JPH0770095A - Rhodanine derivative - Google Patents

Abstract

(57) [Summary] [Structure] General formula (I) (In the formula, R ¹ is a C4-12 alkyl group, a C4-12 alkenyl group, a C3-7 cycloalkyl group, or C
It represents a cycloalkyl (C1-4) alkyl group of 3 to 7. ] The rhodanin derivative shown by these, and its nontoxic salt, its manufacturing method, and a drug containing them. [Effect] The compound represented by the general formula (I) has a hypoglycemic action and is useful for the prevention and / or treatment of diabetes and the like.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel rhodanine derivative. More specifically, it has a hypoglycemic effect. 1) General formula (I)

[0002]

[Chemical 2]

[0003] The present invention relates to a rhodanin derivative represented by the formula (wherein R ¹ has the same meaning as described below) and a non-toxic salt thereof, 2) a method for producing them, and 3) a drug containing them.

[0004]

BACKGROUND OF THE INVENTION Blood glucose is an important substance used as an energy source for cells. Its concentration is mainly regulated by muscle, liver and pancreas, and specifically, two factors are responsible for glucose metabolism in muscle and adipose tissue and gluconeogenesis from liver. These two elements are regulated by insulin secreted by pancreatic β cells. In diabetic patients, decreased glucose metabolism in muscle and accelerated gluconeogenesis from liver [Diabetes Care, 15 (3), 318-368 (199)
2); Science, 251 , 1200-1205 (1991)]. In addition, an increase in blood glucose level due to non-response to insulin, particularly in muscle, is considered to be the cause of diabetes [Diabetes, 39 (1), 6
-11 (1990); J. Clin. Invest, 89 , 1367-1374 (1992)
]. Currently used oral hypoglycemic agents include sulfonylurea agents (SU agents) and biguanide agents (B
G agent). However, the SU drug causes hypoglycemia, and the BG drug is less effective than the SU drug.
I have a problem of causing lactic acidosis.

[0005]

2. Description of the Related Art It is already known that certain derivatives having a rhodanine skeleton have a hypoglycemic effect. For example, Japanese Patent Laid-Open No. 1-71873 discloses a compound represented by the general formula (A)

[0006]

[Chemical 3]

(Wherein R ^1A is benzisoxazolyl, methoxybenzisoxazolyl, tetrahydrobenzisoxazolyl, or

[0008]

[Chemical 4]

(Detailed definition of R ^{2A in} the formula is omitted.)
Represents ), JP-A-1-9989 discloses a general formula (B)

[0010]

[Chemical 5]

(Detailed definitions of the symbols in the formula are omitted.), JP-A-63-179873 discloses a general formula (C).

[0012]

[Chemical 6]

(Detailed definitions of the symbols in the formula are omitted.), JP-A-62-238286 discloses a general formula (D).

[0014]

[Chemical 7]

(Detailed definitions of symbols in the formula are omitted.), JP-A-61-27984 discloses a general formula (E).

[0016]

[Chemical 8]

(Detailed definitions of symbols in the formula are omitted.), JP-A-62-12776 discloses a general formula (F).

[0018]

[Chemical 9]

(Detailed definitions of symbols in the formula are omitted.)
And European Patent Publication No. 258914 has the general formula (G)

[0020]

[Chemical 10]

(Detailed definitions of symbols in the formula are omitted.)
The compounds represented by are disclosed. However, all of these compounds have a substituent such as acetic acid at the nitrogen atom in the rhodanine skeleton (the compound of the present invention has no substituent), and the ring present in the substituent at the 5-position of rhodanin is A hetero ring (specifically, an isoxazole, a benzisoxazole ring, etc.) (a carbocycle (specifically, a benzene ring) in the compound of the present invention) is structurally completely different from the compound of the present invention. is there. On the other hand, some compounds having a structure similar to that of the compound of the present invention are known. For example, (1) Japanese Unexamined Patent Publication No. 1-52765 discloses a general formula (K)

[0022]

[Chemical 11]

(In the formula, R ^1K represents a hydrogen atom, a carboxyl group, etc., R ^2K represents a hydrogen atom or a lower alkyl group, and R ^3K represents

[0024]

[Chemical 12]

(Wherein R ^5K and R ^8K represent a hydrogen atom, lower alkyl, lower alkoxy, etc.) and the like,
X ^K represents an oxygen atom or a sulfur atom. Details of other symbols are omitted. (2) JP-A-3-
No. 72471 has the general formula (L)

[0026]

[Chemical 13]

(In the formula, R ^1L represents a hydrogen atom, a C1-8 alkyl group or the like, and R ^2L is —CH ₂ CH ₂ R ^3L — (CH
= CH) _m R ^3L (m represents 0 or 1), -CR
^L = CHR ^4L or - represents a ^{_{(CH2) n CONHR 4L, R}} 3L is C1~3 alkyl, etc. 1-3 substituents phenyl group which may be substituted with a group selected from C1~3 alkoxy such R ^4L is C 1-3 alkyl, C 1
It represents a phenyl group which may be substituted with 1 to 3 substituents selected from 3 alkoxy and the like. ), A compound represented by the formula (M) in (3) JP-A-4-99770

[0028]

[Chemical 14]

(In the formula, R ^1M represents a hydrogen atom, a carboxymethyl group or the like, R ^2M represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and R ^3M represents a hydrogen atom, a lower alkyl group or the like. R ^4M represents a lower alkyl group, a lower alkanoyl group or the like), and (4) in JP-A-2-62864, a compound represented by the general formula (N)

[0030]

[Chemical 15]

(In the formula, X ^N represents a sulfur atom, an oxygen atom, etc., X ^1N represents NH or NCH ₃ , Y ^N and Y ^1N each represent an oxygen atom or a sulfur atom, and Ar
Represents a phenyl group or a phenyl group substituted with 1 to 3 groups such as a lower alkyl group and a lower alkoxy group. ) Is disclosed.

In the above-mentioned specification (1), the compound represented by the general formula (K) is represented by R corresponding to the benzene ring of the compound of the present invention.
^Be sure to use -OA-CO on the benzene ring represented by ^3K .
The OR ^4K group is substituted and is structurally different from the compound of the present invention. In the above specification (2), the compound represented by the general formula (L) has a benzene ring represented by rhodanine and R ^3L and R ^4L of -CH ₂ CH ₂ -,-(CH = C.
^{_{H) m -, - CR L}} = CH- or - (CH _{2) n} -C
It is bound via ONH-. Also, Rhodanine and R ^3L
The benzene ring represented by-(CH = CH) _m-
And m is 0, the general formula (L1)

[0033]

[Chemical 16]

(In the formula, R ^1L and R ^3L have the same meanings as described above.) In some cases, a compound represented by the formula: However, the substituent of the benzene ring represented by R ^3L and R ^4L is a C1-3 alkyl group, a C1-3 alkoxy group, or the like. On the other hand, the substituent of the benzene ring of the compound of the present invention represented by the general formula (I) is -OR
^1a (in the formula, R ¹ represents a C4-12 alkyl group), that is, C4-12 as a substituent on the benzene ring.
May be an alkoxy group of the general formula (L)
It does not overlap with the compound shown by.

In the above specification (3), the compound represented by the general formula (M) corresponds to the benzene ring of the compound of the present invention,
Be sure to connect to the benzene ring from the 5th position of Rhodanine

[0036]

[Chemical 17]

Is substituted and is structurally completely different from the compound of the present invention. Furthermore, the above (1),
In the specifications of (2) and (3), the general formula
It is only described that the compounds represented by (K), (L) and (M) have an aldose reductase inhibitory action, but no hypoglycemic action is described at all. Further, in the composition represented by the general formula (N) in the specification of (4), X ^N and Y ^N are sulfur atoms, X ^1N is NH and Y ^1N.
When represents an oxygen atom, it represents a rhodanine compound. Further, as to Ar, it represents a phenyl group substituted by 1 to 3 groups such as a lower alkyl group and a lower alkoxy group, and in the specification, lower alkoxy means methoxy, ethoxypropoxy, butoxy, pentyl. It is stated to mean oxy or hexyloxy and their isomers. This is because the compound of the present invention has the general formula (Ia)

[0038]

[Chemical 18]

(Wherein R ^1a has the same meaning as described above), R ^1a is C 4-6.
A compound represented by the formula (1) is included. However, in the above specification (4), C is used as a substituent.
There is no specific disclosure of compounds of general formula (N) having 4 to 6 alkoxy groups, ie butoxy, pentyloxy or hexyloxy and their isomers. Further, the description of the above (4) only describes that the compound represented by the general formula (N) has a 5-lipoxygenase or cyclooxygenase inhibitory action, but does not describe the hypoglycemic action at all. Not not.

[0040]

DISCLOSURE OF THE INVENTION The present inventors have conducted extensive studies to find a novel rhodanine derivative having a hypoglycemic effect, and as a result, found that the rhodanine derivative represented by the general formula (I) achieves the object. Completed the invention.

[0041]

DISCLOSURE OF THE INVENTION The present invention includes 1) general formula (I)

[0042]

[Chemical 19]

(Wherein R ¹ is a C4-12 alkyl group,
It represents a C4-12 alkenyl group, a C3-7 cycloalkyl group or a C3-7 cycloalkyl (C1-4) alkyl group. And a non-toxic salt thereof, 2) a method for producing them, and 3) a drug containing them.

In the present invention, isomers include all of them unless otherwise specified. For example, alkyl and alkenyl groups include straight and branched ones, the double bonds in the alkenyl groups include E, Z and mixtures of EZ. Also included are isomers formed by the presence of asymmetric carbon atoms, such as when a branched chain alkyl group is present.

In the general formula (I), the C4-12 alkyl group represented by R ¹ is butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl group and their isomeric groups (i- Propyl, i-butyl, s-butyl, t-butyl, i-pentyl, i-hexyl and the like). In formula (I), C4-1 represented by R ¹
The alkenyl group of 2 means butyl, pentyl, hexyl,
A heptyl, octyl, nonyl, decyl, undecyl, dodecyl group and a group containing one double bond in these isomer groups. In the general formula (I), the C3-7 cycloalkyl group represented by R ¹ is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

In the general formula (I), the C3-7 cycloalkyl (C1-4) alkyl group represented by R ¹ is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group which is methyl, ethyl, propyl, A butyl group or a group bonded to these isomer groups (cyclopropylmethyl, cyclobutylethyl, cyclopentylpropyl, cyclohexylbutyl, etc.).

[0047]

[Salt] The compound of the present invention represented by the general formula (I) can be converted into the corresponding salt by a known method. It is preferable that the salt is a non-toxic water-soluble salt. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine). , Dimethylamine, cyclopetylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucamine, etc.).

[0048]

[Method for producing the compound of the present invention] The compound of the present invention represented by the general formula (I) has the formula (II)

[0049]

[Chemical 20]

Rhodanine represented by the general formula (III)

[0051]

[Chemical 21]

It is produced by reacting with a compound represented by the formula (wherein R ¹ has the same meaning as described above). This reaction is known and, for example, in an inert organic solvent (methanol, ethanol, isopropyl alcohol, dimethylformamide, acetic acid or a mixed solvent thereof, etc.), an organic acid salt (sodium acetate, potassium acetate,
It is carried out by reacting at 0 to 150 ° C. in the presence of an ammonium acetate or the like) or an organic base (piperidine, morpholine or the like). The compound represented by the general formula (III) is

[0053]

[Chemical formula 22]

(In the reaction formula, Z is a halogen atom, -OSO
It represents ₂ CH ₃ group or _{-OSO 2 C 6 H 4 -p-} CH 3 group, R ¹ is as defined above. Also, Z is −
KI (potassium iodide) is also used during the reaction when it represents an OSO ₂ CH ₃ group. DMF stands for dimethylformamide, DMSO stands for dimethylsulfoxide, THF stands for tetrahydrofuran, DEAD stands for diethylazodicarboxylate. ) It can manufacture by the reaction formula shown. In each reaction in the present specification, the reaction product is a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing. , Can be purified by a method such as recrystallization.
Purification may be carried out for each reaction or after completion of some reactions.

[0055]

[Starting material] The starting material and each reagent in the present invention are
It is known per se or can be produced by a known method. For example, the compounds represented by the general formulas (II) and (IV) are commercially available. For example, among the compounds represented by the general formula (V),

[Chemical formula 23] The compound represented by is commercially available.

[0056]

[Pharmacological activity of the compound of the present invention] The compound of the present invention represented by the general formula (I) has a hypoglycemic action as described above. For example, in laboratory experiments, L6 cells, a muscle cell line [Endocrinology, 130 (5), 2535-2543 (1992); Diabete
S Care, 13 (6), 696-704 (1990)] was used to measure the sugar uptake activity. This is due to the fact that diabetic patients with elevated blood glucose levels have decreased glucose metabolism in muscles, which is due to a decrease in intracellular glucose uptake activity [Diabetes Care, 15 (3), 318-368
(1992); Science, 251 , 1200-1205 (1991); Diabetes,
39 (1), 6-11 (1990); J. Clin.Invest, 89 , 1367-1374 (1
992)].

[Experimental Method] L6 cells (1 × 10 ⁵ cells /
A 35 mm diameter dish) was cultured at 37 ° C. for 8 days in a 5% CO ₂ incubator using Dulbecco's modified Eagle medium (containing 10% fetal bovine serum). Then, the cells differentiated from myoblasts into myocytes. The differentiated cells were treated with a serum-free Dulbecco's modified Eagle medium for 2 hours, various test drugs (10 μM) were added, and the cells were further cultured for 2 hours. Then, Krebs Ringer phosphate buffer (p
After culturing for 20 minutes in H7.4), ³ H-2-deoxyglucose (0.05 μCi / ml, 5 μM) was added. After the addition, the amount of the label incorporated into the cells in the initial 3 minutes was measured by a liquefaction scintillation counter.

[Results] The results are shown in Table 1.

[0059]

[Table 1]

Comparative compound 1 has the following formula

[0061]

[Chemical formula 24]

A compound represented by the formula (1), which has a aldose reductase inhibitory action, is disclosed in JP-A-1-
It corresponds to the compound of Example 64 in the specification of 52765. Comparative compound 2 has the following formula

[0063]

[Chemical 25]

It corresponds to the compound of Example 24 in the specification of JP-A-2-62864 in which a pharmaceutical composition having a 5-lipoxygenase or cyclooxygenase inhibitory action is disclosed. From the results shown in Table 1, it was confirmed that the compound of the present invention has a strong sugar uptake activity, that is, a compound having a strong hypoglycemic action. It was also confirmed that the compound had stronger activity than the comparative compounds 1 and 2.

[0065]

[Toxicity] The toxicity of the compound of the present invention is sufficiently low,
It was confirmed to be safe enough for use as a medicine.

[0066]

[Application to Pharmaceuticals] The compound of the present invention represented by the general formula (I) has a hypoglycemic action and is therefore useful for the prevention and / or treatment of diabetes and the like. When the compound of the present invention represented by the general formula (I) is used for the above purpose, it is usually administered systemically or locally, orally or parenterally.
The dosage varies depending on the age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually within the range of 0.01 to 1,000 mg per adult, and is orally administered once to several times a day. Per adult, once per adult
In the range of 0.1 to 100 mg, it may be administered parenterally (preferably intravenously) once to several times a day, or once a day.
It is continuously administered intravenously within the range of 24 hours to 24 hours. Of course, since the dose varies depending on various conditions as described above, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be required in some cases.

When the compound of the present invention is administered, it is used as solid compositions, liquid compositions and other compositions for oral administration, injections for parenteral administration, external preparations, suppositories and the like. Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules.

In such solid compositions, the one or more active substances comprise at least one inert diluent such as lactose, mannitol, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, It is mixed with polyvinylpyrrolidone and magnesium aluminometasilicate. The composition may be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium fibrin glycolate, a solubilizing agent such as glutamic acid or aspartic acid, according to a conventional method. May be contained. If necessary, tablets or pills should be sucrose, gelatin,
It may be coated with a film of a gastric or enteric substance such as hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Also included are capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such a liquid composition, one or more active substances are contained in a generally used inert diluent (eg, purified water, ethanol).
The composition may contain, in addition to an inert diluent, auxiliary agents such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent, and a preservative. Other compositions for oral administration include spray formulations which contain one or more active substances and are formulated in a manner known per se.
In addition to an inert diluent, this composition contains a stabilizer such as sodium bisulfite and a stabilizer that imparts isotonicity, an isotonic agent such as sodium chloride, sodium citrate or citric acid. May be. The method for producing the spray agent is described in, for example, U.S. Pat.
It is described in detail in 5,355.

The injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of water-insoluble solutions and suspensions include propylene, glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). Such a composition may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers and solubilizing agents (eg glutamic acid, aspartic acid). These are sterilized by filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. They can also be used by preparing a sterile solid composition and dissolving it in sterilized or sterile distilled water for injection or other solvent before use. Other compositions for parenteral administration include external preparations containing one or more active substances and formulated by a conventional method,
Soft ko, application, suppositories for rectal administration, pessaries for vaginal administration and the like are included.

[0071]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in the parentheses shown in the chromatographic separation indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. NMR is measured with d6-dimethylsulfoxide unless otherwise stated.

Reference Example 1 4- (3-methylbutoxy) benzaldehyde

[0073]

[Chemical formula 26]

To a suspension of 60% sodium hydride (400 mg) in dimethylformamide (DMF) (40 ml) was added p-hydroxybenzaldehyde (1.22 g) in DM.
The F solution (10 ml) was added under ice cooling. After stirring the mixture at room temperature for 30 minutes, 1-bromo-3-methylbutane (1.2 ml) was added thereto. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate / n-hexane (1: 1). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (1.57 g) having the following physical data. TLC (ethyl acetate: n-hexane = 1: 4): Rf
0.49.

Reference Example 2 2-Cyclohexylethyl mesylate

[0076]

[Chemical 27]

2-Cyclohexyl ethanol (2.56 g)
Methylene chloride solution (40 ml) was cooled to -5 ° C.
Methanesulfonyl chloride (1.6 ml) was added dropwise to the solution, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into 1N hydrochloric acid containing ice, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the title compound (3.56 g) having the following physical data. TLC (ethyl acetate: n-hexane = 1: 4): Rf
0.33.

Reference Example 3 4- (2-cyclohexylethyloxy) benzaldehyde

[0079]

[Chemical 28]

A DMF solution (10 ml) of p-hydroxybenzaldehyde (2.04 g) was added to a DMF suspension (50 ml) of 60% sodium hydride (672 mg) under ice cooling. The mixture was stirred at room temperature for 30 minutes. A DMF solution (10 ml) of the compound (3.56 g) produced in Reference Example 2 and potassium iodide (2.7 g) were added to the reaction mixture, and the mixture was stirred at 80 ° C. for 30 minutes on an oil bath. After allowing to cool, the reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to give the title compound (3.38 g) having the following physical data. TLC (ethyl acetate: n-hexane = 1: 4): Rf
0.61.

Reference Example 4 4-Cyclohexyloxybenzaldehyde

[0082]

[Chemical 29]

Diethylazodicarboxylate (1.58 ml) was added dropwise to a tetrahydrofuran solution of cyclohexanol (1.50 g), p-hydroxybenzaldehyde (1.22 g) and triphenylphosphine (2.62 g). The mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to give the title compound (360 mg) having the following physical data. TLC (ethyl acetate: n-hexane = 1: 4): Rf
0.66. The following compounds were obtained by the same procedure as in Reference Example 1, Reference Example 2 → Reference Example 3 or Reference Example 4 using the corresponding compounds.

Reference Example 5 4-Butoxybenzaldehyde

[0085]

[Chemical 30]

TLC (ethyl acetate: n-hexane = 1: 1)
4): Rf 0.38.

Reference Example 6 4-Pentyloxybenzaldehyde

[0088]

[Chemical 31]

TLC (ethyl acetate: n-hexane = 1: 1)
4): Rf 0.39.

Reference Example 7 4-hexyloxybenzaldehyde

[0091]

[Chemical 32]

TLC (ethyl acetate: n-hexane = 1: 1)
4): Rf 0.40.

Reference Example 8 4-heptyloxybenzaldehyde

[0094]

[Chemical 33]

TLC (ethyl acetate: n-hexane = 1: 1)
4): Rf 0.42.

Reference Example 9 4-octyloxybenzaldehyde

[0097]

[Chemical 34]

TLC (ethyl acetate: n-hexane = 1: 1)
4): Rf 0.45.

Reference Example 10 4- (2-Methylpropyloxy) benzaldehyde

[0100]

[Chemical 35]

TLC (ethyl acetate: n-hexane = 1: 1)
4): Rf 0.42.

Reference Example 11 4- (4-methylpentyloxy) benzaldehyde

[0103]

[Chemical 36]

TLC (ethyl acetate: n-hexane = 1: 1)
1): Rf 0.76.

Reference Example 12 4- (3-Methyl-2-butenyloxy) benzaldehyde

[0106]

[Chemical 37]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.71.

Reference Example 13 4- (4-methyl-3-pentenyloxy) benzaldehyde

[0109]

[Chemical 38]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.59.

Reference Example 14 4- (2-Cyclopropylethyloxy) benzaldehyde

[0112]

[Chemical Formula 39]

TLC (ethyl acetate: n-hexane = 1: 1)
4): Rf 0.68.

Reference Example 15 4- (2-Cyclobutylethyloxy) benzaldehyde

[0115]

[Chemical 40]

TLC (ethyl acetate: n-hexane = 1: 1)
3): Rf 0.50.

Reference Example 16 4- (2-Cyclopentylethyloxy) benzaldehyde

[0118]

[Chemical 41]

TLC (ethyl acetate: n-hexane = 1: 1)
6): Rf 0.33.

Reference Example 17 4- (2-Cycloheptylethyloxy) benzaldehyde

[0121]

[Chemical 42]

TLC (ethyl acetate: n-hexane = 1: 1)
8): Rf 0.37.

Reference Example 18 4-Cyclobutyloxybenzaldehyde

[0124]

[Chemical 43]

TLC (chloroform: ethanol = 2)
0: 1): Rf 0.26.

Reference Example 19 4-Cyclopentyloxybenzaldehyde

[0127]

[Chemical 44]

TLC (ethyl acetate: n-hexane = 1: 1)
3): Rf 0.62.

Reference Example 20 4-Cyclopropylmethyloxybenzaldehyde

[0130]

[Chemical formula 45]

TLC (chloroform: ethyl acetate = 1
9: 1): Rf 0.36.

Reference Example 21 4-Cyclobutylmethyloxybenzaldehyde

[0133]

[Chemical formula 46]

TLC (chloroform: ethyl acetate = 1
9: 1): Rf 0.41.

Reference Example 22 4-Cyclopentylmethyloxybenzaldehyde

[0136]

[Chemical 47]

TLC (chloroform: ethyl acetate = 1
9: 1): Rf 0.45.

Example 1 5- [4- (3-Methylbutoxy) benzylidene] rhodanine

[0139]

[Chemical 48]

The compound prepared in Reference Example 1 (1.92 g), rhodanine (1.33 g) and sodium acetate (700 mg)
Of ethanol solution (20 ml) was refluxed for 3 hours. After cooling, the crude crystals precipitated were filtered, washed with ethanol and recrystallized from ethanol to give the title compound (2.56 g) having the following physical data.

TLC (ethyl acetate: n-hexane = 1: 1)
1): Rf 0.61; NMR: δ 7.69 (1H, s), 7.63 (2H, d), 7.08 (2H,
d), 4.07 (2H, t), 1.68 (1H, m), 1.63 (2H, q), 0.93
(6H, d).

By using the corresponding compounds in Reference Examples 3 to 22 and operating in the same manner as in Example 1, the following compounds were obtained.

Example 2 5- (4-Butoxybenzylidene) Rhodanine

[0144]

[Chemical 49]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.41; NMR: δ 13.70 (1H, br.s), 7.60 (1H, s), 7.54
(2H, d), 7.09 (2H, d), 4.05 (2H, q), 1.73 (2H, m),
1.44 (2H, m), 0.94 (3H, t).

Example 3 5- (4-Pentyloxybenzylidene) rhodanine

[0147]

[Chemical 50]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.42; NMR: δ 13.72 (1H, br.s), 7.60 (1H, s), 7.54
(2H, d), 7.08 (2H, d), 4.04 (2H, q), 1.75 (2H, m),
1.37 (4H, m), 0.90 (3H, t).

Example 4 5- (4-hexyloxybenzylidene) rhodanine

[0150]

[Chemical 51]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.44; NMR: δ 13.74 (1H, br.s), 7.60 (1H, s), 7.54
(2H, d), 7.07 (2H, d), 4.04 (2H, q), 1.72 (2H, m),
1.20-1.50 (6H, m), 0.89 (3H, t).

Example 5 5- (4-heptyloxybenzylidene) rhodanine

[0153]

[Chemical 52]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.45; NMR: δ 13.72 (1H, br.s), 7.60 (1H, s), 7.54
(2H, d), 7.08 (2H, d), 4.04 (2H, d), 1.73 (2H, m),
1.20-1.50 (8H, m), 0.87 (3H, t).

Example 6 5- (4-octyloxybenzylidene) rhodanine

[0156]

[Chemical 53]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.46; NMR: δ 7.60 (1H, s), 7.54 (2H, d), 7.08 (2H,
d), 4.04 (2H, d), 1.72 (2H, m), 1.20-1.50 (10H, m),
0.86 (3H, t).

Example 7 5- [4- (2-Methylpropyloxy) benzylidene] rhodanine

[0159]

[Chemical 54]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.46; NMR: δ 7.95 (1H, s), 7.53 (2H, d), 7.09 (2H,
d), 3.82 (2H, d), 2.03 (1H, m), 0.99 (6H, d).

Example 8 5- [4- (4-Methylpentyloxy) benzylidene] rhodanine

[0162]

[Chemical 55]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.49; NMR: δ 7.53 (1H, s), 7.50 (2H, d), 7.05 (2
H, d), 4.02 (2H, d), 1.80-1.40 (3H, m), 1.36-1.17
(2H, m), 0.84 (6H, d).

Example 9 5- [4- (3-Methyl-2-butenyloxy) benzylidene] rhodanine

[0165]

[Chemical 56]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.42; NMR: δ 7.57 (1H, s), 7.51 (2H, d), 7.06 (2H,
d), 5.40 (1H, bt), 4.57 (2H, d), 1.70 (3H, s), 1.6
8 (3H, s).

Example 10 5- [4- (4-Methyl-3-pentenyloxy) benzylidene] rhodanine

[0168]

[Chemical 57]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.45; NMR: δ 7.56 (1H, s), 7.51 (2H, d), 7.05 (2H,
d), 5.17 (1H, bt), 3.99 (2H, t), 2.38 (2H, dt), 1.
65 (3H, s), 1.58 (3H, s).

Example 11 5- [4- (2-Cyclopropylethyloxy) benzylidene] rhodanine

[0171]

[Chemical 58]

TLC (chloroform: ethanol = 2)
0: 1): Rf 0.65; NMR: δ 7.54 (1H, s), 7.50 (2H, d), 7.06 (2H,
d), 4.07 (2H, t), 1.61 (2H, dt), 0.93-0.70 (1H, m),
0.50-0.36 (2H, m), 0.17-0.05 (2H, m).

Example 12 5- [4- (2-Cyclobutylethyloxy) benzylidene] rhodanine

[0174]

[Chemical 59]

TLC (chloroform: ethanol = 2)
0: 1): Rf 0.39; NMR: δ 7.57 (1H, s), 7.53 (2H, d), 7.06 (2H,
d), 4.98 (2H, t), 2.50-2.35 (1H, m), 2.15-1.55 (8
H, m).

Example 13 5- [4- (2-Cyclopentylethyloxy) benzylidene] rhodanine

[0177]

[Chemical 60]

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf 0.45; NMR: δ 13.70 (1H, br.s), 7.61 (1H, s), 7.54
(2H, d), 7.09 (2H, d), 4.06 (2H, t), 1.90 (1H, m),
1.78 (4H, m), 1.52 (4H, m), 1.18 (2H, m).

Example 14 5- [4- (2-Cyclohexylethyloxy) benzylidene] rhodanine

[0180]

[Chemical formula 61]

TLC (chloroform): Rf 0.19; NMR: δ 14.1-13.3 (1H, br), 7.60 (1H, s), 7.54
(2H, d), 7.09 (2H, d), 4.08 (2H, t), 1.80-0.80 (1
3H, m).

Example 15 5- [4- (2-Cycloheptylethyloxy) benzylidene] rhodanine

[0183]

[Chemical formula 62]

TLC (chloroform: ethanol = 2)
0: 1): Rf 0.44; NMR: δ 14.2-13.2 (1H, br), 7.57 (1H, s), 7.51
(2H, d), 7.06 (2H, d), 4.04 (2H, t), 1.78-1.04 (1
5H, br.m).

Example 16 5- (4-Cyclobutyloxybenzylidene) rhodanine

[0186]

[Chemical formula 63]

TLC (chloroform: ethanol = 2)
0: 1): Rf 0.56; NMR: δ 14.2-13.2 (1H, br), 7.59 (1H, s), 7.53
(2H, d), 7.00 (2H, d), 4.78 (1H, quintet), 2.50-
2.35 (2H, m), 2.20-1.95 (2H, m), 1.94-1.55 (2H, m)
.

Example 17 5- (4-Cyclopentyloxybenzylidene) rhodanine

[0189]

[Chemical 64]

TLC (chloroform: methanol = 2
0: 1): Rf 0.67; NMR: δ 14.1-13.3 (1H, br), 7.59 (1H, s), 7.53
(2H, d), 7.05 (2H, d), 4.98-4.85 (1H, m), 2.10-1.
84 (2H, m), 1.84-1.48 (6H, m).

Example 18 5- (4-Cyclopentyloxybenzylidene) rhodanine

[0192]

[Chemical 65]

TLC (chloroform: methanol = 2
0: 1): Rf 0.72; NMR: δ 14.0-13.3 (1H, br), 7.59 (1H, s), 7.53
(2H, d), 7.08 (2H, d), 4.55-4.37 (1H, m), 2.05-1.
83 (2H, m), 1.82-1.62 (2H, m), 1.61-1.14 (6H, m).

Example 19 5- (4-Cyclopropylmethyloxybenzylidene)
Rhodanine

[0195]

[Chemical formula 66]

TLC (chloroform: ethyl acetate = 1
9: 1): Rf 0.31; NMR: δ 13.70 (1H, br.s), 7.60 (1H, s), 7.53
(2H, d), 7.18 (2H, d), 3.90 (2H, d), 1.23 (1H, m),
0.60 (2H, m), 0.35 (2H, m).

Example 20 5- (4-Cyclobutylmethyloxybenzylidene) rhodanine

[0198]

[Chemical formula 67]

TLC (chloroform: ethyl acetate = 1
9: 1): Rf 0.33; NMR: δ 13.74 (1H, br.s), 7.60 (1H, s), 7.54
(2H, d), 7.09 (2H, d), 4.03 (2H, d), 2.74 (1H, m),
1.72-2.15 (6H, m).

Example 21 5- (4-Cyclopentylmethyloxybenzylidene)
Rhodanine

[0201]

[Chemical 68]

TLC (chloroform: ethyl acetate = 1
9: 1): Rf 0.35; NMR: δ 13.70 (1H, br.s), 7.59 (1H, s), 7.54
(2H, d), 7.08 (2H, d), 3.92 (2H, d), 2.32 (1H, m),
1.21-1.88 (8H, m).

Formulation Example 1 The following components were admixed in a conventional method and punched out to give 100 tablets each containing 5 mg of the active ingredient.・ 5- [4- (3-Methylbutoxy) benzylidene] rhodanine …… 500 mg ・ Carboxymethylcellulose calcium ・ ・ ・ 200 mg ・ Magnesium stearate ・ ・ ・ 100 mg ・ Microcrystalline cellulose ・ ・ ・ 9.2 g

Formulation Example 2 The components below were mixed by a conventional method, then the solution was sterilized by a conventional method, 10 ml each was filled in an ampoule, and lyophilized by a conventional method to contain 2 mg of the active ingredient in 1 ampoule. I got 100 ampoules.・ 5- [4- (3-Methylbutoxy) benzylidene] rhodanin ...... 200 mg ・ Mannit ・ ・ ・ 50 g ・ Distilled water ・ ・ ・ 1,000 ml

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ is a C4-12 alkyl group, a C4-12 alkenyl group, a C3-7 cycloalkyl group, or C
It represents a cycloalkyl (C1-4) alkyl group of 3 to 7. ) Rhodanine derivative or a non-toxic salt thereof.