6(1H,m), 4.8-4.9(1H,m), 6.80(2H,d,J=8.5Hz), 7.07(2H,d,J=8.5Hz).

Reference Example 37

[0197] Titanium tetrachloride (3.67 g) was added dropwise to a solution of 5-[2-(4-isopropoxyphenyl)ethyl]-2,4-thiazolidinedione (1.35g) in dichloromethane (70 ml) at 0°C. After stirring for 2 hours, the mixture was poured into ice-cooled water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - hexane (1:3, v/v) gave 5-[2-(4-hydroxyphenyl)ethyl]-2,4-thiazolidinedione (0.72 g, 63%). This product was recrystallized from acetone - isopropyl ether. Colorless prisms, mp: 175-176°C.

Elemental Analysis:
Calcd. for C11H11NO3S	C, 55.68;	H, 4.67;	N, 5.90
Found	C, 55.63;	H, 4.57;	N, 5.83

Reference Examples 38 to 40

[0198] According to the same manner as that described in Reference Example 37, the compounds in Table 7 were obtained.

Reference Example 41

[0199] A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (0.623 g), triphenylphosphine (0.787 g) and acetonitrile (10 ml) was heated under reflux for 24 hours. After cooling, precipitated crystals of (5-methyl-2-phenyl-4-oxazolylmethyl)-triphenylphosphonium chloride (1.25 g, 89%) were obtained. mp. 277-278°C.

Elemental Analysis:
Calcd. for C29H25ClNOP	C, 74.12;	H, 5.36;	N, 2.98
Found	C, 73.79;	H, 5.32;	N, 2.97

Reference Example 42

[0200] (5-Methyl-2-phenyl-4-oxazolylmethyl)triphenyl-phosphoni um chloride (25.4 g) was added to a solution of sodium ethoxide in ethanol [prepared from sodium (1.4 g) and ethanol (300 ml)] under cooling. The mixture was stirred at room temperature for 5 minutes, and then 4-bromobenzaldehyde (10.0 g) was added. After stirring at room temperature for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ether-hexane (1:20, v/v) gave (E)-4-[2-(4-bromophenyl)vinyl]-5-methyl-2-phenyloxazole (13.1 g, 71%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 138-139°C.

Reference Example 43

[0201] A solution of n-butyllithium in hexane (1.6M, 28.7 ml) was added dropwise to a solution of (E)-4-[2-(4-bromophenyl)vinyl]-5-methyl-2-phenyloxazole (13.0 g) in tetrahydrofuran (140 ml) at -70°C. The mixture was stirred at -70°C for 15 minutes, and then a solution of N,N-dimethylformamide (4.2 g) in tetrahydrofuran (10 ml) was added dropwise at the same temperature. The reaction mixture was stirred at -70°C for 30 minutes, and then warmed to room temperature. 1N hydrochloric acid (150 ml) was added dropwise, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - hexane (1:2, v/v) gave (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]-benzaldehyde (5.9 g, 54%). The product was recrystallized from ethyl acetate - hexane. Pale brown prisms, mp: 158-159°C.

Reference Example 44

[0202] A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (9.2g), p-hydroxyacetophenone (7.9g),potassium carbonate (6.73 g) and N,N-dimethylformamide (100 ml) was stirred at 70 to 80°C for 2.5 hours. The mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)acetophenone (11.6 g, 85%). This product was recrystallized from ethyl acetate - ether. Colorless prisms, mp: 126-127°C.

Reference Example 45

[0203] A mixture of methyl 2-bromo-3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)p henyl]propionate (14.2 g), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (4.83 g) and toluene (150 ml) was stirred at 80 to 90°C for 2 hours, and then poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-cinnamate (10.0 g, 86%). This product was recrystallized from dichloromethane-methanol. Colorless prisms, mp: 167-168°C.

Reference Example 46

[0204] According to the same manner as that described in Reference Example 45, methyl 2-bromo-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-trifluo romethylphenyl]propionate was debrominated to give methyl 4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-trifluoromethylci nnamate (yield: 80%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 148-149°C.

Reference Example 47

[0205] According to the same manner as that described in Reference Example 1, 3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzalde hyde was reacted with trimethyl phosphonoacetate to give methyl 3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]cinnamat e (yield: 90%). This product was recrystallized from dichloromethane - diethyl ether. Colorless prisms, mp: 129-130°C.

Reference Example 48

[0206] According to the same manner as that described in Reference Example 1, 3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)-benzaldehyde was reacted with triethyl phosphonoacetate to give ethyl 3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamate (yield: 96%). This product was recrystallized from ethyl acetate - hexane. Colorless needles, mp: 128-129°C.

Reference Example 49

[0207] According to the same manner as that described in Reference Example 1, 3-methoxy-4-(2-phenyl-4-thiazolyl-methoxy)benzaldehyde was reacted with triethyl phosphonoacetate to give ethyl 3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)cinnamate (yield: 93%). This product was recrystallized from ethyl acetate - hexane. Colorless needles, mp: 92-93°C.

Reference Example 50

[0208] According to the same manner as that described in Reference Example 1, 4-isopropoxy-3-methoxybenzaldehyde was reacted with triethyl phosphonoacetate to give ethyl 4-isopropoxy-3-methoxycinnamate (yield: 91%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 103-104°C.

Reference Example 51

[0209] According to the same manner as that described in Reference Example 1, 4-benzyloxy-3,5-dimethoxybenzaldehyde was reacted with triethyl phosphonoacetate to give ethyl 4-benzyloxy-3,5-dimethoxycinnamate (yield: 96%). This product was recrystallized from diethyl ether-hexane. Colorless plates, mp: 68-69°C.

Reference Example 52

[0210] According to the same manner as that described in Reference Example 10, methyl 4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-trifluoromethylci nnamate was reduced to give (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-trifluorome thyl-phenyl]-2-propenol (yield: 87%). This product was recrystallized from dichloromethane - isopropyl ether. Colorless prisms, mp: 152-153°C.

Reference Example 53

[0211] According to the same manner as that described in Reference Example 10, methyl 3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)cinnamat e was reduced to give (E)-3-[3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]p henyl]-2-propenol (yield: 84%). This product was recrystallized from dichloromethane - diethyl ether. Colorless needles, mp: 128-129°C.

Reference Example 54

[0212] According to the same manner as that described in Reference Example 10, ethyl 3-methoxy-4-(2-phenyl-4-oxazolyl-methoxy)cinnamate was reduced to give (E)-3-[3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)phenyl]-2-pro penol (yield: 98%). This product was recrystallized from ethyl acetate - hexane. Colorless needles, mp: 113-114°C.

Reference Example 55

[0213] According to the same manner as that described in Reference Example 10, ethyl 3-methoxy-4-(2-phenyl-4-thiazolyl-methoxy)cinnamate was reduced to give (E)-3-[3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)phenyl]-2-pr openol (yield: 86%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 71-72°C.

Reference Example 56

[0214] A solution of aluminium chloride (AlCl₃) (6.1 g) in diethyl ether (70 ml) was added dropwise to a suspension of lithium aluminum hydride (LiAlH₄) (6.4 g) in diethyl ether (270 ml) at 0°C, and the mixture was stirred at room temperature for 10 minutes. Then, a solution of ethyl 4-isopropoxy-3-methoxycinnamate (35.4 g) in diethyl ether - tetrahydrofuran (3:1, 220 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. Then water (170 ml) and 6N sulfuric acid (270 ml) were added dropwise under ice-cooling, and the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with water, dried over magnesium sulfate, and concentrated. The residue was subjected to chromatography on silica gel. The fractions eluted with ethyl acetate - hexane (1:2, v/v) gave (E)-3-(4-isopropoxy-3-methoxyphenyl)-2-propenol (27.0 g, 91%) as an oil.

[0215] NMR (δ ppm in CDCl₃) : 1.37(6H,d,J=6Hz), 1.52(1H,s), 3.87(3H,s), 4.30 (2H,dd,J=6&1Hz), 4.52(1H,m), 6.24(1H,dd, J=16&6Hz), 6.55(1H,d,J=16Hz), 6.83(1H,d,J=8Hz), 6.90(1H,dd, J=8&2Hz), 6.94(1H,d,J=2Hz).

Reference Example 57

[0216] According to the same manner as that described in Reference Example 56, ethyl 4-benzyloxy-3,5-dimethoxycinnamate was reduced to give (E)-3-(4-benzyloxy-3,5-dimethoxyphenyl)-2-propenol (yield: 91%). This product was recrystallized fromethyl acetate - hexane. Colorless needles, mp: 72-73°C.

Reference Example 58

[0217] According to the same manner as that described in Reference Example 20, (E)-3-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-trifluorom ethylphenyl]-2-propenol was oxidized to give 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-trifluoro-methylci nnamaldehyde (yield: 89%). This product was recrystallized from dichloromethane - isopropyl ether. Colorless prisms, mp: 138-139°C.

Reference Example 59

[0218] According to the same manner as that described in Reference Example 20, (E)-3- [3-methoxy-4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy]p henyl]-2-propenol was oxidized to give 3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-cinnama ldehyde (yield: 94%). This product was recrystallized from dichloromethane - diethyl ether. Colorless prisms, mp: 125-126°C.

Reference Example 60

[0219] According to the same manner as that described in Reference Example 20, (E)-3-[3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)phenyl]-2-pro penol was oxidized to give 3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (yield: 88%). This product was recrystallized from ethyl acetate - hexane. Colorless needles, mp: 144-145°C.

Reference Example 61

[0220] According to the same manner as that described in Reference Example 20, (E)-3-[3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)phenyl]-2-pr openol was oxidized to give 3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)cinnamaldehyde (yield: 80%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 115-116°C.

Reference Example 62

[0221] According to the same manner as that described in Reference Example 20, (E)-3-(4-isopropoxy-3-methoxyphenyl)-2-propenol was oxidized to give 4-isopropoxy-3-methoxycinnam-aldehyde (yield: 90%). This product was recrystallized from ethyl acetate - hexane. Colorless plates, mp: 93-94°C.

Reference Example 63

[0222] According to the same manner as that described in Reference Example 20, (E)-3-(4-benzyl-3,5-dimethoxyphenyl)-2-propenol was oxidized to give 4-benzyloxy-3,5-dimethoxycinnam-aldehyde (yield: 93%). This product was recrystallized from ethyl acetate - hexane. Colorless plates, mp: 114-115°C.

Reference Example 64

[0223] According to the same manner as that described in Reference Example 37, 5-[3-(4-isopropoxy-3-methoxyphenyl)-propyl]-2,4-thiazolidine dione was treated with titanium tetrachloride to give 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-thiazolidinedion e as an oil (yield: 87%).

[0224] NMR (δ ppm in CDCl₃) : 1.65-2.2 (4H,m), 2.61(2H,t, J=7Hz), 3.89(3H,s), 4.28(1H,dd,J=9&4Hz), 5.51(1H,s), 6.66 (1H,dd,J=9&2Hz), 6.66(1H,d,J=2Hz), 6.84(1H,d,J=9Hz), 8.37 (1H,br s).

Reference Example 65

[0225] According to the same manner as that described in Reference Example 37, 5-[3-(4-benzyloxy-3,5-dimethoxyphenyl)-propyl]-2,4-thiazolid inedione was treated with titanium tetrachloride to give 5-[3-(4-hydroxy-3,5-dimethoxyphenyl)-propyl]-2,4-thiazolidin edione as an oil (yield: 82%).

[0226] NMR (δ ppm in CDCl₃) : 1.75-2.15(4H,m), 2.61 (2H,t,J=7Hz), 3.88(6H,s), 4.29(1H,dd,J=8&4Hz), 5.42(1H,s), 6.39(2H,s).

Reference Example 66

[0227] A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (19.2 g), 6-hydroxytetralone (15.0 g), potassium carbonate (15.4 g) and dimethylformamide (DMF) (100 ml) was stirred at 80 to 90°C for 2 hours. The reaction mixture was poured into water, and the precipitated crystals of 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)tetralone (29.5 g, 96%) were collected by filtration and recrystallized from dichloromethane-methanol. Colorless prisms, mp: 143-144°C.

Reference Example 67

[0228] Sodium methoxide (28%, 43.4 g) was concentrated to dryness, and a solution of 6-(5-methyl-2-phenyl-4-oxazoly-methoxy)tetralone (15.0 g) and dimethyl carbonate (81.0 g) in tetrahydrofuran (THF) (40 ml) was added dropwise at room temperature with stirring. After heating under reflux for 1 hour, conc. hydrochloric acid was added at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - chloroform (2:98, v/v) gave an oil (17.6 g). This oil was dissolved in THF (40 ml) - methanol (120 ml), and sodium borohydride (850 mg) was added little by little at 0C°. After stirring for 2 hours, the reaction mixture was poured into 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - chloroform (2:98, v/v) gave methyl 1-hydroxy-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1,2,3,4-te trahydronaphthalene-2-carboxylate (5.77 g, 33%). This product was recrystallized from dichloromethane-methanol. Colorless prisms, mp: 146-147°C.

Reference Example 68

[0229] Boron trifluoride diethyl ether complex (4.14 g) was added dropwise to a solution of methyl 1-hydroxy-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1,2,3,4-te trahydronaphthalene-2-carboxylate (5.46 g) in dichloromethane (200 ml) at 0°C. The mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was washed with water, dried over magnesium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave methyl 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3,4-dihydronaphthale ne-2-carboxylate (4.30g, 83%). This product was recrystallized from dichloromethane - isopropyl ether. Colorless prisms, mp: 130-131°C.

Reference Example 69

[0230] According to the same manner as that described in Reference Example 10, methyl 6-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3,4-dihydronaphthal ene-2-carboxylate was reduced to give 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3,4-dihydro-2-naphth ylmethanol. This product was recrystallized from acetone - isopropyl ether. Colorless prisms, mp: 141-142°C.

Reference Example 70

[0231] According to the same manner as that described in Reference Example 20, 6-(5-methyl-2-phenyl-4-oxazolylmethoxy-3,4-dihydro-2-naphthy lmethanol was oxidized to give 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3,4-dihydro-2-naphth oaldehyde. This product was recrystallized from dichloromethane - isopropyl ether. Colorless prisms, mp: 114-115°C.

Reference Example 71

[0232] Methylhydrazine (3.49 g) was added dropwise to a solution of methyl benzimidate hydrochloride in methanol (80 ml) at 0°C. After stirring for 3 hours, the reaction mixture was concentrated to give 2-methyl-3-phenylamidrazone hydrochloride (12.5 g, 89%). This product was recrystallized from methanol- diethyl ether. Colorless prisms, mp: 197-198°C.

Reference Example 72

[0233] A mixture of 2-methyl-3-phenylamidrazone hydrochloride (3.15 g), chloroacetyl chloride (1.92 g) and benzene (40 ml) was heated under reflux for 2 hours with stirring. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, dried over magnesium sulfate, and concentrated to give 3-chloromethyl-1-methyl-5-phenyl-lH-triazole (1.00 g, 28%). This product was recrystallized from diethyl ether - hexane. Colorless prisms, mp: 112-113°C.

Reference Example 73

[0234] A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl-methoxy)cinnamaldehyde (2.4 g), 2,4-thiazolidinedione (1.8 g), piperidine (0.192 g) and ethanol (50 ml) was heated under reflux for 5 hours. After cooling, the precipitated crystals of 5-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamilidene]-2,4 -thiazolidinedione (1.3g, 42%) were filtered, and recrystallized from ethyl acetate - methanol. Pale yellow prisms, mp: 226-227°C.

Elemental Analysis:
Calcd. for C23H18N2O4S	C, 66.01;	H, 4.34;	N, 6.69
Found	C, 65.91;	H, 4.26;	N, 6.64

Reference Example 74-76

[0235] According to the same manner as that described in Reference Example 73, the compounds in Table 8 were obtained.

Reference Example 77

[0236] According to the same manner as that described in Reference Example 73, (E) -4- [2- (5-methyl-2-phenyl-4-oxazolyl) vinyl] -cinnamaldehyde was condensed with 2,4-thiazolidinedione to give (E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]-cinnamilide ne]-2,4-thiazolidinedione (yield: 33%). This product was recrystallized from N,N-dimethylformamide - water. Yellow needles, mp: not less than 300°C.

Reference Example 78

[0237] According to the same manner as that described in Reference Example 73, (E)-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthyl] ac rolein was condensed with 2,4-thiazolidinedione to give 5-[3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthyl]pro penylidene]-2,4-thiazolidinedione (yield: 73%). This product was recrystallized from chloroform - methanol. Yellow prisms, mp: 267-268°C.

Reference Example 79

[0238] According to the same manner as that described in Example 1, 5-[3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthyl]pro penylidene]-2,4-thiazolidinedione was subjected to catalytic hydrogenation to give 5-[3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthyl]pro pyl]-2,4-thiazolidinedione (yield: 50%). This product was recrystallized from chloroform-ethanol. Pale yellow prisms, mp. 208-209°C.

Reference Example 80

[0239] According to the same manner as that described in Example 6, (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-phenyl]-2-but enal was condensed with 2,4-thiazolidinedione, and then the resulting compound was subjected to catalytic hydrogenation to give 5-[3-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)phenyl]butyl]-2,4-thiazolidinedione (yield: 6%). This product was recrystallized from isopropyl ether. Pale yellow prisms, mp: 64-65°C.

Reference Example 81

[0240] A mixture of ethyl 2-chloro-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl ]butyrate (0.20 g), thiourea (0.145 g), sodium acetate (0.115 g) and ethanol (15 ml) was heated under reflux for 30 hours. 6N hydrochloric acid (15 ml) was added, and the mixture was heated under reflux for 15 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with methanol-chloroform (2:98, v/v) gave 5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]ethyl ]-2,4-thiazolidinedione (0.11 g, 56%). This product was recrystallized from dichloromethane-ethanol. Colorless prisms, mp: 151-152°C.

Reference Example 82

[0241] According to the same manner as that described in Reference Example 81, 5-[2-(4-isopropoxyphenyl)ethyl]-2,4-thiazolidinedione was obtained (yield: 100%) as an oil from ethyl 2-chloro-4-(4-isopropoxyphenyl)butyrate.

[0242] NMR (δ ppm in CDCl₃) : 1.32 (6H,d,J=6Hz), 2.05-2.9(4H,m), 4.19(1H,dd,J=9.5&4Hz), 4.4-4.6(1H,m), 6.83(2H,d,J=8.5Hz), 7:08(2H,d,J=8.5Hz), 8.29(1H,br s).

Reference Example 83

[0243] Oily sodium hydride (60%, 0.10 g) was added to a solution of 5-[2-(4-hydroxyphenyl)ethyl]-2,4-thiazolidinedione (0.30 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 15 minutes. Then, 4-chloro-methyl-5-methyl-2-phenyloxazole (0.29 g) was added, and the mixture was stirred at 90 to 100°C for 2 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - chloroform (1:9, v/v) gave 5-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-2 ,4-thiazolidinedione (0.30 g, 59%). This product was recrystallized from dichloromethane - isopropyl ether. Colorless needles, mp: 146-147°C.

Reference Example 84 to 86

[0244] According to the same manner as that described in Reference Example 83, the compounds in Table 9 were obtained.

Reference Example 87

[0245] A mixture of 4-isopropoxycinnamaldehyde (6.00 g), 2,4-thiazolidinedione (5.54 g), piperidine (2.69 g) and acetic acid (30 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure to give precipitated crystals of 5-(4-isopropoxycinnamylidene)-2,4-thiazolidinedione, and the crystals (4.40 g) were collected by filtration and washed with ethyl acetate. The crystals were dissolved in tetrahydrofuran (100 ml), 5% palladium-carbon (2.20 g) was added, and the mixture was subjected to catalytic hydrogenation at room temperature at a hydrogen pressure of 3.8 kgf/cm². The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - chloroform (1:9, precipitated crystals of 5-(4-isopropoxycinnamylidene)-2,4-thiazolidinedione, and the crystals (4.40 g) were collected by filtration and washed with ethyl acetate. The crystals were dissolved in tetrahydrofuran (100 ml), 5% palladium-carbon (2.20 g) was added, and the mixture was subjected to catalytic hydrogenation at room temperature at a hydrogen pressure of 3.8 kgf/cm². The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - chloroform (1:9, v/v) gave 5-[3-(4-isopropoxyphenyl)propyl]-2,4-thiazolidinedione (3.61 g, 39%) as an oil.

[0246] NMR (δ ppm in CDCl₃) : 1.32(6H,d,J=6Hz), 1.6-2.3(4H,m), 2.61(2H,t,J=7.5Hz), 4.28(1H,dd,J=8.5&4.5Hz), 4.4-4.65(1H,m), 6.82(2H,d,J=8.5Hz), 7.06(2H,d,J=8.5Hz), 8.34(1H,br s).

Reference Example 88

[0247] According to the same manner as that described in Reference Example 87, 2-[3-(4-isopropoxyphenyl)propyl]-1,3-dioxolane was condensed with 2,4-thiazolidinedione, and the resulting compound was subjected to catalytic hydrogenation to give crystals of 5-[4-(4-isopropoxyphenyl)butyl]-2,4-thiazolidinedione (yield: 68%). This product was recrystallized from ether-hexane. Colorless prisms, mp: 72-73°C.

Reference Example 89

[0248] According to the same manner as that described in Reference Example 87, (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienal was condensed with 2,4-thiazolidinedione, and the resulting compound was subjected to catalytic hydrogenation to give 5-[5-(4-isopropoxyphenyl)pentyl]-2,4-thiazolidinedione as an oil (yield: 26%).

[0249] NMR (δ ppm in CDCl₃) : 1.2-1.75 (6H,m), 1.32 (6H,d,J=6Hz), 1.8-2.3(2H,m), 2.54(2H,t,J=7.5Hz), 4.26(1H,dd,J=9&4.5Hz), 4.4-4.6(1H,m), 6.80(2H,d,J=8.5Hz), 7.05(2H,d,J=8.5Hz), 8.06(1H,br s).

Reference Example 90

[0250] According to the same manner as that described in Reference Example 73 above, 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3,4-dihydro-2-naphth oaldehyde was condensed with 2,4-thiazolidinedione to give 5-[6-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3,4-dihydro-2-na phthylmethylidene]-2,4-thiazolidine-dione (yield: 50%). This product was recrystallized from dichloromethane-methanol. Yellow needles, mp: 271-272°C.

Reference Example 91

[0251] According to the same manner as that described in Reference Example 73, (E)-3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnam-aldehyde was condensed with 2,4-thiazolidinedione to give 5-[3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamylidene]-2, 4-thiazolidinedione (yield: 57%). This product was recrystallized from chloroform-methanol. Yellow needles, mp: 230-231°C.

Reference Example 92

[0252] According to the same manner as that described in Reference Example 73, (E)-3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)-cinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-[3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)-cinnamylidene]-2,4-thiazolidinedione (yield: 49%). This product was recrystallized from chloroform-methanol. Yellow needles, mp: 248-249°C.

Reference Example 93

[0253] According to the same manner as that described in Example 6, 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-trifluoromethylcin namaldehyde was condensed with 2,4-thiazolidinedione, and the resulting product was subjected to catalytic hydrogenation to give 5-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-trifluoromet hylphenyl]propyl]-2,4-thiazolidinedione (yield: 31%). This product was recrystallized from dichloromethane-methanol. Colorless prisms, mp: 154-155°C.

Reference Example 94

[0254] According to the same manner as that described in Reference Example 83, 5-[3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy ]phenyl]propyl]-2,4-thiazolidinedione was obtained (yield: 37%) and recrystallized from chloroform-ethanol. Pale yellow prisms, mp: 154-155°C.

Reference Example 95

[0255] According to the same manner as that described in Reference Example 83, 5-[3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-thiazolylmethox y]phenyl]propyl]-2,4-thiazolidinedione was obtained (yield: 30%) and recrystallized from chloroform-ethanol. Pale yellow prisms, mp: 161-162°C.

Reference Example 96

[0256] According to the same manner as that described in Reference Example 83, 5-[3-[3,5-dimethoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmet hoxy]phenyl]propyl]-2,4-thiazolidinedione was obtained (yield: 37%) and recrystallized from ethyl acetate -hexane. Pale yellow prisms, mp: 163-164°C.

Reference Example 97

[0257] According to the same manner as that described in Reference Example 73, 4-isopropoxy-3-methoxycinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-(4-isopropoxy-3-methoxy-cinnamylidene)-2,4-thiazolidinedio ne (yield: 61%). This product was recrystallized from ethyl acetate - hexane. Yellow prisms, mp: 230-231°C.

Reference Example 98

[0258] According to the same manner as that described in Reference Example 73, 4-benzyloxy-3,5-dimethoxycinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)-2,4-thiazolidined ione (yield: 57%). This product was recrystallized from chloroform-ethanol. Yellow prisms, mp: 217-218°C.

Reference Example 99

[0259] According to the same manner as that described in Example 1, 5-(4-isopropoxy-3-methoxycinnamylidene)-2,4-thiazolidinedion e was subjected to catalytic hydrogenation to give 5-[3-(4-isopropoxy-3-methoxyphenyl)propyl]-2,4-thiazolidined ione as an oil (yield: 75%).

[0260] NMR (δ ppm in CDCl₃) : 1.35(6H,d,J=6Hz), 1.65-2.2 (4H,m), 2.62(2H,t,J=7Hz), 3.85(3H,s), 4.28(1H,dd,J=8&4Hz), 4.47(1H,m), 6.67(1H,dd,J=8&2Hz), 6.69(1H,s), 6.83(1H,d,J=8Hz), 8.45(1H,br s) .

Reference Example 100

[0261] According to the same manner as that described in Example 1, 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)-2,4-thiazolidined ione was subjected to catalytic hydrogenation to give 5-[3-(4-benzyloxy-3,5-dimethoxyphenyl)propyl]-2,4-thiazolidi nedione (yield: 76%). This product was recrystallized from ethyl acetate - hexane. Colorless prisms, mp: 101-102°C.

Claims

1. A 2,4-thiazolidinedione derivative of the formula (I):

wherein
   R is an aromatic heterocyclic group
which may be attached through a straight or branched and saturated or unsaturated hydrocarbon chain having 1 to 8 carbon atoms, the aromatic heterocyclic group having the formula:

wherein B¹ is a sulfur atom, an oxygen atom or NR⁴ in which R⁴ is a hydrogen atom, an alkyl group having I to 3 carbon atoms or an aralkyl group selected from benzyl and phenethyl;
   B² is a nitrogen atom or C-R⁵ in which R⁵ is

(1) a hydrogen atom,

(2) a hydrocarbon group selected from

a) saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms

b) saturated or unsaturated alicyclic hydrocarbon group having 3 to 7 carbon atoms

c) saturated or unsaturated alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms

d) aromatic carbocycle-aliphatic hydrocarbon group selected from phenylalkyl having 7 to 9 carbon atoms and naphthylalkyl having 11 to 13 carbon atoms, and

e) aromatic hydrocarbon group selected from phenyl and naphthyl,
   when the hydrocarbon group contains an alicyclic group, the alicyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms, and
   when the hydrocarbon group contains an aromatic hydrocarbon group, the hydrocarbon group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylythio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms,

(3) 5- or 6-membered cyclic group which contains 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and which is attached through a ring-constituting carbon atom,
   when the cyclic group is saturated, the cyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms,
   when the cyclic group is unsaturated, the cyclic group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylthio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms, and
   when the cyclic group is substituted by at least 2 hydrocarbon groups at adjacent positions to each other on the cycle, these hydrocarbon groups may be linked together to form a condensed ring;

R³ is

(1) a hydrogen atom,

(2) a hydrocarbon group selected from

a) saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms

b) saturated or unsaturated hydrocarbon group having 3 to 7 carbon atoms

c) saturated or unsaturated alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms

d) aromatic carbocycle-aliphatic hydrocarbon group selected from phenylalkyl having 7 to 9 carbon atoms and naphthylalkyl having 11 to 13 carbon atoms, and

e) aromatic hydrocarbon group selected from phenyl and naphthyl,

   when the hydrocarbon group contains an alicyclic group, the alicyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms, and
   when the hydrocarbon group contains an aromatic hydrocarbon group, the hydrocarbon group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having I to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylythio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms,

(3) 5- or 6-membered cyclic group which contains 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and which is attached through a ring-constituting carbon atom,
   when the cyclic group is saturated, the cyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms,
   when the cyclic group is unsaturated, the cyclic group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkokycarbonyl having 2 to 4 carbon atoms, alkylthio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms, and
   when the cyclic group is substituted by at least 2 hydrocarbon groups at adjacent positions to each other on the cycle, these hydrocarbon groups may be linked together to form a condensed ring;

R³ and R⁵ may be linked together to form a condensed ring when R³ and R⁵ are attached to adjacent carbon atoms to each other;
n is 0 or 1;
X is CH;
Y is -CH₂CH₂-;
R¹ and R² are the same or different and are

(1) a hydrogen atom;

(2) a halogen atom;

(3) an optionally substituted hydroxyl group selected from a hydroxyl group and alkoxy groups having 1 to 4 carbon atoms;

(4) a hydrocarbon group selected from

a) saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms

b) saturated or unsaturated alicyclic hydrocarbon group having 3 to 7 carbon atoms

c) saturated or unsaturated alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms

d) aromatic carbocycle-aliphatic hydrocarbon group selected from phenylalkyl having 7 to 9 carbon atoms and naphthylalkyl having 11 to 13 carbon atoms, and

e) aromatic hydrocarbon group selected from phenyl and naphthyl,

   when the hydrocarbon group contains an alicyclic group, the alicyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms, and
   when the hydrocarbon group contains an aromatic hydrocarbon group, the hydrocarbon group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylythio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms, and either R¹ or R² and a part of Y may be linked together to form a ring; and

   L and M are a hydrogen atom, or L and M are linked together to form a bond; or a salt thereof.

2. The compound according to claim 1, which is represented by the formula (I-A1):

or a salt thereof.

3. The compound according to claim 1, where in n is 1, and R is the aromatic heterocyclic group which is attached through a hydrocarbon chain having 1 to 8 carbon atoms, or a salt thereof.

4. The compound according to claim 3, wherein the hydrocarbon chain is -CH=CH- or -CH₂CH₂-, or a salt thereof.

5. The compound according to claim 1, wherein the aromatic heterocyclic group is represented by the formula:

wherein R⁵ and R⁶ are the same and different and are a hydrogen atom, a hydrocarbon group selected from

1) saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms

2) saturated or unsaturated alicyclic hydrocarbon group having 3 to 7 carbon atoms

3) saturated or unsaturated alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms

4) aromatic carbocycle-aliphatic hydrocarbon group selected from phenylalkyl having 7 to 9 carbon atoms and naphthylalkyl having 11 to 13 carbon atoms, and

5) aromatic hydrocarbon group selected from phenyl and naphthyl,

   when the hydrocarbon group contains an alicyclic group, the alicyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms, and
   when the hydrocarbon group contains an aromatic hydrocarbon group, the hydrocarbon group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylthio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms, or 5- or 6-membered cyclic group which contains 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and which is attached through a ring-constituting carbon atom,
   when the cyclic group is saturated, the cyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms,
   when the cyclic group is unsaturated, the cyclic group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylthio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms, and
   when the cyclic group is substituted by at least 2 hydrocarbon groups at adjacent positions to each other on the cycle, these hydrocarbon groups may be linked together to form a condensed ring, B is an oxygen atom or a sulfur atom, or a salt thereof.

6. . The compound according to claim 1, wherein the aromatic heterocyclic group is represented by the formula:

wherein B is an oxygen atom or a sulfur atom, R⁷ and R⁸ are the same or different and are a hydrogen,
a hydrocarbon group selected from

1) saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms

2) saturated or unsaturated alicyclic hydrocarbon group having 3 to 7 carbon atoms

3) saturated or unsaturated alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms

4) aromatic carbocycle-aliphatic hydrocarbon group selected from phenylalkyl having 7 to 9 carbon atoms and naphthylalkyl having 11 to 13 carbon atoms, and

5) aromatic hydrocarbon group selected from phenyl and naphthyl,

   when the hydrocarbon group contains an alicyclic group, the alicyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms, and
   when the hydrocarbon group contains an aromatic hydrocarbon group, the hydrocarbon group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylythio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms, or 5- or 6-membered cyclic group which contains 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and which is attached through a ring-constituting carbon atom,
   when the cyclic group is saturated, the cyclic group may be substituted by 1 to 3 alkyl groups having 1 to 3 carbon atoms,
   when the cyclic group is unsaturated, the cyclic group may have the same or different 1 to 4 substituents selected from halogen, hydroxy, cyano, nitro, trifluoromethyl, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 4 carbon atoms, alkylthio having 1 to 3 carbon atoms, and alkylamino having 1 to 4 carbon atoms, and
   when the cyclic group is substituted by at least 2 hydrocarbon groups at adjacent positions to each other on the cycle, these hydrocarbon groups may be linked together to form a condensed ring, or R⁷ and R⁸ are linked together to form a ring, or a salt thereof.

7. The compound according to claim 1, wherein B¹ is NR⁴ in which R⁴ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an aralkyl group selected from benzyl and phenethyl, and B² is a nitrogen atom, or a salt thereof.

8. The compound according to claim 1, wherein L and M are a hydrogen atom, or a salt thereof.

9. The compound according to claim 1, wherein R¹ and R² are a hydrogen atom, or a salt thereof.

10. The compound according to claim 2, wherein n is 1, R is the aromatic heterocyclic group which is attached through a hydrocarbon chain having 1 to 2 carbon atoms, L and M are a hydrogen atom, and R¹ and R² are a hydrogen atom, or a salt thereof.

11. The compound according to claim 2, wherein n is 1, R is the aromatic heterocyclic group which is attached through a hydrocarbon chain having 1 to 2 carbon atoms, L and M are a hydrogen atom R¹ is a halogen atom, and R² is a hydrogen atom, or a salt thereof.

12. The compound according to claim 2, wherein n is 1, R is the aromatic heterocyclic group which is attached through a hydrocarbon chain having 1 to 2 carbon atoms, L and M are a hydrogen atom, R¹ is an optionally substituted hydroxyl group, selected from a hydroxyl group and alkoxy groups having 1 to 4 carbon atoms, and R² is a hydrogen atom, or a salt thereof.

13. The compound according to claim 2, wherein n is 0, R is the aromatic heterocyclic group which is attached through an ethylene group or a vinylene group, L and M are a hydrogen atom, R¹ and R² are a hydrogen atom, or a salt thereof.

14. The compound according to claim 1, which is 5-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidinedione, or a salt thereof.

15. The compound according to claim 1, which is 5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidinedione, or a salt thereof.

16. The compound according to claim 1, which is 5-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidinedione, or a salt thereof.

17. The compound according to claim 1, which is 5-[3-[4-(5-methyl-2-naphthyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidinedione, or a salt thereof.

18. A pharmaceutical composition which comprises a 2,4-thiazolidinedione derivative of the formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition according to claim 18, which is for enhancing insulin sensitivity.

20. The pharmaceutical composition according to claim 18, which is for treating diabetes.

21. The pharmaceutical composition according to claim 18, which is for treating hyperlipemia.

22. A process for producing a 2,4-thiazolidinedione derivative of the formula (I-B2):

wherein R, n, X, Y, R¹ and R⁵ are as defined in claim 1 which comprises hydrolyzing an iminothiazolidinone compound of the formula (III):

wherein each symbol is as defined above.

23. A process for producing a 2,4-thiazolidinedione derivative of the formula (I-B2a):

wherein
   R' is the aromatic heterocyclic group as defined in claim 1, which may be attached through a straight or branched saturated hydrocarbon chain having 1 to 8 carbon atoms;
   n is 0 or 1;
   X is CH;
   Y¹ -CH₂CH₂-
   R¹ and R² are as defined in claim 1,
and either R¹ or R² and a part of Y' may be linked to form a ring;
which comprises reducing a compound of the formula (I-B1):

wherein R, Y, R¹ and R² are as defined in claim 1, provided that

and the other symbols are as defined above.

24. A process for producing a 2,4-thiazolidinedione derivative of the formula (I-D1):

wherein
   R" is the aromatic heterocyclic group as defined in claim 1,
   Y, R¹ and R² are as defined in claim 1, and
   L and M are a hydrogen atom, or L and M are linked together to form a bond; which comprises reacting a compound of the formula (V):

   wherein each symbol is as defined above, with a compound of the formula (VI):

        R"-CH₂-Q     (VI)

   wherein Q is a leaving group and R" is as defined above.

25. Use of a compound according to claim I for the manufacture of a medicament for enhancing insulin sensitivity in a mammal in need thereof.

26. Use of a compound according to claim 1 for the manufacture of a medicament for treating diabetes in a mammal in need thereof.

27. Use of a compound according to claim 1 for the manufacture of a medicament for treating hyperlipemia in a mammal in need thereof.

28. Use of a compound according to claim 1 for the manufacture of a pharmaceutical composition for enhancing insulin sensitivity.

Ansprüche

1. 2,4-Thiazolidindionderivat der Formel (I)

worin
R eine aromatische heterocyclische Gruppe ist, die über eine gerade oder verzweigte und gesättigte oder ungesättigte Kohlenwasserstoffkette mit 1 bis 8 Kohlenstoffatomen gebunden sein kann, wobei die aromatische heterocyclische Gruppe die Formel

aufweist, worin B¹ ein Schwefelatom, ein Sauerstoffatom oder NR⁴ ist, worin R⁴ ein Wasserstoffatom, eine Alkylgruppe mit 1 bis 3 Kohlenstoffatomen oder eine aus Benzyl und Phenethyl ausgewählte Aralkylgruppe ist;
B² ein Stickstoffatom oder C-R⁵ ist, worin R⁵

(1) ein Wasserstoffatom,

(2) eine Kohlenwasserstoffgruppe ausgewählt aus einer

a) gesättigten oder ungesättigten aliphatischen Kohlenwasserstoffgruppe mit 1 bis 8 Kohlenstoffatomen,

b) gesättigten oder ungesättigten alicyclischen Kohlenwasserstoffgruppe mit 3 bis 7 Kohlenstoffatomen,

c) gesättigten oder ungesättigten aiicyclisch-aliphatischen Kohlenwasserstoffgruppe mit 4 bis 9 Kohlenstoffatomen,

d) aromatischen carbocyclisch-aliphatischen Kohlenwasserstoffgruppe, die aus Phenylalkyl mit 7 bis 9 Kohlenstoffatomen und Naphthylalkyl mit 11 bis 13 Kohlenstoffatomen ausgewählt ist, und

e) aromatischen Kohlenwasserstoffgruppe, die aus Phenyl und Naphthyl ausgewählt ist,

und wenn die Kohlenwasserstoffgruppe eine alicyclische Gruppe enthält, die alicyclische Gruppe durch 1 bis 3 Alkylgruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein kann, und
wenn die Kohlenwasserstoffgruppe eine aromatische Kohlenwasserstoffgruppe enthält, die Kohlenwasserstoffgruppe die gleichen oder verschiedenen 1 bis 4 Substituenten aufweisen kann, die aus Halogen, Hydroxy, Cyan, Nitro, Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 4 Kohlenstoffatomen, Alkylthio mit 1 bis 3 Kohlenstoffatomen und Alkylamino mit 1 bis 4 Kohlenstoffatomen ausgewählt sind, oder

(3) eine 5- oder 6gliedrige cyclische Gruppe ist, die außer einem Kohlenstoffatom 1 bis 3 aus einem Stickstoffatom, einem Sauerstoffatom und einem Schwefelatom ausgewählte Heteroatome enthält und die über ein Ringkohlenstoffatom gebunden ist, und
wenn die cyclische Gruppe gesättigt ist, die cyclische Gruppe durch 1 bis 3 Alkylgruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein kann, und
wenn die cyclische Gruppe ungesättigt ist, die cyclische Gruppe die gleichen oder verschiedenen 1 bis 4 Substituenten aufweisen kann, die aus Halogen, Hydroxy, Cyan, Nitro, Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 4 Kohlenstoffatomen, Alkylthio mit 1 bis 3 Kohlenstoffatomen und Alkylamino mit 1 bis 4 Kohlenstoffatomen ausgewählt sind, und
wenn die cyclische Gruppe durch wenigstens 2 Kohlenwasserstoffgruppen in einander benachbarten Positionen am Ring substituiert ist, diese Kohlenwasserstoffgruppen miteinander unter Bilden eines kondensierten Ringes verbunden sein können;

R³

(1) ein Wasserstoffatom,

(2) eine Kohlenwasserstoffgruppe ausgewählt aus einer

a) gesättigten oder ungesättigten aliphatischen Kohlenwasserstoffgruppe mit 1 bis 8 Kohlenstoffatomen,

b) gesättigten oder ungesättigten Kohlenwasserstoffgruppe mit 3 bis 7 Kohlenstoffatomen,

c) gesättigten oder ungesättigten aiicyclisch-aiiphatischen Kohlenwasserstoffgruppe mit 4 bis 9 Kohlenstoffatomen,

d) aromatischen carbocyclus-aliphatischen Kohlenwasserstoffgruppe, die aus Phenylalkyl mit 7 bis 9 Kohlenstoffatomen und Naphthylalkyl mit 11 bis 13 Kohlenstoffatomen ausgewählt ist, und

e) aromatischen Kohlenwasserstoffgruppe, die aus Phenyl und Naphthyl ausgewählt ist, und

wenn die Kohlenwasserstoffgruppe eine alicyclische Gruppe enthält, die alicyclische Gruppe durch 1 bis 3 Alkylgruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein kann, und
wenn die Kohlenwasserstoffgruppe eine aromatische Kohlenwasserstoffgruppe enthält, die Kohlenwasserstoffgruppe die gleichen oder verschiedenen 1 bis 4 Substituenten aufweisen kann, die aus Halogen, Hydroxy, Cyan, Nitro, Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 4 Kohlenstoffatomen, Alkylthio mit 1 bis 3 Kohlenstoffatomen und Alkylamino mit 1 bis 4 Kohlenstoffatomen ausgewählt sind, oder

(3) eine 5- oder 6gliedrige cyclische Gruppe ist, die außer einem Kohlenstoffatom 1 bis 3 aus einem Stickstoffatom, einem Sauerstoffatom und einem Schwefelatom ausgewählte Heteroatome enthält und die über ein Ringkohlenstoffatom gebunden ist, und
wenn die cyclische Gruppe gesättigt ist, die cyclische Gruppe durch 1 bis 3 Alkylgruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein kann, und
wenn die cyclische Gruppe ungesättigt ist, die cyclische Gruppe die gleichen oder verschiedenen 1 bis 4 Substituenten aufweisen kann, die aus Halogen, Hydroxy, Cyan, Nitro, Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxycarbonyl mit 2-4 Kohlenstoffatomen, Alkylthio mit 1 bis 3 Kohlenstoffatomen und Alkylamino mit 1 bis 4 Kohlenstoffatomen ausgewählt sind, und
wenn die cyclische Gruppe durch wenigstens 2 Kohlenwasserstoffgruppen in einander benachbarten Positionen am Ring substituiert ist, diese Kohlenwasserstoffgruppen miteinander unter Bilden eines kondensierten Ringes verbunden sein können;

R³ und R⁵ miteinander unter Bilden eines kondensierten Ringes verbunden sein können, wenn R³ und R⁵ an einander benachbarte Kohlenstoffatome gebunden sind;
n 0 oder 1 ist;
X CH ist;
Y -CH₂CH₂- ist;
R¹ und R² gleich oder verschieden sind und

(1) ein Wasserstoffatom;

(2) ein Halogenatom;

(3) eine gegebenenfalls substituierte, aus einer Hydroxygruppe und Alkoxygruppen mit 1 bis 4 Kohlenstoffatomen ausgewählte Hydroxygruppe oder

(4) eine Kohlenwasserstoffgruppe sind, ausgewählt aus einer

a) gesättigten oder ungesättigten aliphatischen Kohlenwasserstoffgruppe mit 3 bis 7 Kohlenstoffatomen,

b) gesättigten oder ungesättigten alicyclischen Kohlenwasserstoffgruppe mit 3 bis 7 Kohlenstoffatomen,

c) gesättigten oder ungesättigten alicycllsch-aliphatischen Kohlenwasserstoffgruppe mit 4 bis 9 Kohlenstoffatomen,

d) aromatischen carbocyclisch-aliphatischen Kohlenwasserstoffgruppe, die aus Phenylalkyl mit 7 bis 9 Kohlenstoffatomen und Naphthylalkyl mit 11 bis 13 Kohlenstoffatomen ausgewählt ist, und

e) aromatischen Kohlenwasserstoffgruppe, die aus Phenyl und Naphthyl ausgewählt ist, und

wenn die Kohlenwasserstoffgruppe eine alicyclische Gruppe enthält, die alicyclische Gruppe durch 1 bis 3 Alkylgruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein kann, und
wenn die Kohlenwasserstoffgruppe eine aromatische Kohlenwasserstoffgruppe enthält, die Kohlenwasserstoffgruppe die gleichen oder verschiedenen 1 bis 4 Substituenten aufweisen kann, die aus Halogen, Hydroxy, Cyan, Nitro, Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 4 Kohlenstoffatomen, Alkylthio mit 1 bis 3 Kohlenstoffatomen und Alkylamino mit 1 bis 4 Kohlenstoffatomen ausgewählt sind,
und entweder R¹ oder R² und ein Teil von Y miteinander unter Bilden eines Ringes verbunden sein können, und
L und M ein Wasserstoffatom sind oder L und M miteinander unter Bilden einer Bindung verbunden sind; oder ein Salz davon.

2. Verbindung gemäß Anspruch 1, die durch die Formel (I-A1)

dargestellt wird, oder ein Salz davon.

3. Verbindung gemäß Anspruch 1, bei der n 1 ist und R eine aromatische heterocyclische Gruppe ist, die über eine Kohlenwasserstoffkette mit 1 bis 8 Kohlenstoffatomen gebunden ist, oder ein Salz davon.

4. Verbindung gemäß Anspruch 3, wobei die Kohlenwasserstoffkette -CH=CH- oder -CH₂CH₂- ist, oder ein Salz davon.

5. Verbindung gemäß Anspruch 1, wobei die aromatische heterocyclische Gruppe durch die Formel

dargestellt wird, worin R⁵ und R⁶ gleich oder verschieden sind und ein Wasserstoffatom, eine Kohlenwasserstoffgruppe ausgewählt aus einer

1) gesättigten oder ungesättigten aliphatischen Kohlenwasserstoffgruppe mit 1 bis 8 Kohlenstoffatomen,

2) gesättigten oder ungesättigten alicyclischen Kohlenwasserstoffgruppe mit 3 bis 7 Kohlenstoffatomen,

3) gesättigten oder ungesättigten alicyclisch-aliphatischen Kohlenwasserstoffgruppe mit 4 bis 9 Kohlenstoffatomen,

4) aromatischen carbocyclisch-aliphatischen Kohlenwasserstoffgruppe, die aus Phenylalkyl mit 7 bis 9 Kohlenstoffatomen und Naphthylalkyl mit 11 bis 13 Kohlenstoffatomen ausgewählt ist, und

5) aromatischen Kohlenwasserstoffgruppe, die aus Phenyl und Naphthyl ausgewählt ist, und

wenn die Kohlenwasserstoffgruppe eine alicyclische Gruppe enthält, die alicyclische Gruppe durch 1 bis 3 Alkylgruppen mit 1 bis 3 Kohtenstoffatomen substituiert sein kann, und
wenn die Kohlenwasserstoffgruppe eine aromatische Kohlenwasserstoffgruppe enthält, die Kohlenwasserstoffgruppe die gleichen oder verschiedenen 1 bis 4 Substituenten aufweisen kann, die aus Halogen, Hydroxy, Cyan, Nitro, Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 4 Kohlenstoffatomen, Alkylthio mit 1 bis 3 Kohlenstoffatomen und Alkylamino mit 1 bis 4 Kohlenstoffatomen ausgewählt sind, oder
eine 5- oder 6gliedrige cyclische Gruppe sind, die außer einem Kohlenstoffatom 1 bis 3 aus einem Stickstoffatom, einem Sauerstoffatom und einem Schwefelatom ausgewählte Heteroatome enthält und die über ein Ringkohlenstoffatom gebunden ist, und
wenn die cyclische Gruppe gesättigt ist, die cyclische Gruppe durch 1 bis 3 Alkylgruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein kann, und
wenn die cyclische Gruppe ungesättigt ist, die cyclische Gruppe die gleichen oder verschiedenen 1 bis 4 Substituenten aufweisen kann, die aus Halogen, Hydroxy, Cyan, Nitro, Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 4 Kohlenstoffatomen, Alkylthio mit 1 bis 3 Kohlenstoffatomen und Alkylamino mit 1 bis 4 Kohlenstoffatomen ausgewählt sind, und
wenn die cyclische Gruppe durch wenigstens 2 Kohlenwasserstoffgruppen in einander benachbarten Positionen am Ring substituiert ist, diese Kohlenwasserstoffgruppen miteinander unter Bilden eines kondensierten Ringes gebunden sein können, B ein Sauerstoffatom oder ein Schwefelatom ist, oder ein Salz davon.

6. Verbindung gemäß Anspruch 1, wobei die aromatische heterocyclische Gruppe durch die Formel

dargestellt wird, wobei B ein Sauerstoffatom oder ein Schwefelatom ist, R⁷ und R⁸ gleich oder verschieden sind und Wasserstoff, eine Kohlenwasserstoffgruppe ausgewählt aus einer

1) gesättigten oder ungesättigten aliphatischen Kohlenwasserstoffgruppe mit 1 bis 8 Kohlenstoffatomen,

2) gesättigten oder ungesättigten alicyclischen Kohlenwasserstoffgruppe mit 3 bis 7 Kohlenstoffatomen,

3) gesättigten oder ungesättigten alicyclisch-aliphatischen Kohlenwasserstoffgruppe mit 4 bis 9 Kohlenstoffatomen,

4) aromatischen carbocyclisch-aliphatischen Kohlenwasserstoffgruppe, die aus Phenylalkyl mit 7 bis 9 Kohlenstoffatomen und Naphthylalkyl mit 11 bis 13 Kohlenstoffatomen ausgewählt ist, und

5) aromatischen Kohlenwasserstoffgruppe, die aus Phenyl und Naphthyl ausgewählt ist, und

wenn die Kohlenwasserstoffgruppe eine alicyclische Gruppe enthält, die alicyclische Gruppe durch 1 bis 3 Alkylgruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein kann, und
wenn die Kohlenwasserstoffgruppe eine aromatische Kohlenwasserstoffgruppe enthält, die Kohlenwasserstoffgruppe die gleichen oder verschiedenen 1 bis 4 Substituenten aufweisen kann, die aus Halogen, Hydroxy, Cyan, Nitro, Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 4 Kohlenstoffatomen, Alkylthio mit 1 bis 3 Kohlenstoffatomen und Alkylamino mit 1 bis 4 Kohlenstoffatomen ausgewählt sind, oder
eine 5- oder 6gliedrige cyclische Gruppe sind, die außer einem Kohlenstoffatom 1 bis 3 aus einem Stickstoffatom, einem Sauerstoffatom und einem Schwefelatom ausgewählte Heteroatome enthält und die über ein Ringkohlenstoffatom gebunden ist, und
wenn die cyclische Gruppe gesättigt ist, die cyclische Gruppe durch 1 bis 3 Alkylgruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein kann, und
wenn die cyclische Gruppe ungesättigt ist, die cyclische Gruppe die gleichen oder verschiedenen 1 bis 4 Substituenten aufweisen kann, die aus Halogen, Hydroxy, Cyan, Nitro, Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 4 Kohlenstoffatomen, Alkylthio mit 1 bis 3 Kohlenstoffatomen und Alkylamino mit 1 bis 4 Kohlenstoffatomen ausgewählt sind, und
wenn die cyclische Gruppe durch wenigstens 2 Kohlenwasserstoffgruppen in einander benachbarten Positionen am Ring substituiert ist, diese Kohlenwasserstoffgruppen miteinander unter Bilden eines kondensierten Ringes verbunden sein können, oder R⁷ und R⁸ miteinander unter Bilden eines Ringes miteinander verbunden sind, oder ein Salz davon.

7. Verbindung gemäß Anspruch 1, wobei B¹ NR⁴ ist, worin R⁴ ein Wasserstoffatom, eine Alkylgruppe mit 1 bis 3 Kohlenstoffatomen oder eine aus Benzyl und Phenethyl ausgewählte Aralkylgruppe ist und B² ein Stickstoffatom ist, oder ein Salz davon.

8. Verbindung gemäß Anspruch 1, wobei L und M ein Wasserstoffatom sind, oder ein Salz davon.

9. Verbindung gemäß Anspruch 1, wobei R¹ und R² ein Wasserstoffatom sind, oder ein Salz davon.

10. Verbindung gemäß Anspruch 2, wobei n 1 ist, R eine aromatische heterocyclische Gruppe ist, die über eine Kohlenwasserstoffkette mit 1 bis 2 Kohlenstoffatomen gebunden ist, L und M ein Wasserstoffatom sind und R¹ und R² ein Wasserstoffatom sind, oder ein Salz davon.

11. Verbindung gemäß Anspruch 2, wobei n 1 ist, R eine aromatische heterocyclische Gruppe ist, die über eine Kohlenwasserstoffkette mit 1 bis 2 Kohlenstoffatomen gebunden ist, L und M ein Wasserstoffatom sind, oder ein Salz davon.

12. Verbindung gemäß Anspruch 2, wobei n 1 ist, R eine aromatische heterocyclische Gruppe ist, die über eine Kohlenwasserstoffkette mit 1 bis 2 Kohlenstoffatomen gebunden ist, L und M ein Wasserstoffatom sind, R¹ eine gegebenenfalls substituierte, aus einer Hydroxygruppe und Alkoxygruppen mit 1 bis 4 Kohlenstoffatomen ausgewählte Hydroxygruppe ist und R² ein Wasserstoffatom ist, oder ein Salz davon.

13. Verbindung gemäß Anspruch 2, wobei n 0 ist, R eine aromatische heterocyclische Gruppe ist, die über eine Ethylengruppe oder eine Vinylengruppe gebunden ist, L und M ein Wasserstoffatom sind, R¹ und R² ein Wasserstoffatom sind, oder ein Salz davon.

14. Verbindung gemäß Anspruch 1, die 5-[3-[3-Methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidindion oder ein Salz davon ist.

15. Verbindung gemäß Anspruch 1, die 5-[3-[3-Fluor-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidindion oder ein Salz davon ist.

16. Verbindung gemäß Anspruch 1, die 5-[3-[4-(5-Methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidindion oder ein Salz davon ist.

17. Verbindung gemäß Anspruch 1, die 5-[3-[4-(5-Methyl-2-naphthyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidindion oder ein Salz davon ist.

18. Pharmazeutische Zusammensetzung, die ein 2,4-Thlazolidindionderivat der in Anspruch 1 definierten Formel (I) oder ein pharmazeutisch annehmbares Salz davon und einen pharmazeutisch annehmbaren Träger umfaßt.

19. Pharmazeutische Zusammensetzung gemäß Anspruch 18 zum Verstärken der Insulinempfindlichkeit.

20. Pharmazeutische Zusammensetzung gemäß Anspruch 18 zum Behandeln von Diabetes.

21. Pharmazeutische Zusammensetzung gemäß Anspruch 18 zum Behandeln von Hyperlipidämie.

22. Verfahren zum Herstellen eines 2,4-Thiazolidindionderivats der Formel (I-B2)

worin R, n, X, Y, R¹ und R⁵ wie in Anspruch 1 definiert sind, das das Hydrolysieren einer Iminothiazolidinonverbindung der Formel (III) umfaßt,

worin jedes Symbol wie vorstehend definiert ist.

23. Verfahren zum Herstellen eines 2,4-Thiazolidindionderivats der Formel (I-B2a)

worin
R' die in Anspruch 1 definierte aromatische heterocyclische Gruppe ist, die über eine gerade oder verzweigte, gesättigte Kohlenwasserstoffkette mit 1 bis 8 Kohlenstoffatomen gebunden sein kann;
n 0 oder 1 ist;
X CH ist;
Y¹ -CH₂CH₂- ist;
R¹ und R² wie in Anspruch 1 definiert sind, und entweder R¹ oder R² und ein Teil von Y¹ unter Bilden eines Rings verbunden sein können, das das Reduzieren einer Verbindung der Formel (I-B1) umfaßt

worin R, Y, R¹ und R² wie in Anspruch 1 definiert sind, vorausgesetzt daß

verschieden ist und die anderen Symbole wie vorstehend definiert sind.

24. Verfahren zum Herstellen eines 2,4-Thiazolidindionderivats der Formel (I-D1)

worin
R" die in Anspruch 1 definierte aromatische heterocyclische Gruppe ist,
Y, R¹ und R² wie in Anspruch 1 definiert sind und
L und M ein Wasserstoffatom sind oder L und M miteinander unter Bilden einer Bindung verbunden sind, das das Umsetzen einer Verbindung der Formel (V)

worin jedes Symbol wie vorstehend definiert ist, mit einer Verbindung der Formel (VI) umfaßt

        R"-CH₂-Q     (VI)

worin Q eine Abgangsgruppe ist und R" wie vorstehend definiert ist.

25. Verwendung einer Verbindung gemäß Anspruch 1 zur Herstellung eines Arzneimittels zum Verstärken der Insulinempfindlichkeit bei einem Säuger, der dessen bedarf.

26. Verwendung einer Verbindung gemäß Anspruch 1 zur Herstellung eines Arzneimittels zum Behandeln von Diabetes bei einem Säuger, der dessen bedarf.

27. Verwendung einer Verbindung gemäß Anspruch 1 zur Herstellung eines Arzneimittels zum Behandeln von Hyperlipidämie bei einem Säuger, der dessen bedarf.

28. Verwendung einer Verbindung gemäß Anspruch 1 zur Herstellung einer pharmazeutischen Zusammensetzung zum Verstärken der Insulinempfindlichkeit.

Revendications

1. Dérivé de 2,4-thiazolidinedione de formule (I)

dans laquelle
R est un groupement hétérocyclique aromatique qui peut être fixé par une chaîne hydrocarbonée linéaire ou ramifiée et saturée ou insaturée, présentant 1 à 8 atomes de carbone, le groupement hétérocyclique aromatique étant de formule

dans laquelle B¹ est un atome de soufre, un atome d'oxygène ou le groupement NR⁴ dans lequel R⁴ est un atome d'hydrogène, un groupement alkyle présentant 1 à 3 atomes de carbone ou un groupement aralkyle sectionné parmi benzyle et phénéthyle;
   B² est un atome d'azote ou le groupement C-R⁵ dans lequel R⁵ est

(1) un atome d'hydrogène

(2) un groupement hydrocarboné sélectionné parmi

(a) groupement hydrocarboné aliphatique saturé ou insaturé présentant 1 à 8 atomes de carbone

(b) groupe hydrocarboné alicyclique saturé ou insaturé présentant 3 à 7 atomes de carbone

(c) groupement hydrocarboné alicyclique aliphatique saturé ou insaturé présentant 4 à 9 atomes de carbone

(d) groupement hydrocarboné aliphatique à carbocycle aromatique sélectionné parmi un phénylalkyle présentant 7 à 9 atomes de carbone et un naphtylalkyle présentant 11 à 13 atomes de carbone, et

(e) groupement hydrocarboné aromatique sélectionné parmi phényle et naphtyle,

lorsque le groupement hydrocarboné contient un groupement alicyclique, le groupement alicyclique peut être substitué par 1 à 3 groupements alkyle présentant 1 à 3 atomes de carbone, et lorsque le groupement hydrocarboné contient un groupement hydrocarboné aromatique, le groupement hydrocarboné peut présenter 1 à 4 substituants identiques ou différents, sélectionnés parmi halogène, hydroxy, cyano, nitro, trifluorométhyle, alkoxy avec 1 à 4 atomes de carbone, alkyle avec 1 à 4 atomes de carbone, alkoxycarbonyle avec 2 à 4 atomes de carbone, alkylthio avec 1 à 3 atomes de carbone et alkylamino avec 1 à 4 atomes de carbones,

(3) groupement cyclique pentagonal ou hexagonal qui contient 1 à 3 hétéroatomes sélectionnés parmi un atome d'azote, un atome d'oxygène et un atome de soufre en plus d'un atome de carbone et qui est fixé par un atome de carbone constituant un cycle, lorsque le groupement cyclique est saturé, le groupement cyclique peut être substitué par 1 à 3 groupements alkyle présentant 1 à 3 atomes de carbone, lorsque le groupement cyclique est insaturé le groupement cyclique peut présenter 1 à 4 substituants identiques ou différents sélectionnés parmi halogène, hydroxy, cyano, nitro, trifluorométhyle, alkoxy avec 1 à 4 atomes de carbone, alkyle avec 1 à 4 atomes de carbone, alkoxycarbonyle avec 2 à 4 atomes de carbone, alkylthio avec 1 à 3 atomes de carbone, et alkylamino avec 1 à 4 atomes de carbone et lorsque le groupement cyclique est substitué par au moins 2 groupements hydrocarbonés à des positions adjacentes l'une par rapport à l'autre sur le cycle, ces groupements hydrocarbonés peuvent être reliés de façon à former un cycle condensé;

   R³ est

(1) un atome d'hydrogène,

(2) un groupement hydrocarboné sélectionné parmi

(a) groupement hydrocarboné aliphatique saturé ou insaturé présentant 1 à 8 atomes de carbone

(b) groupement hydrocarboné saturé ou insaturé présentant 3 à 7 atomes de carbone

(c) groupement hydrocarboné alicyclique-aliphatique saturé ou insaturé, présentant 4 à 9 atomes de carbone

(d) groupement hydrocarboné aliphatique à carbocycle aromatique sélectionné parmi un phénylalkyle présentant 7 à 9 atomes de carbone et un naphtylalkyle présentant 11 à 13 atomes de carbone, et

(e) groupement hydrocarboné aromatique sélectionné parmi phényle et naphtyle,

lorsque le groupement hydrocarboné contient un groupement alicyclique, le groupement alicyclique peut être substitué par 1 à 3 groupements alkyle présentant 1 à 3 atomes de carbone, et lorsque le groupement hydrocarboné contient un groupement hydrocarboné aromatique, le groupement hydrocarboné peut présenter 1 à 4 substituants identiques ou différents, sélectionnés parmi halogène, hydroxy, cyano, nitro, trifluorométhyle, alkoxy avec 1 à 4 atomes de carbone, alkyle avec 1 à 4 atomes de carbone, alkoxycarbonyle avec 2 à 4 atomes de carbone, et alkylamino avec 1 à 4 atomes de carbones,

(3) groupement cyclique pentagonal ou hexagonal qui contient 1 à 3 hétéroatomes sélectionnés parmi un atome d'azote, un atome d'oxygène et un atome de soufre en plus d'un atome de carbone et qui est fixé par un atome de carbone constituant un cycle, lorsque le groupement cyclique est saturé, le groupement cyclique peut être substitué par 1 à 3 groupements alkyle présentant 1 à 3 atomes de carbone, lorsque le groupement cyclique est insaturé le groupement cyclique peut présenter 1 à 4 substituants identiques ou différents sélectionnés parmi halogène, hydroxy, cyano, nitro, trifluorométhyle, alkoxy avec 1 à 4 atomes de carbone, alkyle avec 1 à 4 atomes de carbone, alkoxycarbonyle avec 2 à 4 atomes de carbone, alkylthio avec 1 à 3 atomes de carbone, et alkylamino avec 1 à 4 atomes de carbone et lorsque le groupement cyclique est substitué par au moins 2 groupements hydrocarbonés à des positions adjacentes l'une par rapport à l'autre sur le cycle, ces groupements hydrocarbonés peuvent être reliés de façon à former un cycle condensé;

R³ et R⁵ peuvent être reliés de façon à former un cycle condensé lorsque R³ et R⁵ sont fixés à des atomes de carbone adjacents l'un de l'autre;
n est 0 ou 1;
X est CH;
Y est -CH₂CH₂-;
R¹ et R² sont identiques ou différents et sont

(1) un atome d'hydrogène

(2) un atome d'halogène

(3) un groupement hydroxyle facultativement substitué sélectionné parmi un groupement hydroxyle et des groupements alkoxy présentant 1 à 4 atomes de carbone

(4) un groupement hydrocarboné sélectionné parmi

(a) groupement hydrocarboné aliphatique saturé ou insaturé présentant 1 à 8 atomes de carbone

(b) groupe hydrocarboné alicyclique saturé ou insaturé présentant 3 à 7 atomes de carbone

(c) groupement hydrocarboné alicyclique aliphatique saturé ou insaturé présentant 4 à 9 atomes de carbone

(d) groupement hydrocarboné aliphatique à carbocycle aromatique sélectionné parmi phénylalkyle présentant 7 à 9 atomes de carbone et un naphtylalkyle présentant 11 à 13 atomes de carbone, et

(e) groupement hydrocarboné aromatique sélectionné parmi phényle et naphtyle,

lorsque le groupement hydrocarboné contient un groupement alicyclique, le groupement alicyclique peut être substitué par 1 à 3 groupements alkyle présentant 1 à 3 atomes de carbone, et lorsque le groupement hydrocarboné contient un groupement hydrocarboné aromatique, le groupement hydrocarboné peut présenter 1 à 4 substituants identiques ou différents, sélectionnés parmi halogène, hydroxy, cyano, nitro, trifluorométhyle, alkoxy avec 1 à 4 atomes de carbone, alkyle avec 1 à 4 atomes de carbone, alkoxycarbonyle avec 2 à 4 atomes de carbone, alkylthio avec 1 à 3 atomes de carbone et alkylamino avec 1 à 4 atomes de carbones,
et soit R¹ soit R² et une partie de Y peuvent être reliés de façon à former un cycle; et
L et M sont un atome d'hydrogène, ou
L et M sont reliés de façon à former une liaison; ou un sel de celui-ci.

2. Composé selon la revendication 1, qui est représenté par la formule (I-A₁)

ou un sel de celui-ci.

3. Composé selon la revendication 1, dans lequel n est 1, et R est le groupement hétérocyclique aromatique qui est fixé par l'intermédiaire d'une chaîne hydrocarbonée présentant 1 à 8 atomes de carbone, ou un sel de celui-ci.

4. Composé selon la revendication 3, dans lequel la chaîne hydrocarbonée est -CH=CH- ou -CH₂CH₂-, ou un sel de celui-ci.

5. Composé selon la revendication 1, dans lequel le groupement hétérocyclique aromatique est représenté par la formule

dans laquelle R⁵ et R⁶ sont identiques ou différents et sont un atome d'hydrogène, un groupement hydrocarboné sélectionné parmi

(1) groupement hydrocarboné aliphatique saturé ou insaturé présentant 1 à 8 atomes de carbone

(2) groupe hydrocarboné alicyclique saturé ou insaturé présentant 3 à 7 atomes de carbone

(3) groupement hydrocarboné alicyclique aliphatique saturé ou insaturé présentant 4 à 9 atomes de carbone

(4) groupement hydrocarboné aliphatique à carbocycle aromatique sélectionné parmi un phénylalkyle présentant 7 à 9 atomes de carbone et un naphtylalkyle présentant 11 à 13 atomes de carbone,et

(5) groupement hydrocarboné aromatique sélectionné parmi phényle et naphtyle,

lorsque le groupement hydrocarboné contient un groupement alicyclique, le groupement alicyclique peut être substitué par 1 à 3 groupements alkyle présentant 1 à 3 atomes de carbone, et lorsque le groupement hydrocarboné contient un groupement hydrocarboné aromatique, le groupement hydrocarboné peut présenter 1 à 4 substituants identiques ou différents, sélectionnés parmi halogène, hydroxy, cyano, nitro, trifluorométhyle, alkoxy avec 1 à 4 atomes de carbone, alkyle avec 1 à 4 atomes de carbone, alkoxycarbonyle avec 2 à 4 atomes de carbone, alkylthio avec 1 à 3 atomes de carbone et alkylamino avec 1 à 4 atomes de carbone, ou
groupement cyclique pentagonal ou hexagonal qui contient 1 à 3 hétéroatomes sélectionnés parmi un atome d'azote, un atome d'oxygène et un atome de soufre en plus d'un atome de carbone et qui est fixé par un atome de carbone constituant un cycle; lorsque le groupement cyclique est saturé, le groupement cyclique peut être substitué par 1 à 3 groupements alkyle présentant 1 à 3 atomes de carbone, lorsque le groupement cyclique est insaturé le groupement cyclique peut présenter 1 à 4 substituants identiques ou différents sélectionnés parmi halogène, hydroxy, cyano, nitro, trifluorométhyle, alkoxy avec 1 à 4 atomes de carbone, alkyle avec 1 à 4 atomes de carbone, alkoxycarbonyle avec 2 à 4 atomes de carbone, alkylthio avec 1 à 3 atomes de carbone et alkylamino avec 1 à 4 atomes de carbone, et lorsque le groupement cyclique est substitué par au moins 2 groupements hydrocarbonés à des positions adjacentes l'une par rapport à l'autre sur le cycle, ces groupements hydrocarbonés peuvent être reliés de façon à former un cycle condensé, B est un atome d'oxygène ou un atome de soufre, ou un sel de celui-ci.

6. Composé selon la revendication 1, dans lequel le groupement hétérocyclique aromatique de formule

dans laquelle B est un atome d'oxygène ou un atome de soufre, R⁷ et R⁸ sont identiques ou différents et sont un hydrogène, un groupement hydrocarboné sélectionné parmi

(1) groupement hydrocarboné aliphatique saturé ou insaturé présentant 1 à 8 atomes de carbone

(2) groupe hydrocarboné alicyclique saturé ou insaturé présentant 3 à 7 atomes de carbone

(3) groupement hydrocarboné alicyclique-aliphatique saturé ou insaturé présentant 4 à 9 atomes de carbone

(4) groupement hydrocarboné aliphatique à carbocycle aromatique sélectionné parmi un phénylalkyle présentant 7 à 9 atomes de carbone et un naphtylalkyle présentant 11 à 13 atomes de carbone, et

(5) groupement hydrocarboné aromatique sélectionné parmi phényle et naphtyle,

lorsque le groupement hydrocarboné contient un groupement alicyclique, le groupe alicyclique peut être substitué par 1 à 3 groupements alkyle présentant 1 à 3 atomes de carbone, et lorsque le groupement hydrocarboné contient un groupement hydrocarboné aromatique, le groupement hydrocarboné peut présenter 1 à 4 substituants identiques ou différents, sélectionnés parmi halogène, hydroxy, cyano, nitro, trifluorométhyle, alkoxy avec 1 à 4 atomes de carbone, alkyle avec 1 à 4 atomes de carbone, alkoxycarbonyle avec 2 à 4 atomes de carbone, alkylthio avec 1 à 3 atomes de carbone et alkylamino avec 1 à 4 atomes de carbone, ou
groupement cyclique pentagonal ou hexagonal qui contient 1 à 3 hétéroatomes sélectionnés parmi un atome d'azote, un atome d'oxygène et un atome de soufre en plus d'un atome de carbone et qui est fixé par un atome de carbone constituant un cycle; lorsque le groupement cyclique est saturé, le groupement cyclique peut être substitué par 1 à 3 groupements alkyle présentant 1 à 3 atomes de carbone, lorsque le groupement cyclique est insaturé le groupement cyclique peut présenter 1 à 4 substituants identiques ou différents sélectionnés parmi halogène, hydroxy, cyano, nitro, trifluorométhyle, alkoxy avec 1 à 4 atomes de carbone, alkyle avec 1 à 4 atomes de carbone, alkoxycarbonyle avec 2 à 4 atomes de carbone, alkylthio avec 1 à 3 atomes de carbone et alkylamino avec 1 à 4 atomes de carbone,
lorsque le groupement cyclique est substitué par au moins 2 groupements hydrocarbonés à des positions adjacentes l'une par rapport à l'autre sur le cycle, ces groupements hydrocarbonés peuvent être reliés de façon à former un cycle condensé ou R⁷ et R⁸ sont reliés de façon à former un cycle, ou un sel de celui-ci.

7. Composé selon la revendication 1 dans lequel B¹ est le groupement NR⁴ dans lequel R⁴ est un atome d'hydrogène, un groupement alkyle présentant 1 à 3 atomes de carbone ou un groupement aralkyle sélectionné parmi benzyle et phénethyle, et B² un atome d'azote, ou un sel de celui-ci.

8. Composé selon la revendication 1, dans lequel L et M sont un atome d'hydrogène, ou un sel de celui-ci.

9. Composé selon la revendication 1, dans lequel R¹ et R² sont un atome d'hydrogène, ou un sel de celui-ci.

10. Composé selon la revendication 2, dans lequel n est 1, R est le groupement hétérocyclique aromatique qui est fixé par l'intermédiaire d'une chaîne hydrocarbonée présentant 1 à 2 atomes de carbone, L et M sont un atome d'hydrogène, et R¹ et R² sont un atome d'hydrogène, ou un sel de celui-ci.

11. Composé selon la revendication 2,dans lequel n est 1, R est le groupement hétérocyclique aromatique qui est fixé par une chaîne hydrocarbonée présentant 1 à 2 atomes de carbone, L et M sont un atome d'hydrogène, R¹ est un atome d'halogène, et R² est un atome d'hydrogène, ou un sel de celui-ci.

12. Composé selon la revendication 2, dans lequel n est 1, R est le groupement hétérocyclique aromatique qui est fixé par une chaîne hydrocarbonée présentant 1 à 2 atomes de carbone, L et M sont un atome d'hydrogène, R¹ est un groupement hydroxyle facultativement substitué, sélectionné parmi un groupement hydroxyle et des groupements alkoxy présentant 1 à 4 atomes de carbone, et R² est un atome d'hydrogène, ou un sel de celui-ci.

13. Composé selon la revendication 2, dans lequel n est 0, R est le groupement hétérocyclique aromatique qui est fixé par un groupement éthylène ou un groupement vinylène, L et M sont un atome d'hydrogène et R¹ et R² sont un atome d'hydrogène, ou un sel de celui-ci.

14. Composé selon la revendication 1, qui est la 5-[3-[3-méthoxy-4-(5-méthyl-2-phényl-4-oxazolylméthoxy)phényl]propyl]-2,4-thiazolidinedione, ou un sel de celui-ci.

15. Composé selon la revendication 1, qui est la 5-[3-[3-fluoro-4-(5-méthyl-2-phényl-4-oxazolylméthoxy)phényl]propyl]-2,4-thiazolidinedione, ou un sel de celui-ci.

16. Composé selon la revendication 1, qui est la 5-[3-[4-(5-méthyl-2-phényl-4-oxazolylméthoxy)phényl]propyl]-2,4-thiazolidinedione, ou un sel de celui-ci.

17. Composé selon la revendication 1, qui est la 5-[3-[4-(5-méthyl-2-napthyl-4-oxazolylméthoxy)phényl]propyl]-2,4-thiazolidinedione, ou un sel de celui-ci.

18. Composition pharmaceutique qui contient un dérivé de 2,4-thiazolidinedione de formule (I) défini dans la revendication 1, ou un sel pharmaceutiquement acceptable de celui-ci, et un excipient pharmaceutiquement acceptable.

19. Composition pharmaceutique selon la revendication 18, qui est destinée à augmenter la sensibilité à l'insuline.

20. Composition pharmaceutique selon la revendication 18, qui est destinée à traiter le diabète.

21. Composition pharmaceutique selon la revendication 18, qui est destinée à traiter l'hyperlipémie.

22. Procédé de production d'un dérivé de 2,4-thiazolidinedione de formule (I-B₂) :

dans laquelle R, n, X, Y, R¹ et R⁵ sont tels que définis dans la revendication 1, lequel comprend l'hydrolyse d'un composé iminothiazolidinone de formule (III);

dans laquelle chaque symbole est défini ci-dessus.

23. Procédé de production d'un dérivé de 2,4-thiazolidinedione de formule (I-B_2a) :

dans laquelle
   R' est le groupement hétérocyclique aromatique tel que défini dans la revendication 1, qui peut être fixé par une chaîne hydrocarbonée linéaire ou ramifiée présentant 1 à 8 atomes de carbone;
   n est 0 ou 1;
   X est CH;
   Y¹ est -CH₂CH₂-;
   R¹ et R² sont comme définis à la revendication 1, et soit R¹ soit R² et une partie de Y¹ peut être liée de façon à former un cycle;
lequel comprend la réduction d'un composé de formule (1-B₁) :

dans laquelle R, Y, R¹ et R² sont comme définis à la revendication 1, à condition que

et les autres symboles sont définis ci-dessus.

24. Procédé de production d'un dérivé de 2,4-thiazolidinedione de formule (I-D₁):

dans laquelle
   R" est le groupement hétérocyclique aromatique tel que défini dans la revendication 1;
   Y, R¹ et R² sont tels que définis à la revendication 1, et
   L et M sont un atome d'hydrogène, ou L et
   M sont reliés de façon à fermer une liaison;
lequel comprend la mise en réaction d'un composé de formule (V):

dans laquelle chaque symbole est défini ci-dessus, avec un composé de formule (VI):

        R"-CH₂-Q     (VI)

Q étant un groupement partant et R" étant tel que défini ci-dessus.

25. Utilisation d'un composé selon la revendication 1 pour la fabrication d'un médicament destiné à augmenter la sensibilité à l'insuline chez un mammifère en ayant besoin.

26. Utilisation d'un composé selon la revendication 1 pour la fabrication d'un médicament destiné à traiter le diabète chez un mammifère en ayant besoin.

27. Utilisation d'un composé selon la revendication 1 pour la fabrication d'un médicament destiné à traiter l'hyperlipémie chez un mammifère en ayant besoin.

28. Utilisation d'un composé selon la revendication 1 pour la fabrication d'une composition pharmaceutique destinée à augmenter la sensibilité à l'insuline.