JPH0588693B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel caproic acid derivatives.
That is, the present invention has the following general formula:

[Formula, R ₁ and R ₂ are each H or CH ₃
, R ₃ is H, CH ₃ , C ₂ H ₅ ,

[Formula] or

This invention relates to a novel 6-{4'-[4-phenylbutyl]phenoxy}-2,2-dimethylcaproic acid derivative represented by the following formula. As described below, the compound represented by the general formula according to the present invention exhibits a significant physiological effect in animal tests, and this physiological effect is effective against symptoms generally referred to as adult diseases, so it can be used as a medicine. It is a useful compound. As a method for producing the compound according to the present invention, a method as shown in the following reaction formula can be exemplified.

【formula】

[ka]

【formula】

[ka]

[Chemical Formula] (In the formula, R ₁ and R ₂ each represent H or CH ₃ , R ₃ represents an alkyl group such as CH ₃ , C ₂ H ₅ , C ₃ H ₇ or C ₄ H ₉ , X' represents a halogen such as Cl, Br, I, etc., and Me is
Represents an alkali metal such as Li, Na, or K. ) This manufacturing method will be explained in detail below. The phenol compound of the above formula [1] is mixed with an aprotic solvent such as dimethyl ether, diethyl ether, dipropyl ether, THF, dioxane, benzene, toluene, xylene, pentane,
Bases such as sodium hydride, lithium hydride, aluminum hydride, ethyllithium, n-propyllithium, isopropyllithium, n-butyllithium, isobutyl in solution in hexane, heptane, petroleum ether, dimethyl sulfoxide, etc. Lithium, n-pentyllithium, phenyllithium, sodium ethoxide,
Sodium propoxide, sodium butoxide, lithium ethoxide, lithium propoxide, lithium butoxide, potassium propoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, etc. are added at -10 to 20°C. In this case, the ratio of the above base/compound of formula [] is 1
-3, preferably 1-1.2. The reaction temperature at this time is 10 to 40°C, preferably 20 to 25°C, and the reaction time is 10 to 60 minutes, preferably 30 to 40 minutes. After the reaction is complete, 1,4-dihalogeno is added to the reaction mixture.
n-butane, e.g. 1,4-dichloro-n-butane, 1,4-dibromo-n-butane, 1,4-
Add diiodo-n-butane, 1-chloro-4-bromo-n-butane, 1-chloro-4-iodo-n-butane, etc. for 2 to 30 hours, preferably 5 to 15 hours.
Heat to reflux for an hour. Then, by treating the reactant according to a conventional method, 1- represented by the above formula []
Phenyl-4-[4'-(4-halogenobutoxy)phenyl]-butane[] is obtained. Apart from the above, alkali metal salts of isobutyric acid,
For example, salts of lithium, potassium, sodium, rubidium, etc. are mixed with aprotic solvents such as dimethyl ether, diethyl ether, dipropyl ether, THF, benzene, toluene, xylene, etc.
pentane, hexane, heptane, petroleum ether,
dimethyl sulfoxide, etc., and a dialkylamine such as diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, etc. is added.
At this time, the ratio of amine/isobutyric acid is 0.5 to 2.0,
It is preferably 0.9 to 1.2. To the resulting mixture, -
Alkyllithium, such as ethyllithium, n-propyllithium, isopropyllithium, n-butyllithium, isobutyllithium, n-pentyllithium, isopentyllithium, n-hexyl at 10-15°C, preferably -10-5°C. Saturated hydrocarbon solutions such as lithium, isohexyllithium, etc., such as n-pentane, n-hexane, n-
Add a solution of heptane, petroleum ether, etc. for 10~
0.5 to 4 hours at 40℃, preferably 20 to 30℃,
Preferably, the reaction is allowed to proceed for 1 to 2 hours. To this reaction mixture, a solution of the compound of formula [] obtained above in an aprotic solvent was added at -10 to 20°C, preferably -5 to 5°C, and the mixture was heated to 2 to 25°C at 15 to 25°C. The reaction is allowed to proceed for 6 hours, preferably from 3 to 6 hours. In this case, the ratio of alkyllithium/compound of the above formula [] is 1 to 2, preferably 1 to 1.5. The reaction product is treated in a conventional manner to obtain 6-{4'-[4-phenyl-n-butyl]phenoxy}-2,2 dimethylcaproic acid. To produce the ester from the above compound [], the following method may be used, for example. 1) A method by reacting a salt of an alkali metal such as Na or K [formula below] of the compound [] with an alkyl halide [formula below], for example, an alkyl halide such as alkyl chloride, alkyl bromide, or alkyl iodide. R'COOM+RX→R'OOR+MX [] [] [] (In the formula, M represents Na or K, and X is Cl,
Represents Br or. ) 2) A method involving a reaction in which the acid chloride compound [formula below] of the compound [] and an alcohol [formula below] are condensed in the presence of a base, for example an inorganic base such as caustic alkali or an organic base such as a tertiary amine. R′COCl+ROH+(AlK) ₃ ·N→ [] [] R′COOR+(AlK) ₃ N·HCl [] In addition, any known and commonly used method for producing a carboxylic acid ester can be used. for example,
Ester [formula] can also be synthesized by the route shown by the following reaction formula.

For example, taking 4-(4-phenyl-n-butyl)-phenol as an example, this phenol can be mixed with an aprotic solvent such as dimethyl ether, diethyl ether, dipropyl ether, THF, dioxane, benzene, etc. ,toluene,
Bases such as lithium hydride, sodium hydride, aluminum hydride, ethyllithium, n-propyllithium, isopropyllithium, in solution in xylene, pentane, hexane, heptane, petroleum ether, dimethyl sulfoxide, etc. n-butyllithium, isobutyllithium,
Add n-pentyllithium, phenyllithium, sodium ethoxide, sodium propoxide, sodium butoxide, lithium ethoxide, lithium propoxide, lithium butoxide, potassium propoxide, sodium hydroxide, potassium hydroxide, and the like. In this case, the ratio of the above base/compound of formula [] is 1 to 3, preferably 1 to 3.
The ratio is 1.2. After reacting this mixture at 10-40°C, preferably 20-25°C, for 10-60 minutes, preferably 30-40 minutes, the reaction product contains 5-halogen-
Add 2,2 dimethylcaproic acid ester (the halogen atom at position 5 is a chlorine atom, a bromine atom, or an iodine atom). In this case, the ratio of caproic acid ester/compound of formula [] is 1 to 5,
Preferably it is 1 to 1.2. Total reaction mixture 2-30
Heat to reflux for an hour, preferably 7 to 12 hours.
When the reaction product is treated according to a conventional method, 5-[4'-(4
-Phenyl-n-butyl)-phenoxy]-2,2
-Dimethylcaproic acid ester [] is obtained. When the compound according to the present invention is orally administered to rats that have developed hyperlipidemia after being fed a high-fat diet, it lowers the total cholesterol level, increases the high-density lipoprotein cholesterol level, and , which exhibits ideal physiological effects that hardly increase liver weight. Hyperlipidemia drugs used to date include soysterol, melinamide, clofibrate, probucol, linoleic acid, nicomol,
However, there are issues that need to be resolved in all of these. For example, soysterol causes hypersensitivity, melinamide causes liver dysfunction, hypersensitivity, and dizziness, clofibrate causes gastric, intestinal, and liver damage and carcinogenicity, probucol causes diarrhea, nausea, and anorexia, and linoleic acid causes rash.
Gastrointestinal disorders, nicomol hypersensitivity, neuropsychiatric disorders,
It exhibits various side effects such as. The physiological effects of these antihypertensive drugs are expected to primarily be to decrease blood TC and increase HDL-C. However, although there are many compounds that lower TC, there are few that lower TC and increase HDL-C. Anything that increases HDL-C almost always leads to an increase in liver weight, and the possibility of carcinogenesis cannot be excluded. These have been common drawbacks of the antihyperlipidemic drugs used to date. The present inventors searched for a compound with antihyperlipidemic effect that overcomes these drawbacks, and as a result of intensive research, they lowered TC,
We succeeded in obtaining a compound that exhibits extremely ideal physiological activity, increasing HDL-C and causing almost no change in liver weight. The present invention will be explained in more detail with reference to Examples below. Example 1 6-[4'-(4-phenylbutyl)phenoxy]
-Synthesis of 2,2 dimethylcaproic acid 0.96 g (0.02 mol) of 55% sodium hydride was suspended in 10 ml of anhydrous THF, and 4.5 ml of 4-(4-phenyl-n-butyl)-phenol was dissolved in 20 ml of anhydrous THF under ice cooling. g (0.02 mol) and stirred at room temperature for 30 minutes. To this, 1-bromo-4-chlorobutane
After adding 5.1 g (0.03 mol) and heating under reflux for 10 hours, the reaction solution was decomposed with water, acidified with mineral acid, extracted with ether, and the ether phase was extracted with caustic alkaline water. The obtained product was purified by silica gel column chromatography to obtain 4-[4'-(4-phenylbutyl) as a colorless oil.
-Phenoxy}butyl chloride (5.3 g) was obtained (yield: 84%). Separately, 2.8g of sodium isobutyrate
(0.025 mol) was suspended in 20 ml of anhydrous THF, and after adding 2.5 g (0,025 mol) of diisopropylamine, a solution of n-butyllithium in hexane was added under ice cooling.
Add 0.25 ml and stir at 30°C for 1 hour, and add 5.3 g of 4-[4'-(4-phenylbutyl)phenoxy]butyl chloride obtained above under ice cooling.
(0.017 mol) was added and stirred at room temperature for 4 hours.
After the reaction, the mixture was poured into 100 ml of water, acidified with mineral acid, and the target product was extracted using ether. After the solvent of this ether phase was distilled off, isobutyric acid was distilled off under reduced pressure. When the product is recrystallized from petroleum ether,
4.7 g of white crystals with mp 87-89°C were obtained (yield
76%). 1) TLC (ethyl acetate 1: hexane 2) Rf=
0.44 2) H-NMR (CDCl ₃ ) δ = 10.6 (s: 1H, OH) δ = 7.4 ~ 6.7 (m: 9H, arom-H) δ = 4.2 ~ 3.8 (t: 2H, -CH ₂ -) δ =2.9~1.5 (m: 14H, CH ₂ - x 7) δ = 1.25 (s: 6H, CH ₃ x 2) Example 2 6-[4'-(4-phenyl-n-butyl)phenoxy]-2 Synthesis of ethyl ,2-dimethylcaproate 6-[4'(4-phenyl-n-butyl)phenoxy]-2,2-dimethylcaproic acid, 3.7 g
(10 mmol) was dissolved in 100 ml of ethanol, 2 ml of sulfuric acid was added thereto, and the mixture was heated under reflux for 20 hours. The reaction mixture was concentrated under reduced pressure to 20 ml, poured into 50 ml of water, and extracted three times with 100 ml of ether. This ether phase was washed with water and then dried to remove ether and ethanol, yielding 3.8 g of a colorless oil (yield 95%). 1) TLC (ethyl acetate 1: hexane 2) RF=
0.62 2) H-NMR (CDCl ₃ ) δ = 7.4 ~ 6.6 (m: 9H, arom-H) δ = 4.3 ~ 3.7 (m: 4H, -CH ₂ - (ester) and -OCH ₂ ) δ = 2.8 ~ 1.4 (m: 14H, -CH ₂ - x 7) δ = 1.3 ~ 1.0 (q: 9H, CH ₃ (ester) and
CH ₃ ×2) Example 3 Synthesis of 6-[4'-(4-phenyl-n-butyl)phenoxy]-2,2-dimethylcaproate-(3'-pyridyl)methyl 3-oxymethylpyridine 6.54 g ( 60mmol),
Dimethyl-aminopyridine 1.2g (10mmol), 6
-(4-phenyl-n-butyl)phenoxy]-
7.4g (20mmol) of 2,2dimethylcaproic acid
It was dissolved in 150 ml of dry dichloromethane, and to this solution was added 30 ml of a dichloromethane solution containing 6.2 Å (30 mmol) of dichlorohexylcarbodiimide at -5-0° C. while stirring. After 5 hours, the precipitated dicyclohexane urea is collected by filtration. After distilling off didichloromethane from the reaction mixture, 150 ml of ethyl acetate was added.
ml was added, and the whole was washed with 0.5% HCl and NaHCO ₃ water, dried, and then ethyl acetate was distilled off. 3.95 g of colorless oil was obtained (44% yield). 1) TLC (ethyl acetate 4: n-hexane 1) Rf
= 0.48 2) H-NMR (CDCl ₃ ) δ = 6.8 to 6.6 (m: 13H, arom-H) δ = 5.1 (s: 2H, -CO-O-CH ₂ ) δ = 3.9 to 3.7 (t: 2H ，

[Formula]) δ=2.8-1.2 (m: 20H, -CH ₂ -, CH ₃ ) Example 4 6-[4'-(4-phenyl-n-butyl)phenoxy]-2,2 dimethylcaproic acid- [5-
(2'-Methylpiperazinyl)] Synthesis of methyl 2-methyl-5-hydroxymethyl-piperazine 7.4g (60mmol), dimethylaminopyridine 1.2
g (10 mmol), 7.4 g (20 mmol) of 6-[4'-(4-phenyl-n-butyl)phenoxy]-2,2-dimethylcaproic acid was dissolved in dry dichloromethane, and the solution was heated at -5 to 0°C. While stirring, 30 ml of a dichloromethane solution containing 6.2 g (30 mmol) of dicyclohexylcarbodiimide was added. Dicyclohexylurea precipitated after 5 hours was filtered off. After distilling off dichloromethane from the reaction mixture, ethyl acetate was added.
150 ml of the solution was added, and the whole was washed with 0.5% HCl and NaHCO ₃ water, dried, and then ethyl acetate was distilled off. 3.76 g of colorless oil was obtained (40% yield). 1) TLC (ethyl acetate 4: n-hexane 1) Rf
= 0.525 2) H-NMR (CDCl ₃ ) δ = 8.5 to 6.6 (m: 11H, arom-H) δ = 5.15 (s: 2H, -COO-CH ₂ ) δ = 4.0 to 3.7 (t: 2H

[Formula]) δ=2.8-1.1 (m: 23H, _-CH2 -,- _CH3 ) Example 5 Synthesis of 3-(2',5'-dimethylbenzoyl)propionic acid Succinic anhydride 18.5g (185mmol) and xylene 25
ml (204 mmol) suspended in 60 ml of nitroethane,
To this, 54.3 g of aluminum chloride at 10℃
(407 mmol) was added in small portions over 90 minutes and brought to room temperature.
Stir for 90 minutes. The reaction mixture was poured into water, the pH of the whole was adjusted to 1 using hydrochloric acid, and the mixture was extracted with 200 ml of ether. After washing the obtained organic phase with water, 10%
The organic acid was extracted with 200 ml of sodium hydroxide aqueous solution. The resulting aqueous phase was adjusted to pH 1 using hydrochloric acid, extracted with 200 ml of ether, and then the ether was distilled off. The residue was purified by recrystallization with a mixed solvent of ether-hexane to obtain 31.3 g of white crystals (mp 87-88°C) (yield 82%). 1) TLC (hexane 1: ethyl acetate 1) Rf=
0.33 2) H-NMR (CDCl ₃ ) δ = 2.2 to 2.6 (d: 6H, -CH ₃ ) δ = 2.6 to 3.0 (t: 2H, -CH ₂ -) δ = 3.0 to 3.4 (t: 2H, - _CH2- ) δ=7.0-7.6 (d:3H, arom-H) Example 6 Synthesis of 4-(2',5'-dimethylphenyl)butyric acid 3-(2',5'-dimethylbenzoyl)propion 10.3g (50mmol) of acid in diethylene glycol
9.4 ml (150 mmol) of 80% hydrazine hydrate and 10.0 g (250 mmol) of sodium hydroxide were added to this solution, and the mixture was heated under reflux for 3 hours. The reaction product was then stirred for 10 hours while removing excess hydrazine and water. After cooling, the pH was adjusted to 1 using hydrochloric acid and extracted with 200 ml of benzene. After distilling off benzene from the obtained benzene layer, the residue was recrystallized from ether-pentane. mp75-76℃ white crystals 8.0g (yield 83%)
was gotten. 1) TLC (hexane 1: ethyl acetate 1) Rf=
0.45 2) H-NMR (CDCl ₃ ) δ = 1.6 to 2.9 (m: 6H, -CH ₂ -) δ = 2.2 to 2.4 (s: 6H, -CH ₃ -) δ = 6.8 to 7.0 (s: 3H, arom-H) δ=11.9-12.0 (s: 1H, -COOH) Example 7 Synthesis of 1-(2',5'-dimethylphenyl)-4-(4'-methoxybenzoyl)-butane 4-( 8.6 g (40.8 mmol) of 2',5'-dimethylphenyl)butyric acid chloride in 45 ml of anisole
(400 mmol) was added dropwise at 5°C to a solution of 6.5 g (49 mmol) of aluminum chloride dissolved in 45 ml of anisole, and the mixture was reacted for 30 minutes at the same temperature. The reaction mixture was poured into water, the pH was adjusted to 1 with 10% hydrochloric acid, and the organic phase was separated. After distilling off anisole from the organic phase, the residue was recrystallized from ether-pentane. Diethylene glycol 50
5ml of 80% hydrazine hydrate dissolved in ml
(81 mmol) and 5.4 g of sodium hydroxide
(135 mmol) was added and heated under reflux for 4 hours. Thereafter, the reaction product was kept at 200° C. for 7 hours while gradually distilling off hydrazine and water. After cooling, water was added and the pH was adjusted to 1 using hydrochloric acid, the benzine was distilled off, and the residue was distilled under reduced pressure to obtain bp142-143.
C. (1 mmHg) 6 g of a colorless oil was obtained (yield 55.7%). 1) TLC (hexane 1: ethyl acetate 1) Rf=
0.64 2) H-NMR (CDCl ₃ ) δ = 1.4 to 2.0 (m: 4H, CH ₂ -) δ = 2.1 to 2.4 (d: 6H, -CH ₃ ) δ = 3.7 (s: 3H, -OCH ₃ ) δ=6.6-7.2 (m: 7H, arom-H) Example 8 Synthesis of 4-[4-(2',5'-dimethylphenyl)butyl]phenol 1-(2',5'-dimethylphenyl) )−4−(4′−
Add 25.9 g (224 mmol) of pyridine hydrochloride to 30 g (112 mmol) of methoxyphenyl)butane and heat at 200°C.
The mixture was heated for 4 hours. After cooling the reaction product, the pH was adjusted to 1 using 10% hydrochloric acid and extracted with 300 ml of ether. After distilling off the ether from the extract, vacuum distillation was performed to obtain 27.1 g of a colorless oil with a bp of 166-168°C (1 mmHg) (yield: 95.1%). 1) TLC (hexane 1: ethyl acetate 1) RF=
0.55 2) H-NMR (CDCl ₃ ) δ = 1.3 to 1.9 (m: 4H, -CH ₂ -) δ = 2.1 to 2.3 (d: 6H, -CH ₃ ) δ = 2.3 to 2.8 (m: 4H, - _CH2- ) δ=5.3 (s: 1H, -OH) δ=6.5-7.1 (m: 7H, arom-H) Example 9 2,2-dimethyl-{4-[4-(2', 5' Synthesis of -dimethylphenyl)butyl]phenoxy}caproic acid 4-(4-phenyl-butyl) in Example 1
The reaction was carried out in the same manner as in Example 1 except that 4-[4-(2',5'-dimethylphenyl)butyl]phenol was used in place of phenol. When the product was purified using column chromatography, a pale yellow oil was obtained (yield 82%). 1) TLC (3 hexane: 1 ethyl acetate) RF=
0.36 2) H-NMR (CDCl ₃ ) δ = 1.2 (s: 6H, -CH ₃ ) δ = 1.4 to 2.0 (m: 10H, -CH ₂ -) δ = 2.1 to 2.3 (d: 6H, aroma-CH ₃ ) δ=2.3~2.7 (m: 4H, -CH ₂ -) δ = 3.2 - 4.0 (m: 2H, -OCH ₂ -) δ = 6.6 - 7.2 (m: 7H, arom-H) 6-[4 -(4-Phenyl-n-butyl)phenoxy]-2,2 dimethylcaproic acid ester's serum lipid-lowering effect. Wistar rats, 4 weeks old, male, fed high-fat diet (1% cholesterol, 1% bile acid, 6% cottonseed oil) %,
The rats were fed a prepared rat diet (92%), and the following test compounds were orally administered daily. TC, TDL in serum after 2 weeks
-C, triglyceride (TG), and liver weight were measured. TC, HDL-C, and TG were quantified using a measurement kit manufactured by Wako Pure Chemical Industries, Ltd., and liver weight was measured by extracting the organ. One group consisted of 7 animals, and diemfibrozil and clofibrate were used as comparison controls.
The results are shown in Table 1. In Table 1, the symbols displayed as samples indicate each compound represented by the general formula below, and the groups in the structural formula of the compound represented by each symbol.
R ₁ , R ₂ and R ₃ have the meanings shown below.

【table】

【table】

Claims (1)

[Claims] 1 General formula, [Formula] (wherein R ₁ and R ₂ each represent H or CH 3 , R ₃ is H, _{CH 3 ,} C ₂ H ₅ , [Formula] or [Formula] ) is a caproic acid derivative represented by