JPH06145125A - Carboxamide derivative - Google Patents

Abstract

PURPOSE:To provide a novel carboxamide derivative having a strong ACAT- inhibiting activity and expected as a therapeutic medicine for hyperlipidemia or atherosclerosis. CONSTITUTION:A compound of formula I (R<1>, R<2> are 1-3C alkyl, or R<1> and R<2> together form 1-3C alkylene; R<3> is H, 1-3C alkyl, 2-7C acyl, NH2, 1-3C monoalkyl-substituted amino, 2-6C dialkyl-substituted amino, pyrrolidino, piperidino, morpholino, NO2, OH, 2-7C acyloxy, 1-3C alkoxy, halogeno; R<4> is H, 1-10C alkyl; R<5> is 1-10C alkyl, or R us combined with R to form 2-7C alkylene; R<6>, R<7> are 1-5C alkyl, 1-5C alkoxy, halogen; R<8> is H, 1-5C alkyl, 1-5C alkoxy, NH2, 1-3C monoalkyl-substituted amino, 2-6C dialkyl-substituted amino, pyrrolidino, piperidino, morpholino, halogeno; m,n,p are 0-3), e.g. N-(2,6- diisopropylphenyl)-3-(2,3-me thylenedioxyphenyl) octanamide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a carboxamide derivative useful as a therapeutic drug for hyperlipidemia and a therapeutic drug for atherosclerosis, which has a strong lipid lowering effect.

[0002]

2. Description of the Related Art Hyperlipidemia due to abnormal lipid metabolism is considered to be the cause of arteriosclerosis,
It is also considered to be a risk factor for ischemic heart disease and cerebral infarction. Recently, it was revealed that the enzyme acyl coenzyme cholesterol acyltransferase (ACAT) plays an important role in cholesterol metabolism in lipid metabolism, especially cholesterol metabolism.
Compounds having T inhibitory activity are expected to inhibit cholesterol absorption in the intestinal tract, lower cholesterol in the blood, and inhibit cholesterol ester deposition in the arterial wall.

Therefore, a compound which inhibits ACAT is useful as a therapeutic drug for hyperlipidemia, and further as a therapeutic drug for atherosclerosis. An amide derivative having such an ACAT inhibitory activity is disclosed in Japanese Patent Publication No. 63-54718.
JP-A-63-253060, JP-A-3-1789
No. 54, etc.

[0004]

Means for Solving the Problems The inventors of the present invention searched for compounds having further excellent ACAT inhibitory ability on the basis of these prior arts, found new and useful amide derivatives, and completed the present invention. I came to that. That is, the gist of the present invention is the following general formula (I)

[0005]

[Chemical 2]

(In the above general formula (I), R¹And R²Is
Each independently C₁~ C₃Represents an alkyl group of
¹And R²Are connected and C₁~ C₃To form an alkylene group of
May be R³Is a hydrogen atom, C₁~ C₃An alkyl group of
C₂~ C₇Acyl group, amino group, C₁~ C₃Monoa
Rualkyl-substituted amino group, C₂~ C₆Dialkyl-substituted amino
Group, pyrrolidino group, piperidino group, morpholino group,
Toro group, hydroxyl group, C₂~ C₇Acyloxy
Base, C₁~ C₃The alkoxy group or halogen atom of
And R^FourIs a hydrogen atom or C₁~ C_TenThe alkyl group of
And R^FiveIs C₁~ C _TenRepresents an alkyl group of^FourAnd R
^FiveAre connected and C₂~ C₇May form an alkylene group of
R⁶And R⁷Are each independently C₁~ C_FiveA
Rukiru group, C ₁~ C_FiveAlkoxy group or halogen source
Represents a child, R⁸Is a hydrogen atom, C₁~ C _FiveAn alkyl group of
C₁~ C_FiveAlkoxy group, amino group, C₁~ C₃Mo
Noalkyl-substituted amino group, C₂~ C₆Dialkyl substitution of
Amino group, pyrrolidino group, piperidino group, morpholino group
Or represents a halogen atom, and m, n and p are respectively
It independently represents an integer of 0 to 3. ) Carboxa
The amide derivative or a pharmaceutically acceptable salt thereof.

The present invention will be described in detail below. Starting
The clear compound is represented by the general formula (I). In the formula,
R¹, R²At C₁~ C₃The alkyl group of
Cyl group, ethyl group, n-propyl group, isopropyl group
Can be mentioned. R³C₁~ C₃The alkyl group of
Cyl group, ethyl group, n-propyl group, isopropyl group, etc.
But C₂~ C₇As the acyl group of acetyl group,
Onyl group, benzoyl group, etc. are C ₁~ C₃The monoarch
-Substituted amino groups include methylamino and ethylamino
The base is C₂~ C₆The dialkyl-substituted amino group of is
Dimethylamino group, diethylamino group, etc. are C₂~ C₇
Examples of the acyloxy group include acetyloxy group and propio
Nyloxy group, benzoyloxy group, etc. are C₁~ C₃of
As the alkoxy group, methoxy group, ethoxy group, n-type
Ropoxy group, isopropoxy group, etc.
Fluorine atom, chlorine atom, bromine atom, iodine atom, etc.
Can be mentioned.

Examples of the C ₁ -C ₁₀ alkyl group for R ⁴ and R ⁵ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n.
-Pentyl group, isopentyl group, neopentyl group, n-
Hexyl group, isohexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group and the like can be mentioned. The C ₁ -C ₅ alkyl group of R ⁶ , R ⁷ and R ⁸ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group. , N-pentyl group, sec-pentyl group, neopentyl group and the like, and as the C _{1 to} C ₅ alkoxy group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group. , Sec-butoxy group, tert-butoxy group, n-pentoxy group, sec-pentoxy group, neopentoxy group and the like, and the halogen atom includes fluorine atom, chlorine atom, bromine atom, iodine atom and the like. Examples of the C _{1 to} C ₃ monoalkylamino group of R ⁸ include C _{2 to} C ₆ such as methylamino group and ethylamino group.
Examples of the dialkylamino group include dimethylamino group and diethylamino group.

Some of the compounds of the present invention contain an asymmetric carbon in the molecule, and the optical isomers of these compounds are included in the present invention, not to mention the racemate. In the present invention, R ¹ and R ² : a methyl group, an ethyl group or a linked methylene group and an ethylene group, R ³ : a hydrogen atom, a C _{2 to} C ₄ acyl group, a C _{1 to} C ₃ monoalkylamino group, or dialkylamino group C ₂ ~C _6, R ^4: a hydrogen atom, R ^5: an alkyl group of ^{_{C 2 ~C 8, R 6,}} R 7: alkyl C ₁ -C _5, a C ₁ -C ₅ Alkoxy group or halogen atom, R ⁸ : hydrogen atom, C _{1 to} C ₅ alkoxy group, C _{1 to} C
A compound having a monoalkylamino group of ₃ , a dialkylamino group of C _{2 to} C ₆ or a halogen atom, m: 0 or an integer of n: 0 to 3 and a substituent of p: 0 is preferable, and R ¹ and R ² are Methyl group or linked methylene group, R ³ , R ^{8 respectively}
Is a hydrogen atom or a C ₂ -C ₆ dialkylamino group, R
A compound in which ⁴ represents a hydrogen atom, R ⁵ represents a C _{2 to} C ₈ alkyl group, R ⁶ and R ⁷ represent isopropyl groups, m and p represent 0, and n represents 1 or 2 is particularly preferable.

Next, a method for producing the compound of the present invention will be described.

[0011]

[Chemical 3]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
^{R 6, R 7, R 8} , m, n and p are as previously defined, X is a halogen atom, an alkyloxycarbonyl group, pivaloyloxy group, dichloro phosphoryl group, (- OP (O) Cl 2) , A phthalimidooxy group, a succinimidooxy group, a 1-imidazolyl group, an alkyloxy group and the like. ) The compound (I) of the present invention can be synthesized by converting the phenylalkylcarboxylic acid derivative (II) into the reactive intermediate (III) and then reacting it with the aniline derivative (IV).

The above-mentioned reactive intermediate (III) is a phenylalkylcarboxylic acid chloride (in the formula, X is obtained by reacting a phenylalkylcarboxylic acid derivative (II) with thionyl chloride, phosphorus pentachloride, phosphorus trichloride or the like. A chlorine atom); a mixed acid anhydride obtained by reacting phenylalkylcarboxylic acid (II) with alkyl chloroformate or pivaloyl chloride (wherein X represents an alkyloxycarbonyloxy group or a pivaloyloxy group) Anhydride obtained by reacting phenylalkylcarboxylic acid (II) with phosphoryl chloride (when X represents a dichlorophosphoryloxy group); phenylalkylcarboxylic acid (II) and N-hydroxyphthalimide or N
-Active ester obtained by reacting hydroxysuccinimide (where X represents a phthalimidooxy group or succinimidooxy group); N obtained by reacting phenylalkylcarboxylic acid (II) with carbonyldiimidazole -Acyl derivative (wherein X represents a 1-imidazolyl group); phenylalkylcarboxylic acid (I
Examples thereof include ester derivatives (wherein X represents an alkyloxy group) obtained by reacting I) with a normal alcohol, and the reaction solvent in this case is not particularly limited as long as it does not participate in the reaction. However, for example, methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene, hexane, heptane, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate,
N, N-dimethylformamide etc. are mentioned.

Organic amines not involved in the reaction; for example, triethylamine, pyridine, etc., or inorganic bases;
For example, the presence of sodium hydrogen carbonate, potassium carbonate, etc. allows the reaction to proceed smoothly. The reaction temperature is −
It is 15 ° C to 100 ° C, preferably 0 ° C to 80 ° C. When n = 0, the starting material phenylalkylcarboxylic acid (II) in this production method can be synthesized by a method similar to the synthesis method described in Tetrahedron, 1985 , 4095 by JP, Pieu et al. n
Is 1 to 3, it is derived by a method of increasing the number of carbon atoms by 1 to 3 using a phenylalkylcarboxylic acid having n = 0 as a starting compound. These syntheses can be carried out, for example, by the method described in Shin Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (II) edited by The Chemical Society of Japan, Maruzen (1977), p921.

To give a concrete example, the phenylalkylcarboxylic acid of n = 1 is reduced to a phenylalkylalcohol derivative by reducing the phenylalkylcarboxylic acid of n = 0 with a reducing agent such as lithium aluminum hydride (LiAlH ₄ ). , It is reacted with methanesulfonyl chloride to convert to methanesulfonic acid ester or to phenylalkyl halide using phosphorus halide or the like, and then to phenylalkyl cyanide using sodium cyanide etc. It can be synthesized by hydrolysis using an alkali.

The compound of p = 0 in the amine derivative (IV) as a starting material is publicly known or can be easily obtained by publicly known methods. The compound of p = 1 to 3 is derived from a phenylcarboxylic acid derivative or a phenylhalide derivative by a method of increasing the carbon number by 1 to 3. For example, New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (III), edited by The Chemical Society of Japan, Maruzen (1978).
It can be carried out by the method described in p1332.

The compound of the present invention is administered to humans as a therapeutic agent for hyperlipidemia and a therapeutic agent for atherosclerosis, preferably by oral administration. As the dosage form for oral administration, tablets, granules, powders, capsules and the like are used, and these are the usual additives for the compound of the present invention, such as glucose, lactose, corn starch or mannitol. Forming agent, hydroxypropyl cellulose (H
PC), carboxymethyl cellulose (CMC) and other binders, starch, gelatin powder and other disintegrants, talc, magnesium stearate and other lubricants, and the like, for production.

In the case of oral administration, the dose of the compound of the present invention is about 0.1 mg to 300 mg per day with respect to the components. However, the particular dosage used will vary depending on the needs of the patient, the severity of the illness being treated and the activity of the compound used.

[0019]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples as long as the gist of the present invention is not exceeded. Reference Example 1 3-Synthesis of lithium aluminum hydride (2,3-methylenedioxyphenyl) octanoic acid (LiAlH ₄₎
1.26 g (33 mmol) of tetrahydrofuran (T
HF) 50 ml, and 5.01 g of 2- (2,3-methylenedioxyphenyl) heptanoic acid (20 mmo
1) was added little by little under water cooling. After the reaction solution was stirred at room temperature for 3 hours, 1.26 ml of water, 1.26 ml of 15% sodium hydroxide aqueous solution and 3.78 ml of water were added in that order, and 50 ml of ethyl ether was further added and stirred. The white solid precipitated was filtered off, and the filtrate was concentrated under reduced pressure to give an oily 2- (2,2
3-Methylenedioxyphenyl) heptanol 4.65
g was obtained.

Next, a solution of 6.65 g (28.1 mmol) of 2- (2,3-methylenedioxyphenyl) heptanol in 80 ml of methylene chloride was added with 4.3 ml of triethylamine.
After adding 0 ml (30.9 mmol), 2.28 ml (29.5 mmo) of methanesulfonyl chloride under ice cooling.
l) was added dropwise. After stirring the reaction solution at room temperature for 30 minutes,
It was washed twice with water and dried over anhydrous magnesium sulfate.

The solvent was distilled off to obtain 8.76 g of oily 2- (2,3-methylenedioxyphenyl) heptyl methanesulfonate. The resulting 2- (2,3-methylenedioxyphenyl) heptyl methanesulfonate 8.
76 g (27.9 mmol) of methyl ethyl ketone 70
Dissolve in 10 ml, add 6.6 g of sodium iodide and add 10
Heated to reflux for hours. After cooling, the precipitated salt was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/20), and oily 2- (2,3- 8.36 g of methylenedioxyphenyl) heptyl iodide was obtained.

Next, 8.36 g (24.1 mmo) of 2- (2,3-methylenedioxyphenyl) heptyl iodide.
l) was dissolved in 25 ml of dimethylsulfoxide, 1.42 g (29 mmol) of sodium cyanide was added, and
The mixture was heated and stirred at 0 ° C for 3 hours. After cooling, 75 ml of water was added and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/10) to obtain 3.00 g of oily 2- (2,3-methylenedioxyphenyl) heptyl cyanide.

Next, 3.00 g (12.2 mmo) of 2- (2,3-methylenedioxyphenyl) heptyl cyanide
18 ml of ethylene glycol, 6 ml of water, 3.65 g of potassium hydroxide (purity 85%, 55.3 mmol) in 1).
Was added and the mixture was heated under reflux for 3 hours. After cooling, 60 ml of water was added and hydrochloric acid was added to acidify the mixture. The mixture was extracted twice with ethyl acetate, the extract was washed with saturated brine, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/2) to give an oily 3-
(2,3-methylenedioxyphenyl) octanoic acid 2.
64 g was obtained. ¹ H NMR (CDCl ₃ ): δ = 0.83 (t, 3
H), 1.1-1.3 (m, 6H), 1.57-1.7.
0 (m, 2H), 2.61 to 2.78 (m, 2H),
3.12-3.24 (m, 1H), 5.91 (s, 2
H), 6.63 to 6.79 (m, 3H)

Reference Example 2 Synthesis of (R) -2- (2,3-methylenedioxyphenyl) heptanoic acid (±) -2- (2,3-methylenedioxyphenyl) heptanoic acid and (S) -1 -The salt obtained with phenylethylamine was mixed with a mixed solvent of ethyl acetate-heptane (1: 9) to give 3
Recrystallized twice. Hydrochloric acid was added to this salt and extracted with methylene chloride. The organic layer was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain (R) -2- (2,3-methylenedioxyphenyl) heptanoic acid. Yield 39
%, Mp 47-48 ° C., [α] _D ²⁵ -64.5 ° (M
eOH, c = 1.01)

Reference Example 3 In the same manner as in Reference Example 1 except that various carboxylic acids were used instead of 2- (2,3-methylenedioxyphenylheptanoic acid) in Reference Example 1, the number of carbon atoms shown below was increased by one. Carboxylic acid was synthesized 3- (2,3-dimethoxyphenyl) octanoic acid 3- (2,3-dimethoxyphenyl) heptanoic acid 3- (2,3-dimethoxyphenyl) nonanoic acid (R) -3- (2 , 3-Methylenedioxyphenyl) octanoic acid (S) -3- (2,3-methylenedioxyphenyl) octanoic acid (S)-(2,3-dimethoxyphenyl) octanoic acid

Reference Example 4 Synthesis of 4- (2,3-methylenedioxyphenyl) nonanoic acid 0.40 g of sodium hydride (60% oil dispersion, 10 mmol) was added to 10 ml of N, N-dimethylformamide and added thereto. 1.60 g (10 mmol) of malonic acid diethyl ester was added dropwise under ice cooling. Thirty
After stirring for 2 minutes, 2- which is the synthetic intermediate in Reference Example 1
A solution of 3.14 g (10 mmol) of (2,3-methylenedioxyphenyl) heptylmethanesulfonate in 6 ml of N, N-dimethylformamide was added, and 1.50 g (10 mmol) of sodium iodine was added to give 100.
The mixture was stirred at 0 ° C for 2 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/10) to give an oily 2-
1.49 g of (2,3-methylenedioxyphenyl) heptylmalonic acid diethyl ester was obtained.

The resulting 2- (2,3-methylenedioxyphenyl) heptylmalonic acid diethyl ester 1.
Dissolve 49 g (3.94 mmol) in 10 ml of ethanol, add 6.6 g of 10% sodium hydroxide aqueous solution,
The mixture was heated under reflux for 2 hours and 30 minutes. The reaction solution is concentrated under reduced pressure and water 5
ml and concentrated sulfuric acid 0.8 ml were added, and the mixture was heated under reflux for 4 hours.
After cooling, the mixture was extracted with ethyl acetate, the extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/2), and oily 4- (2,3-methylenedioxyphenyl) was obtained.
0.92 g of nonanoic acid was obtained. ¹ H NMR (CDCl ₃ ): δ = 0.84 (t, 3
H), 1.05 to 1.30 (m, 6H), 1.55
1.70 (m, 2H), 1.85 to 2.07 (m, 2)
H), 2.19 to 2.26 (m, 2H), 2.66 to
2.78 (m, 1H), 5.91 (s, 2H), 6.6
0 to 6.80 (m, 3H)

Reference Example 5 Synthesis of 4- (2,3-dimethoxyphenyl) nonanoic acid Instead of 2- (2,3-methylenedioxyphenyl) heptylmethanesulfonate in Reference Example 4, 2- (2,3-methylenedioxyphenyl) heptylmethanesulfonate was used.
In the same manner as in Reference Example 4 using (2,3-dimethoxyphenyl) heptyl methanesulfonate, 4- (2,3-
Dimethoxyphenyl) nonanoic acid was synthesized.

Reference Example 6 Synthesis of 3- (5-acetyl-2,3-dimethoxyphenyl) octanoic acid 800 mg (6.00 mmol) of anhydrous aluminum chloride
0.43 ml (6.05 mmol) of acetyl chloride was added to a mixed solution of 5 ml of methylene chloride of 4 under stirring with ice cooling, and further 3
A solution of 925 mg (3.00 mmol) of-(2,3-dimethoxyphenyl) octanoic acid ethyl ester in 3 ml of methylene chloride was added dropwise. After reacting for 20 minutes under ice-cooling, the reaction solution was added little by little to ice water and then separated to separate the organic layer. The aqueous layer was extracted with methylene chloride, the organic layers were combined, washed with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/5) to give 3- (5-acetyl-2,
3-Dimethoxyphenyl) octanoic acid ethyl ester 9
00 mg (yield 86%) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ): δ = 0.83 (3H,
t), 1.14 (3H, t), 1.22 (6H, m),
1.62 (2H, m), 2.58 (3H, s), 2.6
4 (2H, m), 3.56 (1H, m), 3.91 (6
H, s), 4.04 (2H, q), 7.40 (2H,
m) To a solution of 890 mg (2.54 mmol) of the oil obtained above in 10 ml of ethanol was added 180 m of 95% sodium hydroxide.
3 ml of an aqueous solution of g (4.27 mmol) was added and the mixture was heated under reflux for 1 hour. Ethanol was distilled off under reduced pressure, the remaining aqueous solution was acidified with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the desired 3- (5-acetyl-2,3).
820 mg of -dimethoxyphenyl) octanoic acid (yield 1
00%).

Reference Example 7 Synthesis of 2- (2,3-dimethoxybenzyl) heptanoic acid A suspension of 440 mg (11 mmol) of 60% sodium hydride in 5 ml of dimethylformamide was stirred while cooling with ice.
2.30 g of pentylmalonic acid diethyl ester (10 m
mol) in 5 ml of dimethylformamide and added to 30
After stirring for 1 minute, 2,3-dimethoxybenzyl chloride 1.86 g (10 mmol) dimethylformamide 5
The ml solution was added dropwise. The reaction mixture was stirred at 70 ° C. for 1 hour, cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate /
Purified with hexane = 1/12), 2,3-dimethoxybenzyl-n-pentylmalonic acid diethyl ester 2.
78 g (73% yield) was obtained as a colorless oil.

2.77 g (7.28 mmo) of the above oil
10 ml of an aqueous solution of 1.25 g (29.7 mmol) of 95% sodium hydroxide was added to a solution of 1) in 20 ml of ethanol, and the mixture was heated under reflux at 100 ° for 4 hours and then post-treated as usual to obtain only one ethyl ester. 1.54 g (yield 75%) of the hydrolyzed half ester compound was obtained. 560 mg of this half ester was collected, 4 ml of ethylene glycol and 2 ml of water were added, 500 mg of 85% potassium hydroxide was further added, and the reaction mixture was reacted for 4 hours on an oil bath heated to 150 °. After cooling, water was added and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 430 mg of the desired 2- (2,3-dimethoxybenzyl) heptanoic acid as a colorless oil. ¹ H NMR (CDCl ₃ ): δ = 0.87 (3H,
t), 1.27 (6H, m), 1.55 (2H, m),
2.77 (1H, m), 2.90 (2H, m), 3.8
3 (3H, s), 3.85 (3H, s), 6.78 (2
H, m), 6.96 (1H, m)

Example 1 N- (2,6-diisopropylphenyl) -3- (2,2
Synthesis of 3-methylenedioxyphenyl) octanamide To a solution of 2.64 g (10 mmol) of 3- (2,3-methylenedioxyphenyl) octanoic acid in 25 ml of methylene chloride, 1.46 ml (20 mmol) of thionyl chloride, N,
After adding 0.1 ml of N-dimethylformamide and stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure to give crude oil 3-
(2,3-Methylenedioxyphenyl) octanoic acid chloride was obtained. This acid chloride was dissolved in 15 ml of methylene chloride and cooled with water to give 2,6-diisopropylaniline.
95 g (11 mmol), triethylamine 1.67 m
1 (12 mmol) of 40 ml of methylene chloride was added dropwise with stirring. After stirring for 2 hours, the reaction solution was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/6), crystallized from hexane, and 3.60 g (yield 85%) of N- (2 , 6-
Diisopropylphenyl) -3- (2,3-methylenedioxyphenyl) octanamide was obtained as white crystals. Melting point: 114-115 ° C ¹ H NMR (CDCl ₃ ): δ = 0.85 (t, 3
H), 1.0 to 1.2 (m, 12H), 1.20 to 1.
32 (m, 6H), 1.57 to 1.74 (m, 2H),
2.50 to 2.92 (m, 4H), 3.22 to 3.40
(M, 1H), 5.94 (d, 2H), 6.54 (s,
1H), 6.72 to 6.84 (m, 3H), 7.07 to
7.26 (m, 4H)

Example 2-12 In the same manner as in Example 1, except that the carboxylic acid synthesized in Reference Examples 2 to 7 was used instead of 3- (2,3-methylenedioxyphenyl) octanoic acid in Example 1. The following compounds were synthesized.

Example 2 N- (2,6-diisopropylphenyl) -3- (2,2
3-dimethoxyphenyl) octanamide Melting point: 102-103 ° C. ¹ H NMR (CDCl ₃ ): δ = 0.84 (3H,
t), 1.02 (12H, m), 1.25 (6H,
m), 1.68 (2H, m), 2.59 (2H, m),
2.78 (2H, m), 3.63 (1H, m), 3.8
5 (6H, s), 6.82 (3H, m), 7.07 (3
H, m), 7.22 (1H, m)

Example 3 N- (2,6-diisopropylphenyl) -3- (2,2
3-dimethoxyphenyl) heptanamide Melting point: 89-91 ° C ¹ H NMR (CDCl ₃ ): δ = 0.85 (t, 3)
H), 1.00 to 1.10 (m, 12H), 1.12
1.36 (m, 4H), 1.64 to 1.75 (m, 2
H), 2.55 to 2.65 (m, 2H), 2.79.
(D, 2H), 3.57 to 3.71 (m, 1H), 3.
85 (s, 3H), 3.86 (s, 3H), 6.79-
6.90 (m, 3H), 7.04 to 7.11 (m, 3)
H), 7.19 to 7.25 (m, 1H)

Example 4 N- (2,6-diisopropylphenyl) -3- (2,2
3-dimethoxyphenyl) nonanamide Melting point: 101-102 ° C. ¹ H NMR (CDCl ₃ ): δ = 0.85 (t, 3)
H), 1.03 (t, 12H), 1.07 to 1.33
(M, 8H), 1.57 to 1.73 (m, 2H), 2.
55-2.71 (m, 2H), 2.79 (d, 2H),
3.56 to 3.70 (m, 1H), 3.84 (s, 3
H), 3.85 (s, 3H), 6.79 to 6.95.
(M, 3H), 7.04 to 7.10 (m, 3H), 7.
14 to 7.25 (m, 1H)

Example 5 N- (2,6-diisopropylphenyl) -2- (2,2
3-Methylenedioxyphenyl) heptanamide Melting point: 142-143 ° C ¹ H NMR (CDCl ₃ ): δ = 0.89 (t, 3)
H), 1.06 (t, 12H), 1.28 to 1.43
(M, 6H), 1.86 to 1.98 (m, 1H), 2.
24-2.33 (m, 1H), 2.79-2.88
(M, 2H), 3.79 (t, 1H), 5.98-6.
00 (m, 2H), 6.72 to 7.27 (m, 7H)

Example 6 (R) -N- (2,6-diisopropylphenyl) -3
-(2,3-Methylenedioxyphenyl) octanamide Melting point: 127-128 ° C ¹ H NMR (CDCl ₃ ): racemic example 1
N- (2,6-diisopropylphenyl) -synthesized in
Similar to 3- (2,3-methylenedioxyphenyl) octanamide. This compound was subjected to high performance liquid chromatography (column; ULTRON ES-OVM) equipped with an optically active column.
(Manufactured by Shinwa Kako Co., Ltd.), eluent; methanol-water = 43.
5: 56.5, flow rate; 0.7 ml / min, detection; UV27
Peak at 17 minutes at 0 nm).

Example 7 (S) -N- (2,6-diisopropylphenyl) -3
-(2,3-Methylenedioxyphenyl) octanamide Melting point: 126-127 ° C ¹ H NMR (CDCl ₃ ): racemic N-
(2,6-diisopropylphenyl) -3- (2,3-
Similar to methylenedioxyphenyl) octanamide. This compound showed a peak at 33 minutes in high performance liquid chromatography equipped with an optically active column (conditions were the same as in Example 6).

Example 8 N- (2,6-diisopropylphenyl) -4- (2,2
3-Methylenedioxyphenyl) nonanamide Melting point: 123 ° C. ¹ H NMR (CDCl ₃ ): δ = 0.84 (t, 3)
H), 1.02 to 1.26 (m, 18H), 1.40
2.30 (m, 6H), 2.78 to 2.84 (m, 1
H), 2.98-3.10 (m, 2H), 5.91-
5.94 (m, 2H), 6.44 to 6.85 (m, 4
H), 7.11 to 7.32 (m, 3H)

Example 9 N- (2,6-diisopropylphenyl) -4- (2,2
3-dimethoxyphenyl) nonanamide Melting point: 99-100 ° C. ¹ H NMR (CDCl ₃ ): δ = 0.85 (t, 3)
H), 1.02 to 1.27 (m, 18H), 1.63 to
2.20 (m, 6H), 3.00 to 3.11 (m, 2
H), 3.11 to 3.30 (m, 1H), 3.80.
(S, 3H), 3.88 (s, 3H), 6.78-6.
89 (m, 3H), 7.05 to 7.28 (m, 4H)

Example 10 N- (2,6-diisopropylphenyl) -3- (5-
Acetyl-2,3-dimethoxyphenyl) octanamide Melting point: 99-101 ° C ¹ H NMR (CDCl ₃ ): δ = 0.84 (3H,
t), 1.00 (12H, m), 1.25 (6H,
m), 1.69 (2H, m), 2.58 (2H, m),
2.59 (3H, s), 2.83 (2H, m), 3.7
4 (1H, m), 3.92 (6H, s), 6.75 (1
H, s), 7.07 (2H, m), 7.21 (1H,
m), 7.44 (1H, d, J = 1.9 Hz), 7.5
2 (1H, d, J = 1.9Hz)

Example 11 N- (2,6-diisopropylphenyl) -2- (2,2
3-dimethoxybenzyl) heptanamide Melting point: 128-130.5 ° C. ¹ H NMR (CDCl ₃ ): δ = 0.90 (3H,
t), 1.07 (12H, m), 1.3 to 1.6 (7
H, m), 1.84 (1H, m), 2.7 to 3.1 (5
H, m), 3.87 (6H, s), 6.62 (1H,
s), 6.8 to 7.3 (6H, m)

Example 12 (S) -N- (2,6-diisopropylphenyl) -3
-(2,3-Dimethoxyphenyl) octanamide Melting point: 100-101 ° C ¹ H NMR (CDCl ₃ ): racemic example 2
Similar to compound. This compound was subjected to high performance liquid chromatography equipped with an optically active column (conditions are similar to those in Example 6).
It showed a peak at 4 minutes. Under this condition, the racemic compound of Example 2 showed the same intensity peaks at 11.3 minutes and 18.4 minutes.

Example 13 (R) -N- (2,4,6-trifluorophenyl)-
Synthesis of 3- (2,3-methylenedioxyphenyl) octaneamide From (R) -3- (2,3-methylenedioxyphenyl) octanoic acid 0.86 g (3.25 mmol), the same procedure as in Example 1 was conducted. Acid chloride was synthesized. This acid chloride was dissolved in 5 ml of methylene chloride and added dropwise to a solution of 571 mg (3.88 mmol) of 2,4,6-trifluoroaniline and 0.54 ml (3.9 mmol) of triethylamine in 15 ml of methylene chloride. After stirring overnight, the reaction solution was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/5) and recrystallized from a mixed solvent of hexane and a small amount of ethyl acetate to give white crystals (R ) -N- (2,4,6-Trifluorophenyl) -3- (2,3-methylenedioxyphenyl) octanamide (1.11 g, yield 87%) was obtained. Melting point: 88-89 ° C. ¹ H NMR (CDCl ₃ ): δ = 0.84 (t, 3
H), 1.15 to 1.30 (m, 6H), 1.70 to
1.73 (m, 2H), 2.70 to 2.80 (m, 2)
H), 3.21 to 3.33 (m, 1H), 5.92 to
9.95 (m, 2H), 6.61 to 6.82 (m, 6
H)

Example 14 (R) -N- (2,4,6-trimethoxyphenyl)-
3- (2,3-Methylenedioxyphenyl) octanamide In the same manner as in Example 12, except that 2,4,6-trimethoxyaniline was used instead of 2,4,6-trifluoroaniline in Example 12. (R) -N- (2,4,6-
Trimethoxyphenyl) -3- (2,4-methylenedioxyphenyl) octanamide was obtained as an oil. ¹ H NMR (CDCl ₃ ): δ = 0.83 (t, 3
H), 1.20 to 1.30 (m, 6H), 1.65
1.80 (m, 2H), 2.66 to 2.78 (m, 2
H), 3.21 to 3.33 (m, 1H), 3.71
(S, 6H), 3.78 (s, 3H), 5.91-5.
94 (m, 2H), 6.10 (s, 2H), 6.44
(S, 1H), 6.70 to 6.77 (m, 3H)

Reference Example 8 Synthesis of 2,6-diisopropylbenzylamine 7.09 g (40 mm) of 2,6-diisopropylaniline
ol) was added to a solution of 54 ml of water and 18 ml of concentrated hydrochloric acid, and 2.76 g of sodium nitrite (4
0 mmol) aqueous solution (water, 16 ml) was added dropwise, and the mixture was further stirred for 10 minutes. 6.64 g of potassium iodide
An aqueous solution of (40 mmol) (6 ml of water) was added, and the mixture was stirred at room temperature for 4 hours and then heated under reflux for 1 hour. After cooling, the mixture was extracted with hexane, the extract was washed with an aqueous solution of sodium sulfite, then with saturated saline, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent: hexane) to obtain 5.09 g of oily 2,6-diisopropylphenyl iodide.

Next, 5.09 g (17.7 mmol) of 2,6-diisopropylphenyl iodide was dissolved in 70 ml of anhydrous ethyl ether, and 11.1 ml (17 ml of 1.6M n-butyllithium hexane solution at -20 ° C). 0.8 mm
ol) was added dropwise. The reaction solution was heated to 0 ° C., stirred for 1 hour, and then poured into about 100 g of dry ice. After gradually warming to room temperature, 50 ml of water was added, and the aqueous layer was made alkaline with an aqueous sodium hydroxide solution. The organic layer was separated, the aqueous layer was washed with ethyl ether, acidified with concentrated hydrochloric acid, and extracted with ethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain 2.53 g of white solid 2,6-diisopropylbenzoic acid.

Next, 1.35 g (35.6 mmol) of lithium aluminum hydride was added to 60 ml of anhydrous tetrahydrofuran, 3.71 g (18 mmol) of 2,6-diisopropylbenzoic acid was further added, and the mixture was heated under reflux for 16 hours. After cooling, 80 ml of water was added little by little, then 90 ml of ethyl ether was added, and then concentrated hydrochloric acid was added to make the aqueous layer strongly acidic. The layers were separated, the aqueous layer was extracted with ethyl ether, the combined organic layers were washed with aqueous sodium hydroxide solution, then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 2,6-as a white solid.
1.37 g of diisopropylbenzyl alcohol was obtained.

Then, 1.37 g (7.12 mmol) of 2,6-diisopropylbenzyl alcohol was added to toluene 20.
Dissolve in 0.7 ml of thionyl chloride 0.78 ml (10.7 m
(mol) was added and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.49 g of oily 2,6-diisopropylbenzyl chloride.

Next, 0.92 g (4.4 mmol) of 2,6-diisopropylbenzyl chloride and 0.97 g (5.24 mmol) of potassium phthalimide were added to 8 ml of N, N-dimethylformamide, and the mixture was kept at 70 ° C. for 1.5 hours. It was stirred. It was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 15 ml of hexane in the residue,
After adding 2 ml of ethyl acetate and stirring at room temperature, the precipitated crystals were collected by filtration to obtain 1.01 g of N- (2,6-diisopropylbenzyl) phthalimide.

Next, 1.01 g (3.14 mmol) of N- (2,6-diisopropylbenzyl) phthalimide,
0.3 ml of hydrazine hydrate was added to 15 ml of methanol, and the mixture was heated under reflux for 3.5 hours. The reaction solution was concentrated under reduced pressure, 20 ml of water and 40 ml of methylene chloride were added, and the mixture was made alkaline with an aqueous sodium hydroxide solution. The organic layer was separated, washed with dilute aqueous sodium hydroxide and then with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give an oily 2.
0.53 g of 6-diisopropylbenzylamine was obtained. ¹ H NMR (CDCl ₃ ): δ = 1.27 (d, 12
H), 1.37 (broad S, 2H), 3.20 ~.
3.37 (m, 2H), 3.93 (s, 2H), 7.1
4 to 7.27 (m, 3H)

Example 15 (R) -N- (2,6-diisopropylbenzyl) -3
Synthesis of-(2,3-methylenedioxyphenyl) octanamide (R) -3- (2,3-methylenedioxyphenyl) octanoic acid 407 mg (1.54 mmol) of THF 8m
Under ice cooling, 0.24 ml of triethylamine and then 0.15 ml (1.6 mmol) of ethyl chloroformate were added to the 1 solution. After stirring for 20 minutes, a tetrahydrofuran solution of 264 mg (1.38 mmol) of 2,6-diisopropylbenzylamine was added, and the mixture was stirred at room temperature for 2 hours. Water (10 ml) was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give (R) -N- (2,6-diisopropylbenzyl) -3- (2,2). 3-Methylenedioxyphenyl) octanamide 348 mg (yield 52%)
Was obtained as white crystals. Melting point: 133-134 ° C ¹ H NMR (CDCl ₃ ): δ = 0.83 (t, 3)
H), 1.15 to 1.26 (m, 18H), 1.60
1.70 (m, 2H), 2.48 to 2.52 (m, 2)
H), 2.90 to 3.06 (m, 2H), 3.12 to
3.21 (m, 1H), 4.31 (dd, 1H), 4.
50 (dd, 1H), 5.23 (broadS, 1
H), 5.64 (d, 1H), 5.78 (d, 1H),
6.62-6.78 (m, 3H), 7.14-7.32.
(M, 3H)

Example 16 N- (2,6-diisopropylbenzyl) -2- (2,2
Synthesis of 3-methylenedioxyphenyl) heptanamide Instead of (R) -3- (2,3-methylenedioxyphenyl) octanoic acid in Example 14, (R) -2-
N- (2,6-diisopropylbenzyl) -2- (2,3-methylenedioxyphenyl) heptanamide was obtained in the same manner as in Example 14 using (2,3-methylenedioxyphenyl) heptanoic acid. It was Melting point: 134-135 ° C ¹ H NMR (CDCl ₃ ): δ = 0.88 (t, 3)
H), 1.11 to 1.35 (m, 18H), 1.74 to
1.83 (m, 1H), 2.12 to 2.20 (m, 1
H), 3.02 to 3.12 (m, 2H), 3.46.
(T, 1H), 4.42 (dd, 1H), 4.52 (d
d, 1H), 5.49 (broad S, 1H), 5.
73-5.76 (m, 2H), 6.68-6.86
(m, 3H), 7.12-7.31 (m, 3H)

Reference Example 9 Synthesis of 3- (2,3-dimethoxy-5-nitrophenyl) octanoic acid 1.13 g (3.66 mmol) of ethyl 3- (2,3-dimethoxyphenyl) octanoate was added to 60% nitric acid. Stirred in 3 ml at room temperature for 2 hours. After adding water, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/5) to give 3-
1.15 g (yield 89%) of (2,3-dimethoxy-5-nitrophenyl) octanoic acid ethyl ester was obtained as a yellow oil. This product is ¹ H NMR (CDCl ₃ )
Gives a coupling constant of J = 2.6 Hz, which indicates meta-coupling at. Furthermore, 3- (2,3-dimethoxy-6)
-Nitrophenyl) octanoic acid ethyl ester 0.10
g (yield 7.7%) was also obtained, and ¹ H NMR
The coupling constant in (CDCl ₃ ) is J = 9.1 Hz
Met.

3- (2,3-Dimethoxy-5-nitrophenyl) octanoic acid ethyl ester obtained above 1.
A mixture of 15 g (3.25 mmol) and 85% potassium hydroxide 0.46 g (698 mmol) was added to ethanol 2
After reacting in 5 ml and 10 ml of water at room temperature for 2 hours and further at 50 ° for 30 minutes, the mixture was distilled off under reduced pressure with ethanol, the remaining aqueous solution was acidified with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give the desired 3- (2,3-dimethoxy-5-nitrophenyl) octanoic acid 1.06 g.
(Yield 100%) was obtained.

Example 17 N- (2,6-diisopropylphenyl) -3- (2,2
Synthesis of 3-dimethoxy-5-dimethylaminophenyl) octanamide 3- (2,3-dimethoxy-5-nitrophenyl) octanoic acid and 2,6-diisopropylaniline are condensed by a conventional method to give N- (2,6 -Diisopropylphenyl) -3- (2,3-dimethoxy-5-nitrophenyl) octanamide was obtained. Obtained amide 1.17
g (2.41 mmol) in 5% ethanol 40 ml solution
% Palladium-carbon (200 mg), and under hydrogen atmosphere
Contact hydrogenation was carried out at 0 ° for 4 hours. After removing the catalyst by filtration, 2
After adding 1 ml of a 2% hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure. 40 ml of ethanol, 1 ml of 37% aqueous formalin solution and 300 mg of 5% palladium-carbon were added, and contact hydrogenation was carried out again at 50 ° for 4 hours in a hydrogen atmosphere. The catalyst was filtered off, ethanol was distilled off, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added and the layers were separated, and the organic layer was separated. After drying over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent:
Purified with ethyl acetate / hexane = 1/3) and crystallized from hexane to give white crystals of N- (2,6-diisopropylphenyl) -3- (2,3-dimethoxy-5-dimethylaminophenyl) octane. 620 mg (53% yield) of amide was obtained. Melting point: mp121-123 ° C. ¹ H NMR (CDCl ₃ ): δ = 0.88 (3H,
t), 1.04 (12H, m), 1.28 (6H,
m), 1.68 (2H, m), 2.65 (2H, m)
2.81 (2H, m), 2.93 (6H, s), 3.5
2 (1H, m), 3.78 (3H, s), 3.84 (3
H, s), 6.16 (1H, d, J = 2.6 Hz),
6.22 (1H, d, J = 2.6 Hz), 7.02 (1
H, s), 7.1-7.3 (3H, m)

Reference Example 10 Synthesis of 2,6-diisopropyl-3-dimethylaminoaniline 2,6-diisopropylformanilide was nitrated in 98% sulfuric acid and 60% nitric acid to prepare 2,6-diisopropyl-
3-Nitroformanilide was obtained. The nitro group was reduced to 3-amino-2,6-diisopropylformanilide according to a conventional method, and then hydrogenated using palladium as a catalyst in the presence of formalin to give 2,6-diisopropyl-3-dimethylaminoform. I got Anilid. This was heat-treated with concentrated hydrochloric acid in ethanol and then neutralized with 25% aqueous sodium hydroxide to obtain 2,6-diisopropyl-3-dimethylaminoaniline.

Reference Example 11 Synthesis of 2,6-diisopropyl-4-dimethylaminoaniline 8.7 g of N- (2,6-diisopropylphenyl) -p-toluenesulfonamide was added to 6.3 ml of 60% nitric acid, 50 ml of water and acetic acid. After adding 50 ml and further adding 0.18 g of sodium nitrite, the mixture was stirred with heating under reflux for 5 hours. After cooling the reaction solution, 200 ml of water was added and the precipitated crystals were collected by filtration and recrystallized with 50 ml of ethanol to give N- (2,
There was obtained 4.7 g of 6-diisopropyl-4-nitrophenyl) -p-toluenesulfonamide. This was hydrolyzed in sulfuric acid-water to obtain 2.7 g of 2,6-diisopropyl-4-nitroaniline.

Next, 2,6-diisopropyl-4-nitroaniline was converted to 2,6-diisopropyl-4-nitroformanilide by a conventional method, and hydrogenated in the presence of formalin using palladium as a catalyst to give 2,6- Diisopropyl-4-dimethylaminoformanilide was obtained, which was heat-treated with concentrated hydrochloric acid in ethanol and then neutralized with 25% aqueous sodium hydroxide to obtain 2,6-diisopropyl-4-dimethylaminoaniline.

Example 18 Synthesis of (R) -N- (2,6-diisopropyl-3-dimethylaminophenyl) -3- (2,3-methylenedioxyphenyl) octanamide hydrochloride (R) -3- 1.3 g (4.9 mmol) of (2,3-methylenedioxyphenyl) octanoic acid was added to methylene chloride 2
It was dissolved in 0 ml, thionyl chloride (1.1 ml) and N, N-dimethylformamide (0.1 ml) were added, and the mixture was stirred under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and (R) -3- (2,3-
An oil of methylenedioxyphenyl) octanoic acid chloride was obtained. Dissolve this oil in methylene chloride,
-Diisopropyl-3-dimethylaniline 1.08 g
(4.9 mmol), 1.0 ml of triethylamine and 20 ml of methylene chloride were added dropwise to a solution cooled to 5 to 10 ° C. After overnight reaction at room temperature, purification by silica gel column chromatography (eluent, ethyl acetate / hexane) gave 1.16 g of a candy-like substance. Dissolve this in acetone and add 2 ml of hydrogen chloride in ethyl acetate (concentration 22%).
Is added to form a hydrochloride, which is then concentrated and crystallized from hexane. 1.23 g of salt was obtained. (Yield 50%) Melting point: 114-116 ° C. ¹ H NMR (CDCl ₃ ): δ = 0.86 (t, 3)
H), 0.99 (m, 6H), 1.26 (d, 12)
H), 1.70 (m, 2H), 2.73 to 3.34.
(M, 10H), 3.82 (broad S, 1H),
5.93 (d, 2H), 6.70 to 6.80 (m, 3
H), 7.01 (broad S, 1H), 7.24
(Broad S, 2H)

Example 19 Synthesis of (R) -N- (2,6-diisopropyl-4-dimethylaminophenyl) -3- (2,3-methylenedioxyphenyl) octane amide hydrochloride 2,2 in Example 17 2,6-Diisopropyl-4-dimethylaminoaniline was used in place of 6-diisopropyl-3-dimethylaminoaniline in the same manner as in Example 17 to obtain (R) -N- (2,6-diisopropyl-4).
-Dimethylaminophenyl) -3- (2,3-methylenedioxyphenyl) octanamide, hydrochloride was obtained. Melting point: 158-160 ° C. ¹ H NMR (CDCl ₃ ): δ = 0.85 (t, 3
H), 1.03 (d, 12H), 1.14 (m, 6
H), 1.69 (m, 2H), 2.73 to 2.96.
(M, 4H), 3.05 (s, 6H), 3.32 (m,
1H), 5.94 (dd, 2H), 6.72 to 6.83
(M, 3H), 6.89 (broad S, 1H),
7.27 (broad S, 2H) The following Table 1 was prepared by the same method as in Examples 1 to 19 below.
Compounds 1-152 shown in 2, 3, 4, 5, 6 and 7 can be synthesized.

The meaning of each symbol in the following Table-1 to Table-7 is as follows. Me: methyl group, Et: ethyl group, n-Pr: normal propyl group, i-Pr: isopropyl group, n-Bu: normal butyl group, n-P
e: normal pentyl group, n-Hex: normal hexyl group, n-Hep: normal heptyl group, Ph: phenyl group, Pip: piperidino group, and the number before the substituent indicates a substitution position, and the number is a phenyl group Corresponds to the number attached to.

[0064]

[Table 1]

[0065]

[Table 2]

[0066]

[Table 3]

[0067]

[Table 4]

[0068]

[Table 5]

[0069]

[Table 6]

[0070]

[Table 7]

[0071]

[Table 8]

Test Example The ACAT inhibitory action of the compound of the present invention was measured by the following method. Human liver cancer cell-derived HepG2 cells were used to measure the activity of ACAT. It was determined by adding a radiolabeled oleic acid-bovine serum albumin complex to the culture medium of the same cells and measuring the amount of radiolabeled cholesterol oleate formed from the radiolabeled oleic acid in the cells. Therefore, the activity of the compound of the present invention that inhibits ACAT was determined by determining what percentage the addition of each concentration (μM) of the test drug reduced the cholesterol oleate production of the control group to which the test drug was not added, Than that I
The C50 value, that is, the concentration of the test compound required to inhibit 50% expression of the enzyme was expressed. The results are shown in Table 8 below.

[0073]

[Table 9]

[0074]

INDUSTRIAL APPLICABILITY The compound of the present invention has a strong ACAT inhibitory activity and is expected to be used as a therapeutic drug for hyperlipidemia or a therapeutic drug for atherosclerosis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical display location C07D 295/08 Z 317/60 (72) Inventor Kazuo Suzuki 1000, Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa Sanryo Kasei Co., Ltd.

Claims (1)

[Claims] 1. The following general formula (I):(In the above general formula (I), R¹And R²Are independent
Then C₁~ C₃Represents an alkyl group of¹And R²Are
Tie and C₁~ C₃R may form an alkylene group of R
³Is a hydrogen atom, C₁~ C₃Alkyl group of C₂~ C₇of
Acyl group, amino group, C₁~ C₃The monoalkyl-substituted
Mino group, C₂~ C₆Dialkyl-substituted amino group of
Dino group, piperidino group, morpholino group, nitro group, hydr
Roxyl group, C₂~ C₇Acyloxy group, C₁~ C₃
Represents an alkoxy group or a halogen atom of R,^FourIs hydrogen
Atom or C₁~ C_TenRepresents an alkyl group of R,^FiveIs C₁
~ C _TenRepresents an alkyl group of^FourAnd R^FiveAre connected and C
₂~ C₇R may form an alkylene group of R⁶and
R⁷Are each independently C₁~ C_FiveAlkyl group of C ₁
~ C_FiveRepresents an alkoxy group or a halogen atom of R,⁸
Is a hydrogen atom, C₁~ C _FiveAlkyl group of C₁~ C_FiveA
Lucoxy group, amino group, C₁~ C₃Monoalkyl substitution of
Amino group, C₂~ C₆A dialkyl-substituted amino group of, pyro
Lysino group, piperidino group, morpholino group or halogen
Represents an atom, and m, n and p are each independently 0 to 3
Represents the integer. ) Carboxamide derivative represented by
Is a pharmaceutically acceptable salt thereof.