JPH0610164B2 - Isoprenyl benzoate derivative and process for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Wherein R and R'are the same or different and each represents hydrogen, a lower alkyl group, a carboxyl group, a nitro group or an amino group, A and B represent hydrogen or together, a carbon-carbon direct bond, and n is an integer of 8 or 9, provided that R and R'represent hydrogen at the same time), and an isoprenyl nucleus-substituted benzoic acid ester derivative and a process for producing the same.

Dextran sulfate, β-sitosterol, clofibrate, etc. are known as compounds having an antilipemic effect and used for the treatment of arteriosclerosis, etc., but for example, clofibrate lowers serum cholesterol. Although the rate is high, it has side effects such as liver weight increasing action. The present inventors have known that an isoprenylamide derivative, which is a derivative of isoprenol, has a strong serum cholesterol-lowering effect, and have previously proposed it (Japanese Patent Laid-Open No. 59-152354), but this time, it is represented by the general formula (I). The present inventors have found that the novel isoprenyl nucleus-substituted benzoic acid ester derivative has a strong serum cholesterol-lowering effect and has few side effects such as increase in liver weight, leading to the present invention. Therefore, the compound of the present invention can be expected as a therapeutic or prophylactic drug for heart diseases and cardiovascular diseases.

The compound of the present invention represented by the general formula (I) has the general formula (Wherein A, B and n have the above-mentioned meanings) and an isoprenol derivative or an ester-forming derivative thereof represented by the general formula (Wherein R and R ′ have the above-mentioned meanings) and can be easily produced by reacting with a nuclear-substituted benzoic acid or an ester-forming derivative thereof.

This reaction is carried out by a conventional method for ester synthesis. That is, typically, the above-mentioned isoprenol and nuclear-substituted benzoic acid are reacted under esterification conditions in the presence or absence of an inert solvent to synthesize an ester. This reaction is preferably carried out in the presence of an acid catalyst, for example, an inorganic acid such as sulfuric acid or phosphoric acid, or an organic acid such as p-toluenesulfonic acid or a strong acid ion exchange resin. As the inert solvent, hydrocarbons such as benzene, toluene and n-hexane, dichloromethane, chloroform, dichloroethane,
Halogenated hydrocarbons such as trichloroethane, diethyl ether, diisopropyl ether, ethers such as tetrahydrofuran, acetone, lower aliphatic ketones such as methyl ethyl ketone, ethyl acetate, esters such as butyl acetate, other acetonitrile, N, N-dimethylformamide, etc. Common organic solvents are used. The reaction can be carried out at a temperature from room temperature to the boiling temperature of the reaction mixture, but it is preferable to use a reaction temperature and a reaction solvent system in which the reaction solvent used and the produced water are removed out of the reaction system by azeotropic distillation. .

This esterification reaction can also be carried out using isoprenol and an ester-forming derivative of a nuclear-substituted benzoic acid. Examples of the ester-forming derivative of nuclear-substituted benzoic acid include acid halides, anhydrides, and esters of nuclear-substituted benzoic acid. Examples of the acid halide of the nucleus-substituted benzoic acid include chloride, bromide and iodide of the acid.When these nucleus-substituted benzoic acid halides are used as one of the reactants, a basic compound such as carbonation is used as an acid acceptor in the reaction system. It is preferable that a small amount of an inorganic base such as sodium or potassium carbonate, or an organic base such as triethylamine, dimethylaniline, pyridine or hycholine be present. Also in this case, the reaction solvent in the esterification reaction described above is used. Also in this reaction, the corresponding alkali metal isoprenyl oxide may be used instead of isoprenol. And 0 °
The reaction is carried out at a temperature in the range of ~ 100 ° C, preferably in the range of 0 ° to room temperature. When a nucleus-substituted benzoic anhydride is used as one of the reactants, the desired ester can be obtained very easily. When a nucleus-substituted benzoic acid ester is used as one of the reactants, this ester is usually preferably a lower alkyl ester. When this nuclear-substituted benzoic acid lower alkyl ester is used, it is preferable to carry out it while removing the lower alcohol produced, and in the reaction, sodium alkoxide, sodium hydroxide, potassium hydroxide, titanium as an ester exchange catalyst is used. It is preferable to use an acid ester or the like.

This esterification reaction is also carried out with an inorganic acid ester of isoprenol, for example, isoprenyl chloride, isoprenyl bromide, isoprenyl halide such as isoprenyl iodide, or diisoprenyl sulfone, and a nuclear-substituted benzoate such as sodium salt, potassium salt Alternatively, a silver salt or the like can be used.

In the esterification reaction product thus obtained, the catalyst is removed by washing if necessary after the completion of the reaction, and if necessary, a solid by-product such as a salt is produced by filtering the reaction mixture. Separately, concentrate and subject to high vacuum distillation, or after subjecting the reaction compound to an extraction treatment with an extraction solvent such as ethyl acetate, chloroform, hexanebenzene, etc., it is purified by a chromatographic means using an adsorbent such as silica gel or alumina. It

General formula used in this esterification reaction Specific examples of the nuclear-substituted benzoic acid represented by are: p-nitro-, m-nitro-, p-amino-, 3,5-dinitro-,
3-amino-5-nitro- and pt-butyl-substituted benzoic acid and the like can be mentioned.

Also, the general formula used in this esterification reaction Specific examples of the isoprenol represented by are solanesol, decaprenol, α-saturated decaprenol and the like.

In the compound of the present invention in which either or both of R and R'in the general formula (I) are amino groups, a compound of the general formula (I) in which R and R'are nitro groups is used.
To produce the corresponding nitro group-containing compound, which is then reduced by a conventional method such as sodium hydrosulfide or hydrogen sulfide, or catalytically reduced in the presence of a reducing catalyst such as Raney nickel under atmospheric pressure or pressure to reduce the nitro group to an amino group. Alternatively, the amino group in the general formula (III) may be protected with a suitable protecting group to remove the protecting group after the reaction with the compound of the general formula (II).

The compound of the present invention thus obtained has a serum cholesterol lowering action as shown in the following table.

The serum cholesterol reduction rate in the above table was calculated by the following formula.

Further, the rate of increase in relative liver weight was calculated by the following formula.

Next, the present invention will be specifically described with reference to examples.

Example 1 Solanesyl-p-nitrobenzoate Solanesol 95g, pyridine 50ml, ethyl acetate 300m
25 g of p-nitrobenzoyl chloride was added little by little to the solution 1 at room temperature with stirring over 1 hour. Further, the mixture was reacted at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, and the ethyl acetate was concentrated under reduced pressure. 125 g of the obtained residue was purified by silica gel column chromatography using a mixed solvent of benzene and hexane to give oily solanesyl-p-nitrobenzoate 7
1.1 g was obtained. Part of 10g of this oil is 50m of acetone
It was dissolved in 1 and left in a refrigerator overnight, and the precipitated white crystal was separated and dried to obtain 6.3 g of solanesyl-p-nitrobenzoate white powder crystal.

Solanesyl-p-nitrobenzoate mp 51.0-52.3 ° C IR 1720,1660,1530 cm ^-1 Example 2 Decaprenyl-m-nitrobenzoate Decaprenol and m-nitrobenzoyl chloride were used and reacted in the same manner as in Example 1 to give decaprenyl-m-
Obtained nitrobenzoate.

Decaprenyl-p-nitrobenzoate mp37.5-38.2 ° C IR (neat) 1720,1665,1595 cm ^-1 Example 3 Solanesyl-p-aminobenzoate 16.5 g of solanesyl-p-nitrobenzoate obtained in Example 1 was mixed with an ethanol: ethyl acetate (1: 1) mixed solvent.
Dissolved in 300 ml, 10% palladium-charcoal 200 mg
And hydrogenate under normal pressure. After 1313 ml of hydrogen was absorbed in about 2 hours (theoretical amount of hydrogen absorption was 27 ° C, 1.56), the catalyst was separated and then concentrated under reduced pressure to obtain 17.8 g of residue. The residue is purified by silica gel column chromatography using a benzene-hexane mixed solvent,
Oily solanesyl-p-amino-benzoate 10.8
g was obtained. 10.8 g of this oil was dissolved in 50 ml of acetone and left overnight in the refrigerator, and the precipitated crystals were separately dried to give solanesyl-p-aminobenzoate yellow powder crystals 6.2
g was obtained.

Solanesyl-p-aminobenzoate mp 55.2-56.7 ° C IR (neat) 3420,3350,3210,1675, 1625,1600,1510 cm ^-1 Example 4 α-saturated decaprenyl-p-aminobenzoate Reaction was carried out in the same manner as in Example 1, and α-saturated decaprenyl-p
-Nitrobenzoate was obtained and then reduced as in Example 2 to give α-saturated decaprenyl-p-aminobenzoate.

α-Saturated decaprenyl-p-aminobenzoate n ²⁵ _D = 1.5232 IR (neat) 3475,3360,3220,1710, 1690,1620,1600,1510 cm ^-1 Example 5 Decaprenyl-p-aminobenzoate In the same manner as in Example 1, decaprenyl-p-nitrobenzoate was obtained, and then in the same manner as in Example 2, decaprenyl-p-aminobenzoate was obtained.

Decaprenyl-p-aminobenzoate mp 58.5-60.3 ° C IR (neat) 3420,3350,3210,1675, 1625,1600,1510 cm ^-1 Example 6 Solanesyl-3,5-dinitrobenzoate Solanesol 68.4g, triethylamine, ethyl acetate 30
25 ml of 3,4-dinitrobenzoyl chloride was added to 0 ml mixed solution.
g was added little by little under stirring at room temperature for 30 minutes, and further reacted for 6 hours under stirring at room temperature. After allowing to stand at room temperature overnight, the reaction product was poured into water and extracted with ethyl acetate. The extract layer was washed successively with 5% hydrochloric acid, 5% sodium bicarbonate water, water and saturated saline, and then the solvent was concentrated under reduced pressure. . 88.6 g of the obtained residue was added to benzene-
Purification by silica gel column chromatography using a hexane mixed solvent gave 57.7 g of semi-crystalline solanesyl-3,5-dinitrobenzoate. This crystalline product is n-hexane
The crystals were dissolved in 400 ml, left at room temperature overnight, and the precipitated crystals were separately dried to obtain 47.8 g of solanesyl-3,5-dinitrobenzoate as yellow powder crystals.

Solanesyl-3,5-dinitrobenzoate mp 60.7-62.3 ° C IR (neat) 1720,1630,1540 cm ^-1 Example 7 Solanesyl-3-amino-5-nitrobenzoate 39.1 g of solanesyl-3,5-dinitrobenzoate obtained in Example 6 was added to 250 ml of methanol and 150 ml of toluene.
Dissolve in water, and stir at room temperature under stirring with sodium hydrosulfide (70% Na
20 g of SH.xH ₂ O) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, the residue was dissolved in 300 ml of n-hexane, and the insoluble material was separated. After distilling off n-hexane, the residue 3
6.5 g of the product was purified by silica gel column chromatography using benzene to obtain 10.7 g of decomposed solanesol and 10.5 g of oily solanesyl-3-amino-5-nitrobenzoate. It was dissolved in 50 ml of acetone and left overnight in the refrigerator, and the precipitated crystals were dried separately, solanesyl-3 as pale yellow powder crystals.
7.2 g of -amino-5-nitrobenzoate was obtained.

Solanesyl-3-amino-5-nitrobenzoate mp 65.8-67.0 ° C IR (neat) 3470,3380,1705,1660,1640,1580,1530 cm ^-1 Example 8 Solanesyl-p-tert-butylbenzoate To a mixed solution of 46.5 g of solanesol, 27.0 g of triethylamine and 300 ml of benzene, 14.4 g of pt-butylbenzoyl chloride was added dropwise little by little under stirring at room temperature for 1 hour. Further, the mixture was reacted at room temperature for 7 hours. After standing overnight at room temperature, the reaction product was poured into water and extracted with benzene. The benzene layer was washed successively with 5% hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, and the solvent was concentrated to dryness under reduced pressure. . Residue 6
5.5 g was purified by silica gel column chromatography using a mixed solvent of benzene and hexane to give oily solanesyl-p-
36.5 g of t-butyl benzoate was obtained. This oil was dissolved in 180 ml of acetone and left overnight in a refrigerator, and the precipitated crystals were separated by filtration and dried to obtain 33.1 g of solanesyl-pt-butylbenzoate.

Solanesyl-pt-butylbenzoate mp33.2-33.8 ° C IR (neat) 1715,1660,1605cm ^-1 Example 9 Solanesyl-o-carboxybenzoate While stirring at room temperature, 20 g of phthalic anhydride was gradually added to a mixed solvent of 75 g of solanesol, 15 ml of triethylamine and 300 ml of chloroform. After stirring for 2 hours, the mixture was extracted with chloroform, washed with water, and concentrated. 99.0 g of the obtained residue was purified by silica gel chromatography using a mixed solvent of chloroform-ethyl acetate to obtain 33.5 g of oily solanesyl-o-carboxybenzoate. This oil was dissolved in 200 ml of acetone and left in the refrigerator overnight. The precipitated crystals were separately dried to obtain 28.8 g of solanesyl-o-carboxybenzoate as white powder crystals.

Solanesyl-o-carboxybenzoate mp 59.1-59.6 ° C IR (neat) 3200,1720,1700,1660, 1595,1575 cm ^-1 Example 10 Solanesyl-3,5-diaminobenzoate To a solution of 3,5-diaminobenzoic acid (12 g) and tetrahydrofuran (50 ml), trifluoroacetic anhydride (50 ml) was added dropwise under an ice bath. After the dropping, the mixture is stirred for 1 hour at room temperature and further for 30 minutes in a 55 ° C warm bath. The solvent is concentrated to dryness under reduced pressure,
A residue is obtained.

Next, solanesol 28.6g, tetrahydrofuran 100m
l solution, 30 ml of triethylamine and 300 mg of 4dimethylaminopyridine are added, and the mixture is stirred at room temperature for 1 hour. Let stand overnight at room temperature and concentrate the reaction station under reduced pressure.
49 g of the obtained residue was purified by silica gel column chromatography using a mixed solvent of benzene and hexane to give oily solanesyl-3,5-ditrifluoroaminobenzoate 20.8.
get g.

Next, 20.8 g of this oily substance was dissolved in 300 ml of ethanol, 50 ml of concentrated aqueous ammonia was added, and the mixture was left stirring at room temperature for 3 nights. The reaction solution was poured into water, extracted with isopropyl ether, washed with water, and concentrated under reduced pressure to obtain 18.2 g of a residue. Residue 2
0.8 g of the product is purified by silica gel column chromatography using chloroform to obtain 18.2 g of oily solanesyl-3,5-diaminobenzoate. This is dissolved in 50 ml of hexane and left in the refrigerator overnight. Separately dry the precipitated crystals,
7.3 g of solanesyl-3,5-diaminobenzoate as yellow powder crystals were obtained.

Solanesyl-3,5-diaminobenzoate mp55.3-56.0 ° C IR (neat) 3440,3360,3210,1700 1660,1615,1595cm ^-1

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location // A61K 31/235 ADN 8413-4C 31/24 8413-4C 31/245 8413-4C (72) Inventor Koichiro Hagiwara 3-4, Suehiro-cho, Kawagoe-shi, Saitama Prefecture (56) Reference US Patent 4199587 Bulletin of the Chemical Society of Japan, 43 (7), 2174-2176 (1970)

Claims (2)

[Claims] 1. A general formula (In the formula, R and R'are the same or different and each represents hydrogen, a lower alkyl group, a carboxyl group, a nitro group or an amino group, A and B are each hydrogen or both of them are taken together and carbon-carbon A direct bond and n is an integer of 8 or 9, except when R and R'represent hydrogen at the same time). 2. General formula (Wherein A and B are each hydrogen or both of them together represent a carbon-carbon direct bond) and an isoprenol represented by the general formula (In the formula, R and R'are the same or different and each represents hydrogen, a lower alkyl group, a carboxyl group, a nitro group or an amino group, provided that R and R'represent hydrogen at the same time) General formula characterized by reacting with a substituted benzoic acid or its ester-forming derivative (However, R, R ', A, B and n have the above-mentioned meaning in the formula) A process for producing an isoprenyl nucleus-substituted benzoic acid ester derivative.