JP2000026438A - Novel 2- (N-cyanoimino) thiazolidine-4-one derivatives - Google Patents

Abstract

(57) [Summary] (Corrected) [PROBLEMS] To provide a compound having an excellent cholesterol lowering action and triglyceride lowering action, and useful for preventing or treating hyperlipidemia and diseases caused by it. A novel 2- (N-cyanoimino) thiazolidine-4-one derivative represented by the following formula, a solvate thereof, and a pharmaceutically acceptable salt thereof. [In the formula, ring A represents a benzene ring, a condensed ring or a heterocyclic ring which may be substituted with a linear or branched alkyl group having 1 to 4 carbon atoms, a halogenated alkyl group, or the like; R ₁ represents a single bond,
O represents a linear or branched alkylene group having 1 to 4 carbon atoms which may be substituted with an oxygen atom, a sulfur atom, methine, or a phenyl group; R ₂ and R ₃ represent a hydrogen atom and an alkyl group having 1 to 4 carbon atoms; R ₄ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. The substitution position of the methylene group at the 5-position of thiazolidine represents both E and Z. ]

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 2- (N-cyanoimino) thiazolidine-4-one derivative. More specifically, the present invention provides a compound having excellent triglyceride lowering action and cholesterol lowering action, and useful for preventing or treating hyperlipidemia and diseases caused thereby.

[0002]

BACKGROUND OF THE INVENTION Numerous epidemiological studies have shown that hypercholesterolemia is a risk factor for coronary artery disease. More recently, hypertriglyceridemia has also been shown to be an independent risk factor for hypercholesterolemia (Arteriosclerosis 25 (1.2) pp. 1-34 (1997) -high. Guidelines for the management of lipidemia).

Hitherto, as a first-line drug for hypertriglyceridemia, drugs called dextran sulfate, nicotinic acid derivatives and fibrate have been used for a long time, and bezafibrate is well known. In hypercholesterolemia, HMG-CoA reductase inhibitors called statins, such as pravastatin and simvastatin, are widely used clinically.

[0004] Generally, when only cholesterol is high, an HMG-CoA reductase inhibitor is used.
If both cholesterol and triglyceride are high, or if one agent is not sufficiently effective, multiple agents will be used in combination. However, fibrates, H
It is known that the combined use of an MG-CoA reductase inhibitor or nicotinic acid increases the risk of developing rhabdomyolysis.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a new therapeutic agent having a more potent action for lowering both blood triglyceride and cholesterol.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, the following general formula (I)
Have been found to have excellent blood triglyceride and cholesterol lowering effects, and have completed the present invention.

Although hypoglycemic agents such as troglitazone and pioglitazone are disclosed as analogous compounds of the substance of the present invention, all of them are thiazolidine-2,4-dione derivatives and differ in structure from the compounds of the present invention. In terms of action, pioglitazone has been shown to have no effect on total cholesterol and triglyceride in hypercholesterolemic rabbits, and thus is recognized as a completely different compound (Abstracts of the 28th Annual Meeting of the Japanese Society of Atherosclerosis) : No. 024, June 1996, Osaka).

In the present invention, the compound represented by the general formula (I)

[0009]

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Wherein the ring A is a straight-chain or branched C 1
To 4 alkyl group, a halogenated alkyl group, (wherein R ₅ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.) R 5 _O-group and benzene ring which may be substituted by halogen,
Represents a condensed ring or a heterocyclic ring; R ₁ is a single bond, an oxygen atom,
A linear or branched alkylene or alkenylene group having 1 to 4 carbon atoms which may be substituted with a sulfur atom, methine, or a phenyl group; R ₆ -X (where R ₆ is a linear or branched C 1 to C 4 X represents an oxygen atom or a sulfur atom.), XR ₆ (R ₆ , X represents the same as above), XR ₆ -X (R ₆ , X represents the same as described above), R ₆ -X-R ₆ (R ₆ , X
Represents the same as above. ), - C (= O) -NR 7 -
Or —NR ₇ —C (＝ O) — (where R ₇ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms);
R ₂ and R ₃ are the same or different and each represent a hydrogen atom,
An R ₈ O— group (R ₈ is a hydrogen atom, a carbon atom of 1)
Represents an alkyl group or an aralkyl group. ) Or a halogen atom; R ₄ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. The substitution position of the methylene group at the 5-position of thiazolidine represents both E and Z. Or a solvate or salt thereof as an active ingredient for the prevention or treatment of hyperlipidemia and diseases caused by the hyperlipidemia.

Here, specific examples of the salt include sodium, potassium, ammonium and low-toxic organic amine salts. Further, the alkyl group having 1 to 4 carbon atoms is methyl, ethyl, n-propyl and isopropyl,
Examples include n-butyl and tert-butyl groups.

Alkoxy groups having 1 to 4 carbon atoms include methoxy, ethoxy, n-propoxy and isopropoxy, n
-Butoxy, tert-butoxy group and the like, and the halogen is generally fluorine, chlorine, bromine or iodine. Preferably it means fluorine or chlorine.

Specific examples of the ring A include benzene, benzodioxole, benzofuran, benzothiazole, fluorene, indane, indoline, pyridine and the like. The substitution may be at any position.

Among the compounds represented by the general formula (Formula I),
Particularly preferred compounds are: 2- (N-cyanoimino) -5-{(E) -4-styrylbenzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5-{(E) -4- (α-methylstyryl) benzylidene {thiazolidine-4-one, 2- (N-cyanoimino) -5- {4- (benzyloxymethyl) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5-{(E) -4- (β-methylstyryl) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- {4- (3-phenylpropoxy) benzylidene} thiazolidine-4-one , 2- (N-cyanoimino) -5- {4- (4-chlorophenoxy) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- (4-fe Nylthiobenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) -5
{(E) -4- (2-fluorostyryl) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- {4- (2,5-dimethylphenoxy) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- (4-phenethyloxybenzylidene)
Thiazolidine-4-one, 2- (N-cyanoimino)-
5- {4- (2-phenylpropoxy) benzylidene}
Thiazolidine-4-one, 2- (N-cyanoimino)-
5- (3-phenethyloxybenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) -5- (4-
Benzyloxybenzylidene) thiazolidine-4-one,
2- (N-cyanoimino) -5- {4- (5-chlorobenzofuran-2-yl) benzylidene} thiazolidine-
4-one, 2- (N-cyanoimino) -5-{(E)-
4- (4-methoxystyryl) benzylidenethiazolidine-4-one, 2- (N-cyanoimino) -5- (3
-Phenoxybenzylidene) thiazolidine-4-one,
2- (N-cyanoimino) -5- {4- (1,3-benzodioxol-5-ylmethoxy) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5
-{4- (4-methylbenzyloxy) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5
-{4- (4-chlorobenzyloxy) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5
-{3-methoxy- (E) -4-styrylbenzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- (2-phenethyloxybenzylidene) thiazolidine-4-one, 2- (N-cyanoimino ) -5
(4-phenoxybenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) -5- {3- (benzyloxy) benzylidene} thiazolidine-4-one, 2-
(N-cyanoimino) -5- {4- (benzylthio) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- (4-phenethylbenzylidene) thiazolidine-4-one, 2- (N-cyanoimino ) -5
[4- {2- (4-chlorophenyl) ethoxy} benzylidene] thiazolidine-4-one, 2- (N-cyanoimino) -5- [1-{(E) -4- (4-methoxystyryl) phenyl} ethylidene Thiazolidine-4-one, 2- (N-cyanoimino) -5- (4-benzyloxy-2,5-dimethylbenzylidene) thiazolidine-4
-One, 2- (N-cyanoimino) -5-{(E) -3
-Styrylbenzylidenethiazolidine-4-one.

The compounds of the present invention are novel compounds which have not been described in any literature, and can be produced, for example, by the following method. That is, chemical formula (II):

[0016]

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2- (N-cyanoimino) thiazolidine-4-one or a salt thereof represented by the following formula:
I),

[0018]

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[Wherein the ring A is a straight-chain or branched C 1
To 4 alkyl group, a halogenated alkyl group, (wherein R ₅ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.) R 5 _O-group and benzene ring which may be substituted by halogen,
Represents a condensed ring or a heterocyclic ring; R ₁ is a single bond, an oxygen atom,
A linear or branched alkylene or alkenylene group having 1 to 4 carbon atoms which may be substituted with a sulfur atom, methine, or a phenyl group; R ₆ -X (where R ₆ is a linear or branched C 1 to C 4 X represents an oxygen atom or a sulfur atom.), XR ₆ (R ₆ , X represents the same as above), XR ₆ -X (R ₆ , X represents the same as described above), R ₆ -X-R ₆ (R ₆ , X
Represents the same as above. ), - C (= O) -NR 7 -
Or —NR ₇ —C (＝ O) — (where R ₇ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms);
R ₂ and R ₃ are the same or different and each represent a hydrogen atom,
An R ₈ O— group (R ₈ is a hydrogen atom, a carbon atom of 1)
Represents an alkyl group or an aralkyl group. ) Or a halogen atom; R ₄ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. The aldehyde or ketone compound represented by the above, in a solvent such as ethanol, acetonitrile, dioxane, dimethylformamide, dimethylsulfoxide, pyridine, toluene, xylene or without solvent, in the presence of ammonium acetate at room temperature to 200 ° C., preferably 70 ° C to 150 ° C, 10 minutes to 10 hours, usually 20
It can be manufactured by mixing and stirring for minutes to 5 hours.

The obtained compound has two types of geometric isomers, E-form and Z-isomer, and can be alternately converted by light or heat in a solution.

[0021]

The compound of the present invention has a blood triglyceride lowering effect and a cholesterol lowering effect, and can be used as a medicament effective in preventing or treating hyperlipidemia and diseases caused by it.

When the compound of the present invention and a pharmaceutically acceptable salt thereof are used as the above-mentioned medicament, they can be administered alone as they are, but they are usually mixed with carriers, excipients, diluents, solubilizing agents and the like. It is preferably administered orally or parenterally in the form of tablets, powders, granules, capsules, syrups, injections and the like.

The dose of the compound of the present invention may vary depending on the condition, age, body weight, etc. of the patient and the strength of the activity of each compound. It is preferable to administer once or several times.

Hereinafter, the compound of the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited to these.

[0025]

Example 1 2- (N-cyanoimino) -5-{(E)
-4-styrylbenzylidene @ thiazolidine-4-one 2- (N-cyanoimino) thiazolidine-4-one potassium salt 4.48 g (0.025 mol), trans-4-
5.47 g of stilbene carboxaldehyde (0.026
Mol, 1.05 equivalents), 2.02 g ammonium acetate
(0.026 mol, 1.05 eq), ethanol 100
The mixture was heated to reflux for 2 hours. After allowing to cool, ether was added, and the potassium salt was collected by filtration, suspended in 50 ml of acetone, 5 ml of concentrated hydrochloric acid and 250 ml of water were added, and the precipitated crystals were collected by filtration and dried. Yield 7.32 g (0.022 mol). Yield 88%. Yellow crystals.

Melting point: 265 ° C. (decomposition) (ethanol-DMF) Mass spec: 331 (M ⁺ ), 236, 202, 179 Elemental analysis: Assuming C ₁₉ H ₁₃ N ₃ OS = 331.399 Theoretical values: H 3.95, C 68.86, N 12.68 (%) Actual values: H 4.15, C 68.94, N 12.40 (%)

[0027]

Example 2 2- (N-cyanoimino) -5-{(E)
-4- (α-Methylstyryl) benzylidenedithiazolidine-4-one In the same manner as described above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and (E) -4-
The title compound was obtained from (α-methylstyryl) benzaldehyde. Yield 84%. Orange-yellow crystals.

Melting point: 222-27.5 ° C. (ethanol-DMF) Mass spec: 345 (M ⁺ ), 258, 243, 162 Elemental analysis: Assuming that C ₂₀ H ₁₅ N ₃ OS = 345.425 Theoretical values: H 4.38, C 69.54, N 12.16 (%) Actual values: H 4.59, C 69.51, N 11.99 (%)

[0029]

Example 3 2- (N-cyanoimino) -5- {4-
(Benzyloxymethyl) benzylidenethiazolidine-
4-one Example 1 In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (benzyloxymethyl) benzaldehyde. 90% yield. Pale yellow crystals.

Melting point: 170.5-171.5 ° C. (ethanol-DMF) Mass spectrometry: 349 (M ⁺ ), 320, 258, 243,
230, 162, 147, 135, 115, 103, 9
1,79,77 Elemental analysis: Assuming that C ₁₉ H ₁₅ N ₃ O ₂ S = 349.413 Theoretical values: H 4.33, C 65.31, N 12.03 (%) Observed values: H 4.64, C 65.54, N 11.70 (%)

[0031]

Example 4 2- (N-cyanoimino) -5-{(E)
-4- (β-methylstyryl) benzylidenedithiazolidine-4-one In the same manner as described above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and (E) -4-
The title compound was obtained from (β-methylstyryl) benzaldehyde. Yield 66%. Yellow needles.

Melting point: 236.5-237.5 ° C. (ethanol-DMF) Mass spectrometry: 345 (M ⁺ ), 320, 249, 233
205 Elemental _{analysis: C 20 H 15 N 3 OS} = 345.425 theoretically: H4.38, C69.54, N12.16 (% ) Found: H4.65, C69.62, N11.76 (% )

[0033]

Example 5 2- (N-cyanoimino) -5- {4-
(3-Phenylpropoxy) benzylidenethiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (3-phenylpropoxy) benzaldehyde. Yield 78%. Yellow crystals.

Melting point: 212.5-213 ° C. (decomposition)
(Ethanol-DMF) Mass spec: 363 (M ⁺ ), 272, 268, 245,
176,150,121,91,65 Elemental _{analysis: C 20 H 17 N 3 O} 2 S = 363.441 theoretically: H4.71, C66.10, N11.56 (% ) Found: H4.85, C66.05, N11.53 (% )

[0035]

Example 6 2- (N-cyanoimino) -5- {4-
(4-Chlorophenoxy) benzylidenethiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (4-chlorophenoxy) benzaldehyde. Yield 69%. Yellow-orange needles.

Melting point: 225-26.5 ° C. (decomposition)
(Ethanol-DMF) mass spectrometry: 357 [(M + 2) ⁺ ], 355 (M ⁺ ),
262,260,149 Elemental analysis: C ₁₇ H ₁₀ ClN ₃ O ₂ S = 355.805 Theoretical values: H2.83, C57.39, N11.81 (%) Observed values: H3.13, C57.44, N11.54 (%) )

[0037]

Example 7 2- (N-cyanoimino) -5- (4-phenylthiobenzylidene) thiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-phenylthiobenzaldehyde in the same manner as in the above. Yield 76
%. Orange crystals.

Melting point: 204.5-205.5 ° C. (decomposition) (ethanol-DMF) Mass spec: 337 (M ⁺ ), 242, 200, 197,
165 Elemental analysis: Assuming that C ₁₇ H ₁₁ N ₃ OS ₂ = 337.427 Theoretical values: H 3.29, C 60.51, N 12.45 (%) Observed values: H 3.57, C 60.27, N 12.38 (%)

[0039]

Example 8 2- (N-cyanoimino) -5-{(E)
-4- (2-fluorostyryl) benzylidenethiazolidine-4-one In the same manner as described above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and (E) -4-
The title compound was obtained from (2-fluorostyryl) benzaldehyde. Yield 91%. Yellow crystals.

Melting point: 271-272 ° C. (ethanol-DMF) Mass spec: 349 (M ⁺ ), 254 Elemental analysis: C ₁₉ H ₁₂ FN ₃ OS = 349.388 Theoretical values: H 3.46, C 65.32, N 12.03 (%) Actual values: H 3.73, C 65.53, N 11.78 (%)

[0041]

Example 9 2- (N-cyanoimino) -5- {4-
(2,5-dimethylphenoxy) benzylidenedithiazolidine-4-one In the same manner as described above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and 4- (2,5
-Dimethylphenoxy) benzaldehyde to give the title compound. Yield 62%. Yellow orange plate crystals.

Melting point: 196-17.5 ° C. (decomposition)
(Ethanol) Mass spec: 349 (M ⁺ ), 254, 121, 149,
134, 121, 105, 79 Elemental analysis: Assuming C ₁₉ H ₁₅ N ₃ O ₂ S = 349.414 Theoretical values: H 4.33, C 65.31, N 12.03 (%) Observed values: H 4.50, C 64.91, N 11.66 (% )

[0043]

Example 10 2- (N-cyanoimino) -5- (4-
Phenethyloxybenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-phenethyloxybenzaldehyde. Yield 78%. Pale yellow crystals.

Melting point: 193 ° -194 ° C. (decomposition) (isopropanol-DMF) Mass spec: 349 (M ⁺ ), 150, 105, 79 Elemental analysis: Assuming C ₁₉ H ₁₅ N ₃ O ₂ S = 349.414 Theoretical values: H 4.33, C 65.31, N 12.03 (%) Actual values: H 4.45, C 65.27, N 11.93 (% )

[0045]

Example 11 2- (N-cyanoimino) -5- {4-
(2-phenylpropoxy) benzylidenedithiazolidine-4-one In the same manner as in the above, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (2-phenylpropoxy) benzaldehyde. Yield 66%. Pale yellow crystals.

Melting point: 190-191 ° C. (ethanol-DMF) Mass spec: 363 (M ⁺ ), 244, 210, 149 Elemental _{analysis: C 20 H 17 N 3 O} 2 S = 363.441 theoretically: H4.71, C66.10, N11.56 (% ) Found: H4.76, C65.76, N11.57 (% )

[0047]

Example 12 2- (N-cyanoimino) -5- (3-
Phenethyloxybenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 3-phenethyloxybenzaldehyde. Yield 80%. Pale yellow crystals.

Melting point: 172-173 ° C. (decomposition) (ethanol-DMF) Mass spectrometry: 349 (M ⁺ ), 150, 105 Elemental analysis: Assuming C ₁₉ H ₁₅ N ₃ O ₂ S = 349.414 Theoretical values: H 4.33, C 65.31, N 12.03 (%) Actual values: H 4.53, C 65.64, N 11.96 (%) )

[0049]

Example 13 2- (N-cyanoimino) -5- (4-
Benzyloxybenzylidene) thiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-benzyloxybenzaldehyde in the same manner as described above. Yield 66
%. Yellow-brown crystals.

Melting point: 230-231 ° C. (decomposition) (ethanol-DMF) Mass spec: 335 (M ⁺ ), 149, 121, 91 Elemental analysis: Assuming that C ₁₈ H ₁₃ N ₃ O ₂ S = 335.387 Theoretical values: H 3.90, C 64.46, N 12.53 (%) Observed values: H 4.20, C 64.52, N 12.20 (%) )

[0051]

Example 14 2- (N-cyanoimino) -5- {4-
(5-chlorobenzofuran-2-yl) benzylidene}
Example 1 Thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (5-chlorobenzofuran-2-yl) benzaldehyde. 56% yield. Yellow needles.

Melting point: 265 ° C. (decomposition) (DMF) Mass spec: 379 (M ⁺ ), 286, 284 Elemental analysis: C ₁₉ H ₁₀ ClN ₃ O ₂ S = 379.827 Theoretical values: H 2.65, C 60.09, N 11.06 (%) Observed values: H 3.06, C 60.51, N 10.91 (% )

[0053]

Example 15 2- (N-cyanoimino) -5
{(E) -4- (4-Methoxystyryl) benzylidene} thiazolidine-4-one In the same manner as described above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and (E) -4-
The title compound was obtained from (4-methoxystyryl) benzaldehyde. Yield quant. . Dark yellow crystals.

Melting point: 161 ° -162 ° C. (ethanol-DMF) Mass spectrometry: 361 (M ⁺ ), 266, 251, 234,
221,189,179,165,133,105,8
9,77 Elemental _{analysis: C 20 H 15 N 3 O} 2 S · 1 / 2H 2 O = 370.432 theoretically: H4.35, C64.85, N11.34 (% ) Found: H4.23, C64.87 , N 11.29 (%)

[0055]

Example 16 2- (N-cyanoimino) -5- (3-
Phenoxybenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and m-phenoxybenzaldehyde. Yield 93
%. Light brown crystals.

Melting point: 202.5-203.5 ° C. (ethanol-DMF) Mass spectrometry: 321 (M ⁺ ), 226, 197, 165 Elemental analysis: C ₁₇ H ₁₁ N ₃ O ₂ S = 321.359 Theoretical values: H 3.45, C 63.54, N 13.08 (%) Observed values: H 3.72, C 63.61, N 12.80 (%) )

[0057]

Example 17 2- (N-cyanoimino) -5- {4-
(1,3-benzodioxol-5-ylmethoxy) benzylidenedithiazolidine-4-one In the same manner as in the above, 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (1,3
The title compound was obtained from -benzodioxol-5-ylmethoxy) benzaldehyde. 95% yield. Yellow crystals.

Melting point: 217-218 ° C. (decomposition) (ethanol-DMF) Mass spec: 379 (M ⁺ ), 245, 150, 135
105,77 Elemental analysis: Assuming C ₁₉ H ₁₃ N ₃ O ₄ S = 379.396 Theoretical values: H 3.45, C 60.15, N 11.08 (%) Observed values: H 3.74, C 59.82, N 10.96 (% )

[0059]

Example 18 2- (N-cyanoimino) -5- {4-
(4-Methylbenzyloxy) benzylidenedithiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (4-methylbenzyloxy) benzaldehyde. Yield 84%. Pale yellow-orange crystals.

Melting point: 248.5-249.5 ° C. (decomposition) (ethanol-DMF) Mass spec: 349 (M ⁺ ), 150, 105 Elemental analysis: C ₁₉ H ₁₅ N ₃ O ₂ S = 349.414 Theoretical values: H 4.33, C 65.31, N 12.03 (%) Observed values: H 4.52, C 65.40, N 11.78 (% )

[0061]

Example 19 2- (N-cyanoimino) -5- {4-
(4-Chlorobenzyloxy) benzylidenedithiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (4-chlorobenzyloxy) benzaldehyde. Yield 54%. Orange crystals.

Melting point: 220-221 ° C. (decomposition) (ethanol-DMF) Mass spectrometry: 371 [(M + 2) ⁺ ], 369 (M ⁺ ),
149, 127, 125, 105 Elemental analysis: C ₁₈ H ₁₂ ClN ₃ O ₂ S = 369.832 Theoretical values: H 3.27, C 58.46, N 11.36 (%) Observed values: H 3.52, C 58.65, N 11.09 (% )

[0063]

Example 20 2- (N-cyanoimino) -5- {3-
Methoxy- (E) -4-styrylbenzylidenedithiazolidine-4-one 2- (N-cyanoimino) thiazolidine-4-one and 3-methoxy- (E)-
The title compound was obtained from 4-styrylbenzaldehyde.
89% yield. Red crystals.

Melting point: 250.5 ° C. (decomposition) (ethanol-DMF) Mass spec: 361 (M ⁺ ), 262, 234, 223
206 Elemental _{analysis: C 20 H 15 N 3 O} 2 S = 361.424 theoretically: H4.18, C66.47, N11.63 (% ) Found: H4.35, C66.71, N11.35 (% )

[0065]

Example 21 2- (N-cyanoimino) -5- (2-
Phenethyloxybenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one and 2-phenethyloxybenzaldehyde. Yield 52%. Yellow crystals.

Melting point: 204-205.5 ° C. (decomposition)
(Ethanol-DMF) mass spec: 349 (M ⁺ ), 178, 149, 105,
77 Elemental analysis: Assuming C ₁₉ H ₁₅ N ₃ O ₂ S = 349.414 Theoretical values: H 4.33, C 65.31, N 12.03 (%) Observed values: H 4.48, C 65.34, N 12.09 (%) )

[0067]

Example 22 2- (N-cyanoimino) -5- (4-
Phenoxybenzylidene) thiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one and 4-phenoxybenzaldehyde in the same manner as in the above. Yield 84%. Pale yellow crystals.

Melting point: 218-219 ° C. (decomposition) (ethanol-DMF) Mass spectrometry: 321 (M ⁺ ), 226, 197, 149,
121,77 Elemental analysis: C ₁₇ H ₁₁ N ₃ O ₂ S = 321.36 Theoretical values: H 3.45, C 63.53, N 13.08 (%) Actual values: H 3.79, C 63.69, N 12.93 (%) )

[0069]

Example 23 2- (N-cyanoimino) -5- (4-
Methoxy-3-phenethyloxybenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-methoxy-3-phenethyloxybenzaldehyde. Yield 84%. Yellow-orange crystals.

Melting point: 195-195.5 ° C. (ethanol-DMF) Mass spectrometry: 379 (M ⁺ ), 274, 180, 105,
79 Elemental analysis: C ₂₀ H ₁₇ N ₃ O ₃ S = 379.44 Theoretical values: H 4.52, C 63.31, N 11.07 (%) Observed values: H 4.73, C 63.64, N 11.00 (%) )

[0071]

Example 24 2- (N-cyanoimino) -5- (4-
Anilinocarbonylbenzylidene) thiazolidine-4-
ON Example 1 The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one and 4-anilinocarbonylbenzaldehyde in the same manner as in the above. Yield 59%.
Pale yellow crystals.

Melting point: 275 ° C. (decomposition) (ethanol-DMF) Mass spec: 348 (M ⁺ ), 256, 161, 133,
91 Elemental _{analysis: C 18 H 12 N 4 O} 2 S = 348.386 theoretically: H3.47, C62.06, N16.08
(%) Found: H 3.71, C 62.11, N 15.92.
(%)

[0073]

Example 25 2- (N-cyanoimino) -5- [4-
{{2- (2-Pyridyl) ethenyl} benzylidene] thiazolidine-4-one 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- {2-
The title compound was obtained from (2-pyridyl) ethenyl dibenzaldehyde. 79% yield. Yellow crystals.

Melting point: 295-296 ° C. (decomposition) (D
MF) Mass spec: 331 [(M-1) ⁺ ], 236, 204,
158, 113, 79, 51 Elemental _{analysis: C 18 H 12 N 4 OS} · 1/3 (H 2 O) = 338.392 theoretically: H3.77, C63.89, N16.56 (% ) Found: H4.03, C63. 70, N 16.32 (%)

[0075]

Example 26 2- (N-cyanoimino) -5- (3,3
5-dimethoxy-4-phenethyloxybenzylidene)
Example 1 Thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 3,5-dimethoxy-4-phenethyloxybenzaldehyde. Yield 65%. Yellow crystals.

Melting point: 194-195 ° C. (ethanol) Mass spec: 409 (M ⁺ ), 305, 210, 105,
79 Elemental analysis: C ₂₁ H ₁₉ N ₃ O ₄ S = 409.466 Theoretical values: H 4.68, C 61.60, N 10.26 (%) Observed values: H 4.75, C 61.64, N 10.19 (% )

[0077]

Example 27 2- (N-cyanoimino) -5- {4-
(N-benzoyl-N-methylamino) benzylidene}
Example 1 Thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (N-benzoyl-N-methylamino) benzaldehyde. 79% yield. Orange platelets.

Melting point: 202.5-203.5 ° C. (decomposition) (ethanol) Mass spectrometry: 362 (M ⁺ ), 105, 77 Elemental _{analysis: C 19 H 14 N 4 O} 2 S · 1/2 (C 2 H 5 OH) = 385.448 theoretically: H4.45, C62.32, N14.54 (% ) Found: H4. 56, C62.19, N14.16 (%)

[0079]

Example 28 2- (N-cyanoimino) -5- {4-
(2-Fluoro-4-bromobenzyloxy) benzylidenethiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (2-fluoro-4-bromobenzyloxy) benzaldehyde in the same manner as described above. 95% yield. Light brown crystals.

Melting point: 270-271 ° C. (ethanol-DMF) Mass spectrometry: 433 [(M + 2) ⁺ ], 431 (M ⁺ ),
189, 187, 149, 107 Elemental _{analysis: C 18 H 11 BrFN 3 O} 2 S = 432.273 theoretically: H2.56, C50.01, N9.72 (% ) Found: H2.87, C50.22, N9.68 (% )

[0081]

Example 29 2- (N-cyanoimino) -5- {4-
(2-oxoindoline-3-ylidenemethyl) benzylidenedithiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (2-oxoindoline-3-ylidenemethyl) benzaldehyde. Yield 65%. Orange crystals.

Melting point:> 300 ° C. (ethanol-DM
F) Mass spec: 372 (M ⁺ ), 277. Elemental _{analysis: C 20 H 12 N 4 O} 2 S · 1/2 (C 3 H 7 NO) = 408.956 theoretically: H3.82, C63.15, N15.41 (% ) Found: H4. 12, C62.96, N15.40 (%)

[0083]

Example 30 2- (N-cyanoimino) -5- {4-
(1-oxoindane-2-ylidenemethyl) benzylidene @ thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (1-oxoindane-2-ylidenemethyl) benzaldehyde. Yield 68%. Pale yellow crystals.

Melting point:> 300 ° C. (DMF) Mass spec: 371 (M ⁺ ), 276, 247, 213
139,114,89 Elemental analysis: Assuming that C ₂₁ H ₁₃ N ₃ O ₂ S = 371.42 Theoretical value: H 3.53, C 67.91, N 11.31 (%) Actual value: H 3.88, C 68.11, N 11.12 (%) )

[0085]

Example 31 2- (N-cyanoimino) -5- [4-
{2- (Benzothiazol-2-yl) ethenyl} benzylidene] thiazolidine-4-one 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- {2-
The title compound was obtained from (benzothiazol-2-yl) ethenyl dibenzaldehyde. 79% yield. Yellow crystals.

Melting point:> 300 ° C. (DMF) Mass spec: 390 [(M + 2) ⁺ ], 388 (M ⁺ ),
294,292,260,249,236,163,1
49,77 Elemental _{analysis: C 20 H 12 N 4 OS} 2 · 1/3 (C 3 H 7 NO) = 412.840 theoretically: H3.50, C61.10, N14.70 (% ) Found: H3.71 , C61.02, N14.57 (%)

[0087]

Example 32 2- (N-cyanoimino) -5- {4-
(1-Phenylpropoxy) benzylidenethiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (1-phenylpropoxy) benzaldehyde. Yield 70%. Pale yellow crystals.

Melting point: 144-145.5 ° C. (ethyl acetate-hexane) Mass spec: 363 (M ⁺ ), 244, 210, 149 Elemental _{analysis: C 20 H 17 N 3 O} 2 S = 363.441 theoretically: H4.71, C66.10, N11.56 (% ) Found: H4.89, C66.00, N11.38 (% )

[0089]

Example 33 2- (N-cyanoimino) -5- {4-
(Phenoxymethyl) benzylidenethiazolidine-4
-ON Example 1 In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (phenoxymethyl) benzaldehyde.
94% yield. Yellow crystals.

Melting point: 238.5-240 ° C. (ethanol-DMF) Mass spec: 335 (M ⁺ ), 250, 240, 173,
147 Elemental _{analysis: C 18 H 13 N 3 O} 2 S = 335.386 theoretically: H3.91, C64.46, N12.53 (% ) Found: H4.07, C64.44, N12.17 (% )

[0091]

Example 34 2- (N-cyanoimino) -5- (4-
Phenylbenzylidene) thiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-phenylbenzaldehyde in the same manner as in the above. Yield 93%.
Dark yellow crystals.

Melting point: 253.5-255 ° C. (ethanol-DMF) Mass spectrometry: 305 (M ⁺ ), 210 Elemental analysis: C ₁₇ H ₁₁ N ₃ OS = 305.360 Theoretical values: H 3.63, C 66.87, N 13.76 (%) Observed values: C 66.93, H 3.96, N 13.70 (%)

[0093]

Example 35 2- (N-cyanoimino) -5
{(E) -4- (4-isopropylstyryl) benzylidene} -4-oxothiazolidine In the same manner as described above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and (E) -4-
The title compound was obtained from (4-isopropylstyryl) benzaldehyde. 82% yield. Orange crystals.

Melting point: 240 ° C. (decomposition) (ethanol-acetone) Mass spec: 373 (M ⁺ ), 358, 278, 263,
230, 202, 129, 91, 68 Elemental _{analysis: C 22 H 19 N 3 OS} = 373.48 theoretically: H5.13, C70.75, N11.25 (% ) Found: H5.29, C70.81, N11.21 (% )

[0095]

Example 36 2- (N-cyanoimino) -5- (4-
Cinnamyloxybenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-cinnamyloxybenzaldehyde. Yield 85%. Pale yellow crystals.

Melting point: 219.5-220.5 ° C. (decomposition) (ethanol-DMF) Mass spec: 361 (M ⁺ ), 150, 117, 91 Elemental _{analysis: C 20 H 15 N 3 O} 2 S = 361.425 theoretically: H4.19, C66.50, N11.63 (% ) Found: H4.40, C66.46, N11.41 (% )

[0097]

Example 37 2- (N-cyanoimino) -5- (3,
4-diphenethyloxybenzylidene) thiazolidine-
4-one Example 1 The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 3,4-diphenethyloxybenzaldehyde in the same manner as in the above. Yield 37%. Yellow crystals.

Melting point: 161.5-162.5 ° C. (ethanol) Mass spec: 469 (M ⁺ ), 364, 267, 105,
77 Elemental _{analysis: C 27 H 23 N 3 O} 3 S = 469.565 theoretically: H4.94, C69.06, N8.95 (% ) Found: H5.09, C69.02, N8.64 (% )

[0099]

Working Example 38 2- (N-cyanoimino) -5- (3-
Hydroxy-4-phenethyloxybenzylidene) thiazolidine-4-one In the same manner as in 1, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 3-hydroxy-4-phenethyloxybenzaldehyde. 73% yield. Orange-yellow crystals.

Melting point: 189.5-190.5 ° C. (decomposition) (methanol) Mass spec: 365 (M ⁺ ), 166, 105, 79 Elemental analysis: Assuming that C ₁₉ H ₁₅ N ₃ O ₃ S = 365.413 Theoretical values: H 4.14, C 62.45, N 11.50 (%) Observed values: H 4.30, C 62.16, N 11.13 (% )

[0101]

Working Example 39 2- (N-cyanoimino) -5- (4-
Benzoylaminobenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-benzoylaminobenzaldehyde. Yield 57%. Yellow-orange crystals.

Melting point: 297 ° C. (decomposition) (ethanol-DMF) Mass spec: 348 (M ⁺ ), 197, 148, 105 Elemental _{analysis: C 18 H 12 N 4 O} 2 S = 348.386 theoretically: H3.47, C62.06, N16.08 (% ) Found: H3.74, C62.12, N15.86 (% )

[0103]

Example 40 2- (N-cyanoimino) -5- {4-
(Fluoren-9-ylidenemethyl) benzylidenedithiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (fluoren-9-ylidenemethyl) benzaldehyde in the same manner as described above. 55% yield. Orange crystals.

Melting point: 257-259 ° C. (decomposition) (ethanol-DMF) Mass spec: 405 (M ⁺ ), 310, 253, 165 Elemental _{analysis: C 25 H 15 N 3 OS} · C 2 H 5 OH = 451.55 theoretically: H4.69, C71.82, N9.31 (% ) Found: H4.80, C72.12, N9 .18 (%)

[0105]

Example 41 2- (N-cyanoimino) -5- {4-
(2-phenoxyethoxy) benzylidenedithiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (2-phenoxyethoxy) benzaldehyde in the same manner as described above. Yield 80%. Yellow crystals.

Melting point: 225-26.5 ° C. (decomposition)
(Ethanol-DMF) mass spec: 365 (M ⁺ ), 270, 245, 176,
150, 121, 93, 77 Elemental _{analysis: C 19 H 15 N 3 O} 3 S = 365.413 theoretically: H4.14, C62.45, N11.50 (% ) Found: H4.32, C62.39, N11.44 (% )

[0107]

Example 42 2- (N-cyanoimino) -5- {2-}
Methoxy- (E) -5-styrylbenzylidenedithiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 2-methoxy- (E) -5-styrylbenzaldehyde. Yield 76%. Orange crystals.

Melting point: 273-275 ° C. (decomposition) (ethanol-DMF) Mass spectrometry: 361 (M ⁺ ), 189, 177, 165,
147 Elemental _{analysis: C 20 H 15 N 3 O} 2 S = 361.424 theoretically: H4.18, C66.47, N11.63 (% ) Found: H4.44, C66.43, N11.27 (% )

[0109]

Example 43 2- (N-cyanoimino) -5- (4-
Hydroxy-3-phenethyloxybenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-hydroxy-3-phenethyloxybenzaldehyde. Yield 76%. Yellow crystals.

Melting point: 206-207 ° C. (decomposition) (ethanol) Mass spec: 365 (M ⁺ ), 166, 105, 79 Elemental _{analysis: C 19 H 15 N 3 O} 3 S = 365.413 theoretically: H4.14, C62.45, N11.50 (% ) Found: H4.28, C62.26, N11.33 (% )

[0111]

Example 44 2- (N-cyanoimino) -5
{(Z) -4- (β-ethylstyryl) benzylidene}
Example 1 Thiazolidine-4-one In the same manner as described above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and (Z) -4-
The title compound was obtained from (β-ethylstyryl) benzaldehyde. Yield 49%. Brown crystals.

Melting point: 198-200 ° C. (ethanol-DMF) Mass spec: 359 (M ⁺ ), 344, 330, 283
264,249,216,188,147,129,1
16,114,91 Elemental analysis: C ₂₁ H ₁₇ N ₃ OS = 359.452 Theoretical values: H 4.77, C 70.17, N 11.69 (%) Actual values: H 4.96, C 70.15, N 11.52 (%)

[0113]

Example 45 2- (N-cyanoimino) -5- (3-
Phenylbenzylidene) thiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 3-phenylbenzaldehyde in the same manner as in the above. Yield 85%.
Yellow crystals.

Melting point: 242 to 243 ° C. (ethanol-DMF) Mass spectrometry: 305 (M ⁺ ), 304, 210, 165 Elemental analysis: C ₁₇ H ₁₁ N ₃ OS = 305.360 Theoretical values: H 3.63, 66.87, N 13.76 (%) Actual values: H 3.99, C 66.96, N 13.49 (%)

[0115]

Working Example 46 2- (N-cyanoimino) -5- (3-
Benzyloxymethyl-4-methoxybenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 3-benzyloxymethyl-4-methoxybenzaldehyde. 55% yield. Reddish brown crystals.

Melting point: 183.5-185 ° C. (ethanol-DMF) Mass spectrometry: 379 (M ⁺ ), 289, 273, 244,
178, 147, 91 Elemental _{analysis: C 20 H 17 N 3 O} 3 S = 379.439 theoretically: H4.52, C63.31, N11.07 (% ) Found: H4.64, C63.20, N10.79 (% )

[0117]

Example 47 2- (N-cyanoimino) -5- {4-
Example 1 (β-phenylstyryl) benzylidenethiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (β-phenylstyryl) benzaldehyde. Yield 62%. Yellow crystals.

Melting point: 238-239 ° C. (ethanol-DMF) Mass spec: 407 (M ⁺ ), 312, 235, 203 Elemental analysis: C ₂₅ H ₁₇ N ₃ OS = 407.496 Theoretical values: H 4.20, C 73.69, N 10.31 (%) Observed values: H 4.47, C 73.83, N 10.00 (%)

[0119]

Example 48 2- (N-cyanoimino) -5- {4-
(2-phthalimidoethoxy) benzylidenedithiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (2-phthalimidoethoxy) benzaldehyde. Yield 71%. Pale yellow crystals.

Melting point: 235-236 ° C. (decomposition) (ethanol-DMF) Mass spec: 418 (M ⁺ ), 174, 130, 78 Elemental analysis: Assuming C ₂₁ H ₁₄ N ₄ O ₄ S = 418.433 Theoretical values: H 3.37, C 60.28, N 13.39 (%) Observed values: H 3.62, C 60.27, N 13.10 (% )

[0121]

Example 49 2- (N-cyanoimino) -5- {4-
(2-benzothiazolylthio) methylbenzylidenethiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (2-benzothiazolylthio) methylbenzaldehyde in the same manner as described above. Yield 70%. Pale yellow crystals.

Melting point: 200-201.5 ° C. (ethanol-DMF) Mass spec: 408 (M ⁺ ), 375, 280, 242,
147,91 Elemental _{analysis: C 19 H 12 N 4 OS} 3 · 2/3 (C 3 H 7 NO) = 457.26 and to the theoretical value: H3.67, C55.16, N14.30 (% ) Found: H3 .75, C55.46, N14.00 (%)

[0123]

Example 50 2- (N-cyanoimino) -5
{(E) -4- (4-chlorostyryl) benzylidene}
Example 1 Thiazolidine-4-one In the same manner as described above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and (E) -4-
The title compound was obtained from (4-chlorostyryl) benzaldehyde. 79% yield. Dark yellow crystals.

Melting point:> 300 ° C. (DMF) Mass spec: 367 [(M + 2) ⁺ ], 365 (M ⁺ ),
272,270,234,202,178 Elemental analysis: C ₁₀ H ₁₂ ClN ₃ OS = 365.843 Theoretical values: H 3.31, C 62.38, N 11.49 (%) Observed values: H 3.53, C 62.48, N 11.46 (%)

[0125]

Working Example 51 2- (N-cyanoimino) -5- [1-
{4- (2-phenylethoxy) phenyl} ethylidene] thiazolidine-4-one 4- (2-phenylethoxy) acetophenone 11.3
7 g (47.3 mmol), 2- (N-cyanoimino)
A mixture of 4.77 g (33.8 mmol) of -4-oxothiazolidine and 1.04 g (13.5 mmol) of ammonium acetate was stirred at 130 ° C for 10 minutes. Chloroform (150 ml), 2M hydrochloric acid (35 m
l) was added thereto, and the mixture was stirred at room temperature for 15 minutes. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography (chloroform / hexane = 1/3 to 1/1). Yield 2.19 g. Yield 18%. Yellow amorphous.

Melting point: 69-71 ° C. Mass spec: 363 (M ⁺ ), 164 Elemental _{analysis: C 20 H 17 N 3 O} 2 S · 1/4 (H 2 O) = 367.944 theoretically: H4.79, C65.29, N11.42 (% ) Found: H4.86, C65.47, N11.02 (%)

[0127]

Example 52 2- (N-cyanoimino) -5
{(E) -4- (4-Trifluoromethylstyryl) benzylidene} thiazolidine-4-one In the same manner as in above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and (E) -4-
The title compound was obtained from (4-trifluoromethylstyryl) benzaldehyde. Yield 91%. Yellow crystals.

Melting point: 275-280 ° C. (decomposition) (ethanol-DMF) Mass spec: 399 (M ⁺ ), 304, 259, 227 Elemental _{analysis: C 20 H 12 F 3 N} 3 OS = 399.393 theoretically: H3.03, C60.15, N10.52 (% ) Found: H3.25, C60.28, N10.63 (% )

[0129]

Example 53 2- (N-cyanoimino) -5- {3-
(Benzyloxy) benzylidenethiazolidine-4-one In the same manner as in the above, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 3- (benzyloxy) benzaldehyde. 94% yield. Pale yellow crystals.

Melting point: 201-202.5 ° C. (ethanol-DMF) Mass spec: 335 (M ⁺ ), 245, 177, 149,
121 Elemental _{analysis: C 18 H 13 N 3 O} 2 S = 335.386 theoretically: H3.91, C64.46, N12.53 (% ) Found: H4.09, C64.35, N12.37 (% )

[0131]

Example 54 2- (N-cyanoimino) -5- {4-
Example 1 (benzylthio) benzylidenethiazolidine-4-one In the same manner as in 1, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (benzylthio) benzaldehyde. 73% yield. Yellow crystals.

Melting point: 282-283 ° C. (ethanol-DMF) Mass spec: 351 (M ⁺ ), 260, 165, 121,
91,65 Elemental analysis: Assuming that C ₁₈ H ₁₃ N ₃ OS ₂ = 351.453 Theoretical value: H 3.73, C 61.52, N 11.96 (%) Actual value: H 3.97, C 61.53, N 12.04 (%)

[0133]

Example 55 2- (N-cyanoimino) -5
{(E) -4- (4-methylstyryl) benzylidene}
Example 1 Thiazolidine-4-one In the same manner as in above, potassium salt of 2- (N-cyanoimino) thiazolidine-4-one and (E) -4-
The title compound was obtained from (4-methylstyryl) benzaldehyde. 86% yield. Dark yellow crystals.

Melting point:> 300 ° C. (ethanol-DM
F) Mass spec: 345 (M ⁺ ), 251, 178. Elemental _{analysis: C 20 H 15 N 3 OS} = 345.425 theoretically: H4.38, C69.54, N12.16 (% ) Found: H4.66, C70.12, N11.48 (% )

[0135]

Working Example 56 2- (N-cyanoimino) -5- [4-
{{2- (4-chlorophenyl) ethoxy} benzylidene] thiazolidine-4-one 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- {2-
The title compound was obtained from (4-chlorophenyl) ethoxydibenzaldehyde. Yield 69%. Orange crystals.

Melting point: 206.5-208.5 ° C. (ethanol-DMF) Mass spec: 385 [(M + 2) ⁺ ], 383 (M ⁺ ),
244, 149, 139 Elemental analysis: Assuming C ₁₉ H ₁₄ ClN ₃ O ₂ S = 383.858 Theoretical values: H 3.68, C 59.45, N 10.95 (%) Actual values: H 3.87, C 59.67, N 10.65 (% )

[0137]

Example 57 2- (N-cyanoimino) -5- (2-
Benzyloxy-5-chlorobenzylidene) thiazolidine-4-one The title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 2-benzyloxy-5-chlorobenzaldehyde in the same manner as described above. 79% yield. Yellow crystals.

Melting point: 190-191 ° C. (ethanol) Mass spec: 371 [(M + 2) ⁺ ], 369 (M ⁺ ),
185, 183, 91 Elemental analysis: Assuming that C ₁₈ H ₁₂ ClN ₃ O ₂ S = 369.832 Theoretical values: H 3.27, C 58.46, N 11.36 (%) Actual values: H 3.49, C 58.35, N 10.98 (% )

[0139]

Example 58 2- (N-cyanoimino) -5- (4-
Phenethylbenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-phenethylbenzaldehyde. Yield 64
%. Yellow-white crystals.

Melting point: 212-214 ° C. (ethanol-DMF) Mass spec: 333 (M ⁺ ), 242, 147, 91 Elemental _{analysis: C 19 H1 5 N 3 OS} = 333.415 theoretically: H4.53, C68.45, N12.60 (% ) Found: H4.72, C68.70, N12.37 (% )

[0141]

Example 59 2- (N-cyanoimino) -5- (3-
Styrylbenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 3-styrylbenzaldehyde. Yield 45%.
Yellow crystals.

Melting point: 247-248 ° C. (ethanol-DMF) Mass spectrometry: 331 (M ⁺ ), 236, 203, 147,
103 Elemental _{analysis: C 10 H 13 N 3 OS} = 331.399 theoretically: H3.95, C68.86, N12.68 (% ) Found: H4.24, C68.90, N12.27 (% )

[0143]

Working Example 60 2- (N-cyanoimino) -5- (4-
Benzyloxy-2,5-dimethylbenzylidene) thiazolidine-4-one In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4-benzyloxy-2,5-dimethylbenzaldehyde. Yield 80%. Yellow-orange needles.

Melting point: 227 to 228 ° C. (decomposition) (ethanol-acetone) Mass spec: 363 (M ⁺ ), 177, 91 Elemental analysis: C20H17N3O2S = 363.441 Theoretical values: H4.71, C66.10, N11.56 (%) Observed values: H4.97, C66.34, N11.34 (%)

[0145]

Working Example 61 2- (N-cyanoimino) -5- [1-
{4- (4-Methoxystyryl) phenyl} ethylidene] thiazolidine-4-one Example 1 with n-butanol as the solvent. In the same manner as in the above, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one and 4- (4-methoxystyryl) acetophenone. Yield 83%. Yellow-brown crystals.

Melting point: 203-204 ° C. (ethanol-DMF) Mass spec: 375 (M ⁺ ), 280, 266, 250,
232,221,210,166 Elemental analysis: C ₂₁ H ₁₇ N ₃ O ₂ 1/3 (H ₂ O) = 381.457 Theoretical values: H 4.67, C 66.12, N 11.02 (%) Observed values: H 4.92, C66. 22, N 10.80 (%)

The results of the pharmacological test are shown below. In addition, Compound No. The compound represented by means the target compound of the Example corresponding to the number.

[0148]

Example 62 Effect on Fructose-Loaded Hyperlipidemic Rat (Hypertriglyceridemia Model): Pharmacological Journal 92
Volume 175-180 (1988), SD rats were divided into groups by the weight stratification method, and a 75% fructose aqueous solution was freely ingested for 1 week instead of drinking water to prepare a hypertriglyceridemia model. did. 3% drug
It was suspended in an aqueous solution of gum arabic and orally administered at a dose of 30 mg / kg once a day for 7 days during the fructose intake period. A 3% aqueous solution of gum arabic was administered to the control group and the normal group. Two hours after the final administration, blood was collected from the abdominal aorta under ether anesthesia, and the serum triglyceride level and total cholesterol level were measured. Rats in the normal group were allowed free access to normal water. The fructose-loaded hyperlipidemic rat is widely used as an evaluation model for hypertriglyceridemia.

Table 1 shows the obtained results. The reduction rate (%) was determined by the following formula (Equation 1).

[0150]

(Equation 1)

The results showed that the compound of the present invention had a serum triglyceride lowering effect.

[0152]

[Table 1]

[0153]

Example 63 Action Pharmacology and Treatment for Cholesterol-Loaded Hamsters (Hypercholesterolemia Model) 23 (suppl 4) s1047-1053 (199)
Referring to the method described in 5), male Syrian hamsters were prepared by adding 1% cholesterol and 10% coconut oil (W / W).
The animals were bred for 3 weeks on an additional feed to prepare a hypercholesterolemia model. Before the start of drug administration, blood was collected from the orbital venous plexus under ether anesthesia, and the serum total cholesterol level was measured and divided into groups so that the values became equal. The normal group was bred on a normal diet. Thereafter, Compound No. 1 and bezafibrate once daily 15 (Compound No. 1 only), 30, 60,
Gavage was administered at a dose of 120 mg / kg for 7 days. During this time, the cholesterol load was continued. Four hours after the final administration, blood was collected by cardiac puncture, and the total cholesterol and triglyceride levels of the obtained serum were measured by an enzyme method.

Table 2 shows the obtained results. The reduction rate (%) of total cholesterol and triglyceride was determined by the following formula (Equation 2) (however, a negative value indicates an increase rate).

[0155]

(Equation 2)

The results show that the compound of the present invention has a serum cholesterol and triglyceride lowering effect and is more potent than bezafibrate.

[0157]

[Table 2]

[0158]

Example 64 Effect on Cholesterol-Loaded Hamster (Hypercholesterolemia Model) In order to find a compound having a stronger activity, the effect of the compound of the present invention was measured in the same manner as in Example 63 at a dose of 15 mg / kg. .

Table 3 shows the results. In addition, reduction rate (%)
Was determined by the following formula (Equation 2).

[0160]

(Equation 2)

[0161]

[Table 3]

Next, the results of the safety test are shown.

[0163]

Example 65 Acute Toxicity Test of Mice in Single Dose 2000 mg / kg of the compound of the present invention (compound N
o. After a single gavage administration of 1 and 10), general symptoms were observed for 2 weeks. As a result, each compound was 3
All three survived.

[0164]

Example 66 Mutagenicity test To examine the presence or absence of mutagenicity, Compound No.
1 was subjected to a reverse mutation test using Salmonella typhimurium TA100 and TA98. Compound No. In one treatment group, no clear increase in the number of revertant colonies was observed in both the direct method (-s9mix) and the metabolic activation method (+ s9mix) strains, and the gene mutagenicity was negative.

[0165]

Reference Example 1 2- (N-cyanoimino) -5- {4-
(2-Benzoylethenyl) benzylidene dioxothiazolidine In the same manner as in 2, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (phenacylidenemethyl) benzaldehyde. 79% yield. Pale yellow crystals.

Melting point: 271.5-272.5 ° C. (decomposition) (ethanol-DMF) Mass spec: 359 (M ⁺ ), 105 Elemental _{analysis: C 20 H 13 N 3 O} 2 S = 359.409 theoretically: H3.65, C66.84, N11.69 (% ) Found: H3.89, C66.88, N11.35 (% )

[0167]

Reference Example 2 2- (N-cyanoimino) -5- {4-
(Benzoylmethoxy) benzylidenethiazolidine-
4-one Example 1 In the same manner as in 1, the title compound was obtained from 2- (N-cyanoimino) thiazolidine-4-one potassium salt and 4- (benzoylmethoxy) benzaldehyde. Yield 61%. Brown crystals.

Melting point: 269.5-270.5 ° C. (ethanol-DMF) Mass spec: 363 (M ⁺ ), 228, 161, 133,
121, 105, 91, 89, 77 Elemental analysis: Assuming C ₁₉ H ₁₃ N ₃ O ₃ 1/2 (H ₂ O) = 372.405 Theoretical values: H 3.79, C 61.28, N 11.28 (%) Observed values: H 3.81, C61. 49, N 10.85 (%)

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) C07D 417/10 307 C07D 417/10 307 (72) Inventor Takuya Asa 1-3-40 Nishiotsuka, Matsubara-shi, Osaka Prefecture Fujimoto Pharmaceutical (72) Inventor Yuko Uegaki 1-34 Nishi-Otsuka, Matsubara-shi, Osaka Fujimoto Pharmaceutical Co., Ltd. (72) Hirohiro Oide 1-3-3 Nishi-Otsuka, Matsubara-shi, Osaka No. 40 Inside the Drug Discovery Laboratory of Fujimoto Pharmaceutical Co., Ltd. (72) Inventor Fumio Yoneda 1-340 Nishi-Otsuka, Matsubara-shi, Osaka Prefecture F-term in the Drug Discovery Laboratory of Fujimoto Pharmaceutical Co., Ltd. BB07 CC62 DD06 DD12 DD62 EE01 4C086 AA01 AA02 AA03 AA04 BC82 GA06 GA08 GA10 MA04 NA14 ZC02 ZC33

Claims (11)

[Claims] 1. A compound represented by the following general formula (I): [In the formula, the ring A is a linear or branched alkyl group having 1 to 4 carbon atoms, a halogenated alkyl group, an R ₅ O- group (here, R ₅
Represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ) And a benzene ring, a condensed ring or a heterocyclic ring which may be substituted with halogen; R ₁ is a straight-chain or branched carbon atom which may be substituted with a single bond, an oxygen atom, a sulfur atom, methine or a phenyl group. To 4 alkylene groups and alkenylene groups, R ₆ —
X (where R ₆ represents a linear or branched alkylene group having 1 to 4 carbon atoms and alkenylene group, X represents an oxygen atom and a sulfur atom), XR ₆ (R ₆ and X are as defined above) represent the same _{thing.), X-R 6 -X} (R 6, X represents the same meaning as defined _{above.), R 6 -X-R} 6 (R 6, X represents the same meaning as defined above.) —C (＝ O) —NR ₇ —or—NR
₇ -C (= O)-(where R ₇ is a hydrogen atom or a carbon atom 1
Represents an alkyl group of 4 to 4. R ₂ and R ₃ are the same or different and are each a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
_{An 8} O-group (R ₈ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an aralkyl group) or a halogen atom;
R ₄ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. The substitution position of the methylene group at the 5-position of thiazolidine represents both E and Z. A 2- (N-cyanoimino) thiazolidine-4-one derivative, a solvate thereof, and a pharmaceutically acceptable salt thereof. 2. A straight or branched alkyl group having 1 to 4 carbon atoms, a halogenated alkyl group or an R ₅ O— group wherein R ₅ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. And benzene, benzodioxole, benzofuran, benzothiazole, fluorene, indane, indoline and pyridine, which may be substituted with halogen, and 2- (N-cyanoimino) thiazolidine-4-. On derivatives, solvates thereof and pharmaceutically acceptable salts thereof. 3. A straight-chain or branched alkyl group having 1 to 4 carbon atoms, a halogenated alkyl group, or an R ₅ O— group wherein R ₅ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. A 2- (N-cyanoimino) thiazolidine-4-one derivative according to claim 1, which is a benzene ring which may be substituted with halogen, a solvate thereof, and a pharmaceutically acceptable salt thereof. 4. The novel 2- according to claim 1, wherein R ₁ is a linear or branched alkylene group and alkenylene group having 1 to 4 carbon atoms which may be substituted with a methine or phenyl group.
(N-cyanoimino) thiazolidine-4-one derivatives,
The solvates and pharmaceutically acceptable salts thereof. 5. The novel 2- (N-cyanoimino) thiazolidine-4-one derivative according to claim 1, wherein R ₁ is an oxygen atom or a sulfur atom, a solvate thereof and a pharmaceutically acceptable salt thereof. 6. The novel 2- (N-cyanoimino) thiazolidine-4-one derivative according to claim 1, wherein R ₁ is a single bond, a solvate thereof, and a pharmaceutically acceptable salt thereof. 7. R ₁ is R ₆ -X (where R ₆ represents a linear or branched alkylene group and alkenylene group having 1 to 4 carbon atoms, and X represents an oxygen atom or a sulfur atom), X -R
₆ (R ₆ and X represent the same as described above), XR _6-
X (R ₆ and X represent the same as described above) or R ₆ -X
-R _{6 (R 6,} X represents. The same as above) novel 2-(N-cyanoimino) thiazolidin-4-one derivative according to claim 1, wherein a, solvates and pharmaceutically acceptable Possible salt. 8. R ₁ is —C (＝ O) —NR ₇ — or —.
The novel 2- (N-cyanoimino) thiazolidine-4- according to claim 1, which is NR ₇ -C (＝ O)-(where R ₇ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms). On derivatives, solvates thereof and pharmaceutically acceptable salts thereof. 9. A compound represented by the general formula (Formula I)
-(N-cyanoimino) -5-{(E) -4-styrylbenzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5-{(E) -4- (α-methylstyryl) benzylidene} Thiazolidine-4-one, 2- (N
-Cyanoimino) -5- {4- (benzyloxymethyl)
Benzylidene {thiazolidine-4-one, 2- (N-cyanoimino) -5-{(E) -4- (β-methylstyryl) benzylidene} thiazolidine-4-one, 2- (N
-Cyanoimino) -5- {4- (3-phenylpropoxy) benzylidene} thiazolidine-4-one, 2- (N
-Cyanoimino) -5- {4- (4-chlorophenoxy) benzylidene} thiazolidine-4-one, 2- (N
-Cyanoimino) -5- (4-phenylthiobenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) -5-{(E) -4- (2-fluorostyryl) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- {4- (2,5-dimethylphenoxy) benzylidene} thiazolidine-4-one, 2- (N
-Cyanoimino) -5- (4-phenethyloxybenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) -5- {4- (2-phenylpropoxy) benzylidene} thiazolidine-4-one, 2- (N -Cyanoimino) -5- (3-phenethyloxybenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) -5
-(4-benzyloxybenzylidene) thiazolidine-4
-One, 2- (N-cyanoimino) -5- {4- (5-
Chlorobenzofuran-2-yl) benzylidene {thiazolidine-4-one, 2- (N-cyanoimino) -5-
{(E) -4- (4-Methoxystyryl) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- (3-phenoxybenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) −5- ｛4-
(1,3-benzodioxol-5-ylmethoxy) benzylidene {thiazolidine-4-one, 2- (N-cyanoimino) -5- {4- (4-methylbenzyloxy) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- {4- (4-chlorobenzyloxy) benzylidene} thiazolidine-4-one, 2- (N-cyanoimino) -5- {3-methoxy- (E) -4-styryl Benzylidene dithiazolidine-4-one, 2- (N-
(Cyanoimino) -5- (2-phenethyloxybenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) -5- (4-phenoxybenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) -5- $ 3-
(Benzyloxy) benzylidene {thiazolidine-4-one, 2- (N-cyanoimino) -5- {4- (benzylthio) benzylidene} thiazolidine-4-one, 2-
(N-cyanoimino) -5- (4-phenethylbenzylidene) thiazolidine-4-one, 2- (N-cyanoimino) -5- [4- {2- (4-chlorophenyl) ethoxy} benzylidene] thiazolidine-4-one , 2- (N
-Cyanoimino) -5- [1-{(E) -4- (4-methoxystyryl) phenyl} ethylidene] thiazolidine-4-one, 2- (N-cyanoimino) -5- (4-benzyloxy-2,5 -Dimethylbenzylidene) thiazolidine-4-one or 2- (N-cyanoimino) -5
{(E) -3-styrylbenzylidene} thiazolidine-
The novel 2- (N) according to claim 1, which is any one of 4-one or a solvate thereof and a pharmaceutically acceptable salt thereof.
-Cyanoimino) thiazolidine-4-one derivatives. 10. The following (Formula 2) 2- (N-cyanoimino) thiazolidine-4 represented by
-One or a salt thereof, and the following general formula (Chemical Formula 3) [In the formula, the ring A is a linear or branched alkyl group having 1 to 4 carbon atoms, a halogenated alkyl group, an R ₅ O- group (here, R ₅
Represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ) And a benzene ring, a condensed ring or a heterocyclic ring which may be substituted with halogen; R ₁ is a straight-chain or branched carbon atom which may be substituted with a single bond, an oxygen atom, a sulfur atom, methine or a phenyl group. To 4 alkylene groups and alkenylene groups, R ₆ —
X (where R ₆ represents a linear or branched alkylene group having 1 to 4 carbon atoms and alkenylene group, X represents an oxygen atom and a sulfur atom), XR ₆ (R ₆ and X are as defined above) represent the same _{thing.), X-R 6 -X} (R 6, X represents the same meaning as defined _{above.), R 6 -X-R} 6 (R 6, X represents the same meaning as defined above.) —C (＝ O) —NR ₇ —or—NR
₇ -C (= O)-(where R ₇ is a hydrogen atom or a carbon atom 1
Represents an alkyl group of 4 to 4. R ₂ and R ₃ are the same or different and are each a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
_{An 8} O-group (R ₈ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an aralkyl group) or a halogen atom;
R ₄ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ]
A compound represented by the following general formula (I): wherein the ring A is a straight-chain or branched C1-C4
An alkyl group, a halogenated alkyl group, an R ₅ O— group (where R ₅ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) and a benzene ring, a condensed ring or a heterocyclic group which may be substituted with halogen. R ₁ represents a single bond, an oxygen atom, a sulfur atom, methine, a linear or branched alkylene or alkenylene group having 1 to 4 carbon atoms which may be substituted with a phenyl group, R ₆ -X (here, R ₆ is a linear or branched C 1
And X represents an alkylene group or an alkenylene group, and X represents an oxygen atom or a sulfur atom. ), XR ₆ (R ₆ and X represent the same as described above), XR ₆ -X (R ₆ and X represent the same as described above), R ₆ -XR ₆ ( R _6, X represents the same meaning as defined above), -. C (= O ) -NR 7 - or _{-NR 7 -C (= O) -} ( wherein _{R 7} represents a hydrogen atom or 1 to 4 carbon atoms Represents an alkyl group); R ₂ ,
R ₃ is the same or different and represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an R ₈ O— group (R ₈ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an aralkyl group) or a halogen atom. And R ₄ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. The substitution position of the methylene group at the 5-position of thiazolidine represents both E and Z. ] The method for producing a 2- (N-cyanoimino) thiazolidine-4-one derivative or a salt thereof represented by the formula: 11. A therapeutic agent for hyperlipidemia containing the compound according to any one of claims 1 to 10 as an active ingredient.