JPS63159359A - Benzoic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> and R<2> are H or alkyl). EXAMPLE:4-[2-(3-Methylbenzamido)ethoxy]benzoic acid. USE:It has activity to lower lipid level in blood and is useful for the remedy and prevention of hyperlipemia and arteriosclerosis. PREPARATION:A carboxylic acid of formula II or its reactive derivative is made to react with a compound of formula III in a solvent (e.g. methylene chloride) using a condensation agent (e.g. N,N'-dicyclohexylcarbodiimide) at -10 deg.C - room temperature to obtain the objective compound of formula I. The amount of the compound of formula II is 1-1.2mol per 1mol of the compound of formula III.

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a novel benzoic acid derivative represented by the following general formula [I] that exhibits a blood lipid-lowering effect and is useful for the treatment and prevention of hyperlipidemia and arteriosclerosis. Regarding its physiologically acceptable salts. In the formula, R1 and R2 are the same or different and represent hydrogen or alkyl. (Prior Art) Various drugs have been used as therapeutic agents for hyperlipidemia and arteriosclerosis, but none have yet been satisfactory in terms of efficacy and safety. On the other hand, IIB-699 is known as a compound similar to the compound of the present invention (Acta
Endocrinol, 100.5upp1. 2
47. 26 (1982)]. This drug is used as an anti-diabetic agent.
Nothing is known that would suggest a pharmacological action related to the present invention. (Problems to be Solved by the Invention) The present inventors have conducted extensive research with the aim of obtaining a compound that has a novel structure and has superior effects to conventionally known blood lipid-lowering agents. . (Means for Solving the Problems) In order to develop a compound that has a blood lipid-lowering effect, the present inventors conducted extensive research on various compounds having novel structures, and as a result, the general formula [I The inventors have discovered that a compound represented by the following formula is suitable for the purpose, and have completed the present invention. The compound according to the present invention is a novel compound that has not been described in any literature, and its chemical structure is characterized by the fact that amidoethyl benzoate is bonded to benzoic acid via an oxygen atom. The alkyl represented by R1 and R2 in the general formula [1] is preferably a linear or branched one having 1 to 7 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, dobutyl, isobutyl, Examples include tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and the like. Particularly preferred are those having 1 to 4 carbon atoms. When R2 is hydrogen, it may be used in its free form, but it can also be used in the form of a pharmacologically acceptable salt by a method known per se. Such salts include sodium salts, calcium salts, and the like. In addition to the compounds described in the examples related to the production method described below, the compounds according to the present invention include the following compounds, but these are listed for illustrating some of the compounds of the present invention. However, the compounds of the present invention are not limited to these. 4-(2-(3-methylbenzamide)ethoxy]benzoic acid 4-(2-(2-methylbenzamido)ethoxy)benzoic acid methyl ester 4-(2-(3-isopropylbenzamide)ethoxy)benzoic acid methyl ester 4 -(2-(2-isopropylbenzamide)ethoxy)benzoic acid ethyl ester 4-(2-(3-isopropylbenzamide)ethoxy)benzoic acid 4-(2-(2-isopropylbenzamide)ethoxy)benzoic acid sodium salt 4 ( 2-(3-jert-butylbenzamide)
(2-tert-butylbenzamido)ethoxy]benzoic acid sodium salt 3- (2-(benzamido)ethoxy)benzoic acid 3-
(2-(3-methylbenzamido)ethoxy)benzoic acid ethyl ester 3-(2-(3-isopropylbenzamido)ethoxy)benzoic acid 3- (2-(3-tert-butylbenzamido)ethoxy)benzoic acid 2- ( 2-(benzamido)ethoxy]benzoic acid sodium salt 2-(2-(2-methylbenzamido)ethoxy)benzoic acid 2-(2-(3-isopropylbenzamido)ethoxy)benzoic acid sodium salt 2-(2-(2 -tert-butylbenzamido)ethoxy]benzoic acid methyl ester Compound N) of the present invention is a new compound that has not been published in any literature, and can be produced, for example, by the method shown below. [In the formula, R1 and R2 are Same as above.] That is, compound (III) can be reacted with carboxylic acid (IT) or a reactive derivative thereof to produce CI]. This acylation reaction can be performed by a method known per se. For example, it is possible to use a method in which (II) and (1) are directly bonded using a condensing agent, or a method in which a reactive derivative of CII), such as an acid halide, an imidazolide, or a mixed acid anhydride, is reacted as appropriate. When using an acid halide (e.g., acid chloride, acid bromide, etc.), the reaction is usually carried out in a suitable solvent (e.g., an ether solvent such as ether, tetrahydrofuran, dioxane, or a halogenated hydrocarbon such as methylene chloride, chloroform, etc.). Solvents, hydrocarbon solvents such as benzene, toluene, xylene, etc.
bases (e.g., inorganic bases such as potassium carbonate, sodium hydroxide, potassium hydroxide, etc.);
Tertiary organic bases such as pyridine, triethylamine, etc.)
It is carried out at -20°C to +30°C in the presence of. The amount of acid halide used is usually 1 to 1.2 mol per 1 mol [■]. When using a mixed acid or anhydride, first add (n) and a chlorocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) to a base (e.g., an organic base such as pyridine or triethylamine). A mixed acid anhydride solution is prepared by reacting at -20°C to +20°C in a suitable solvent, preferably a halogenated hydrocarbon solvent such as methylene chloride or chloroform, and to this a mixed acid anhydride solution is prepared.
are reacted at -1θ°C to 30°C. The mixed acid anhydride is preferably used in an amount of 1 to 1.2 mol per 1 mol [■]. In the case of direct condensation using a condensing agent, the reaction is usually carried out using a suitable solvent (e.g., halogenated hydrocarbon solvents such as methylene chloride and chloroform, ether solvents such as tetrahydrofuran and dioxane, acetonitrile, N,N-dimethylformamide, etc.). The reaction is carried out at −10° C. to room temperature using a condensing agent (e.g., N,N′-dicyclohexylcarbodiimide, diphenyl phosphoric azide, etc.) in an aprotic solvent such as . Compound (n) is 1 to 1.2 per mole of (III)
Preference is given to using moles. The raw material compound (III) used in the present invention is a known compound and a known method (Japanese Unexamined Patent Publication No. 123671/1983).
However, it can also be produced by the method shown below. [In the formula, R2 is the same as above. ] That is, compound (rV) is refluxed in an alcohol represented by R201 using 1 to 5 times the molar amount of hydrazine. Compound (IV) is a new compound and can be produced by any of the following methods. A: [In the formula, R2 is the same as above.] ] The reaction in Method A is usually carried out at 50°C to 100°C using an equimolar amount of potassium phthalimide in a suitable solvent (eg, acetonitrile, N,N-dimethylformamide, etc.). The reaction in method B is usually carried out in the presence of a suitable deoxidizing agent (e.g., anhydrous potassium carbonate, sodium methoxide, sodium ethoxide, etc.) in an appropriate solvent (e.g., N,N-dimethyl in the case of anhydrous potassium carbonate). formamide, acetonitrile, etc., methanol, etc. for sodium methoxide, ethanol, etc. for sodium ethoxide)
In the formula, R2 is the same as above. ] That is, (Vl) is normally inert to the reaction (e.g., halogenated hydrocarbon solvents such as methylene chloride and chloroform, ether solvents such as tetrahydrofuran and dioxane, hydrocarbon solvents such as benzene and toluene, ([1] can be produced by reacting with aziridine at room temperature to 120 °C in an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, etc.). The amount is 1 to 3 moles per mole of aziridine. Hendinitrile [■] and aziridine are reacted in the same manner as in the above (■) to produce [■].

[In the formula, R1 and R2 are the same as above. ]

(1) can be produced by reacting compounds (V) and (Vl). The reaction is usually carried out using an inert 'G medium (
Examples: halogenated hydrocarbon solvents such as methylene chloride and chloroform; ether solvents such as tetrahydrofuran and dioxane; hydrocarbon solvents such as benzene and toluene; aprotic polar solvents such as acetonitrile and N,N-dimethylformamide; carbonyl solvents such as acetone, methyl ethyl ketone, alcohol solvents such as methanol and ethanol), bases (e.g., inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and tertiary bases such as pyridine and triethylamine). The reaction is carried out at room temperature to 80° C. in the presence of a strong base such as a strong organic base, sodium hydride, sodium methoxide, sodium methoxide, potassium tert-butoxaide, etc.). The amount of (Vl) used is usually at least the same mole, preferably 1 to 1.2 moles, per 1 mole of (V). Raw material compound [V] can be produced by the method shown below. [In the formula, R1 is the same as above. X represents halogen] That is, the acid halide (IX) is usually mixed with a solvent inert to the reaction (e.g., halogenated hydrocarbon solvents such as methylene chloride and chloroform, ether solvents such as tetrahydrofuran and dioxane, benzene, Hydrocarbon solvents such as toluene,
bases (e.g., inorganic bases such as potassium carbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, etc.); (V) can be produced by reacting with aziridine at a temperature of 0°C to room temperature, preferably 5°C or lower, in the presence of a tertiary organic base (tertiary organic base, etc.). The amount of aziridine used is at least the same mole, preferably 1.0 to 1.2 mole, per 1 mole of the acid halide [■]. Among the compounds of the present invention (N), compounds in which R2 is hydrogen can also be produced by hydrolyzing the ester (1?2=lower alkyl) produced by the above method. Such hydrolysis reaction is carried out in the presence of a mineral acid such as hydrochloric acid or sulfuric acid in a hydrous alcohol (eg, methanol, ethanol, etc.) at room temperature to 80°C. The amount of acid used is usually ester (R2
-lower alkyl) 0.1 to 10 mol, preferably 0.2 to 3 mol. This hydrolysis reaction consists of potassium carbonate, sodium hydroxide,
It can also be carried out in the presence of potassium hydroxide or the like in water, methanol, ethanol or a mixed solvent thereof, usually at 0 to 150°C, preferably at 20 to 100°C. The amount of alkali used is 1 to 1 mole of ester (R2-lower alkyl).
5 mol, preferably 2 to 3 mol. Among the compounds of the present invention, compounds in which R2 is alkyl can also be produced by esterifying the carboxylic acid (R2-hydrogen) produced by the above method by a method known per se. Such an esterification reaction can be carried out using esterification methods known per se, for example, diazomethane, alcohols and m (e.g.
(hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc.), or thionyl chloride and alcohol. (1) obtained by the above method is a free carboxylic acid (1?2
=H), a salt with a pharmacologically acceptable base can be formed by a conventional method. For example, in the case of an alkali metal salt, by hydrolyzing the ester (R2=lower alkyl) produced by the above method in alcohol or hydrous alcohol using sodium hydroxide or potassium hydroxide in the same manner as above. Obtainable. Alternatively, the corresponding alkali metal salt can be obtained by adding an equivalent amount of sodium hydroxide or potassium hydroxide to the carboxylic acid (R2=H), preferably in an alcoholic solvent. The target compound CI) or a salt thereof thus obtained can be separated and purified from the reaction mixture using conventional separation and purification methods, such as extraction, acondensation, neutralization, filtration, recrystallization, column chromatography, and thin layer chromatography. It can be isolated and purified by The compounds of the present invention and their pharmacologically acceptable salts have strong lipid-lowering effects and extremely low toxicity, and therefore can be widely used in the treatment of hyperlipidemia and arteriosclerosis. The results of pharmacological tests demonstrating the usefulness of the compounds of the present invention are shown below. (1) Effect on cholesterol-loaded rats Three-week-old male Wistar rats were preliminarily fed with a normal synthetic diet for 7 days and then divided into groups. A high-cholesterol diet containing 0.1% of the test drug was given ad libitum for 3 days, and blood was collected after an overnight fast.
The total cholesterol value (TC) of the obtained serum was measured. The group fed a drug-free high-cholesterol diet was defined as a control group, and the group fed a normal synthetic diet was defined as a normal group. The number of animals in each group was 6, but only the control group had 18 animals. The inhibition rate of serum TC increase of the test drug was calculated using the following formula. The results are shown in Table 1. Blood of the compound of the present invention? The i'tTC lowering effect is clear. (2) Test method for serum TCC lowering effect in normal rhesus monkeys: 2 to 100% body weight) were subjected to experiments. During the experiment period, 150 g of solid feed (Oriental Yeast Co., Ltd.! 11J) was given 101 times. The experimental groups were 1 group, 2 to 6, and 11 ffl. The test drug is 0.5
% CMC suspension (experiment numbers 1 and 2) or 0.5% MC
as a suspension (experiment no. 3 and 4) at doses of 30, 100 or 300 mg/kg for 10 days (experiment no. 3)
, orally for 14 days (Experiment No. 1 and 2) or 28 days (Experiment No. 4) using a rubber probe. Blood was collected 1 week before and immediately before drug administration, and at 4, 7, 10, and 4 days after the start of drug administration.
After 14, 21, and 280 days, serum TC was measured from the saphenous vein of the lower limb. blood? The rate of change in nTC was calculated as follows. (TC before test drug administration is the average value one week before and immediately before administration) The results are shown in Table 2. (See next page) Table 2: There is a difference in risk of 5% and 1% for fists and bows, respectively. The serum TC lowering effect of the compound of the present invention is clear. (3) Test method for lowering serum TCC in normal large beagles: Eight 18-year-old male beagles were raised in individual cages and fed 300 g of Okawa solid feed once a day. The experimental groups were 3 animals per group or 6 rJA, and the test drug was filled in gelatin capsules and orally administered at 10 or 30 mg/kg for 28 days. One week before drug administration, just before drug administration, and 7, 14, 21, and 28 days after the start of drug administration, blood was detected from the bare side of the median vein of the forearm. iTC and triglyceride levels (TG) were measured. The rate of change in surface-soaked lipids was calculated using the following formula. (TC before test drug administration is the average value one week before and immediately before administration) (TG before test drug administration is the average value one week before and immediately before administration) The results are shown in Table 3. Table 3 Evening] □ ◆ and 0 have a risk rate of 5% and 1%, respectively, which means there is a difference in the presence of windows. Values represent standard error of the mean. Experimental group 1 is a control group (6 animals), and experimental group 2 is a group in which the compound of Example No. 4 was administered at 10 mg/kg/day (30 n
), and experimental group 3 received 30 mg of the compound of Example No. 4.
This is the group (61121) administered at 61121/kg/day. The serum TC and TG lowering effects of the compounds of the present invention are clear. (4) Test method using acute toxicity fal mice: Six-week-old ddY male mice were fasted for 24 hours and placed on the backside. A suspension of the test drug in physiological saline containing 0.5% methylcellulose was orally administered to the animals, followed by normal rearing and observation for 2 weeks for the appearance of general symptoms and mortality. As a result, all of the example compounds had low toxicity;
No deaths were observed at the 2 g/kg dose. Test method on tb+ rats: SD male rats, 5 weeks old, were used in groups of 4, and after oral administration, the presence or absence of pre-symptoms and death was observed for 2 weeks. As a result, the compound of Example 4 was found to have a concentration of 5 g/kg.
No abnormalities were observed with the dose. When the compound of the present invention is administered as a medicament, the compound of the present invention may be administered as is or in a pharmaceutically acceptable non-toxic and inert carrier, for example 0.1% to 99.5%, preferably 0.
．． It is administered to animals including humans as a pharmaceutical composition containing 5% to 90%. As carriers, one or more solid, semisolid, or liquid diluents, fillers, and other formulation auxiliaries are used. Preferably, the pharmaceutical composition is administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intracellularly, locally (transdermally, etc.), or rectally. Of course, it is administered in a dosage form compatible with these administration methods. For example, oral administration is particularly preferred. Although it is desirable to adjust the dose as a therapeutic agent for arteriosclerosis in consideration of the patient's condition such as age and weight, route of administration, nature and severity of the disease, etc., the dose of the present invention is usually administered to adults. The amount of active ingredient is 100mg to 3 per day.
g/day/person preferably ranges from 500 mg=l
A range of g/day/person is common. In some cases, a lower dose than this may be sufficient, and in other cases, a higher dose may be required. It is also desirable to administer the drug in divided doses three times a day. (Example) The present invention will be explained in more detail by referring to Reference Examples and Examples related to the production of the compound of the present invention. Reference Example 1 (11N-(2-(4-methoxycarbonylphenoxy)ethyl)phthalimide 4-(2-bromoethoxy)benzoic acid methyl ester 1
26.52 g and 99.5 g of potassium salt of phthalimide
g, 600 ml of N,N-dimethylformamide 7
Stir at 8-80°C for 2 hours. Pour the reaction solution into ice water,
Extract with chloroform. The chloroform layer was washed twice with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to crystallize the residue. Add ether to the residue and filter, 149.
23 g of crystals were obtained (yield 94%). Melting point: 129-130.5°C. 12) 4-(2-Aminoethoxy)benzoic acid methyl ester (N-(2-(4-methoxycarbonylphenoxy)ethyl)phthalimide obtained in the same manner as in 11) 158.86
g, and 73.33 g of hydrazine Hitlerde, 1.5
10 in methanol and reflux for 1 hour. The precipitate is filtered off and the filtrate is concentrated under reduced pressure. The residue is extracted with chloroform and washed twice with saturated brine. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized by adding n-hexane and filtered to obtain 85.74 g of crystals (yield 90%). Melting point 53-55.5°C0 Reference example 2 4-(2-aminoethoxy)benzoic acid methyl ester P-hydroxybenzoic acid methyl ester 7.6g was added to 50
Dissolve aziridine 2 in ml of chloroform by heating and stirring.
, 15 g was added dropwise and refluxed for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel C-200, 200 g, f'g solvent: chloroform:methanol = 971). The eluted portion was concentrated under reduced pressure, and the residue was crystallized from n-hexane to obtain 4.9 g of the target compound. Melting point: 53-55.5°C. Reference Example 3 1-(4-isopropylbenzoyl)aziridine 4.52 g of aziridine and 10.62 g of triethylamine are dissolved in 200 ml of benzene. While stirring, 18.26 g of P-isopropylbenzoyl chloride was added dropwise while maintaining the internal temperature at 4 to 5°C. After the dropwise addition, the mixture was stirred at the same temperature for 2 hours. After the reaction, insoluble materials are filtered and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel C-200, 30 h, elution solvent is chloroform). Yield 17.70e (yield 94%). NMR ('H NMR CDCl2 60MI
Iz) δppm: 1, 25 (611 d)
2.36 (411 s) 2.95 (
IH m) 7, 23 (211d) 7.95
(2) 1d) IR (film) 1675cm-1
Example 1 4-(2-(4-isobrovirhenzamiF)ethoxy)benzoic acid methyl ester 4-(2-aminoethoxy)benzoic acid methyl ester 7
8 g and 110.4 g of anhydrous potassium carbonate are added to 700 ml of chloroform, and the mixture is cooled and crushed. Internal temperature 10-2
p-isopropylbenzoyl chloride 73 at 0°C
Drop g. Stir for 3 hours after dropping. Wash the reaction solution with water. The chloroform scum was dried with anhydrous magnesium sulfate,
Concentrate under reduced pressure. The residue was crystallized from n-hexane. The crystals were collected by filtration to obtain 116 g of crystals (yield: 85%) with a melting point of 89 to 91°C. Elemental analysis value (as C2D H23N O4) Calculated value (%) C: 70.36 II: 6.79
N: '4.10 Actual value (%) C: 70.21
H: 6.83 N 74.251-(4-isopropyrhendiyl)aziridine 1.89 g, P
-Hydroxybenzoic acid methyl ester 1.52 g,
Add 2.76 g of anhydrous potassium carbonate to 20 ml of N,N-dimethylformamide and stir at 59-60°C for 17 hours. Pour the reaction solution into ice water and extract with ethyl acetate. The organic layer is washed with a 10% aqueous sodium hydroxide solution and then with water. After drying over anhydrous magnesium sulfate, concentrate under reduced pressure. Add n-hexane to the residue and filter the crystals to obtain a melting point of 89-9.
2.75 g of crystals (yield 8o, 5%) were obtained at 1°C. Elemental analysis value (as C2,023N O4) Calculated value (
%) C near 0.36 H: 6.79 N: 4
．． 10 Actual value (%) C near 0.25 H: 6.6
8 N: 4.0B Example 2 4-(2-(4-tert-butylbenzamido)ethoxy)benzoic acid methyl ester 5.35 g of p-tert-butylbenzoic acid and 3.34 g of triethylamine were added to 70 ml of chloroform. 4-(2-aminoethoxy)benzoic acid methyl ester was added dropwise to the solution, and 3.26 g of ethyl chlorocarbonate was added dropwise while stirring at 0 to 5°C. After stirring at the same temperature for 30 minutes, methyl 4-(2-aminoethoxy)benzoate was added. 86 g was added and further stirred for 6 hours. The reaction solution was washed with 10% hydrochloric acid and then with a saturated aqueous potassium carbonate solution. After washing with water, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized with n-hexane, and 9 .8 g of crystals were obtained. These were recrystallized from ethyl acetate. Yield 7.64 g (yield 71.65%). Melting point 112-1
14℃. Elemental analysis value (as C2, H2sNO4) Calculated value (%
) C: 70.96 I-1: 7.09 N
: 3.94 actual value (%) C near 0.88 H
Ni, 14 N: 3.86 Example 3 4-(2-(4-methylbenzamido)ethoxy)benzoic acid methyl ester 4-(2-aminoethoxy)benzoic acid methyl ester 5
．． 86 g and 4.08 g of p-methylbenzoic acid, 1
Dissolved in 00ml of N,N-dimethylformamide,
, N'-dicyclohexylcarbodiimide 6.19 g
Add 9 portions at room temperature while stirring. After stirring for 10 hours, N,N'-dicyclohexylurea is filtered off, the filtrate is poured into ice water, and extracted with ethyl acetate. The organic layer is washed with 10% hydrochloric acid, then with a saturated aqueous potassium carbonate solution, and then with water. After drying over anhydrous magnesium sulfate, concentrate under reduced pressure. Ether was added to the residue and the crystals were filtered to obtain 8.46 g of crystals. This was recrystallized from ethyl acetate, and 6.83 g of crystals with a melting point of 142-144°C (yield: 7
2.6%). Elemental analysis value (as C+s HIg N O4) Calculated value (%) C: 68.97 1-I: 6.11
N: 4.47 Actual value (%) C: 68.96
H: 6.16 N: 4.49 Example 4 102.42 g of 4-(2-(4-isopropylbenzamido)ethoxy)benzoic acid 4-(2-(4-isopropylbenzamido)ethoxy)benzoic acid methyl ester Heat and melt in 1β ethanol. Sodium hydroxide 14.4g
was dissolved in 200 ml of water, added to the above ethanol solution, and heated under reflux for 2 hours. Depressurize the reaction solution;・S to expand and contract. IN ice water is added to the residue, neutralized with 10% hydrochloric acid, and precipitated crystals are collected by filtration, washed with water, and then dried. Recrystallization from ethanol gave 80.5 g of crystals (yield: 82%) with a melting point of 202-203°C. Elemental analysis value (as CI9H2+NO4) Calculated value (%
) C: 69.70 H: 6.47 N:
19.55 Actual value (%) C: 69.71 I
I: 6.33 N: 19.38 Example 5 4-(2-(4-isopropylbenzamido)ethoxy]benzoic acid sodium salt 3.27 g of 4-(2-(4-isopropylbenzamido)ethoxy)benzoic acid Dissolve in 50 ml of methanol. Dissolve 0.40 g of sodium hydroxide in 5 ml of water, add to the above methanol solution, and concentrate under reduced pressure to crystallize the residue. Recrystallize this with methanol,
Crystals of g were obtained. Melting point 300℃ or higher. I Rv'mR (cm-'): 1640,1
605゜Elemental analysis value (CI9 H20N 04 Na
-V2H20) Calculated value (%) C: 63.68
ti: 5.91 N: 3.91 Actual value (%)
C: 63.44 H: 5.77 N: 3.88
The following compounds were obtained by operating in the same manner as in Examples 1 to 5. Example 6 4-(2-Benzamidoethoxy)benzoic acid methyl ester: Melting point 111-113°C0 Elemental analysis value (as CI?H17NO4) Calculated value (%
) C: 68.22 H: 5.72 N: 4.
68 Actual value (%) C: 6s, 1e H: 5.77
N: 4.65 Example 7 4-(2-benzamidoethoxy)benzoic acid: Melting point 20
7-209.5°C. Elemental analysis value (as CIOHISNO4) Calculated value (%
) C:67.36 1(:5.30 N:4.
91 Actual value (%) C: 67.44 H: 5.13
N: 4.85 Example 8 4-(2-(4-methylbenzamido)ethoxy)benzoic acid: Melting point 214-216°C. Elemental analysis value < CI? HI? NO Calculated value (%) C: 6B , 21 H: 5.73 N
:4.68 Actual value (%) C: 68.31 1.
1: 5.64 N: 4. f33 Example 9 4-(2-(4-isopropylbenzamide)ethoxy]benzoic acid ethyl ester: Melting point 68-71°C. Elemental analysis value (as C211125NO4) Calculated value (
%) C near 0.96 H near, 09 N: 3
．． 94 Actual value (%'IC: 10.14) 1 near, is N: 4.00 Example 10 4 (2-(4-tert-butylbenzamide)
Ethoxy]benzoic acid ethyl ester: melting point 77-79°
C0 elemental analysis value (as C22H2?N O4) Calculated value (%) C near 1.52 H near, 37 N
: 3.79 Actual value (%) C near 1.41 H near, 41 N: 3.75 Example 11 4 (2(4-tert-butylbenzamido)ethoxy)benzoic acid: Melting point 206-207°C. Elemental analysis Value (as C20823NO4) Calculated value (%
) C: 70.36 H: 6.79 N:
4.10 Actual value (%) C near 0.23 H:6
．． 62 N: 4.23 (Efficacy) As is clear from the above results, the compound [I] of the present invention is a novel compound that has not been described in any literature, and when administered to humans and animals, it exhibits a strong lipid-lowering effect. Moreover, since it has extremely low toxicity, it is useful as a therapeutic agent for hyperlipidemia and arteriosclerosis in which blood TC and TG levels are high.

Claims (1)

[Claims] A benzoic acid derivative represented by the following general formula [I] and a pharmacologically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] In the formula, R^1 and R^2 are the same or different and represent hydrogen or alkyl.