JPH08225449A - Remedy for ischemic disease - Google Patents

Abstract

PURPOSE: To provide a remedy useful as a remedy for stenocardia or hypertension or antiarrhythmic agent, etc., by including a specific compound possessing together a vasohypotonic action, a lipid hyperoxidation inhibiting action and a calcium overload inhibiting action as an active component. CONSTITUTION: This remedy contains a compound of formula I [R1 is H or OH, etc.; R2 and R3 are each H or a halogen, etc.; R4 is H or a 1-6C alkyl; A is a group of formula II or B (R5 is H or an aryl, etc.; B is a group of formula III or IV, etc.); (n) is 2-6], its stereoisomer, optical isomer or its salt as an active component. As the compound of the formula I, e.g., 2-(3,5-diisopropyl-4- hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylene dioxyphenoxy) ethyl]amino]propyl]-1,3-thiazolidin-4-one, etc., is exemplified. Preferably, a dose of the compound of formula I or its salt is daily 0.1-200mg/body.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a compound represented by the general formula (I) which has a calcium overload inhibitory action in addition to a vasorelaxant action (calcium antagonistic action) and a lipid peroxidation inhibitory action, or a pharmaceutical agent thereof. Relates to a prophylactic / therapeutic agent for an ischemic disease and an antihypertensive agent, which comprises as an active ingredient a salt which is acceptable to a human or a possible stereochemical isomer and optical isomer thereof.

[0002]

2. Description of the Related Art Cellular damage due to ischemia is (1) a process of damage due to a decrease in intracellular ATP level, increase in intracellular calcium, etc. in an oxygen-deficient state during ischemia; It is roughly divided into two types of disorder processes such as increase of calcium influx due to perfusion and resumption of blood vessels and production of free radicals (Yoshihara et al., Metabolism, Vol, 29, 379, 1992). Typical ischemic diseases include cardiovascular disorders such as atypical angina, unstable angina, myocardial infarction, arrhythmia accompanying coronary flow resumption due to PTCA / PTCR / CABG, or transient. Cerebrovascular disorders such as de-ischemic attacks, head trauma, and aftereffects of brain surgery can be mentioned. For atypical angina and unstable angina, vasodilators such as nitroglycerin, nitro compounds represented by nicorandil, diltiazem, nifedipine, and calcium channel blockers represented by verapamil are used, and myocardial infarction and PTCA /
Use of a 5-lipoxygenase inhibitor, a radical scavenger, or the like is being considered for the disorder when the coronary blood flow is restarted due to PTCR / CABG or the like. Prevention of cerebrovascular disorders
As a therapeutic drug, glyceol (registered trademark), ozagrel, nizophenone, ticlopidine, nicarabene and the like have been used and studied from the viewpoint of prevention of cerebral edema and cerebral vasospasm in the acute phase. On the other hand, in the chronic phase, cerebral circulation improving agents such as calcium antagonists represented by nicardipine, cinnarizine, and flunarizine can be used from the viewpoint of increasing blood flow to tissues that survived ischemic injury and improving metabolism. Cerebral circulatory metabolism improving agents such as vinpocetine, nicergoline, pentoxifylline, and ifenprodil, and cerebral metabolism improving agents such as idebenone, GABA, and calcium hopatate have been used.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have an excellent prevention of ischemic diseases capable of suppressing the production of active oxygen and increase of intracellular calcium, which are considered to be the main causes of ischemic diseases and hypertension. -As a result of intensive studies to search for therapeutic agents and antihypertensive agents, the general formula (I) has vasorelaxant (calcium antagonism), lipid peroxidation inhibitory effect and calcium overload inhibitory effect all in the same drug. By synthesizing the compounds represented by the formula, these compounds were found to be effective as prophylactic / therapeutic agents for ischemic diseases and antihypertensive agents. The present invention has been completed based on this finding.

[0004]

That is, the present invention has the general formula (I)

Embedded image (In the formula, R ₁ represents a hydrogen atom, a hydroxyl group, an acyloxy group having 1 to 9 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms; R ₂ and R ₃ may be the same or different,
Represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms; R ₄ represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms; A is the general formula (II) or the general formula (II
I)

[Chemical 4] Wherein R ₅ represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms which may have a substituent, or a lower alkenyl group having 1 to 6 carbon atoms which may have a substituent. Represents an optionally substituted alkoxy group having 1 to 6 carbon atoms, an optionally substituted aryl group, an optionally substituted heterocyclic group, and R ₅ May form a 5- or 6-membered ring containing two or more oxygen atoms or sulfur atoms with the carbon atom to which it is bonded being a spiro atom;
B is represented by the general formula (IV), (V), (VI), (VI
I), (VIII), (IX), (X), (XI),
Represents a group selected from the group consisting of (XII), (XIII), (XIV), (XV) and (XVI); R ₆ and R ₇ may be the same or different and each is a hydrogen atom or a substituent. A lower alkyl group having 1 to 6 carbon atoms which may have, a lower alkenyl group having 1 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a substituent Represents a heterocyclic group which may have, provided that they are not simultaneously a methyl group; or R ₆ ,
R ₇ may form a ring together (the ring may have a substituent or may be a condensed ring which may have a substituent); n is Represents an integer of 2, 3, 4, 5 or 6. And a pharmaceutically acceptable salt thereof or a possible stereoisomer and optical isomer thereof as an active ingredient.

In the compound represented by the general formula (I),
A lower alkyl group having 1 to 6 carbon atoms which may have a substituent, a lower alkenyl group having 1 to 6 carbon atoms which may have a substituent, and a carbon number 1 which may have a substituent ~ 6 lower alkoxy group, an aryl group which may have a substituent, a substituent in the heterocyclic group which may have a substituent include, for example, a halogen atom such as a chlorine atom or a bromine atom,
Alkoxycarbonyl groups such as hydroxyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, N, N
Carbamoyl group such as dimethylcarbamoyl group, alkoxy group such as methoxy group and ethoxy group, 3,4-methylenedioxyphenoxy group, 3,4,5-trimethoxyphenoxy group, 3,4-dimethoxyphenoxy group, 4- Examples thereof include a phenoxy group such as a methoxyphenoxy group, a phenyl group such as a 3,4-methylenedioxyphenyl group, and a 4-methoxyphenyl group.

The ischemic diseases targeted by the therapeutic agent for ischemic disease of the present invention include, for example, ischemic heart disease and ischemic cerebrovascular disorder. The therapeutic agent for ischemic disease of the present invention includes these diseases. Means a preventive agent and / or a therapeutic agent. The therapeutic agent for ischemic heart disease of the present invention includes therapeutic agents such as therapeutic agent for angina, therapeutic agent for hypertension, antiarrhythmic agent, coronary vasodilator, and preventive agent for myocardial infarction. Further, the therapeutic agent for ischemic cerebrovascular disorder of the present invention includes agents such as therapeutic agent for cerebral infarction in which ischemic cerebrovascular disorder is cerebral infarction, cerebral circulation improving agent, cerebral protective agent and the like.

The pharmaceutically acceptable salt of the compound of the present invention represented by the general formula (I) is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include hydrochloric acid, sulfuric acid, nitric acid and hydrogen bromide. Inorganic acid salts with acid, hydroiodic acid, etc., organic acid salts with formic acid, acetic acid, oxalic acid, tartaric acid, fumaric acid, etc., sodium,
Examples thereof include alkali metal salts with potassium and the like, alkaline earth metal salts with calcium, magnesium and the like, and the like.

The compound of the present invention or a salt thereof is a suitable excipient, auxiliary agent, lubricant, preservative, disintegrating agent, buffer, binder, stabilizer, wetting agent, emulsifier, colorant, flavoring agent or Orally or parenterally administered in the form of tablets, granules, fine granules, powders, capsules, syrups, elixirs, suspensions, emulsions, injections, etc. You can

The dose of the compound of the present invention or a salt thereof can be appropriately selected depending on the patient's body type, age, physical condition, degree of disease, elapsed time after onset, etc., but is 0.1 to 200 mg / day. A body is preferable. Generally, even if the same dose is administered, the blood concentration may vary greatly depending on the patient, so it is ideal to determine the optimal dose of the drug for each patient while monitoring the blood concentration of the drug. is there.

In the case of formulating as an internal preparation, for example, as a carrier for the formulation, a starch or a starch derivative such as lactose, sucrose, sorbit, mannitol, potato starch or corn starch, a starch derivative such as cellulose derivative or gelatin is usually used. Auxiliary agents that can be used are suitable, and at the same time, a lubricant such as magnesium stearate, carbowax or polyethylene glycol can be added, and a mixture of these is made into granules, tablets, capsules and the like by a conventional method. can do.

When formulated as an aqueous preparation, for example, an effective amount of the main component is dissolved in distilled water for injection, and if necessary, an antioxidant, a stabilizer, a solubilizing agent, a buffer, a preservative and the like are added. In addition, after being completely dissolved, an injection can be prepared by sterilizing by filtration, filling, and sealing by a conventional method, and sterilized by a high pressure steam sterilization method, a dry heat sterilization method, or the like.

When formulated as a freeze-drying agent, an aqueous solution in which the main component is dissolved in distilled water for injection may be freeze-dried by a conventional method, and if necessary, as an excipient that is easily freeze-dried. , Mannitol, inositol, lactose, maltose, sucrose and the like, sugars or sugar alcohols, glycine and the like can be added and lyophilized in a conventional manner.

The compound represented by the general formula (I) can be obtained by the following methods A to Q.

[0014]

Embedded image (In the formula, R ₁ represents a hydrogen atom, a hydroxyl group, an acyloxy group having 1 to 9 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms; R ₂ and R ₃ may be the same or different; , A hydroxyl group, a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms; R ₄ represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms; R ₅ Is a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms which may have a substituent, a lower alkenyl group having 1 to 6 carbon atoms which may have a substituent, and a substituent. Represents an optionally substituted aryl group or a heterocyclic group which may have a substituent; R ₆ and R ₇ may be the same or different and each represents a hydrogen atom or a carbon atom which may have a substituent. ~
A lower alkyl group of 6, a lower alkenyl group of 1 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, and a heterocyclic group which may have a substituent. However, R ₆ and R ₇ may together form a ring (the ring may have a substituent or may have a substituent). It may be a condensed ring which may have); n is 2, 3, 4,
Represents an integer of 5 or 6; Z represents a halogen atom. )

[Chemical 6] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ ,
n represents the same as described above, R ₈ represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent; Z represents a chlorine atom or a bromine atom. )

[Chemical 7] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ ,
R ₈ , n and Z are the same as defined above. )

Embedded image (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ ,
n represents the same as above. )

[Chemical 9] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , n, Z
Represents the same as described above; R ₉ represents an alkyl group having 1 to 6 carbon atoms; and m represents an integer of 1 to 7. )

[Chemical 10] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , R ₈ ,
R ₉ , n and m are the same as defined above. )

[Chemical 11] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , R ₈ ,
R ₉ , n and m are the same as defined above. )

[Chemical 12] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , Z,
n and m represent the same as those described above; R ₁₀ and R ₁₁ may be the same or different and each is a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms which may have a substituent, a substituent Represents a lower alkenyl group having 1 to 6 carbon atoms which may have a group, an aryl group which may have a substituent, a heterocyclic group which may have a substituent; or R ₁₀ or R ₁₁ may together form a ring (the ring may have a substituent or may be a condensed ring which may have a substituent).

[0015]

[Chemical 13] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , Z, n
Represents the same as the above; R ₉ represents an optionally substituted lower alkyl group having 1 to 6 carbon atoms. )

Embedded image (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ ,
n represents the same as above. )

[Chemical 15] (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ and n are the same as defined above; R ₁₂ is a carboxylic acid group or a sulfonic acid group; R ₁₃ is a carbonyl group. Or represents a sulfonyl group.)

Embedded image (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ and n are the same as those described above; R ₁₃ is a carbonyl group.)

[Chemical 17] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ and n are the same as the above.)

Embedded image (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ and n represent the same as described above; A represents the general formula (VI) or (VI
II), (XI), (XV), (XVI)

[Chemical 19] Represents a group selected from the group consisting of; X represents a chlorine atom or a bromine atom. )

Embedded image (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , n, X
Represents the same as above. )

[Chemical 21] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ ,
n represents the same as above. )

[Chemical formula 22] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ and R ₇ are the same as above.) Next, the reaction conditions in each of Method A to Method Q will be shown.

(Method A)

[Table 1] (Method B) (7) → (11) → (9) → (14)

[Table 2] (C method) (8) → (16) → (17) → (9)

[Table 3] (D method) (9) → (18)

[Table 4] (E method) (19) → (21) → (22)

[Table 5] (F method) (22) → (23)

[Table 6] (G method) (22) → (24)

[Table 7] (H method) (25) → (27) → (28)

[Table 8] (I method) (29) → (30) → (31) → (32)

[Table 9] (J method) (9) → (33)

[Table 10] (K method) (34) → (35)

[Table 11] (L method) (35) → (36)

[Table 12] (M method) (36) → (37)

[Table 13] (N method) (38) → (40) → (41)

[Table 14] (O method) (42) → (43) → (44) → (45)

[Table 15] (P method) (9) → (46)

[Table 16] (Q method) (1) → (47) → (48) → (49)

[Table 17] The compound of the present invention represented by the formula (1) has 1 in its structure.
Or, since it has two asymmetric carbons, their pure stereochemical isomers and optical isomers can be obtained by applying methods known in the art. For example,
Enantiomers are separated from each other by a chromatographic method using an optical isomer separation column or an optically active acid, preferably, fractional crystallization with (R)-(-)-1,1'-binaphthyl-2,2'-diylhydrogen phosphate. Can be separated. Further, the separation of optical isomers by the above method is applied not only to the final product but also to an intermediate having a carboxyl group, in which case a general optically active base such as brucine is used. As for the cis and trans diastereomeric racemates, similarly to the above, a method known to those skilled in the art is applied to obtain the optical isomers, cis (+), cis (-), trans ( It can be further divided into +) and trans (-).

Stereoisomers and optical isomers of compounds of formula (I) are, of course, intended to be included within the scope of this invention.

[0018]

[Examples] Hereinafter, reference examples, examples, and pharmacological tests will be given.
The present invention will be described more specifically.

Incidentally, N in Reference Examples, Examples and Tables 18-34.
In MR value, the star is Hitachi R-24B (60MHz)
Is the value measured by using, and no mark is JEOL
JNM-FX200 or JEOL JNM-EX27
It is a value measured at 0.

Reference Example 1 2- (3,5-diisopropyl-4-hydroxyphenyl)
) -3- (3-Hydroxypropyl) -1,3-thia
Synthesis of Zolidin-4-one 3,5-Diisopropyl-4-hydroxybenzaldehyde (5.00 g) and 3-aminopropanol (1.82 g) were suspended in benzene (50 ml) under a nitrogen atmosphere, and then Dean-Stark was used. Attach a water separator, 1.5
Heated to reflux for hours. After allowing to cool, α-mercaptoacetic acid (2.23 g) was added to the reaction solution, and the mixture was heated under reflux for 2 hours.
After distilling off benzene and adding water (50 ml) to the residue,
It was extracted with chloroform. Then, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 99: 1) to obtain 1.97 g (24%) of the desired product as a colorless oily substance.

NMR (CDCl ₃ ) δ; 1.23 (12H, d, J = 6.6Hz), 1.0 to (60MHz) 1.8 (2H, m), 2.5 to 3.8 (7H) , M), 3.73 (2H, brs), 5.50 (2H, brs), 6.92 (2H, s) In the same manner as in Reference Example 1, 3,5-diisopropyl-4-
Instead of hydroxybenzaldehyde, the corresponding substituted benzaldehyde or the corresponding ω-aminoalkyl alcohol instead of 3-aminopropanol was used to obtain the alcohols shown in Tables 18-20.

[0022]

[Table 18]

[Table 19]

[Table 20] [Reference Example 16] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- (3-hydroxypropyl) -1,3
-Thiazolidin-4-one Synthesis After suspending 3,5-di-tert-butyl-4-hydroxybenzaldehyde (50.0 g) and β-alanine (20.0 g) in benzene (500 ml) under a nitrogen atmosphere. , Dean-Stark water separator was attached and heated to reflux for 1 hour. After allowing to cool, the reaction solution was mixed with α-mercaptoacetic acid (2
3.6 g) was added, and the mixture was heated under reflux for 24 hours. Benzene was distilled off, water (500 ml) was added to the residue, and the mixture was extracted with chloroform. Then, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 98: 2) to give colorless crystals of 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- (2-carboxy). Ethyl) -1,3-
54.6 g (67%) of thiazolidin-4-one was obtained.
Melting point 164-165 [deg.] C.

NMR (CDCl ₃ ) δ; 1.42 (18H, s), 2.2-2.5 (1H, (200MHz) m), 2.5-2.8 (1H, m), 3. 0-3. 3 (1H, m), 3.5-4.0 (3H, m), 5. 33 (1H, s), 5.64 (1H, s), 7. 09 (2H, s), 8.5 (1H, brs) then obtained 2- (3,5-di-tert-butyl-
4-Hydroxyphenyl) -3- (2-carboxyethyl) -1,3-thiazolidin-4-one (100 mg)
To a tetrahydrofuran (3 ml) solution of triphenylamine (27 mg) and ethyl chlorocarbonate (28 mg) were added dropwise at -10 ° C under a nitrogen atmosphere, and the mixture was -1
Stirred for hours. Sodium borohydride (100 mg) was added to this reaction solution, and the mixture was further stirred at room temperature for 3 hours, poured into ice-water, and extracted with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, chloroform: methanol = 98:
Purified in 2), 70 mg of the same compound as in Reference Example 15
(73%) was obtained.

Reference Example 17 2- (3,5-diisopropyl-4-hydroxyphenyl)
) -3- (3-Chloropropyl) -1,3-thiazoli
Synthesis of Zin-4-one Under a nitrogen atmosphere, 2- (3,5-diisopropyl-4-hydroxyphenyl) -3- (3-hydroxypropyl) -1,3-thiazolidine-4-obtained in Reference Example 1 was obtained. Thionyl chloride (1.04 g) was added to a dichloromethane solution (50 ml) of on (1.97 g), and the mixture was heated under reflux for 1 hour.
Then, the solvent was distilled off under reduced pressure, and saturated saline and chloroform were added to the residue. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is purified by silica gel column chromatography (developing solvent, dichloromethane) to obtain 1.25 g of the target product as pale yellow crystals.
(60%) was obtained. Melting point 105-106 [deg.] C.

NMR (CDCl ₃ ) δ; 1.23 (12H, d, J = 6.6Hz), 1.5 (60MHz) to 2.1 (2H, m), 2.6 to 3.8 (6H) , M), 3.67 (2H, brs), 5.20 (1H, s), 5.50 (1H, brs), 6.88 (2H, s) [Reference Examples 18 to 28] Reference Example 17 and. Similarly, using the corresponding alcohols, the compounds shown in Tables 21 and 22 were obtained.

[0026]

[Table 21]

[Table 22] [Reference Example 29] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- (3-bromopropyl) -1,3-thi
Synthesis of Azolidin-4-one 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3-obtained in Reference Example 15 under nitrogen atmosphere
(3-Hydroxypropyl) -1,3-thiazolidine-
4-one (2.00 g) of diethyl ether (20 m
l) Phosphorus tribromide (0.74 g) was added to the solution, and the mixture was stirred at room temperature for 6 hours. After the reaction, the reaction solution was poured into ice water (100 ml), and the target product was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform) to obtain 1.31 g (56%) of the desired product as pale yellow crystals. Melting point 130-131 ° C NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.6-2.2 (2H, (60MHz) m), 2.6-3.6 (2H, m), 3.28 (2 H, t, J = 6.5 Hz), 3.70 (2 H, br s), 5.28 (1 H, s), 5.53 (1 H, b rs), 7.05 (2 H , S) In the same manner as in Reference Example 29, bromine products shown in Table 23 were obtained using corresponding alcohol compounds.

[0027]

[Table 23] [Example 1] 2- (3,5-diisopropyl-4-hydroxyphenyl)
) -3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyi
Synthesis of 2-]-3,3-thiazolidin-4-one 2- (3,5-diisopropyl-4-hydroxyphenyl) -3- (3- obtained in Reference Example 17 under a nitrogen atmosphere.
Chloropropyl) -1,3-thiazolidin-4-one (0.50 g) and N-methyl-N- [2- (3,4-methylenedioxyphenoxy) ethyl] amine (0.30
g) in dimethylformamide (10 ml), sodium carbonate (0.29 g) and potassium iodide (0.30).
g) was added and the mixture was stirred at 80 ° C. for 24 hours. The solvent was evaporated under reduced pressure, water (20 ml) was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 97: 3) to obtain 0.26 g (36%) of the desired product as a light brown oily substance.

NMR (CDCl ₃ ) δ; 1.23 (12H, d, J = 6.6Hz), 1.4 (60MHz) -1.9 (2H, m), 2.17 (3H, s), 2. 3-3.8 (8H, m), 3.67 (2H, brs), 3.87 (2H, t, J = 5.7Hz), 5. 00 (1H, brs), 5.57 (1H, s), 5.80 (2H, s), 6.0-6.7 (3H, m), 6.90 (2H, s) [Example 2 ~ 25] In the same manner as in Example 1, the corresponding chloro form or the corresponding amine form was used to obtain the compounds shown in Tables 24 to 27.

[0029]

[Table 24]

[Table 25]

[Table 26]

[Table 27] Example 26-A 2- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
No] propyl] -1,3-thiazolidin-4-one
Under formation of nitrogen atmosphere, obtained in Reference Example 29 2- (3,5-di -tert- butyl-4-hydroxyphenyl) -3-
(3-Bromopropyl) -1,3-thiazolidine-4-
ON (89.3 mg) and N-methyl-N- [2-
Potassium carbonate (34.6 mg) was added to an acetone (5 ml) solution of (3,4-methylenedioxyphenoxy) ethyl] amine (48.8 mg), and the mixture was heated under reflux for 10 hours. After cooling, the reaction mixture was filtered to remove inorganic substances, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 97: 3) to obtain 67.4 mg (60%) of the desired product as colorless crystals. Melting point 70-71 [deg.] C.

NMR (CDCl ₃ ) δ; 1.42 (18H, s), 1.4-1.7 (2H, (200MHz) m), 2.20 (3H, s), 2.3-2. 5 (2 H, m), 2.68 (2 H, t, J = 5.9 Hz), 2.7-2.9 (1 H, m), 3.5-3.6 (1 H, m), 3 .66 and 3.80 (2H, ABq, J = 16.0Hz), 3.92 (2H, t, J = 5.9Hz), 5.32 (1H, s), 5.66 (1H, s) 5.90 (2H, s), 6.2-6.7 (3H, m), 7.09 (2H, s) [Examples 27 to 34] Corresponding in the same manner as Example 26-A. Using the bromine form or the corresponding amine form, Table 2
The compounds shown in 8 and 29 were obtained.

[0031]

[Table 28]

[Table 29] [Reference Example 33] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [3- (N-methylamino) propyi
]]-1,3-Thiazolidin-4-one hydrobromide
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3-obtained in Reference Example 29 under a synthetic nitrogen atmosphere of
(3-Bromopropyl) -1,3-thiazolidine-4-
A mixed solution of ON (1.10 g), 40% methylamine in methanol (20 ml) and acetonitrile (15 ml) was stirred at room temperature for 15 hours. After the reaction, the solvent and excess methylamine were distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 95: 5) to obtain 0.90 g (76%) of the desired product as pale orange crystals. Melting point 195-19
6 ° C NMR (CDCl ₃ ) δ; 1.42 (18H, s), 1.6-2.2 (2H, (60MHz) m), 2.67 (3H, s), 2.6-3.6. (4 H, m), 3.77 (2H, brs), 5.33 (1H, s), 5.63 (1H, brs), 7.08 (2H, s) Methyl in the same manner as in Reference Example 33. The compounds shown in Table 30 were obtained using the corresponding amine instead of amine.

In the silica column chromatography of Reference Example 35, a mixed solvent of chloroform: methanol = 95: 5 containing 1% triethylamine was used as a developing solvent.

[0033]

[Table 30] [Example 26-B] 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- (N-methylamino) propyl] obtained in Reference Example 33 under a nitrogen atmosphere. A solution of -1,3-thiazolidin-4-one hydrobromide (380 mg) and 2- (3,4-methylenedioxyphenoxy) ethyl bromide (260 mg) in acetone (10 ml) was added with potassium carbonate (300 mg). ) Was added and the mixture was heated under reflux for 10 hours. After cooling, the reaction mixture was filtered to remove inorganic substances, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 97: 3) to obtain 350 mg (64%) of the same compound as that of Example 26-A.

[Examples 35 to 37] The compounds in Table 31 were obtained by reacting the bromide compounds corresponding to the compounds in Table 30 in the same manner as in Example 26-B.

[0035]

[Table 31] Example 38 2- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -3- [3- [N-methyl-N- [2-hydr
Roxy-3- (3,4-methylenedioxyphenoxy)
Propyl] amino] propyl] -1,3-thiazolidine
Synthesis of -4-one 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- (N-methylamino) propyl] -1,3-obtained in Reference Example 33 Thiazolidine-4-
To a solution of one (0.50 g) in acetonitrile (10 ml) was added 2,3-epoxypropyl-3,4-methylenedioxyphenyl ether (0.26 g) at room temperature, and the mixture was heated under reflux for 8 hours. After allowing to cool, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 98: 2) to obtain 0.72 g (95%) of the desired product as a colorless oily substance.

NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.4 to 1.8 (2H, (270MHz) m), 2.17 (3H, s), 2.2 to 2. 6 (4 H, m), 2.7 to 3.0 (1 H, m), 3.4 to 3.7 (1 H, m), 3.67 and 3.80 (2 H, ABq, J = 16.0 Hz). ) 3.8-4.1 (4H, m), 5.33 (1H, s), 5.57 (1H, s), 5.91 (2H, s), 6.2 to 6. 8 (3H, m), 7.09 (2H, s) [Examples 39 and 40] The compounds shown in Table 32 were obtained using the corresponding epoxy compounds in the same manner as in Example 38.

[0037]

[Table 32] [Reference Example 36] 3- [N-methyl-N- [2- (3,4-methylenedio)
Xyphenoxy) ethyl] amino] propylamine
Forming N- methyl -N- [2- (3,4-methylenedioxy phenoxy) ethyl] amine (1.0 g), N- (3- bromopropyl) phthalimide (1.51 g), and potassium carbonate (0. 78 g) was suspended in acetone (20 ml) and then heated under reflux for 3 hours. After cooling, the inorganic substances in the reaction mixture were filtered off and the filtrate was concentrated. The residue is subjected to silica gel column chromatography (developing solvent, chloroform:
Purification with methanol = 10: 1) and brown oil N-
1.82 g (93%) of [3- [N'-methyl-N '-[2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] phthalimide were obtained.

NMR (CDCl ₃ ) δ; 1.5-2.2 (2H, m), 2.28 (3H, s (60 MHz)), 2.3-2.9 (4H, m), 3. 72 (2H, t, J = 7.0Hz), 3.90 (2H, t, J = 6.0Hz), 5.82 (2H, s), 6.0-6.8 (3H, m), 7.4-8.0 (4H, m) Then, the obtained N- [3- [N'-methyl-N'-
[2- (3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] phthalimide (1.82 g) was dissolved in methanol (10 ml), 40% methylamine methanol solution (10 ml) was added, and the mixture was stirred at room temperature. Stir overnight. After the reaction, the solvent and excess methylamine were distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 1: 1 solution containing 1% triethylamine) to obtain 0.74 g (62%) of the desired product as a light brown oily substance.

NMR (CDCl ₃ ) δ; 1.33 (2H, s), 1.1-2.1 (2H, m (60 MHz)), 2.27 (3H, s), 2.2-3. 0 (6H, m), 3.90 (2H, t, J = 6.0Hz), 5.77 (2H, s), 6.0-6.8 (3H, m) [Reference Example 37] 2- [N-methyl-N- [2- (3,4-methylenedio
Synthesis of xyphenoxy) ethyl] amino] ethylamine In the same manner as in Reference Example 36, N- (3-bromopropyl)
The target compound was obtained by using N- (2-bromoethyl) phthalimide instead of phthalimide.

NMR (CDCl ₃ ) δ; 2.34 (3H, s), 2.0-3.2 (8H, m (60 MHz)), 3.90 (2H, t, J = 6.0 Hz), 5. 85 (2H, s), 6.0-6.9 (3H, m) [Example 41-Method A] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
No] propyl] -5-methyl-1,3-thiazolidine-
Synthesis of 4- one In the same manner as in Reference Example 1, 3- [N-methyl-N- [2- (3,4-methylenedioxyphenoxy) ethyl] amino] propylamine was used instead of 3-aminopropanol. , 2-mercaptopropionic acid was used in place of α-mercaptoacetic acid to obtain the desired product.

NMR (CDCl ₃ ) δ; 1.42 (18H, s), 1.2-1.8 (2H, (270MHz) m), 1.58 (3 × 2 / 5H, d, J = 6) .9H z), 1.65 (3 × 3 / 5H, d, J = 6.9H z), 2.20 (3 × 3 / 5H, s), 2.23 (3 × 2 / 5H, s) 2.2-2.5 (2H, m), 2.6-2.9 (3H, m), 3.4-3.7 (1H, m), 3.8-4.1 (3H, m), 5.29 (2 / 5H, s), 5.30 (3 / 5H, s), 5.56 (3 / 5H, s), 5.57 (2 / 5H, brs), 5. 90 (2H, s), 6.2-6.8 (3H, m), 7.05 (2 x 2 / 5H, s), 7. 11 (2 × 3 / 5H, s) [Example 42] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [2- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
Synthesis of [no] ethyl] -1,3-thiazolidin-4- one In the same manner as in Reference Example 1, 2- [N-methyl-N- [2- (3,4-methylenedidiene) was used instead of 3-aminopropanol. The desired product was obtained using oxyphenoxy) ethyl] amino] ethylamine.

NMR (CDCl ₃ ) δ; 1.40 (18H, s), 2.20 (3H, s), (60MHz) 2.5-3.0 (5H, m) 3.3-4. 1 (3 H, m), 3.65 (2 H, brs), 5.23 (1 H, s), 5.73 (1 H, s), 5.82 (2 H, s), 6.0-6 .8 (3H, m), 7.00 (2H, s) [Example 43] 2- (3-tert-butyl-4-hydroxyphenyi
) -3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyi
Synthesis of l] -1,3-thiazolidin-4-one 2- (3,5-di-tert obtained in Example 26-A
-Butyl-4-hydroxyphenyl) -3- [3- [N
-Methyl-N- [2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one (0.35 g) was dissolved in acetic acid (5 ml), 47% Hydrogen bromide water (5 ml) was added, and the mixture was stirred at room temperature for 7 days. After completion of the reaction, the mixture was poured into an ice-cooled 5% sodium carbonate aqueous solution and extracted with chloroform. Then, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, chloroform: methanol = 98:
Purified in 2), 0.05 g (16 g) of the desired product as a light brown oily substance.
%) Was obtained.

NMR (CDCl ₃ ) δ; 1.37 (9H, s), 1.2-1.9 (2H, m (200MHz)), 2.26 (3H, s), 2.1-2. 5 (2H, m), 2.71 (2H, t, J = 5.7Hz), 2.6-3.0 (1H, m), 3.4-3.8 (1H, m), 3 .67 and 3.80 (2H, ABq, J = 16.0 Hz), 3.94 (2H, t, J = 5.7 Hz), 5.60 (1H, s), 5.82 (1H, s), 5 .88 (2H, s), 6.1-7. 0 (5H, m), 7.14 (1H, s) [Reference Example 38] In the same manner as in Reference Example 1, using 2-mercaptopropionic acid instead of α-mercaptoacetic acid,
2- (3,5-Di-tert-butyl-4-hydroxyphenyl) -3- (3-hydroxypropyl) -5-methyl-1,3-thiazolidin-4-one was obtained.

NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.1-1.7 (2H, (200MHz) m), 1.60 (3 × 1 / 4H, d, J = 6) .9H z), 1.67 (3 × 3 / 4H, d, J = 6.9H z), 3.0-3.3 (1H, m), 3.3-3. 7 (4H, m), 3.9-4.2 (1H, m), 5. 34 (1 / 4H, s), 5.36 (3 / 4H, s), 5.49 (3 / 4H, s), 5.52 (1 / 4H, s), 7.07 (2 × 1) / 4H, s), 7.12 (2 × 3 / 4H, s) [Reference Examples 39 and 40] In the same manner as in Reference Example 38, the corresponding α-mercaptocarboxylic acid was used in place of 2-mercaptopropionic acid. By using, the compounds shown in Table 33 were obtained.

[0045]

[Table 33] [Reference Example 41] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- (3-hydroxypropyl) -5-ca
Ruboxymethyl-1,3-thiazolidin-4-one
Under formation of nitrogen atmosphere, 3,5-di -tert- butyl-4-hydroxybenzaldehyde (23.4 g) and 3-aminopropanol (9.01 g) benzene (200ml)
After suspending in, a Dean-Stark water separator was attached and the mixture was heated under reflux for 2 hours. After allowing to cool, thiomalic acid (19.52 g) was added to the reaction solution, and the mixture was heated under reflux for 3 hours.
Benzene was distilled off, and the obtained white solid was recrystallized from water-containing methanol to obtain 10.5 g (25
%) Was obtained. Melting point 227 to 228 ° C NMR (d ₆ -DMSO) δ; 1.37 (18H, s), 1.2 to 1.8 (2H (200MHz), m), 2.3 to 2.8 (1H, m). ), 3.0 to 3.6 (5H, m), 4.0 to 4.2 (1H, m), 4.37 (1H, brs), 5.73 (1H, s), 7.10 (). 2H, s), 7.13 (1H, s) [Reference Example 42] In the same manner as in Reference Example 17, 2- (3,5)
-Di-tert-butyl-4-hydroxyphenyl)-
3- (3-hydroxypropyl) -5-methyl-1,3
-Thiazolidin-4-one to 2- (3,5-di-te
rt-Butyl-4-hydroxyphenyl) -3- (3-
Chloropropyl) -5-methyl-1,3-thiazolidin-4-one was obtained.

NMR (CDCl ₃ ) δ; 1.42 (18H, s), 1.1-2.2 (5H, m (60MHz)), 2.7-4.2 (5H, m), 5. 23 (1H, s), 5.43 (1H, brs), 6.97 (2H, brs) [Reference Examples 43 and 44] In the same manner as in Reference Example 29, from the compounds obtained in Reference Examples 39 and 40 The compounds shown in Table 34 were obtained.

[0047]

[Table 34] [Reference Example 45] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- (3-bromopropyl) -5-etoki
Cycarbonylmethyl-1,3-thiazolidin-4-one
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3-obtained in Reference Example 41 under a synthetic nitrogen atmosphere of
(3-Hydroxypropyl) -5-carboxymethyl-
Phosphorus tribromide (3.4) was added to a suspension of 1,3-thiazolidin-4-one (2.45 g) in diethyl ether (30 ml).
5 g) was added and the mixture was stirred at room temperature for 3 hours. Then, ethanol (30 ml) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature.
After the reaction, the reaction solution was poured into ice water (100 ml), and the target product was extracted with ethyl acetate. Wash the organic layer with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane = 20: 80) and recrystallized from chloroform / n-hexane to obtain 1.50 g (51%) of the desired product as colorless crystals. It was Melting point 154-155 [deg.] C.

NMR (CDCl ₃ ) δ; 1.26 (3H, t, J = 7.1Hz), 1.43 ((200MHz) 18H, s), 1.6 to 2.2 (2H, m), 2.6-3.1 (2H, m), 3.2-3.6 (4H, m), 4.17 (2H, q, J = 7.1Hz), 4.1-4.4 (1H) , M), 5.33 (1H, s), 5.53 (1H, s), 7.14 (2H, s) [Reference Example 46] In the same manner as in Reference Example 45, isopropyl was used instead of ethanol. 2- (3,5-Di-tert-butyl-4-hydroxyphenyl) -3- (3-bromopropyl) -5-isopropoxycarbonylmethyl-1,3-thiazolidine-4 by using alcohol
-One was obtained as colorless crystals. Melting point 170-171 ° C NMR (CDCl ₃ ) δ; 1.24 (6H, d, J = 5.7Hz), 1.43 ((200MHz) 18H, s), 1.6-2.2 (2H, m). ) 2.6 to 3.7 (6H, m), 4.1 to 4.4 (1H, m), 4.8 to 5.2 (1H, m), 5.33 (1H, s), 5.53 (1H, s), 7.14 (2H, s) [Example 41-B Method] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
No] propyl] -5-methyl-1,3-thiazolidine-
Synthesis of 4- one In the same manner as in Example 1,
(3,5-Di-tert-butyl-4-hydroxyphenyl) -3- (3-chloropropyl) -5-methyl-
The desired product was obtained using 1,3-thiazolidin-4-one. The instrumental analysis data of the obtained compound is shown in Example 41-
It was the same as that of the compound obtained by Method A.

Examples 44 and 45 2- (3,5-di-tert-butyl-4) was prepared in the same manner as in Example 26-A.
-Hydroxyphenyl) -3- (3-bromopropyl)
By substituting the compounds obtained in Reference Examples 43 and 44 for the -1,3-thiazolidin-4-one.
The compound shown in was obtained.

[0050]

[Table 35] Example 46 2- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
[] Propyl] -5-ethoxycarbonylmethyl-1,
Synthesis of 3-thiazolidin-4-one 2- (3,5-di-t was prepared in the same manner as in Example 26-A.
ert-Butyl-4-hydroxyphenyl) -3- (3
-Bromopropyl) -1,3-thiazolidin-4-one was replaced by 2- (3,5-di-, obtained in Reference Example 45.
tert-butyl-4-hydroxyphenyl) -3-
By using (3-bromopropyl) -5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one, the target product was obtained as colorless crystals. Melting point 88 to 89 ° C NMR (CDCl ₃ ) δ; 1.26 (3H, t, J = 7.1Hz), 1.41 ((200MHz) 18H, s), 1.4 to 1.9 (2H, m). ), 2.19 (3H, s), 2.3 to 2.5 (2H, m), 2. 67 (2H, t, J = 5.7 Hz), 2.7 to 3.0 (2H, m), 3.2 to 3.7 (2H, m), 3.9 1 (2H, t, J = 5.7 Hz), 4.17 (2H, q, J = 7.1 Hz), 4.1 to 4.4 (1H, m), 5.29 (1H, s), 5.58 (1H, s). 5 ,. 89 (2H, s), 6.1 to 6.8 (3H, m), 7.09 (2H, s) [Example 47] In the same manner as in Example 46, 2- (3,5-di-). tert
-Butyl-4-hydroxyphenyl) -3- (3-bromopropyl) -5-ethoxycarbonylmethyl-1,3
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3-instead of thiazolidin-4-one
Using (3-bromopropyl) -5-isopropoxycarbonylmethyl-1,3-thiazolidin-4-one,
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -5-isopropoxycarbonylmethyl-1,3-thiazolidin-4-one was obtained as colorless crystals. Melting point 81 to 82 ° C NMR (CDCl ₃ ) δ; 1.23 (6H, d, J = 5.7Hz), 1.41 ((200MHz) 18H, s), 1.4 to 2.0 (2H, m). ), 2.20 (3H, s), 2.2-2.5 (2H, m), 2. 5 to 3.0 (4H, m), 3.1 to 3.7 (2H, m), 3.93 (2H, t, J = 5.7Hz), 4.1 to 4.4 (1H, m). ), 4.8 to 5.2 (1H, m), 5.30 (1H, s), 5.57 (1H, s), 5. 89 (2H, s), 6.1-6.8 (3H, m), 7.10 (2H, s) [Example 48] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
No] propyl] -5-carboxymethyl-1,3-thia
Synthesis of zolidin-4-one 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3 , 4-Methylenedioxyphenoxy) ethyl] amino] propyl] -5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one (100
mg) was dissolved in ethanol (5 ml), a 20% aqueous ethanol solution of sodium hydroxide (200 mg) was added, and the mixture was stirred overnight at room temperature. After the reaction, 1N-
It was neutralized with hydrochloric acid and concentrated under reduced pressure. Then water (5
0 ml) and chloroform (50 ml) mixed solution,
After stirring, the organic layer was separated. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was triturated with n-hexane to obtain 80 mg (84%) of the desired product as a pale yellow solid.

NMR (CDCl ₃ ) δ; 1.41 (18 / 2H, s), 1.42 (18 / 2H (200MHz), s), 1.4 to 2.4 (2H, m), 2. 85 (3 / 2H, s), 2.90 (3 / 2H, s), 2.7 to 3.8 (8H, m), 4.1 to 4.7 (3H, m), 5.2. 5.4 (1H, m), 5.66 (1 / 2H, brs), 5.81 (1 / 2H, brs), 5.89 (2H, s), 6.2-6.7 (3H, m), 7.13 (2 / 2H, s), 7.14 (2 / 2H, s) [Example 49] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
[No] propyl] -5- (2-hydroxyethyl) -1,
Synthesis of 3-thiazolidin-4-one 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one (80 m
Lithium aluminum hydride (20 mg) was added to a solution of g) in dry tetrahydrofuran (5 ml) at -78 ° C.
And stirred at 0 ° C. for 3 hours. Next, hydrous tetrahydrofuran (5 ml) was added to the reaction solution, the mixture was stirred at the same temperature for 1 hour, neutralized with 1N-hydrochloric acid, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (developing solvent,
Purification with chloroform: methanol = 95: 5) yielded 68 mg (86%) of the desired product as a colorless oil.

NMR (CDCl ₃ ) δ; 1.41 (18H, s), 1.3 to 1.8 (4H, m (200MHz)), 2.19 (3H, s), 2.2 to 2. 5 (3H, m), 2.67 (2H, t, J = 5.7Hz), 2. 7-2.9 (1H, m), 3.4-3.6 (1H, m), 3.8-4.0 (2H, m), 3.91 (2H, t, J = 5.7Hz) ), 4.04 (1H, t, J = 5.7 Hz), 5.33 (1H, s), 5.60 (1H, s), 5.90 (2H, s), 6.2 to 6. 7 (3 H, m), 7.12 (2 H, s) [Reference Example 47] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- (3-chloropropyl) -5- (1-
Pyrrolidine carbonylmethyl) -1,3-thiazolidine
Synthesis of -4-one 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- (3-hydroxypropyl) -5-carboxymethyl-1,3-obtained in Reference Example 41 Thiazolidin-4-one (0.61 g) in dichloromethane (2
Thionyl chloride (0.38 g) and a catalytic amount of dimethylformamide were added to the suspension (0 ml) and the mixture was heated under reflux for 2 hours. After standing to cool, this reaction solution was mixed with pyrrolidine (1.02 g).
Was added dropwise to a dichloromethane (20 ml) solution under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. After the reaction, the mixture was poured into ice water and extracted with chloroform. Next, the organic layer was washed with 1N-hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, chloroform: methanol = 9).
7: 3) and then recrystallized from chloroform / n-hexane to give 0.65 of the desired product as colorless crystals.
g (92%) were obtained. Melting point 193-194 ° C NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.4-2.2 (6H, m (200MHz)), 2.5-3.1 (2H, m), 3.2-3.7 (8H, m), 4.2-4.5 (1H, m), 5.29 (1H, s), 5.53 (1H, s), 7.08 (2H) , S) [Reference Examples 48 to 50] In the same manner as in Reference Example 47, the compounds shown in Table 36 were obtained using the corresponding amine instead of pyrrolidine.

[0053]

[Table 36] Example 50 2- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
[] Propyl] -5- (1-pyrrolidinecarbonylmethyl
Le) -1, 3-thiazolidin-4-one Similar procedure as Synthesis Example 1 of 2- (3,5-diisopropyl-4-hydroxyphenyl) -3- (3-chloropropyl) -1,3 -Instead of thiazolidin-4-one,
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- (3-chloropropyl) -5- (1-pyrrolidinecarbonylmethyl) -obtained in Reference Example 47
Using 1,3-thiazolidin-4-one, the target product was obtained as a light brown oil.

NMR (CDCl ₃ ) δ; 1.41 (18H, s), 1.4 to 2.1 (6H, m (200MHz)), 2.20 (3H, s), 2.2 to 2. 5 (2H, m), 2.5-3.1 (4H, m), 3.2-3.8 (6H, m), 3.93 (2H, t, J = 5.7Hz), 4. 2-4.5 (1H, m), 5.29 (1H, s), 5.57 (1H, s), 5.88 (2H, s), 6.1 to 6.8 (3H, m) , 6.9-7.2 (2 H, m) [Examples 51 to 53] In the same manner as in Example 50, 2-
(3,5-Di-tert-butyl-4-hydroxyphenyl) -3- (3-chloropropyl) -5- (1-pyrrolidinecarbonylmethyl) -1,3-thiazolidine-4
The compounds shown in Table 37 were obtained using the compounds obtained in Reference Examples 48 to 50 instead of -one.

[0055]

[Table 37] [Reference Example 51] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- (3-bromopropyl) -5-methoki
Synthesis of Ci-1,3-thiazolidin-4-one 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- (3-bromopropyl) -1, obtained in Reference Example 29 3-thiazolidin-4-one (1.0
Sulfuryl chloride (0.36 g) was added dropwise to a solution of g) in dichloromethane (15 ml) under ice-water cooling, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, methanol (10 ml) was added to the residue, and the mixture was stirred at room temperature overnight. Then, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, chloroform) to obtain 0.59 g (48%) of the desired product as a light brown oily substance.

NMR (CDCl ₃ ) δ; 1.42 (18H, s), 1.5 to 2.3 (2H, m (200MHz)), 2.8 to 3.6 (4H, m), 3. 46 (3 × 2 / 5H, s), 3.52 (3 × 3 / 5H, s), 5. 2 to 6.1 (3H, m), 7.08 (2 x 2 / 5H, s), 7.12 (2 x 3 / 5H, s) [Reference Examples 52 to 53] Method similar to Reference Example 51 Then, the compound shown in Table 38 was obtained by using ethylene glycol instead of methanol.

[0057]

[Table 38] Example 54 2- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
No] propyl] -5-methoxy-1,3-thiazolidine
Synthesis of -4-one In a manner similar to Example 26-A, 2- (3,5-di-t
ert-Butyl-4-hydroxyphenyl) -3- (3
-Bromopropyl) -1,3-thiazolidin-4-one instead of 2- (3,5-di-obtained in Reference Example 51.
tert-butyl-4-hydroxyphenyl) -3-
(3-Bromopropyl) -5-methoxy-1,3-thiazolidin-4-one was used to obtain a light brown oily product.

NMR (CDCl ₃ ) δ; 1.41 (18H, s), 1.4 to 1.9 (2H, m (270MHz)), 2.18 (3 × 2 / 5H, s), 2. 22 (3 × 3 / 5H, s), 2.2-3.1 (5H, m), 3. 46 (3 x 2 / 5H, s), 3.51 (3 x 3 / 5H, s), 3.5 to 3.7 (1H, m), 3.8 to 4. 1 (2H, m), 5.2-5.8 (3H, m), 5. 90 (2H, s), 6.1 to 6.8 (3H, m), 7. 21 (2 x 2/5 H, s), 7.26 (2 x 3/5 H, s) [Examples 55 to 56] 2-
(3,5-Di-tert-butyl-4-hydroxyphenyl) -3- (3-bromopropyl) -5-methoxy-
Reference example 5 instead of 1,3-thiazolidin-4-one
The compounds shown in Table 39 were obtained using the compounds obtained in 2,53.

[0059]

[Table 39] Example 57 2- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
No] propyl] -1,3-thiazolidine-4-thione
2- (3,5-di-tert obtained in Synthesis Example 26-A
-Butyl-4-hydroxyphenyl) -3- [3- [N
-Methyl-N- [2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one (217 mg) and Lawesson's reagent (194 mg) were suspended in THF (5 ml). After clouding, the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, water (20 ml) was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 99: 1) to obtain 181 mg (81%) of the desired product as a pale yellow oily substance.

NMR (CDCl ₃ ) δ: 1.41 (18H, s), 1.3-1.8 (2H, m (200MHz)), 2.20 (3H, s), 2.3-2. 5 (2H, m), 2.70 (2H, t, J = 5.7Hz), 3. 1-3.3 (1H, m), 3.93 (2H, t, J = 5.7Hz), 3.9-4.1 (1H, m), 4.26and4.40 (2H, ABq, J = 16.0 Hz), 5.34 (1H, s), 6.18 (2H, s), 6.04 (1H, s), 6.2-7.0 (3H, m), 7.07. (2H, s) [Example 58] N- [3- [N-methyl-N- [2- (3,4-methyle
Ndioxyphenoxy) ethyl] amino] propyl]-
3,5-di-tert-butyl-4-hydroxybenz
Synthesis of amide To a suspension of 3,5-di-tert-butyl-4-hydroxybenzoic acid (1.00 g) in tetrahydrofuran (17 ml) was added oxalyl chloride (0.76 g) and a catalytic amount of dimethylformamide at 0 ° C. Then, the mixture was stirred at room temperature for 1 hour. The solvent and excess oxalyl chloride were distilled off under reduced pressure, tetrahydrofuran (8 ml) was added to the residue, and this tetrahydrofuran solution was mixed with 3- [N-methyl-N- [2- A solution of (3,4-methylenedioxyphenoxy) ethyl] amino] propylamine (1.01 g) and triethylamine (0.41 g) in tetrahydrofuran (13 ml) was added dropwise at 0 ° C.
After stirring at room temperature for 6 hours, the mixture was poured into cold water and the desired product was extracted with chloroform. Then, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 97: 3) to obtain 1.35 g (70%) of the desired product as a light brown oily substance.

NMR (CDCl ₃ ) δ; 1.34 (18 × 1 / 3H, s), 1.43 (18 × (270MHz) 2 / 3H, s), 1.7 to 1.9 (2H, m) ), 2. 41 (3H, s), 2.6 to 2.7 (2H, m), 2. 8-2.9 (2H, m), 3.5-3.6 (2H, m), 3.9-4.1 (2H, m), 5.48 (1H, s), 5.86 ( 2 × 2 / 3H, s), 5.88 (2 × 1 / 3H, s), 6.1-6.7 (3H, m), 7.64 (2 × 2 / 3H, s), 7. 79 (2 × 1 / 3H, s), 7.8-8.0 (1H, brs) [Example 59] 3,5-di-tert-butyl-4-hydroxybenzoic acid and oxalyl chloride instead of Using 3,5-di-tert-butyl-4-hydroxybenzenesulfonic acid and thionyl chloride, 3,5-
After synthesizing di-tert-butyl-4-hydroxybenzenesulfonyl chloride, the same operation as in Example 58 was carried out, and N- [3- [N-methyl-
N- [2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -3,5-di-tert-butyl-4-hydroxybenzenesulfonamide was obtained.

NMR (CDCl₃ ) Δ; 1.43 (18H, s), 1.3-1.8 (2H, m (200MHz)), 2.25 (3H, s), 2.51 (2H, t, J = 6.3Hz). ), 2.72 (2H, t, J = 6.3Hz), 3.07 (2H, t, J = 6.3Hz), 3. 97 (2H, t, J = 6.3Hz), 5.66 (1H, s), 5.90 (2H, s), 6.2-6.7 (3H, m), 7.67 (2H) , S) [Example 60]N- [3- [N-methyl-N- [2- (3,4-methyle
Ndioxyphenoxy) ethyl] amino] propyl]-
3,5-di-tert-butyl-4-hydroxybenz
Synthesis of thioamide In a manner similar to Example 57, 2- (3,5-di-ter
t-butyl-4-hydroxyphenyl) -3- [3-
[N-methyl-N- [2- (3,4-methylenedioxy
Phenoxy) ethyl] amino] propyl] -1,3-thi
Instead of azolidin-4-one obtained in Example 58
N- [3- [N-methyl-N- [2- (3,4-methyl
Dioxyphenoxy) ethyl] amino] propyl]
-3,5-di-tert-butyl-4-hydroxyben
Using zuamide, the target product as pale yellow crystals was obtained. Melting point 1
14-115 ° C NMR (CDCl₃ ) Δ; 1.42 (18H, s), 1.6 to 2.1 (2H, m (200MHz)), 2.21 (3H, s), 2.5 to 2.9 (4H, m), 3.80 (2H, t, J = 5.7 Hz), 3. 8-4.1 (2H, m), 5.44 (1H, s), 5. 82 (2H, s), 5.8 to 6.7 (3H, m), 7.5 to 7.8 (3H, m) [Example 61]N-cyano-N '-[3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
No] propyl] -3,5-di-tert-butyl-4-
Synthesis of hydroxybenzamidine N- [3- [N-methyl-N-obtained in Example 60
[2- (3,4-methylenedioxyphenoxy) ethyl
Lu] amino] propyl] -3,5-di-tert-butyl
Drying of 4-hydroxybenzthioamide (1.0 g)
In a dry tetrahydrofuran solution, at 0 ° C. under a nitrogen atmosphere.
Sodium hydride (0.16g) was added to the same temperature
After stirring for 1 hour at room temperature, add ethyl iodide (0.31 g).
The mixture was further stirred at room temperature for 2 hours. Then, the reaction solution is again
After cooling to 0 ° C. and adding cyanamide (0.84 g),
Stir for 15 hours at room temperature. After the reaction, pour in ice-water and aim
The product was extracted with chloroform. Wash the organic layer with saturated saline.
After cleaning and drying over anhydrous sodium sulfate, the solvent is removed under reduced pressure.
Was distilled off. Silica gel column chromatography of the residue
-(Developing solvent, chloroform: methanol = 99: 1)
The target product as pale yellow crystals 0.70 g (69%)
Got Melting point 129-130 ° C NMR (CDCl₃ ) Δ; 1.45 (18H, s), 1.6 to 2.1 (2H, m (200MHz)), 2.20 (3H, s), 2.6 to 3.0 (4H, m), 3.6-3.8 (2H, m), 3.83 (2H, t, J = 5.7Hz), 5.56 (1H, s), 5. 84 (2H, s), 5.8 to 6.8 (3H, m), 7.48 (2H, s), 8.44 (1H, brs) [Reference Example 54]3- (3-bromopropyl) -5- (3,5-di-te
rt-Butyl-4-hydroxyphenyl) -1,3,4
-Synthesis of oxadiazol-2 (3H) -one  5- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -1,3,4-oxadiazole-2 (3
H) -one (0.50 g) of dimethylformamide (8
ml) solution, sodium carbonate (0.36 g) and 1,3
-Add dibromopropane (1.74g) at room temperature for 5 hours
Stirred. After the reaction, the mixture was poured into ice-water and the desired product was extracted with ethyl acetate.
And then the organic layer is dried over anhydrous sodium sulfate.
After that, the solvent was distilled off under reduced pressure. The residue is washed with silica gel.
Rum chromatography (developing solvent, chloroform)
Purify and recrystallize from chloroform / n-hexane
As a result, 0.45 g (6
3%) was obtained. Melting point 130-131 ° C NMR (CDCl₃ ) Δ; 1.46 (18H, s), 2.1 to 2.6 (2H, m (200MHz)), 3.46 (2H, t, J = 6.6Hz), 3.93 (2H,). t, J = 6.6 Hz), 5.60 (1H, s), 7.63 (2H, s) [Reference Examples 55 to 58] In the same manner as in Reference Example 54, 5-
(3,5-di-tert-butyl-4-hydroxyphene
Nil) -1,3,4-oxadiazole-2 (3H)-
Using the corresponding 5-membered heterocycle in place of the on,
The compound shown was obtained.

[0063]

[Table 40]Example 625- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
[] Propyl] -1,3,4-oxadiazole-2
Synthesis of (3H) -one  In a manner similar to Example 26-A, 2- (3,5-di-t
ert-Butyl-4-hydroxyphenyl) -3- (3
-Bromopropyl) -1,3-thiazolidin-4-one
Instead of 3- (3-bromopropylene) obtained in Reference Example 54
Ropil) -5- (3,5-di-tert-butyl-4-
Hydroxyphenyl) -1,3,4-oxadiazole
-2 (3H) -one to give the desired product as a colorless oil
Was.

NMR (CDCl ₃ ) δ; 1.45 (18H, s), 1.8 to 2.2 (2H, m (270MHz)), 2.35 (3H, s), 2.4 to 3. 0 (4H, m), 3.7 to 4.2 (4H, m), 5.60 (1H, s), 5.88 (2H, s), 6.1 to 6.8 (3H, m). ), 7.65 (2H, s) [Examples 63 to 66] In the same manner as in Example 62, 3-
(3-Bromopropyl) -5- (3,5-di-tert)
The compounds shown in Table 41 were obtained by using the compounds shown in Table 40 instead of -butyl-4-hydroxyphenyl) -1,3,4-oxadiazol-2 (3H) -one.

[0065]

[Table 41] [Reference Example 59] 5- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -1- (3-hydroxypropyl) imidazo
Synthesis of 3-hydroxy-N- (3,5-di-tert-butyl-4-hydroxybenzylidene) propylamine (1.
Tosylmethyl isocyanide (1.68g) and potassium carbonate (1.43) in a solution of 50g) in methanol (50ml).
g) was added and the mixture was stirred at room temperature for 16 hours. After the reaction, the mixture was poured into ice-water and extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from a chloroform / diethyl ether system to obtain 1.41 g (82%) of the target product as pale yellow crystals.
Melting point 166 to 167 ° C NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.5 to 2.3 (3H, m (60MHz)), 3.53 (2H, t, J = 6.6Hz). ), 4.08 (2H, t, J = 6.6Hz), 5.30 (1H, brs), 6.92 (1H, brs), 7.10 (2H, s), 7.50 (). 1H, s) [Reference Example 60] 5- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -1- (3-chloropropyl) imidazole
Synthesis of 5- (3,5-di-tert-butyl-4-hydroxyphenyl) -1- (3-hydroxypropyl) imidazole (1.20 g) obtained in Reference Example 59 was added to a dichloromethane (30 ml) solution, Thionyl chloride (0.6
5 g) and a catalytic amount of dimethylformamide were added, and the mixture was heated under reflux for 2 hours. After allowing to cool, the reaction solution was cooled with ice-water 5%
It was poured into an aqueous solution of sodium carbonate and the desired product was extracted with dichloromethane. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from a dichloromethane / diethyl ether system to obtain 1.09 g (86%) of the target product as pale yellow crystals. Obtained. Melting point 178-1
79 ° C NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.6 to 2.8 (2H, m (60MHz)), 3.35 (2H, t, J = 6.6Hz), 4 .15 (2H, t, J = 6.6Hz), 5.45 (1H, brs), 6.90 (1H, s), 7.05 (2H, s), 7.43 (1H, s) Example 67 5- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -1- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
Synthesis of [no] propyl] imidazole In the same manner as in Example 1, 2- (3,5-di-isopropyl-4-hydroxyphenyl) -3- (3-chloropropyl) -1,3-thiazolidine-4- Instead of on, the 5- (3,5-di-tert obtained in Reference Example 60 was used.
-Butyl-4-hydroxyphenyl) -1- (3-chloropropyl) imidazole was used to obtain the target product as a colorless oil.

NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.5 to 2.0 (2H, m (200MHz)), 2.16 (3H, s), 2.32 (2H, s). 2. t (J = 6.6 Hz), 2.64 (2H, t, J = 5.7 Hz), 3.88 (2H, t, J = 5.7 Hz), 3. 98 (2H, t, J = 6.6Hz), 5.35 (1H, brs), 5.87 (2H, s), 6.1 to 6.8 (3H, m), 6.96 (1H, s), 7.12 (2 H, s), 7.52 (1 H, s) [Example 68] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
[] Propyl] -1,3-thiazolidin-4-one-1
-Synthesis of oxide 2- (3,5 obtained in Example 26-A or 26-B
-Di-tert-butyl-4-hydroxyphenyl)-
3- [3- [N-methyl-N- [2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl]-
To a solution of 1,3-thiazolidin-4-one (0.30 g) in acetic acid (5 ml), 35% hydrogen peroxide solution (0.20 g) was added.
Was added, and the mixture was stirred at room temperature overnight. After the reaction, 5 with ethyl acetate
% Aqueous solution of sodium carbonate, and the mixture was stirred and the organic layer was separated. Next, the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 98: 2) to obtain the objective colorless oil. 0.12 g (39%) of the product was obtained.

MS (m / z): 558 (M ⁺ ) NMR (CDCl ₃ ) δ; 1.41 (18H, s), 1.4 to 2.0 (2H, m (200MHz)), 2.28 (3H, s), 2.3 to 2.7 (2H, m), 2.72 (2H, t, J = 5.7Hz), 2. 9-3.2 (1H, m), 3.37 and 3.69 (2H, ABq, J = 16Hz), 3.8-4.2 (3H, m), 5.40 (1H, s), 5 .61 (1H, s), 5.87 (2H, s), 6.1 to 6.8 (3H m), 6.94 (2H, s) [Reference Example 61] 2- (3,5-di) -Tert-butyl-4-hydroxy
Synthesis of Phenyl) -1,3-thiazolidine Hydrochloride After dissolving 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5.0 g) in a mixed solvent of methanol (100 ml) and tetrahydrofuran (100 ml), A solution of 2-aminoethanethiol (1.73 g) in methanol (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was cooled with ice water (20
After adding 0 ml), the target substance was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and methanol-hydrochloric acid (5 ml) was added to the residue. Then, by adding diethyl ether and triturating, 5.81 g (82
%) Was obtained.

NMR (CDCl ₃ ) δ; 1.43 (18H, s), 2.9 to 3.2 (2H, m (200MHz)), 3.6 to 3.8 (1H, m), 3. 8-4.0 (1H, m), 5.20 (1H, s), 5.46 (1H, s), 7.2-7.4 (2H, m) [Reference Example 62] 2- (3) , 5-di-tert-butyl-4-hydroxy
Phenyl) -3-acryloyl-1,3-thiazolidine
Of 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,3-thiazolidine hydrochloride (1.65 g) obtained in Reference Example 61 in tetrahydrofuran (20
ml) suspension, triethylamine (1.52 g) was added, and then acrylic acid chloride (0.63 g) was added at 0 ° C.
g) was added, and the mixture was stirred at the same temperature for 3 hours. After the reaction, the mixture was poured into ice-water and the desired product was extracted with chloroform. 1N organic layer
-Washed with hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 98: 2) to obtain 0.93 g of the desired product as colorless crystals.
(54%) was obtained. Melting point 147 to 149 ° C NMR (CDCl ₃ ) δ; 1.40 (18H, s), 3.0 to 3.2 (2H, m (200MHz)), 3.8 to 4.0 (1H, m), 4.2-4.5 (1H, m), 5.20 (1H, brs), 5.5-5. 8 (1H, m), 5.9 to 6.6 (3H, m), 6. 98 (2H, brs) [Example 69] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] ami
Synthesis of [no] propionyl] -1,3-thiazolidine 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3-acryloyl-obtained in Reference Example 62
N-Methyl-2- (3,4-methylenedioxyphenoxy) ethylamine (0.20 g) was added to a chloroform (5 ml) solution of 1,3-thiazolidine (0.35 g), and the mixture was heated under reflux for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 98: 2) to obtain 0.41 g (76%) of a colorless oily target product. It was

NMR (CDCl ₃ ) δ; 1.41 (18H, s), 2.14 (3H, s), 2 (200MHz). 2-2.7 (4H, m), 2.7-2.9 (2H, m), 2.9-3.2 (2H, m), 3.8-4.1 (3H, m), 4.2-4.4 (1H, m), 5.1-5.3 (1H, m), 5.89 (2H, s), 6. 02 (1H, brs), 6.2-7.1 (5H, m) [Example 70] (+)-2- (3,5-di-tert-butyl-4-hi)
Droxyphenyl) -3- [3- [N-methyl-N-
[2- (3,4-methylenedioxyphenoxy) ethyl
Lu] amino] propyl] -1,3-thiazolidine-4-
Preparation Example of on-26-A or 26-B of the compound obtained in 400
mg as an optical isomer separation column (ChiralcelO
D2 cmφ × 25 cm), mobile phase (n-hexane: isopropanol = 80: 20), flow rate 16 ml /
min. Under the condition of an observation wavelength of 280 nm, the product was subjected to high performance liquid column chromatography in several tens of times to obtain 180 mg of the desired product. The optical rotation of the hydrochloride is shown below.

[Α] _D = + 36.14 (EtOH, C = 0.332) [Example 71] (-)-2- (3,5-di-tert-butyl-4-hi)
Droxyphenyl) -3- [3- [N-methyl-N-
[2- (3,4-methylenedioxyphenoxy) ethyl
Lu] amino] propyl] -1,3-thiazolidine-4-
Preparation Example of on-26-A or 26-B of the compound obtained in 400
mg was subjected to high performance liquid column chromatography under the same conditions as in Example 70 in several tens of times to give 17
0 mg was obtained. The optical rotation of the hydrochloride is shown below.

[Α] _D = −36.72 (EtOH, C = 0.610) [Example 72] 2,5-trans-2- (3,5-di-tert-butyl)
L-4-hydroxyphenyl) -3- [3- [N-methyl
Le-N- [2- (3,4-methylenedioxyphenoxy
Ci) Ethyl] amino] propyl] -5-methyl-1,3
-Preparation of thiazolidin-4-one Compound 500 obtained in Example 41-A or 41-B
mg to a silica gel column (YMC-PackSIL
SH-043-5,2 cmφ × 25 cm), mobile phase (chloroform: isopropanol = 97: 3), flow rate 12 ml / min. Under a condition of an observation wavelength of 280 nm, the product was subjected to high performance liquid column chromatography in several tens of times to obtain 150 mg of the desired product. Stereochemistry is described by M. R. J
Ohson et al. (J. Org. Chem., 19
83, 48, 494) ¹ H-NMR data.

NMR (CDCl ₃ ) δ; 1.41 (18 H, s), 1.5-1.9 (2 H, m (270 MHz)), 1.58 (3 H, d, J = 6.9 Hz), 2.2 3 (3H, s), 2.3-2.5 (2H, m), 2. 69 (2H, t, J = 5.6 Hz), 2.7-2.9 (1H, m), 3.5-3.7 (1H, m), 3.94 (2H, t, J = 5.6 Hz), 4.02 (1H, dq, J = 1.7, 6.9 Hz), 5.28 (1H, s), 5.57 (1H, d, J = 1.7 Hz), 5. 90 (2H, s), 6.2-6.8 (3H, m), 7. 05 (2H, s) [Example 73] 2,5-cis-2- (3,5-di-tert-butyl-
4-hydroxyphenyl) -3- [3- [N-methyl-
N- [2- (3,4-methylenedioxyphenoxy) e
Cyl] amino] propyl] -5-methyl-1,3-thia
Preparation of Zolidin-4-one Compound 500 obtained in Example 41-A or 41-B
mg was subjected to high performance liquid column chromatography under the same conditions as in Example 72 in several tens of batches to give 14
0 mg was obtained. Stereochemistry is described by M. R. See Johnson et al. (J. Org. Chem., 1983, 48, 4).
It is estimated from the ¹ H-NMR data of 94).

NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.2-2.0 (2H, m (270MHz)), 1.65 (3H, d, J = 6.9Hz), 2.20 (3H, m), 2.2-2.5 (2H, m), 2. 67 (2H, t, J = 5.6Hz), 2.7-3.0 (1H, m), 3.4-3.8 (1H, m), 3.92 (2H, t, J = 5.6 Hz), 4.02 (1H, q, J = 6.9 Hz), 5.30 (1H, s), 5. 55 (1H, s), 5.91 (2H, s), 6.2-6.8 (3H, m), 7.12 (2H, s) [Example 74] (+)-2,5- Cis-2- [3,5-di-tert-
Butyl-4-hydroxyphenyl) -3- [3- [N-
Methyl-N- [2- (3,4-methylenedioxypheno
Xy) ethyl] amino] propyl] -5-methyl-1,
Synthesis of 3-thiazolidin-4-one The compound obtained in Example 73 was subjected to high performance liquid column chromatography under the same conditions as in Example 70 in several tens of times to obtain the desired product. The optical rotation is shown below.

[Α] _D = + 27.59 (CHCl ₃ , C
= 1,000) [Example 75] (-)-2,5-cis-2- [3,5-di-tert-
Butyl-4-hydroxyphenyl) -3- [3- [N-
Methyl-N- [2- (3,4-methylenedioxypheno
Xy) ethyl] amino] propyl] -5-methyl-1,
Synthesis of 3-thiazolidin-4-one The compound obtained in Example 73 was subjected to high performance liquid column chromatography under the same conditions as in Example 70 in several tens of times to obtain the desired product. The optical rotation is shown below.

[Α] _D = −28.39 (CHCl ₃ , C
= 1.000) The following test examples show that the compound of the present invention represented by the general formula (I) has three actions of a lipid peroxidation inhibitory action, a blood vessel relaxing action and a calcium overload inhibiting action.

[0076]

Test Example 1 In Vitro Lipid Peroxidation Inhibitory Action Test Method A The method of Havel et al. (Havel RJ et al.
1955, J.M. Clin Invest, 34, 134
5) After adding the sample to the rabbit LDL prepared according to
In addition, Soybean lipoxygenase Ty
pe-1S (SLO) solution to a final concentration of 40 μg / ml
In a CO ₂ incubator (37 ° C)
Oxidation was carried out by keeping the temperature at about 24 hours. After separating the oxidized LDL solution by gel filtration HPLC method, L
The fluorescence intensity of the DL fraction was determined to be Ex: 360 nm · Em: 430.
It was measured in nm. Measurement result is% of control
Indicated by. The results are shown in Table 42.

[0077]

[Table 42] Test Method B The method of Havel et al. (Havel RJ et al.
1955, J.M. Clin Invest, 34, 134
5) After adding the sample to the rabbit LDL prepared according to
Further, CuSO _{4 (} 1 μM) was added, and the mixture was shaken at 37 ° C. for about 24 hours for oxidation. Generated TBARS
Uses the Yagi method (Yagi K: 197
6, Biochem Med, 15, 212). The measurement results are shown as% of the control. The results are shown in Table 43.

[0078]

[Table 43]

[0079]

[Test Example 2] In vitro vasorelaxant action test method Male Sprague-Dawl having a body weight of 350 to 550 g
The thoracic aorta was extracted from ey rat (Crj), the fat and connective tissue of blood vessels were removed, and then cut into a ring having a width of 2 to 3 mm to prepare a sample. The sample is 95% O ₂ -5%
Aerated with CO ₂ mixed gas, Krebs-Hensele
It was suspended in an organo bath filled with 10 ml of it solution (KH solution; pH 7.4, 37 ° C.), and its tension was F.
Data was recorded isometrically using a D pickup (TB-611T, Nihon Kohden). The experiment was started after applying an initial tension of 2 g and stabilizing it for 30 minutes (changing the KH solution every 15 minutes). First, the sample was contracted with 30 mM K ⁺ , and the contraction was maintained for 20 minutes, and then the sample was washed with the KH solution. Part 6
After 0 minutes (K-H solution was replaced every 20 minutes), the sample was contracted again in the same manner as above, and after the contraction was stabilized, the sample or diltiazem was cumulatively added at an efficacy ratio of 3 and the concentration action curve was calculated. Obtained.

The contraction by 30 mM K ⁺ is set to 100%,
Each drug concentration when the contraction was relaxed by 50% was expressed as an IC ₅₀ value. The results are shown in Table 44.

[0081]

[Table 44]

[0082]

Test Example 3 In Vitro Calcium Overload Inhibitory Action Test Method A Male Sprague-Dawl with a body weight of 300 to 500 g
ro prepared by enzyme perfusion method from ventricular muscle of ey rat
Normal cardiomyocytes of d shape were treated with the test substance or diltiazem for 30 minutes, and then veratrine (1
(00 μg / ml) was added and the cell morphology was observed after 5 minutes to determine the cell survival rate and evaluate the drug efficacy. The results are shown in Table 45.

[0083]

[Table 45] Test method B By the same operation as test method A, veratrine (10
0 μg / ml) instead of veratridine (5
0 μg / ml) was used to evaluate the drug efficacy. The results are shown in Table 46.

[0084]

[Table 46] Tables 47 to 54 show a list of the example compounds.

[0085]

[Table 47]

[Table 48]

[Table 49]

[Table 50]

[Table 51]

[Table 52]

[Table 53]

[Table 54]

[0086]

Test Example 4 In Vitro Vascular Relaxation Effect on CaCl _{2 The} isolated rat aortic specimen was stabilized in normal nutrient solution for 30 minutes or longer to obtain contraction by 60 mM KCl, and then the specimen was relaxed with normal nutrient solution. . 20 minutes later, 60 mM K ⁺
/ Ca ²⁺ free nutrient solution (containing 0.1 mM EGTA), left for 20 minutes, then 60 m without EGTA
After leaving in M K ⁺ / Ca ²⁺ free nutrient solution for 20 minutes,
CaCl ₂ (0.01-10 mM) was applied cumulatively,
A concentration-response curve was obtained. The sample was washed with a normal nutrient solution and allowed to stand for 20 minutes, then treated with a normal nutrient solution containing the test drug for 200 minutes for the compound of Example 71 and 20 minutes with diltiazem, and then treated with the test drug for 60 mM K ⁺ / Ca ^{2. +20} minutes in a free nutrient solution (containing 0.1 mM EGTA) and 20 minutes in a 60 mM K ⁺ / Ca ²⁺ free nutrient solution containing a test drug but not EGTA (total pretreatment time: Example 71 Compound for 240 minutes, diltiazem = 60 minutes), and the concentration-response curve was obtained again. Reaction is 10 mM C
The contraction rate was converted to 100% by the aCl ₂ contraction.
The result is shown in FIG. In FIG. 1, the data are shown as the average value ± standard error of 5 cases. It is clear from FIG. 1 that the compound of the present invention exhibits an excellent inhibitory effect on CaCl ₂ contraction in a much smaller amount than that of diltiazem. .

[0087]

[Test Example 5] In vitro anti-spasm action 3,4-diaminopyridine ( hereinafter
Below, abbreviated as 3,4-DAP) Action against induced cyclic contraction
The normal nutrient solution in the organ bath was exchanged every 15 minutes for use, and when the tension of the isolated canine coronary artery specimen became stable at 2 g, it was changed to 30 mM K ⁺ nutrient solution to contract the specimen. Again, the normal nutrient solution in the organ bath was replaced to relax the sample, and the normal nutrient solution was replaced every 20 minutes to stabilize for about 1 hour, and then 3,4-DAP (1
0 mM) was added to cause periodic contraction. When the appearance of periodic contraction became stable, the compound of Example 71 or diltiazem was cumulatively added into the organo bath at an efficacy ratio of 3. Elimination Dow was used to determine the drug concentration that completely suppressed the amplitude of 3,4-DAP-induced cyclic contraction.
se. The result is shown in FIG. According to FIG. 2, it is clear that the compound of the present invention suppresses cyclic contraction at a concentration lower than that of diltiazem.

[0088]

[Test Example 6] Effects on cardiovascular system Effects on coronary blood flow Male beagle dogs (9-10 kg) were treated with sodium pe
After anesthesia by intravenous administration of nt-barbital (35 mg / kg), a tracheal cannula is inserted and a ventilator (H
Artificial respiration (16-18 times per minute, 22 ml / kg) was performed using Arvard model 607). Blood pressure was intermittently measured through a pressure transducer (Nihon Kohden, TP-200TL) from an arterial cannula inserted in the right femoral artery, and heart rate was measured from the pulse wave (Nihon Kohden, AT-610G). Sodium p for maintaining anesthesia
Entobarbital (3-5mg / kg / hr)
Was continuously administered via the forelimb venous cannula. From the left femoral artery, microchip catheter (Miller, S
PC-350) was inserted into the left ventricle and the pressure in the left ventricle was measured. Also, a differential amplifier (Nihon Kohden, EQ-601G)
The LVdp / dt was obtained by differentiating the left ventricular pressure waveform using. After opening the left fourth intercostal space and cutting the diaphragmatic nerve, the pericardium was incised and fixed to the chest to expose the heart. Approximately 1 cm from the origin of the left circumflex branch of the coronary artery, 1 cm was peeled off, a blood volume measurement probe was attached, and an electromagnetic blood flow meter (Nihon Kohden, MFV-2
100), the coronary blood flow was measured. The coronary blood flow and the average blood pressure were processed using an operational amplifier (Nihon Kohden, EO-601G) to calculate the coronary vascular resistance. Blood gas (pO ₂ , pC
O ₂ ) and blood pH were measured as needed (Radi
eter, ABL-520), and was confirmed to be within the physiological range. During the experiment, warming mats and lighting were used to prevent the animals from falling.

Example 71 after a recovery period of about 60 minutes after surgery.
(10-300 μg / kg) and diltiazem (10-300 μg / kg) were sequentially administered intravenously through a cannula inserted into the vein of the forelimb, and the next drug was administered when all the parameters returned to the pre-administration values.

The compound of Example 71 was dissolved in DMSO and then diluted with distilled water for injection acidified with hydrochloric acid to prepare a drug solution (1% DMSO, 10 ⁻³ M HCl, pH≈).
5).

Diltiazem (manufactured by Sigma) was dissolved in physiological saline.

All the results are shown as the average value ± standard error of 4 cases. The result is shown in FIG. 3, MBP is blood pressure, HR is heart rate, CBF is coronary blood flow, CVR is coronary vascular resistance, max. LVdP / dt means the maximum rising velocity of the left ventricular pressure. From FIG. 3, it can be seen that the compound of the present invention exhibits an excellent effect of increasing coronary blood flow.

[0093]

[Test Example 7] Effects on cardiovascular system Coronary artery occlusion of rat heart-ventricular irregularity during reperfusion
Inhibition of pulse generation Male Sprague Dawley rats (450 to 600 g) were anesthetized with pentobarbital, thoracotomy was performed under artificial respiration, the left anterior descending coronary artery was ligated with silk thread for 5 minutes, and then the occlusion was released and reperfusion was performed. It was observed for 10 minutes. A standard lead II electrocardiogram was recorded to examine the occurrence of ventricular arrhythmia. The drug was 0.5 mg / k of the compound of Example 26 10 minutes before coronary artery occlusion.
g, 1 mg / kg, 3 mg / kg, or 1 mg / kg, 3 mg / kg of diltiazem was administered as an aqueous solution via a catheter placed in the femoral vein. FIG. 4 shows the results. In FIG. 4, the numbers in parentheses below each graph indicate the number of cases. As is clear from FIG. 4, the compound of the present invention exhibits a far superior inhibitory effect on arrhythmia generation than diltiazem.

Example 76 2- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -3- [3- [N-methyl-N- [3- (2
-Benzimidazolyl) propyl] amino] propyl]
Synthesis of -1,3-thiazolidin-4-one In the same manner as in Example 26-A, N-methyl-N- [2-
The target compound was obtained by using N-methyl-N- [3- (2-benzimidazolyl) propyl] amine instead of (3,4-methylenedioxyphenoxy) ethyl] amine.

NMR (CDCl ₃ ) δ; 1.40 (18H, s), 1.4 to 1.8 (2H, (200MHz) m), 1.8 to 2.2 (2H, m), 2. 22 (3 H, s), 2.3 to 2.7 (4 H, m), 2.7 to 3.2 (3 H, m), 3.5 to 4.3 (4 H, m), 5.57 (1H, s), 7.07 (2H, s), 7.1 to 7.4 (2H, m), 7.24 (1H, s), 7.4 to 7.7 (2H, m) [ Examples 77 to 78] In the same manner as in Example 26-B,
Using the corresponding bromine compound, the compounds shown in Table 55 were obtained.

[0096]

[Table 55] Example 79 2- (3,5-di-tert-butyl-4-hydroxy
Phenyl) -3- [3- [N-methyl-N- [3- (4
-Oxo-1,3-thiazolidin-3-yl) propyi
]] Amino] propyl] -1,3-thiazolidine-4-
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3-obtained in Reference Example 33 under an on-state synthetic nitrogen atmosphere.
[3- (N-Methylamino) propyl] -1,3-thiazolidin-4-one (0.40 g) and 3- (3-chloropropyl) -1,3-thiazolidin-4-one (0.
19 g) in a solution of DMF (5 ml) in potassium carbonate (0.
44 g) and sodium iodide (0.79 g) were added, and 6
Stirred at 0 ° C. for 3 days. After allowing to cool, the mixture was poured into ice water and the desired product was extracted with ethyl acetate. The extract was washed with water and then saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (developing solvent, chloroform: methanol = 98: 2).
The target product (0.32 g, yield: 5) was obtained as a brown oily substance.
9%) was obtained.

NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.5 to 2.0 (4H, (200MHz) m), 2.06 (3H, s), 2.1 to 2. 4 (4 H, m), 2.6 to 3.0 (1 H, m), 3.31 (2 H, t, J = 7.1 Hz), 3.4 to 3.7 (1 H, m), 3 0.53 (2H, s), 3.64 and 3.79 (2H, ABq, J = 16Hz), 4.36 (2H, s), 5.32 (1H, s), 5.56 (1H, s), 7.07 (2H, s) [Examples 80 to 84] In the same manner as in Example 79, using the corresponding chloro form, the compounds shown in Table 56 were obtained.

[0098]

[Table 56] [Reference Example 63] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [3- [N-methyl-N- (2,3-
Epoxypropyl) amino] propyl] -1,3-thia
Synthesis of Zolidin-4-one 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- (N-methylamino) propyl] -1,3 obtained in Reference Example 33 -Thiazolidine-4-
On (0.90 g) and epibromohydrin (0.36
To a solution of g) in acetone (5 ml) was added potassium carbonate (0.66 g) at room temperature, and the mixture was stirred at the same temperature for 15 hours.

The reaction mixture was poured into ice water (50 ml) and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (developing solvent,
Purification with chloroform: methanol = 98: 2) gave the target product (0.53 g, yield: 51%) as a yellow oil.

NMR (CDCl ₃ ) δ; 1.43 (18H, s), 1.2 to 1.9 (2H, (200MHz) m), 2.20 (3H, s), 2.1 to 2. 5 (4 H, m), 2.5 to 3.2 (4 H, m), 3.4 to 3.7 (1 H, m), 3.66 and 3.79 (2 H, ABq, J = 16 Hz). 5.28 (1H, brs), 5.60 (1H, s), 7.09 (2H, s) [Example 85] 2- (3,5-di-tert-butyl-4-hydroxy)
Phenyl) -3- [3- [N-methyl-N- [2-hydr
Roxy-3- (2-methoxyphenylthio) propyl]
Amino] propyl] -1,3-thiazolidin-4-one
Of 2- (3,5-di-tert-) obtained in Reference Example 63.
Butyl-4-hydroxyphenyl) -3- [3- [N-
Methyl-N- (2,3-epoxypropyl) amino] propyl] -1,3-thiazolidin-4-one (0.50
2-Methoxythiophenol (0.64 g) was added to an ethanol (10 ml) solution of g) at room temperature, and the mixture was stirred at room temperature for 15
Stirred for hours. The reaction mixture was poured into ice-cooled 5% aqueous sodium hydroxide solution (100 ml), and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 98: 2) to obtain the desired product (0.64 g, yield: 97%) as a colorless oil.

NMR (CDCl ₃ ) δ; 1.0 to 1.8 (2H, m), 1.43 (18H, (200 MHz) s), 2.10 (3H, s), 2.1 to 2. 6 (4 H, m), 2.6 to 3.2 (3 H, m), 3.3 to 3.9 (3 H, m), 3.66 and 3.79 (2 H, ABq, J = 16 Hz) 3.89 (3H, s), 5.31 (1H, s), 5.53 (1H, s), 6.7 to 7.0 (2H, m), 7.06 (2H, s), 7.1 to 7.5 (2H, m) The names of the compounds of Examples 76 to 85 are described below.

Example 76 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [3- (2
-Benzimidazolyl) propyl] amino] propyl]
-1,3-Thiazolidin-4-one Example 77 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (4
-Hydroxyphenyl) ethyl] amino] propyl]-
1,3-thiazolidin-4-one Example 78 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2-
(2,3-dihydro-2,2-dimethylbenzofuran-
7-yl) oxyethyl] amino] propyl] -1,3
-Thiazolidin-4-one Example 79 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [3- (4
-Oxo-1,3-thiazolidin-3-yl) propyl] amino] propyl] -1,3-thiazolidin-4-
On Example 80 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [3- (2
-Methoxyphenylthio) propyl] amino] propyl] -1,3-thiazolidin-4-one Example 81 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N] -Methyl-N-[(3,4
-Methylenedioxyphenyl) aminocarbonylmethyl] amino] propyl] -1,3-thiazolidine-4-
ON Example 82 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [3-
(2,4-Dioxo-1,3-thiazolidin-3-yl) propyl] amino] propyl] -1,3-thiazolidin-4-one Example 83 2- (3,5-di-tert-butyl-4) -Hydroxyphenyl) -3- [3- [N-methyl-N-[(3,4
-Methylenedioxyphenylmethyl) aminocarbonylmethyl] amino] propyl] -1,3-thiazolidine-
4-one Example 84 2- (3,5-Di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- [5
-(3,4-Methylenedioxyphenyl) -1H-imidazol-1-yl] ethyl] amino] propyl]-
1,3-thiazolidin-4-one Example 85 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2-hydroxy-3-] (2-Methoxyphenylthio) propyl]
Amino] propyl] -1,3-thiazolidin-4-one Table 57 shows a list of the above-mentioned example compounds.

[0103]

[Table 57]

[0104]

As described above, the compound of the present invention has a lipid peroxidation inhibitory action, a vasorelaxant action, and a calcium overload inhibitory action, and is used as a prophylactic / therapeutic agent for an ischemic disease and an antihypertensive agent. It is possible.

[Brief description of drawings]

FIG. 1 is a graph showing the inhibitory effects of the compound of Example 71 and diltiazem on CaCl ₂ contraction in rat isolated aortic preparation.

FIG. 2 is a chart showing the effect of the compound of Example 71 and diltiazem on 3,4-diaminopyridine-induced cyclic contraction in dog isolated coronary artery preparations.

FIG. 3: Compound of Example 71 and diltiazem for blood pressure (MVP), heart rate (HR), coronary blood flow (CVR) and left ventricular maximum rise rate (max.LVdp / dt) in anesthetized thoracotomy dogs. It is a graph which shows an effect.

FIG. 4 is a graph showing the effect of the compound of Example 26 and diltiazem on the incidence of arrhythmia induced by rat coronary artery ligation reperfusion.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/47 ABQ A61K 31/47 ABQ 31/495 ABS 31/495 ABS 31/535 AED 31/535 AED C07D 317/60 C07D 317/60 // C07D 249/12 506 C07D 249/12 506 271/06 271/06 271/10 271/10 277/14 277/14 277/16 277/16 277/34 277 / 34 285/12 291/04 291/04 317/58 317/58 405/12 233 405/12 233 249 249 413/12 317 413/12 317 417/06 211 211 417/06 211 217 217 417/12 317 417 / 12 317 417/14 211 417/14 211 513/10 513/10 285/12 C07M 7:00

Claims (14)

[Claims] 1. A compound of the general formula (I) (In the formula, R ₁ represents a hydrogen atom, a hydroxyl group, an acyloxy group having 1 to 9 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms; R ₂ and R ₃ may be the same or different,
Represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms; R ₄ represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms; A is the general formula (II) or the general formula (II
I) [Chemical formula 2] Wherein R ₅ represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms which may have a substituent, or a lower alkenyl group having 1 to 6 carbon atoms which may have a substituent. A lower alkoxy group having 1 to 6 carbon atoms which may have a substituent,
It represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent, and R ₅ represents two or more oxygen atoms, each having a carbon atom bonded thereto as a spiro atom, or It may form a 5- or 6-membered ring containing a sulfur atom; B is represented by the general formula (IV), (V), (VI), (VI
I), (VIII), (IX), (X), (XI),
Represents a group selected from the group consisting of (XII), (XIII), (XIV), (XV) and (XVI); R ₆ and R ₇ may be the same or different and each is a hydrogen atom or a substituent. A lower alkyl group having 1 to 6 carbon atoms which may have, a lower alkenyl group having 1 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a substituent Represents a heterocyclic group which may have, provided that they are not simultaneously a methyl group; or R ₆ ,
R ₇ may form a ring together (the ring may have a substituent or may be a condensed ring which may have a substituent); n is Represents an integer of 2, 3, 4, 5 or 6. ) Or a possible stereoisomer, optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, a therapeutic agent for ischemic disease. 2. An ischemic heart comprising a compound represented by the above general formula (I) or a possible stereoisomer, optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient. Disease treatment agent. 3. The therapeutic agent for ischemic heart disease according to claim 2, which is used as a therapeutic agent for angina. 4. The therapeutic agent for ischemic heart disease according to claim 2, which is used as a therapeutic agent for hypertension. 5. The therapeutic agent for ischemic heart disease according to claim 2, which is used as an antiarrhythmic agent. 6. The therapeutic agent for ischemic heart disease according to claim 2, which is used as a coronary vasodilator. 7. The therapeutic agent for ischemic heart disease according to claim 2, which is used as a preventive agent for myocardial infarction. 8. An ischemic brain comprising a compound represented by the above general formula (I) or its possible stereoisomers, optical isomers or a pharmaceutically acceptable salt thereof as an active ingredient. Remedy for vascular disorders. 9. The therapeutic agent for ischemic cerebrovascular disorder according to claim 8, wherein the ischemic cerebrovascular disorder is cerebral infarction. 10. The therapeutic agent for ischemic cerebrovascular disorder according to claim 8, which is used as a cerebral circulation improving agent. 11. The therapeutic agent for ischemic cerebrovascular disorder according to claim 8, which is used as a brain protective agent. 12. 2- (3,5-di-t-butyl-4-
Hydroxyphenyl) -3- [3- [N-methyl-N-
[2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidine-4-
ON, (+)-2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, (-)-2- (3,5-di-t-butyl-4-hydroxyphenyl)- 3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3 -[N-ethyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [4- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] butyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [5- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] pentyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl -N- [3- (3,4-
Methylenedioxyphenoxy) propyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-diisopropyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [ 2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [1 [4 -(2,3,4-Trimethoxybenzyl) piperazinyl]] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [ 3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one, 2,5-cis-2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N-
[2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one, (-)-2,5-cis-2- (3,5 -Di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-methylenedioxyphenoxy)
Ethyl] amino] propyl] -5-methyl-1,3-thiazolin-4-one, (+)-2,5-cis-2- (3,5-di-t-butyl-4-hydroxyphenyl)- 3- [3- [N-methyl-N- [2- (3,4-methylenedioxyphenoxy))
Ethyl] amino] propyl] -5-methyl-1,3-thiazolin-4-one, 2,5-trans-2- (3,5-di-t-butyl-4)
-Hydroxyphenyl) -3- [3- [N-methyl-N
-[2- (3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-one Hydroxyphenyl) -3- [3- [N-methyl-N- [4- (3,4-
Methylenedioxyphenoxy) butyl] amino] propyl] -1,3-thiazolidin-4-one, 5- (3,5-di-t-butyl-4-hydroxyphenyl) -1- [3- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] imidazole, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3, 4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidine-4-thione, 5- (3,5-di-t-butyl-4-hydroxyphenyl) -4-ethyl-2- [3- [N-methyl-N- [2
-(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,2,4-triazol-3-one, N- [3- [N-methyl-N- [2- (3,4- Methylenedioxyphenoxy) ethyl] amino] propyl]-
3,5-di-t-butyl-4-hydroxybenzamide, 3- (3,5-di-t-butyl-4-hydroxyphenyl) -5- [3- [N-methyl-N- [2- ( 3,4-
Methylenedioxyphenoxy) ethyl] amino] propoxy] -1,2,4-oxadiazole, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5- (2-hydroxyethyl) -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl)- 3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one, N- [3- [N-methyl-N- [2- (3,4-methylenedi) Oxyphenoxy) ethyl] amino] propyl]-
3,5-di-t-butyl-4-hydroxybenzenesulfonamide, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2 -(3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-methoxy-1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-isopropoxycarbonylmethyl-1,3-
Thiazolidine-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5- (2-hydroxyethoxy) -1,3-thiazolidin-4-one, spiro [2- (3,5-di-t-butyl-4-hydroxyphenyl) ) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one-
5,2 '-[1,3] dioxolane], 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3, 4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-N, N-dimethylcarbamoylmethyl-1,
3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [1- (4-benzyl) piperidyl]
Propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [1- [4- (3,4-methylenedi Oxyphenoxy) piperidyl]] propyl] -1,3-
A therapeutic agent for ischemic disease comprising a compound selected from the group consisting of thiazolidin-4-one and a pharmaceutically acceptable salt thereof as an active ingredient. 13. 2- (3,5-di-t-butyl-4-
Hydroxyphenyl) -3- [3- [N-methyl-N-
[2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidine-4-
ON, (+)-2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, (-)-2- (3,5-di-t-butyl-4-hydroxyphenyl)- 3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3 -[N-ethyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [4- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] butyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [5- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] pentyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl -N- [3- (3,4-
Methylenedioxyphenoxy) propyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-diisopropyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [ 2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [1 [4 -(2,3,4-Trimethoxybenzyl) piperazinyl]] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [ 3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one, 2,5-cis-2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N-
[2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one, (-)-2,5-cis-2- (3,5 -Di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-methylenedioxyphenoxy)
Ethyl] amino] propyl] -5-methyl-1,3-thiazolin-4-one, (+)-2,5-cis-2- (3,5-di-t-butyl-4-hydroxyphenyl)- 3- [3- [N-methyl-N- [2- (3,4-methylenedioxyphenoxy))
Ethyl] amino] propyl] -5-methyl-1,3-thiazolin-4-one, 2,5-trans-2- (3,5-di-t-butyl-4)
-Hydroxyphenyl) -3- [3- [N-methyl-N
-[2- (3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-one Hydroxyphenyl) -3- [3- [N-methyl-N- [4- (3,4-
Methylenedioxyphenoxy) butyl] amino] propyl] -1,3-thiazolidin-4-one, 5- (3,5-di-t-butyl-4-hydroxyphenyl) -1- [3- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] imidazole, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3, 4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidine-4-thione, 5- (3,5-di-t-butyl-4-hydroxyphenyl) -4-ethyl-2- [3- [N-methyl-N- [2
-(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,2,4-triazol-3-one, N- [3- [N-methyl-N- [2- (3,4- Methylenedioxyphenoxy) ethyl] amino] propyl]-
3,5-di-t-butyl-4-hydroxybenzamide, 3- (3,5-di-t-butyl-4-hydroxyphenyl) -5- [3- [N-methyl-N- [2- ( 3,4-
Methylenedioxyphenoxy) ethyl] amino] propoxy] -1,2,4-oxadiazole, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5- (2-hydroxyethyl) -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl)- 3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one, N- [3- [N-methyl-N- [2- (3,4-methylenedi) Oxyphenoxy) ethyl] amino] propyl]-
3,5-di-t-butyl-4-hydroxybenzenesulfonamide, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2 -(3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-methoxy-1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-isopropoxycarbonylmethyl-1,3-
Thiazolidine-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5- (2-hydroxyethoxy) -1,3-thiazolidin-4-one, spiro [2- (3,5-di-t-butyl-4-hydroxyphenyl) ) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one-
5,2 '-[1,3] dioxolane], 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3, 4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-N, N-dimethylcarbamoylmethyl-1,
3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [1- (4-benzyl) piperidyl]
Propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [1- [4- (3,4-methylenedi Oxyphenoxy) piperidyl]] propyl] -1,3-
A therapeutic agent for ischemic heart disease, which comprises a compound selected from the group consisting of thiazolidin-4-one and a pharmaceutically acceptable salt thereof as an active ingredient. 14. 2- (3,5-di-t-butyl-4-
Hydroxyphenyl) -3- [3- [N-methyl-N-
[2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidine-4-
ON, (+)-2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, (-)-2- (3,5-di-t-butyl-4-hydroxyphenyl)- 3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3 -[N-ethyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [4- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] butyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [5- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] pentyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl -N- [3- (3,4-
Methylenedioxyphenoxy) propyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-diisopropyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [ 2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [1 [4 -(2,3,4-Trimethoxybenzyl) piperazinyl]] propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [ 3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one, 2,5-cis-2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N-
[2- (3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one, (-)-2,5-cis-2- (3,5 -Di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-methylenedioxyphenoxy)
Ethyl] amino] propyl] -5-methyl-1,3-thiazolin-4-one, (+)-2,5-cis-2- (3,5-di-t-butyl-4-hydroxyphenyl)- 3- [3- [N-methyl-N- [2- (3,4-methylenedioxyphenoxy))
Ethyl] amino] propyl] -5-methyl-1,3-thiazolin-4-one, 2,5-trans-2- (3,5-di-t-butyl-4)
-Hydroxyphenyl) -3- [3- [N-methyl-N
-[2- (3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-one Hydroxyphenyl) -3- [3- [N-methyl-N- [4- (3,4-
Methylenedioxyphenoxy) butyl] amino] propyl] -1,3-thiazolidin-4-one, 5- (3,5-di-t-butyl-4-hydroxyphenyl) -1- [3- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] imidazole, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3, 4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidine-4-thione, 5- (3,5-di-t-butyl-4-hydroxyphenyl) -4-ethyl-2- [3- [N-methyl-N- [2
-(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,2,4-triazol-3-one, N- [3- [N-methyl-N- [2- (3,4- Methylenedioxyphenoxy) ethyl] amino] propyl]-
3,5-di-t-butyl-4-hydroxybenzamide, 3- (3,5-di-t-butyl-4-hydroxyphenyl) -5- [3- [N-methyl-N- [2- ( 3,4-
Methylenedioxyphenoxy) ethyl] amino] propoxy] -1,2,4-oxadiazole, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl -N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5- (2-hydroxyethyl) -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl)- 3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one, N- [3- [N-methyl-N- [2- (3,4-methylenedi) Oxyphenoxy) ethyl] amino] propyl]-
3,5-di-t-butyl-4-hydroxybenzenesulfonamide, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2 -(3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-methoxy-1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-isopropoxycarbonylmethyl-1,3-
Thiazolidine-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3,4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5- (2-hydroxyethoxy) -1,3-thiazolidin-4-one, spiro [2- (3,5-di-t-butyl-4-hydroxyphenyl) ) -3- [3- [N-methyl-N- [2-
(3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] -1,3-thiazolidin-4-one-
5,2 '-[1,3] dioxolane], 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [N-methyl-N- [2- (3, 4-
Methylenedioxyphenoxy) ethyl] amino] propyl] -5-N, N-dimethylcarbamoylmethyl-1,
3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [1- (4-benzyl) piperidyl]
Propyl] -1,3-thiazolidin-4-one, 2- (3,5-di-t-butyl-4-hydroxyphenyl) -3- [3- [1- [4- (3,4-methylenedi Oxyphenoxy) piperidyl]] propyl] -1,3-
A therapeutic agent for ischemic cerebrovascular disorder, comprising a compound selected from the group consisting of thiazolidin-4-one, or a pharmaceutically acceptable salt thereof as an active ingredient.