JPH0723349B2 - 3,5-Di-tertiary-butyl-4-hydroxycinnamic acid amide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention is a novel compound, 3,5-di-tertiarybutyl-4, which has a cardiotonic action and is useful as an intermediate for many organic compounds. The present invention relates to a hydroxycinnamic acid amide derivative and a salt thereof, and a cardiotonic agent containing the same as an active ingredient.

(Prior Art) The compound according to the present invention is a novel compound not described in the literature,
It was first synthesized by the present inventors.

(Problems to be Solved by the Invention) The present inventors have found that the novel 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative according to the present invention is useful as an intermediate for many organic compounds. Moreover, they have found that they have a cardiotonic effect, and completed the present invention.

(Means and Actions for Solving Problems) The novel compound according to the present invention is represented by the following general formula (1).

[Wherein R ¹ represents hydrogen, a cyano group, a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ hydroxyalkyl group, and n is 0-3.
Represents the integer, and R ² is {X ¹ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ³ O (R ³ represents a C _{1 to} C ₃ alkyl group), Y ¹ represents hydrogen, a hydroxyl group, halogen or R ⁴ A phenyl group represented by O (R ⁴ represents an alkoxy group represented by C _{1 to} C ₃ alkyl group), or (Z ¹ , Z ² and Z ³ each represent hydrogen or a hydroxyl group), The compound represented by the general formula (1) according to the present invention can form a salt with a base, and among the compounds represented by the general formula (1) according to the present invention, , R ² (X ¹ is an amino group, Y ¹ is the same as above), or (Z ¹ , Z ² , Z ³ are the same as above), The compound represented by the pyridyl group represented by is capable of forming a salt with an acid, and the salt of the compound according to the present invention is any compound capable of forming a salt from the compound of the present invention with a base or an acid. . For example, (1) metal salts such as salts with alkali metals, alkaline earth metals and aluminum, (2) ammonium salts, (3) organic base salts such as methylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, piperidine, morpholine. , Salts with hexamethyleneimine, aniline, pyridine, etc.,
(4) Organic acid salts such as formic acid, acetic acid, trifluoroacetic acid,
Salts with maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluene, sulfonic acid, etc., (5) Inorganic acids, such as salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.,
(6) There are salts with amino acids such as arginine, glutamic acid, ornithine and the like. When these salts are used as cardiotonic agents, physiologically acceptable ones should be selected. Table 1 shows typical examples of the compound according to the present invention.

The method for synthesizing the compound represented by the general formula (1) of the present invention includes the following. For example, (1) general formula (1) The compound represented by (R ¹ , R ² and n are the same as above) is H. Zim
Method of mer et al. [J.Org.Chem.], 24 , 23 (1959); Journal of Heterocyclic Chemistry (J.Het.Ch)
em.), 3 , 171 (1965)], etc., and 3,5-di-tert-butyl-4-hydroxybenzaldehyde and the general formula (2) R ⁵ —CH ₂ —CONH (CH ₂ ) mR ⁶ ( 2) [wherein R ⁵ represents hydrogen, a cyano group, a C _{1 to} C ₃ alkyl group, m represents an integer of 0 to 3, and R ⁶ represents {X ² is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ⁷ O (R ⁷ represents a C _{1 to} C ₃ alkyl group), Y ² represents hydrogen, a hydroxyl group, or
A phenyl group represented by R ⁸ O (R ⁸ represents an alkoxy group represented by C _{1 to} C ₃ alkyl group) or (Z ⁴ , Z ⁵ and Z ⁶ are all hydrogen or hydroxyl), A pyridyl group represented by the following formula] can be synthesized in the absence of a catalyst or by condensation with an acid or a base as a catalyst. Examples of the acid used as a catalyst include a protonic acid such as sulfuric acid, benzenesulfonic acid and p-toluenesulfonic acid; and a Lewis acid such as boron trifluoride. Examples of the base that can be used as a catalyst include ammonia, piperidine, pyrrolidine, diethylamine, triethylamine, monoethanolamine, morpholine, pyridine,
Aniline, 1,3-diazabicyclo [3.4.0] undec-7
-Organic bases such as ene; organic acid amine salts such as ammonium acetate and piperidinium acetate; organic acid alkali metal salts such as sodium acetate and potassium acetate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; lithium diisopropylamide Alkali metal amides such as; alkali metal alcoholates such as sodium methylate and sodium ethylate; alkali metal hydrides such as sodium hydride and potassium hydride.

(2) General formula (1) (Wherein R ¹ , R ² and n are the same as above), the compound represented by the general formula (3) {Wherein R ⁹ is hydrogen, a cyano group, a C _{1 to} C ₃ alkyl group or R ¹¹ OR ¹² (wherein R ¹¹ represents hydrogen and a trialkylsilyl group, and R ¹² represents a C _{1 to} C ₃ alkylene group. And a compound of the formula (4) H ₂ N (CH ₂ ) lR ¹³ (4) [wherein R ¹⁰ represents hydrogen or a C ₁ -C ₄ alkyl group]. And R ¹³ is {X ³ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ¹⁴ O (R ¹⁴ represents a C _{1 to} C ₃ alkyl group), Y ³ represents hydrogen, a hydroxyl group or R ¹⁵ O ( R ¹⁵ represents an alkoxy group represented by C _{1 to} C ₃ ), or a phenyl group represented by (Z ⁷ , Z ⁸ and Z ⁹ each represent hydrogen or a hydroxyl group), A pyridyl group represented by the following] is used in the absence of a catalyst, or a commonly used dehydrating condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, or sodium methoxide. Etc. In the presence of a base such as a metal alcoholate such as butyl lithium, an alkyl metal such as butyl lithium, a metal hydride such as sodium hydride, and a halogenating agent such as thionyl chloride or phosphorus pentachloride, the compound of the general formula (3) is acid chloride. After converting to, it can be synthesized by reacting. After the reaction, if the trialkylsilyl group of R ¹¹ remains in the reaction product,
It can be desorbed with water, methanol, acid or fluorine ion.

(3) General formula (1) (R ¹ , R ² , and n are the same as above), the compound is 3,5-
Di-tert-butyl-4-hydroxybenzaldehyde and general formula (5) [Wherein R ¹⁶ represents hydrogen, a cyano group, a C ₁ -C ₃ alkyl group, p represents an integer of 0 to 3, and R ¹⁷ represents {X ⁴ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ¹⁸ O (R ¹⁸ represents a C _{1 to} C ₃ alkyl group), Y ⁴ represents hydrogen, a hydroxyl group or R ¹⁹ O ( R ¹⁹ represents an alkoxy group represented by C _{1 to} C ₃ ), or a phenyl group represented by (Z ¹⁰ , Z ¹¹ and Z ¹² are all hydrogen or a hydroxyl group), Represents a pyridyl group, and Ar represents an aryl group]. This synthetic method uses the so-called Witteich reaction. As the ylide to be reacted with the aldehyde, the ylide derived from trialkylphosphine and triarylarsine is also the same as the compound represented by the general formula (5). Can be used.

The 3,5-di-dicarboxylic acid represented by the general formula (1) according to the present invention
The tert-butyl-4-hydroxycinnamic acid amide derivative and its salt are useful as cardiotonic agents.

The cardiotonic effect was clarified by the left atrial contractile force measurement test in guinea pig isolated and the cardiac contractile force measurement test in anesthetized dogs.

(1) Effect on contractile force of the left atrium isolated from the guinea pig A male guinea pig weighing 200 to 500 g was stunned by a head strike, the heart was rapidly removed, and the mixture was saturated with mixed gas (95% O ₂ and 5% CO ₂ ) in Thailand. Load solution (sodium chloride 8.0
g, potassium chloride 0.2 g, calcium chloride 0.06 g, magnesium chloride 0.1 g, sodium hydrogen carbonate 1.0 g, sodium dihydrogen phosphate 0.05 g, glucose 1 g, and distilled water is added to bring the total amount to 1
The left atrium was taken out. A mixed gas (95% O ₂ and 5% CO ₂ ) was aerated, and a thread was attached to the atrial appendage of the left atrium sample in a magmas tank at 30 to 32 ° C containing Tyrode's solution, and the multi-end of the thread was used as a transducer. Tether,
Isometric shrinkage was measured. The sample was subjected to a resting tension of 0.5 g. Specimens were electrically driven through two platinum electrodes with a square wave of 150 times / min, 1 millisecond duration, 1.5 times the threshold voltage. After stabilizing the sample for 60 minutes, a sample dissolved in dimethyl sulfoxide (final concentration 0.5%) was added to the organ bath, and the contractile force after administration was compared with that before administration to measure the rate of increase in contractile force. .

Table 2 shows the rate of increase in shrinkage force of representative compounds. From this result, it can be seen that the compound represented by the general formula (1) according to the present invention strongly enhances the contractile force of guinea pig heart. The compound numbers correspond to the compound numbers in Table 1.

(2) Effect on cardiac contractile force of anesthetized dog Female beagle dogs having a body weight of 8 to 15 kg were used. Dogs were anesthetized with 30 mg / kg of pentobarbital sodium intravenously and were given artificial respiration. A thoracotomy was performed from the midline and the pericardium was incised to expose the heart. The systolic force was measured by mounting a strain measuring gauge on the wall of the right ventricle. Cardiac output was measured by attaching an electromagnetic flowmeter probe to the ascending aorta. Blood pressure was measured invasively by inserting a cannula into the right femoral artery and via a transducer at the other end of the cannula. Heart rate is
The R wave of the electrocardiogram was measured as a trigger. A cannula was inserted into the right femoral vein for sample administration.

The sample was dissolved in 50% dimethylacetamide (0.2 ml / kg), the sample was administered intravenously, and each parameter was recorded on a thermographic recording paper. The maximum rate of change in cardiac contractility, cardiac output, heart rate, and mean blood pressure after administration with respect to the pre-administration value was determined.
Table 3 shows that the compound of the present invention exhibits an excellent cardiac contraction enhancing effect on anesthetized dogs.

Acute toxicity Using ddY male mice (weight: 27 to 30 g), the number of mice was 6 per group. 0.1 ml / 10 g of a suspension of compounds (1) to (47) in 0.5% sodium carboxymethyl cellulose aqueous solution
Oral administration was performed at a body weight ratio. The 50% lethal dose LD was obtained by observing general symptoms for 2 weeks after administration and determining the number of dead / tested cases.
₅₀ (mg / kg) was estimated. As a result, no deaths were observed with the compounds (1) to (47) of the present invention even after administration of 500 mg / kg, and the LD ₅₀ of the compounds (1) to (47) was estimated to be 500 mg / kg or more, which was low. It turned out to be toxic.

Preparation and Dosage As the preparation of the cardiotonic agent according to the present invention, any preparation prepared by oral, enteral or parenteral administration can be selected. Specific formulations include tablets, capsules, fine granules, syrups, suppositories, ointments, injections and the like.
As a carrier for the preparation of the cardiotonic agent according to the present invention, oral, enteral,
Other organic or inorganic solid or liquid, usually inert, pharmaceutical carrier materials suitable for parenteral administration are used. Specific examples are crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums and polyalkylene glycols. The ratio of the cardiotonic agent of the present invention to the carrier in the formulation can be varied between 0.2 and 100%. The cardiotonic agent according to the present invention may also include other cardiotonic agents and other drugs compatible with it. in this case,
It goes without saying that the cardiotonic agent of the present invention need not be the main component in the preparation.

The cardiotonic agents according to the invention are generally administered in a dose such that the desired effect is achieved without side effects. The specific value should be determined by the judgment of a doctor, but generally, it is usually 10 mg to 10 g, preferably about 20 mg to 5 g per day for an adult. The cardiotonic agent of the present invention can be administered as an active ingredient as a pharmaceutical preparation in a unit of 1 mg to 5 g, preferably 3 mg to 1 g.

(Example) Next, the present invention will be specifically described with reference to production examples of the compound of the present invention, but these examples do not limit the present invention.

Example 1 Synthesis of Compound 1 3,5-di-tert-butyl-4-hydroxycinnamic acid
2.76 g dichloromethane (30 ml) solution in hydrochloric acid 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide 2.
11 g and p-fluorobenzylamine 1.25 g were added. After reacting for 2 hours at room temperature, water was added to the reaction mixture and extraction was performed with chloroform. The liquid obtained after passing the organic layer was concentrated under reduced pressure, and carbon tetrachloride was added to the residue for crystallization to obtain 3.0 g of the desired compound 1 (yield 78.3%).

Example 2 Synthesis of Compound 2 Using 1.23 g of p-hydroxybenzylamine in place of p-fluorobenzylamine in Example 1, the same treatment as in Example 1 was performed to obtain 2.4 g of the target product 2 (yield). Rate 62.3%).

Example 3 Synthesis of compound 3 4.31 g of p-aminobenzylamine hydrochloride was added to 2.80 g of 3,5-di-tert-butyl-4-hydroxycinnamic acid and 1-hydrochloric acid.
A solution of 2.11 g of ethyl-3- (3-dimethylaminopropyl) carbodiimide in dichloromethane (30 ml) was added,
To this, 4 ml of triethylamine was added and reacted at room temperature for 2 hours. Water was added to the reaction mixture, extraction was performed with chloroform, the organic layer was filtered, the resulting liquid was concentrated under reduced pressure, and carbon tetrachloride was added to the residue for crystallization to obtain the target compound 3
Was obtained (yield 31.6%).

Example 4 Synthesis of Compound 11 3.7 g of the target product 3 was obtained by the same procedure as in Example 1, except that 1.67 g of veratrylamine was used in place of p-fluorobenzylamine in Example 1. 86.9
%).

Example 5 Synthesis of compound 16 3,5-di-tert-butyl-4-hydroxy-α-
To a solution of 3.01 g of cyanocinnamic acid in dichloromethane (30 ml) was added 2.11 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1.67 g of veratrylamine,
The reaction was carried out at room temperature for 2 hours. Water was added, extraction was performed with chloroform, the organic layer was filtered, and the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform as a developing solvent and crystallized from carbon tetrachloride to obtain 1.8 g of the target compound 16 (yield:
40.0%).

Example 6 Synthesis of Compound 19 3,5-di-tert-butyl-4-hydroxycinnamic acid
A solution of 4.15 g of dichloromethane (40 ml) in 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
3.07 g and p-aminophenol 1.64 g were added, and the mixture was reacted at room temperature for 2 hours. Water was added and the mixture was extracted with chloroform. The obtained organic layer was concentrated under reduced pressure and ethanol was added to the residue for crystallization to obtain 1.7 g of the target compound 19 (yield 31.6%).

Example 7 Synthesis of Compound 21 3,5-di-tert-butyl-4-hydroxycinnamic acid
Hydrochloric acid 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide 3.
07g and p-chloroaniline 1.91g were added, and it was made to react at room temperature for 2 hours. The precipitate formed by adding water was collected in excess.
Chloroform was added to the obtained solid to carry out crystallization to obtain 4.9 g of the target compound 21 (yield 84.6%).

Example 8 Synthesis of Compound 22 In the same manner as in Example 7, except that 1.75 g of p-aminobenzonitrile was used instead of p-chloroaniline, the same treatment as in Example 7 was performed to obtain 5.0 g of the target product 22 ( Yield 88.5
%).

Example 9 Synthesis of compound 27 In Example 6, instead of p-aminophenol, o-
Using 1.64 g of aminophenol, the following treatment was carried out in the same manner as in Example 6 to obtain 1.3 g of the target product 27, yield 24.1%).

Example 10 Synthesis of compound 28 3,5-di-tert-butyl-4-hydroxycinnamic acid
To a solution of 5.00 g of dichloromethane (40 ml), 3.64 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 2.91 g of o-aminobenzotrifluoride were added and reacted at room temperature for 2 hours. Water was added, extraction was performed with chloroform, and the organic layer was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the desired compound 28
Was obtained (yield 29.5%).

Example 11 Synthesis of Compound 33 The same process as in Example 10 was repeated except that 2.77 g of 3,4-dimethoxyaniline was used instead of o-aminobenzotrifluoride, and 4.4 g of the target product 33 was obtained. (Yield 59.1%).

Example 12 Synthesis of compound 35 In Example 1, 2.07 g of m-nitroaniline was used instead of p-chloroaniline, and the same treatment as in Example 7 was performed to obtain 4.0 g of the target product 35 (yield: 68.0%).

Example 13 Synthesis of compound 37 3,5-di-tert-butyl-4-hydroxycinnamic acid
To a solution of 4.15 g of dichloromethane (40 ml), 3.07 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 2.06 g of tyramine were added, and the mixture was reacted at room temperature for 2 hours. Water was added, extraction was performed with chloroform, the organic layer was filtered, and the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform as a developing solvent, and crystallized from ethyl acetate to obtain 1.6 g of the desired compound 37 (yield 27.1%).

Example 14 Synthesis of Compound 39 In Example 10, instead of o-aminobenzotrifluoride, 1.70 g of 3-aminopyridine was used.
By performing the same treatment as in 0, 4.9 g of the target product 39 was obtained (yield 77.1%).

Example 15 Synthesis of Compound 40 In Example 5, the same treatment as in Example 5 was performed using 2-amino-3-hydroxypyridine (1.65 g) in place of veratrylamine to obtain 0.8 g of the target product 40. (Yield 14.1%).

Example 16 Synthesis of compound 41 3,5-di-tert-butyl-4-hydroxycinnamic acid 1
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added to a solution of 3.8 g of dichloromethane (200 ml).
9.8g and 4-aminomethyl pyridine 5.41g were added, and it was made to react at room temperature for 2 hours. Water was added, the mixture was extracted with chloroform, the organic layer was filtered, and the obtained liquid was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography using chloroform as a developing solvent, and 14 g of the target compound was obtained by crystallization from ethyl ether (yield 76.4
%).

Example 17 Synthesis of compound 44 Pyridoxamine dihydrochloride (3.00 g) of dimethylformamide (6
Triethylamine (9.40 ml) was added to the solution at room temperature.
Stir for minutes, then 3- (3,5-ditertiarybutyl-4-hydroxyphenyl) -2-propenoyl-2-
Thio-thiazolidine 3.87 g of dimethylformamide (60 m
l) Add the solution and react at room temperature for 18 hours with stirring,
The precipitate was removed in excess and the resulting solution was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate, and the obtained organic layer was concentrated under reduced pressure. The residue was purified by column chromatography using chloroform as a developing solvent, and crystallized from chloroform to obtain 3.0 g of the target compound (yield: 68.6
%).

Example 18 Synthesis of compound 45 3,5-di-tert-butyl-4-hydroxy-α-
To a solution of 2.11 g of cyanocinnamic acid in dichloromethane (30 ml), 1-ethyl-3- (3-dimethylaminopropyl) hydrochloride was added.
Carbodiimide 1.53g and 4-aminomethylpyridine 0.76g
Was added, and the mixture was reacted at room temperature for 2 hours. Water was added, the mixture was extracted with chloroform, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform as a developing solvent, and crystallized from methanol-water to obtain 0.7 g of the desired compound (yield 25.5%).

Example 19 Synthesis of compound 46 3,5-di-tert-butyl-4-hydroxy-α-
A solution of 1.80 g of methylcinnamic acid in dichloromethane (20 ml) was added with hydrochloric acid 1-ethyl-3- (3-dimethylaminopropyl).
Carbodiimide 1.73g and 4-aminomethylpyridine 0.92g
Was added, and the mixture was reacted at room temperature for 2 hours. Water was added, extraction was performed with chloroform, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of ethanol / chloroform (1:19 v / v) as a developing solvent and crystallized from ether-acetone to obtain 1.6 g of the desired compound (yield 67.8 %).

Example 20 Synthesis of compound 47 3,5-di-tert-butyl-4-hydroxy-α-
3.2 g of (2-hydroxyethyl) cinnamic acid and 3.32 g of tert-butyldimethyldimethyl chloride chloride were dissolved in 30 ml of dimethylformamide, to which 3.4 g of imidazole was added, and the mixture was reacted at room temperature for 16 hours. 5% aqueous sodium hydrogen carbonate solution
After adding 45 ml and extracting with hexane, the obtained organic layer was washed with water and the solvent was distilled off under reduced pressure. 30 ml of methanol in the residue,
Tetrahydrofuran 10 ml was added, followed by potassium carbonate 1 g.
10 ml of water solution was added, and the mixture was reacted at room temperature for 1 hour. The solution was concentrated under reduced pressure to a volume of 1/4 and diluted with 30 ml of saturated saline, and the solution was adjusted to pH 4-5 with 0.1M potassium hydrogen sulfate. Extraction with ethyl ether and concentration of the organic layer under reduced pressure gave 2.9 g of an oil containing 3,5-di-tert-butyl-4-hydroxy-α- (2-tert-butyldimethyldimethyloxyoxyethyl) cinnamic acid. (Yield 66.4
%).

Next, 2.8 g of cinnamic oxide was dissolved in dichloromethane (20 ml), 1.4 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.72 g of 4-aminomethylpyridine were added thereto, and the mixture was stirred at room temperature. The reaction was carried out for 2 hours. Water was added and the mixture was extracted with chloroform, and the liquid obtained by passing the organic layer was concentrated under reduced pressure. To the residue was added 15 ml of 1 M tetrabutylammonium fluoride tetrafuran solution, and the mixture was reacted at room temperature for 5 minutes to carry out a deprotection reaction. Water is added, the mixture is extracted with chloroform, the organic layer is concentrated under reduced pressure, and the residue obtained is purified by silica gel column chromatography using ethanol-chloroform (1:19) as a developing solvent.
1.0 g was obtained (yield 36.4%).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location C07D 213/75 (72) Inventor Toshiaki Yamashita 8-16-1 Shinjinno, Kakogawa-shi, Hyogo (72) Inventor Kiyoshi Watanabe 5-15-41 Matsugaoka, Akashi-shi, Hyogo (56) References JP-A-63-130570 (JP, A)

Claims (27)

[Claims] 1. A 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative represented by the following general formula (1) and a salt thereof. [Wherein R ¹ represents hydrogen, a cyano group, a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ hydroxyalkyl group, and n is 0-3.
Represents the integer, and R ² is {X ¹ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group or an alkoxy group represented by R ³ O (R ³ represents a C _{1 to} C ₃ alkyl group), Y ¹ represents hydrogen, a hydroxyl group, halogen or R ⁴ O (R ⁴ represents an alkoxy group represented by C _{1 to} C ₃ alkyl group)},
Or (Z ¹ , Z ² and Z ³ each represent hydrogen or a hydroxyl group), Represents a pyridyl group represented by 2. A 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative and a salt thereof according to claim ¹ , wherein R ¹ is hydrogen. 3. A 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative and a salt thereof according to claim 1, wherein R ¹ is a cyano group. 4. The 3,5-di-tertiarybutyl-4- as claimed in claim 1, wherein R ¹ is a C ₁ -C ₃ alkyl group.
Hydroxycinnamic acid amide derivatives and salts thereof. 5. The 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative and a salt thereof according to claim 1, wherein R ¹ is a C ₁ -C ₃ hydroxyalkyl group. 6. The method according to claim 1, wherein n is 0.
3,5-Di-tert-butyl-4-hydroxycinnamic acid amide derivative and salts thereof. 7. The method according to claim 1, wherein n is 1.
3,5-Di-tert-butyl-4-hydroxycinnamic acid amide derivative and salts thereof. 8. The method according to claim 1, wherein n is 2.
3,5-Di-tert-butyl-4-hydroxycinnamic acid amide derivative and salts thereof. 9. R ² is The 3,5-di-tertiarybutyl-4 according to claim 1, which is a group represented by (X ¹ and Y ¹ are the same as above).
-Hydroxycinnamic acid amide derivatives and salts thereof. 10. R ² is The 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative and a salt thereof according to claim 1, which is a pyridyl group represented by (Z ¹ is the same as above). 11. R ² is The 3,5-di-tertiarybutyl-4-hydroxycinnamic acid amide derivative and a salt thereof according to claim 1, which is a pyridyl group represented by (Z ² is the same as above). 12. R ² is The 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative and a salt thereof according to claim 1, which is a pyridyl group represented by (Z ³ is the same as above). 13. R ² is The 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative and a salt thereof according to claim 1, which is a pyridyl group represented by: 14. The following equation Claims represented by 1st, 2nd, 7th,
Or 3,5-di-tertiary butyl-4 described in item 9
-Hydroxycinnamic acid amide derivatives and salts thereof. 15. The following equation Claims represented by 1st, 2nd, 7th,
Or 3,5-di-tertiary butyl-4 described in item 9
-Hydroxycinnamic acid amide derivatives and salts thereof. 16. The following equation Claims represented by 1st, 2nd, 7th,
Or 3,5-di-tertiary butyl-4 described in item 9
-Hydroxycinnamic acid amide derivatives and salts thereof. 17. The following equation Claims represented by 1st, 2nd, 7th,
Or 3,5-di-tertiary butyl-4 described in item 10
-Hydroxycinnamic acid amide derivatives and salts thereof. 18. The following equation Claims represented by 1st, 2nd, 7th,
Or 3,5-di-tertiary butyl-4 described in item 11
-Hydroxycinnamic acid amide derivatives and salts thereof. 19. The following equation Claims represented by 1st, 2nd, 7th,
Or 3,5-di-tert-butyl-4 as described in paragraph 13
-Hydroxycinnamic acid amide derivatives and salts thereof. 20. The following equation Claims represented by 1st, 2nd, 6th,
Or 3,5-di-tertiary butyl-4 described in item 9
-Hydroxycinnamic acid amide derivatives and salts thereof. 21. The following equation Claims represented by 1st, 2nd, 6th,
Or 3,5-di-tertiary butyl-4 described in item 9
-Hydroxycinnamic acid amide derivatives and salts thereof. 22. The following equation Claims represented by 1st, 2nd, 7th,
Or 3,5-di-tertiary butyl-4 described in item 10
-Hydroxycinnamic acid amide derivatives and salts thereof. 23. The following equation Claims represented by Claims 1, 4, and 7,
Or 3,5-di-tertiary butyl-4 described in item 10
-Hydroxycinnamic acid amide derivatives and salts thereof. 24. A cardiotonic agent comprising, as an active ingredient, a 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative represented by the following general formula or a salt thereof. [Wherein R ¹ represents hydrogen, a cyano group, a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ hydroxyalkyl group, and n is 0-3.
Represents the integer, and R ² is {X ¹ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ³ O (R ³ represents a C _{1 to} C ₃ alkyl group), Y ¹ represents hydrogen, a hydroxyl group, halogen or R ⁴ A phenyl group represented by O (R ⁴ represents an alkoxy group represented by C _{1 to} C ₃ alkyl group), or (Z ¹ , Z ² and Z ³ each represent hydrogen or a hydroxyl group), Represents a pyridyl group represented by 25. The general formula (1) [Wherein R ¹ represents hydrogen, a cyano group, a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ hydroxyalkyl group, and n is 0-3.
Represents the integer, and R ² is {X ¹ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ³ O (R ³ represents a C _{1 to} C ₃ alkyl group), Y ¹ represents hydrogen, a hydroxyl group, halogen or R ⁴ A phenyl group represented by O (R ⁴ represents an alkoxy group represented by C _{1 to} C ₃ alkyl group), or (Z ¹ , Z ² and Z ³ each represent hydrogen or a hydroxyl group), A pyridyl group represented by the following formula] is used, wherein 3,5-di-tert-butyl-4-hydroxybenzaldehyde and the general formula (2) R ⁵ —CH ₂ —CONH (CH ₂ ) mR ⁶ (2) [wherein R ⁵ represents hydrogen, a cyano group, a C _{1 to} C ₃ alkyl group, m represents an integer of 0 to 3, and R ⁶ represents {X ² is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ⁷ O (R ⁷ represents a C _{1 to} C ₃ alkyl group), Y ² represents hydrogen, a hydroxyl group, halogen or R ⁸ A phenyl group represented by O (R ⁸ represents an alkoxy group represented by C _{1 to} C ₃ alkyl group), or (Z ⁴ , Z ⁵ and Z ⁶ are all hydrogen or hydroxyl), A pyridyl group represented by] is reacted with a compound represented by
Process for producing 5-di-tert-butyl-4-hydroxycinnamic acid amide derivative. 26. The general formula (1) [Wherein R ¹ represents hydrogen, a cyano group, a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ hydroxyalkyl group, and n is 0-3.
Represents the integer, and R ² is {X ¹ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, an alkoxy group represented by R ³ O (R ³ represents a C ₁ -C ₃ alkyl group), Y ¹ represents hydrogen, a hydroxyl group, halogen or R ⁴ O (R ⁴ represents an alkoxy group represented by C _{1 to} C ₃ alkyl group)},
Or (Z ¹ , Z ² and Z ³ each represent hydrogen or a hydroxyl group), A pyridyl group represented by the formula: {Wherein R ⁹ is hydrogen, a cyano group, a C ₁ -C ₃ alkyl group, or R ¹¹ OR ¹² (wherein R ¹¹ represents hydrogen, a trialkylsilyl group, and R ¹² is a C ₁ -C ₃ alkylene group). A group represented by the formula), R ¹⁰ represents hydrogen or a C ₁ -C ₄ alkyl group} and a compound represented by the general formula (4) H ₂ N (CH ₂ ) lR ¹³ (4) [ Where R ¹³ is {X ³ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ¹⁴ O (R ¹⁴ represents a C _{1 to} C ₃ alkyl group), Y ³ represents hydrogen, a hydroxyl group, halogen or R ¹⁵ O (R ¹⁵ represents a C ₁ -C ₃ alkyl group)
Represents an alkoxy group represented by, or (Z ⁷ , Z ⁸ and Z ⁹ each represent hydrogen or a hydroxyl group), Which represents a pyridyl group represented by the following formula:], and a method for producing a 3,5-di-tertiarybutyl-4-hydroxycinnamic acid amide derivative. 27. The general formula (1) [Wherein R ¹ represents hydrogen, a cyano group, a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ hydroxyalkyl group, and n is 0-3.
Represents the integer, and R ² is {X ¹ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ³ O (R ³ represents a C _{1 to} C ₃ alkyl group), Y ¹ represents hydrogen, a hydroxyl group, halogen or R ⁴ A phenyl group represented by O (R ⁴ represents an alkoxy group represented by C _{1 to} C ₃ alkyl group), or (Z ¹ , Z ² and Z ³ each represent hydrogen or a hydroxyl group), A pyridyl group represented by the following formula] is included in the method for producing a compound represented by the formula: 3,5-di-tert-butyl-4-hydroxybenzaldehyde and the general formula (5) [Wherein R ¹⁶ represents hydrogen, a cyano group, a C ₁ -C ₃ alkyl group, p represents an integer of 0 to 3, and R ¹⁷ represents {X ⁴ is hydrogen, halogen, hydroxyl group, amino group, cyano group,
A nitro group, a trifluoromethyl group, a hydroxymethyl group, or an alkoxy group represented by R ¹⁸ O (R ¹⁸ represents a C _{1 to} C ₃ alkyl group), Y ⁴ represents hydrogen, a hydroxyl group or R ¹⁹ O ( R ¹⁹ represents an alkoxy group represented by C _{1 to} C ₃ ), or a phenyl group represented by (Z ¹⁰ , Z ¹¹ and Z ¹² are all hydrogen or a hydroxyl group), Which represents a pyridyl group, and Ar represents an aryl group]. A method for producing a 3,5-di-tert-butyl-4-hydroxycinnamic acid amide derivative.