JPS6160060B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides an acetic acid derivative represented by the general formula R ¹ CH ₂ COOR ² () (in which R ¹ represents a solanesyl group and R ² represents a hydrogen atom or an alkyl group) and this acetic acid derivative as an active ingredient. This invention relates to an ulcer treatment agent. Conventionally, it has been used as a therapeutic agent for gastric ulcers, duodenal ulcers, etc.
For example, gefalnate [trade name of Sumitomo Chemical Industries, Ltd.;
Gefanil, chemical name; 3,7-dimethyl-2,
6-octadienyl 5,9,13-trimethyl-
A number of compounds having anti-ulcer properties have been reported, such as 4,8,12-tetradecatrienoate], but nothing groundbreaking has yet been found. The inventors of the present invention have conducted various studies in order to find a more excellent ulcer treatment agent, and as a result, have discovered a group of extremely effective compounds. The compound represented by the general formula () according to the present invention can be produced according to the following production process. In the above formula, R ¹ represents a solanesyl group, X represents a halogen atom, R represents a lower alkyl group,
R ² represents an alkyl group. First, an aliphatic halide represented by the general formula () is condensed with a malonic acid dialkyl ester represented by the general formula () in the presence of an alkali metal alcoholate in alcohol to form an aliphatic malonic acid di-lower represented by the general formula (). Obtain the alkyl ester. Alcohols used in this reaction include methanol, ethanol, isopropanol, and tertiary alcohol.
Butanol, etc. can be used, and sodium, potassium, etc. can be used as the alkali metal. Further, the reaction temperature is preferably 60 to 100°C, particularly around 80°C. The reaction time is preferably 2 to 10 hours, and usually the reaction is almost completed in about 5 hours. Next, the aliphatic malonic acid di-lower alkyl ester represented by the general formula () is hydrolyzed with an alkali in alcohol and then neutralized with an acid.
An aliphatic malonic acid represented by is obtained. Examples of the alcohol used in this reaction include methanol, ethanol, and isopropanol, and examples of the alkali include sodium hydroxide and potassium hydroxide. The reaction is suitably carried out at 75-85°C for 3-5 hours. The resulting aliphatic malonic acid represented by the general formula () is heated under reduced pressure to perform a decarboxylation reaction to produce aliphatic acetic acid represented by the general formula ()', which is one of the compounds of the present invention. get. In order to obtain the ester compound of the present invention, the aliphatic acetic acid represented by the general formula ()' is subjected to a condensation reaction with the alcohol represented by the general formula (). The alkyl ester is obtained. This ester formation reaction may be carried out by known methods such as acid chloride method, acid anhydride method, direct esterification method, substitution method, transesterification method, diazoalkyl method, etc. However, in order to prevent side reactions, it is necessary to It is desirable to use mild conditions. For example, when carrying out the acid chloride method, first, an aliphatic acetic acid represented by the general formula ()' or a salt thereof is dissolved or dispersed in a solvent such as benzene or toluene, and while cooling and stirring, oxalyl chloride, thionyl chloride, etc. The acid halide is produced by gradually adding a halogenating agent such as , or phosphorus pentachloride, stirring at room temperature for 1 to 6 hours, and heating if necessary.
Next, an ester is produced by reacting the obtained acid halide with an alcohol in the absence of a solvent or in the presence of a base in a solvent that does not participate in the reaction, such as benzene, toluene, or xylene. The base at this time is pyridine, quinoline, triethylamine, N,N-dimethylaniline, etc.
organic bases, alkali metals, alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, calcium carbonate, alkali metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, alkaline earth metals Metal hydroxides etc. can be used, but pyridine etc.
Class organic base systems are preferred. The reaction is usually carried out at 0 to 80°C for 1 to 5 hours. After the reaction is complete, the reaction mixture is poured into water, extracted using an organic solvent such as ethyl ether in a conventional manner, washed sequentially with water, diluted hydrochloric acid, sodium bicarbonate, and saturated brine, and then dehydrated and dried. The alkyl ester of the present invention is obtained by distilling off the solvent under reduced pressure. Another example is the substitution method, in which aliphatic acetic acid is reacted with an alkali metal salt, silver salt, or salt with a tertiary organic base such as triethylamine, and an alkyl halide or alcohol sulfuric acid ester or sulfonic acid ester. A pure alkyl ester can be obtained. This reaction is carried out using N,N-dimethylformamide as a reaction solvent.
Polar solvents such as N,N-dimethylacetamide, dimethylsulfoxide and hexamethylphosphoric triamide are preferred. The reaction is preferably carried out at room temperature
It is carried out for 2-24 hours at 120°C. After the reaction is completed, the alkyl ester of the present invention is obtained by post-treatment similar to the acid chloride method described above. The acetic acid derivative of the present invention obtained by the above method can be purified by vacuum distillation, column chromatography, or the like, if necessary. Next, the physiological activities of the active ingredients according to the present invention are shown below. The assay method for reserpine ulcers is Arch.Int.Pharmacodym.Ther. 147 , 113
(1964), and acetic acid ulcers were generated in rats according to the method described in Jap.J.Pharmac. 19 , 418 (1969) to determine the effect of administration of the test compound. was measured. 1. Reserpine ulcer After fasting male SD rats (6 animals per group, weighing 150-200 g) for 24 hours, 100 mg/kg of the test compound was administered.
Kg orally, 30 minutes later reserpine 15mg/Kg
Inject intraperitoneally. 18 hours after administration, the rats are killed with chloroform, the stomach is removed, and the area of the ulcer is measured. The cure rate was determined using reserpine 15mg/Kg as a control.
It was calculated using the following formula from the ulcer area of the rat group injected intraperitoneally. Curing rate = Control value - Test value / Control value x 100 (%) Next, the test results are shown in Table 1 below.

[Table] Display ± ＋ ＋＋ ＋＋＋
2. Acetic acid ulcer The stomachs of six male SD rats weighing 150 to 200 g per group are pulled out under ether anesthesia, and 0.05 ml of a 15% acetic acid aqueous solution is injected subserosa while being careful of blood vessels. After injection, 100 mg/Kg of the test compound is orally administered for 14 days, and on the 14th day, the rats are killed with chloroform, the stomachs are removed, and the ulcer area is measured. The healing rate was determined by measuring a control group to which no test compound was administered, and using the formula used in the reserpine ulcer test. Next, the test results are shown in Table 2 below.

[Table] Display ± ＋ ＋＋ ＋＋＋

【table】

[Table] As is clear from the above test results, it can be seen that the active ingredient according to the present invention has an extremely excellent anti-ulcer effect. Furthermore, the compounds of the present invention have excellent effects not only on reserpine ulcers and acetic acid ulcers, but also on various other types of ulcers. Furthermore, the acute toxicity in mice of intraperitoneal administration of the ester, which is the active ingredient of the present invention, is extremely low as shown in Tables 1 and 2. The active ingredient compound of the present invention is administered by intravenous injection, subcutaneous injection, intramuscular injection, orally, and oral administration and intramuscular injection are particularly preferred. The dosage of the active ingredient compound ranges from 100 to 1000 mg per day when used for the treatment of adults, especially from 200 to 300 mg per day.
mg is preferred. When the active ingredient of the present invention is orally administered, it may be administered in the form of tablets, granules, or powders, and in particular, granules and powders can be made into unit dosage forms in the form of capsules, if necessary. These solid preparations for oral administration contain commonly used excipients, such as silicic anhydride, magnesium aluminate metasilicate, synthetic aluminum silicate, lactose, sugar, corn starch, microcrystalline cellulose, hydroxypropyl-
starch, or glycine, binders such as gum arabic, gelatin, tragacanth, hydroxypropylcellulose or polyvinylpyrrolidone,
It may contain lubricants such as magnesium stearate, talc or silica, disintegrants such as potato starch, calcium carboxymethylcellulose or wetting agents such as polyethylene glycol, sorbitan monooleate, polyoxyethylene hydrogenated castor oil, sodium lauryl sulfate and the like. The tablets may be coated according to conventional methods. Oral liquid preparations are aqueous or oily emulsion solutions,
It may be made into a syrup or the like, or it may be a dry product which can be redissolved in a suitable vehicle before use. Such liquid preparations contain commonly used additives such as emulsifying aids such as sorbitol syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, etc., and emulsifying agents such as lecithin, sorbitan monooleate, polyoxyethylene hydrogenated castor oil, non-aqueous Vehicles such as fractionated coconut oil, almond oil, peanut oil, preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate or sorbic acid may be added. Furthermore, these preparations for oral administration may contain preservatives, stabilizers, etc., if necessary. Next, when using this compound as an injection, it may be in the form of an oil solution, emulsion, or aqueous solution.
These solvents may contain commonly used emulsifiers, stabilizers, etc. These compositions can contain the compound at one time depending on the method of administration.
% or more, preferably 5% to 50%. Next, specific production examples and formulation examples of the compounds of the present invention will be given. Reference production example 1 Decaprenyl acid 3.0 g of sodium metal was dissolved in 200 ml of absolute ethanol, and 25.0 g of diethyl malonate was added thereto. Next, 100 g of decaprenyl bromide was added dropwise over 4 hours while heating to reflux at 75-82°C. Further 75-82℃
After stirring for 1 hour, the mixture was poured into water and extracted with ethyl acetate. Next, the ethyl acetate layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. Oily substance obtained by distilling off ethyl acetate under reduced pressure
Add 26.1g of potassium hydroxide to 111.2g of ethanol 500g
ml and add at 78-80℃ under nitrogen stream.
Heated for 3.0 hours. The reaction solution was cooled, concentrated hydrochloric acid was added to adjust the pH to 3, and the mixture was extracted with ether. The ether layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The ether was distilled off under reduced pressure, and the concentrate (89.0 g) was heated at 150°C under reduced pressure (1 to 10
mmHg) for 3 hours to complete the decarboxylation reaction. The product was then purified by silica gel column chromatography to obtain 27.4 g of semicrystalline decaprenyl acetic acid. 1Rν _nax cm ^-1 ; 2800-2400 (COOH), 1710 (C
=O), 1665 (C=C), 840 NMRδ ^CDCl3 _TMS ;

【formula】

[Formula] 2.33(CH ₂ CO),

[Formula] 11.15 (1H, CO ₂ H) Elemental analysis (C ₅₂ H ₈₄ O ₂ ) Calculated value C: 84.26 H: 11.42 (%) Actual value C: 84.47 H: 11.27 (%) Production example 1 Solanesyl acetic acid Reference production Solanesyl acetic acid was produced in the same manner as in Example 1. The physical property values are shown below. Solanesyl acetate 1Rν _nax cm ^-1 ; 2800-2400 (COOH), 1710 (C
=O), 1665 (C=C), 840 NMRδ ^CDCl3 _TMS ;

【formula】

[Formula] 2.33 (CH ₂ CO), 5.05 (9H,

[Formula]), 11.33 (1H, CO ₂ H) Elemental analysis (C ₄₇ H ₇₆ O ₂ ) Calculated value C: 83.87 H: 11.38 (%) Actual value C: 84.25 H: 11.18 (%) Reference production example 2 Decaprenyl Ethyl acetate 0.46g of sodium metal in 200ml of absolute ethanol
After adding 12.2 g of decaprenyl acetic acid and stirring for a while, ethanol was distilled off under reduced pressure. Disperse the residue in 160ml of anhydrous benzene,
To this was added 10 ml of oxalyl chloride over about 15 minutes while stirring on ice, and the mixture was further stirred at room temperature for 2 hours. After concentrating the reaction product under reduced pressure, 200 ml of anhydrous ethylene chloride was added, and the soluble portion was dissolved in 5 ml of ethanol and anhydrous ethylene chloride.
It was added dropwise to a solution dissolved in 100 ml and 6 ml of pyridine over about 15 minutes while stirring on ice, and the mixture was further stirred at room temperature for 2 hours. Pour the reaction mixture into 200ml of ice water while stirring.
Ether is added for extraction, and the ether layer is washed successively with water, dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 8.7 g of decaprenyl ethyl acetate as a colorless oil. 1Rν _nax cm ^-1 ; 1740 (C=O), 1670 (C=C) NMRδ ^CDCl3 _TMS ;

【formula】

[Formula] 1.97 (

[expression] and

[Formula]), 2.30 (CH ₂ CO), 4.03 (2H,
CH ₂ O), 5.05 (10H

[Formula]) Elemental analysis (C ₅₄ H ₈₈ O ₂ ) Calculated value C: 84.31 H: 11.53 (%) Actual value C: 84.60 H: 11.34 (%) Production example 2 Solanesyl acetate Same as reference production example 2 above The following compound was produced by the method. The elemental analysis values of each compound are shown in Table 1, and the nuclear magnetic resonance (NMR) absorption values are shown in Table 2.

[Table] Chill
2 Soraneshi C ₄₉ H ₈₀ O ₂ 83.94 11.50 83.88
11.63
ethyl acetate
Chill

[Table] Formulation Example 1 Hard Capsules for Oral Dissolve 25 g of solanesyl acetic acid and 7.5 g of polyoxyethylene castor oil in acetone, and then mix with 25 g of silicic anhydride. After evaporating the acetone, add 5 g of carboxymethyl cellulose calcium,
Mix 5 g of corn starch, 7.5 g of hydroxypropyl cellulose and 20 g of microcrystalline cellulose, add 30 ml of water, knead, and granulate. This was granulated using a No. 24 mesh (BS) granulator equipped with a screen (Eck pelleter, manufactured by Fuji Paudal Co., Ltd.). The granules were dried to a moisture content of 5% or less and sifted through a No. 16 mesh (BS) sieve. Next, 190 mg of these particles were filled into one capsule using a capsule filling machine. Formulation Example 2 Oral Soft Capsules Mix 50 g of methyl solanesyl acetate and 130 g of fractionated coconut oil to make a homogeneous solution. Separately 93g gelatin, 19g glycerin, 10g D-sorbitol
g, ethyl paraoxybenzoate 0.4g, propyl paraoxybenzoate 0.2g and titanium oxide 0.4g
A gelatin solution with the composition of
Soft capsules containing 180 mg were manufactured. Formulation Example 3 Injection 5 g of isopropyl solanesylacetate, an appropriate amount of peanut oil and 1 g of benzyl alcohol are mixed, and the total amount is made up to 100 c.c. using peanut oil.
Dispense 1 c.c. of this solution into ampoules using aseptic technique and seal.

Claims (1)

[Claims] 1. An acetic acid derivative represented by the general formula R ¹ CH ₂ COOR ² (wherein R ¹ represents a solanesyl group, and R ² represents a hydrogen atom or an alkyl group). 2 characterized by containing an acetic acid derivative represented by the general formula R ¹ CH ₂ COOR ² (wherein R ¹ represents a solanesyl group and R ² represents a hydrogen atom or an alkyl group) as an active ingredient,
Ulcer treatment.