JPS6039257B2 - Novel ulcer therapeutic active acetic acid derivative - Google Patents

Description

Detailed Description of the Invention The present invention provides a novel acetic acid derivative represented by the general formula RI-C ratio COOR2 (where RI represents a decaprenyl group and R2 represents a hydrogen atom and a lower alkyl group), and a method for producing the same. and a treatment for ulcers containing the compound as an active ingredient.

Conventionally, gefalnate (trade name, 3,7-dimethyl-2,6-octadienyl 5,9,13-trimethyl-4,8,12-tetradecatreno) has been used as a therapeutic agent for gastric ulcer, duodenal thinning, etc. A large number of compounds having anti-ulcer properties have been reported, such as [Eatate], but nothing groundbreaking has yet been found. The inventors of the present invention have conducted various studies in order to find a more excellent therapeutic agent for hot water, and as a result, have discovered a group of extremely effective compounds. The compound represented by the general formula (1) according to the present invention can be manufactured according to the following manufacturing process.

RI-X10C ratio (COOR)2→ (0) (m) RI-CH(COOR)2→ (W) RI-CH(COOH)2→RI-CH2COO day (V
) (1)'RI-C ratio COOH+R2-OH
→RIC&COOR2(1)' (W) (1) In the above formula, RI represents a decaprenyl group, X represents a halogen atom, R represents a lower alkyl group, and R2 represents a lower alkyl group.

Note that the decaprenyl group is 3,7,11,15,19,2
3,27,31,35,39-decamethyl-2,6,1
It refers to a 0,14,18,22,26,30,34,38-tetracontadecanyl group. First, the general formula (
Decaprenyl malonic acid represented by general formula (W) is obtained by condensing the decaprenyl halide represented by b) with a malonic acid dialkyl ester represented by general formula (m) in alcohol in the presence of an alkali metal alcoholate. Obtain the lower alkylester.

The alcohol used in this reaction is methanol,
Ethanol, isopropanol, tertiary butanol, etc. can be used, and as the alkali metal, sodium, potassium, etc. can be used. The reaction temperature is 60 to 100℃, especially 80℃.
Preferably around ℃. The reaction time is preferably 2 to 1 hour, and the reaction is usually almost completed in about 5 hours. Next, the general formula (
Decaprenyl malonic acid di-lower alkyl ester represented by N) is hydrolyzed with an alkali in alcohol and then neutralized with acid to obtain decaprenyl malonic acid represented by general formula (V).

The alcohol used in this reaction is methanol,
Examples of the alkali include ethanol and isopropanol, and examples of the alkali include sodium hydroxide and potassium hydroxide. The reaction is carried out at a QO of 75 to 85 and a suitable time period of 3 to 5 hours. The decaprenylmalonic acid represented by the general formula (V) thus obtained is heated under reduced pressure to carry out a decarboxylation reaction to obtain an acetic acid derivative represented by the general formula (1)'. The acetic acid derivative represented by the general formula (1)′ thus obtained is then reacted with a lower alcohol represented by the general formula (W) in the presence of cuprous chloride using dicyclohexylcarposimide as a condensing agent. Accordingly, the estel represented by the general formula (1) is obtained. As a reaction solvent for this reaction, an aprotic solvent such as benzene or toluene can be used, but it is not necessary to use a reaction solvent for this reaction. Further, this reaction is usually suitably carried out at 80 to 100°C for 2 to 1 hour. Note that dicyclohexyl urea generated during the reaction can be removed as crystals by adding n-hexane. The ester represented by the general formula (1) thus obtained can be purified by silica gel chromatography, if necessary. Next, the physiological activities of the active ingredients according to the present invention are shown below.

The test method is Jap. J. Pharmac. , 134
According to the method described in 18 (1969), concentrated acetic acid was generated in rats, and the administration effect of the compound was measured. The stomachs of 6 male SD rats weighing 150-200 kg per group are pulled out under ether anesthesia, and 0.05 ml of a 15% aqueous acetic acid solution is injected subplya, paying attention to the blood vessels.

Test compound 5ri9/k9 was orally administered for 14 days after injection, and 1
Rats were harvested on the fourth day. . After killing the animals with holm, the stomachs are removed and the area of ingestion is measured. The cure rate was calculated using the following formula by measuring a control group to which no test compound was administered.

Curing rate = control u value - test value XI.

〇(%) Control value Next, the test results are shown in Table 1 below.

As is clear from the test results shown in Table 1 and above, it can be seen that the active ingredient according to the present invention has an extremely excellent anti-corrosion effect.

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 is preferably in the range of 100 to 1,000 doses per day, especially 200 to 300 doses per day when used for the treatment of adults. 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 may 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 anhydrous poppy, acid, metal poppy, magnesium aluminate acid, synthetic poppy, aluminum acid, lactose, sugar, corn starch, microcrystalline cellulose, hydroxypropyl starch. , or glycine, a binder such as gum arabic,
gelatin, tragacanth, hydroxypropylcellulose or polyvinylpyrrolidone, 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, etc. Tablets may be coated according to conventional methods. Oral liquid preparations may be in the form of aqueous or oily emulsion solutions, syrups, etc.
Alternatively, it may be a dry product which can be redissolved with a suitable vehicle before use.

Such liquid preparations contain commonly used additives such as emulsification aid Sorbit Silotuf 0, methylcellulose, gelatin, hydroxyethyl cellulose, etc.
Also emulsifiers such as lecithin, sorbitan monooleate,
Polyoxyethylene hydrogenated castor oil, a non-aqueous vehicle 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 oral preparations may contain preservatives, stabilizers, etc., if necessary. Next, when this compound is used as an injection, it may be in the form of an oil solution, emulsion, or aqueous solution, and these solvents may contain commonly used emulsifiers, stabilizers, etc.

These compositions contain 1% or more of the compound depending on the administration method.
Preferably, it can be contained in an amount of 5% to 50%.

Next, specific production examples and formulation examples of the present invention will be given, but the present invention is not limited to the following examples.

Production example 1 3.0 ml of sodium decaprenyl acetate was dissolved in 200 ml of ethanol, and 25.0 ml of diethyl malonate was added thereto.
While heating under reflux at a temperature of 5 to 80°C, 100ml of decaprenyl bromide was added dropwise over 4 hours.

After further stirring at 75-8200 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 1 obtained by distilling off ethyl acetate under reduced pressure
12.2% potassium hydroxide 26.1% ethanol 5%
00' and add it to 78-80' under a nitrogen stream.
3. with oo. Heated for a calm time. The reaction solution was cooled, the pH was adjusted to 3 by adding concentrated hydrochloric acid, and the mixture was extracted with ether. The pale 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
．． The decarboxylation reaction was completed by heating the sample at 15,000 ℃ under reduced pressure (1 to 10 skin Hg) for 3 hours. The product was then purified by silica gel column chromatography to obtain 27.4 ml of semi-crystalline decaprenyl acetic acid.

IR Rem-1; 1710, 1440, 1390NM
R6 Mikkaji 13;11-15broad(-COOH)
, 1.97 (methylene), 5.05 broad 1.6 The elemental analysis values of this product as C-bearing day 8402 are as follows.

Calculated value C 84.26 days II. 42 (%) Actual value C 84.47 days II. 27 (%) Production Example 2 A mixture of 15 parts of decaprenyl ethyl acetate ethanol, 1.81 parts of dicyclohexylcarbodiimide, and 50 parts of cuprous chloride was stirred at 90 to 100 qo for 1 hour under a nitrogen stream.

Next, 5.92 g of decaprenyl acetic acid was added to give a solution of 80 to 80 g.
I heated the lantern for 2 hours at 8qo. After cooling, n-hexane was added, the precipitated solids were removed by filtration, and the furnace liquid was concentrated. The residue was purified with a silica gel column to obtain 4.2 hours of oily decaprenyl ethyl acetate. IR ym Momoka-1; 1740, 1450, 1390, 1160NM
R 6-character 8-tei 13; 5.05 broad 1.97, 1
．． 15 (-COOCH2CH3), 4.03 (-COOCH2-), 1.6 The elemental analysis values of this product as C-Tsunichi 8802 are as follows.

Calculated value C 84.31 days II. 53 (%) Actual value
C 84.80 days II. 24 (%) Methyl decaprenyl acetate was also prepared in the same manner.

Next, its physical properties are as follows. Decaprenyl methyl acetate IR Rem Keihada-1; 1740, 1445, 1435,
1390NMR 6g13;5.05 broad,
2.0, 3.6 (-COOCH3), 1.6 The elemental analysis values of this product as C 8602 are as follows.

Calculated value C 84.29 days II. 48 (%) Actual value C 84.50 days II. 25(%) Furthermore, isopropyl decaprenyl acetate and isoamyl decaprenyl acetate were prepared in the same manner.

Next, its physical properties are as follows. 6 Nao Ryukuro.

Form solution, TMS, 60 MHz) Elemental analysis (Saltfish) Formulation example 1 Hard capsule for oral use 25% of decaprenyl acetic acid and 7.5% of polyoxyethylene castor oil were dissolved in acetone, and then 25% of silicic anhydride was dissolved.
Mix evening.

After evaporating the acetone, further mix 5 parts of hydroxymethyl cellulose calcium, 5 parts of corn starch, 7.5 parts of hydroxypropyl cellulose, and 2 parts of microcrystalline cellulose, add 3 parts of water, knead, and granulate. . This is No. 24 mesh (B.S.) screen ÷
The mixture was granulated using a granulator (Eckberetter, manufactured by Fuji Paudal Co., Ltd.) equipped with a granulator. The forehead grains are dried to a moisture content of 5% or less and are ranked No.
It was sieved through a 16 mesh (B.S.) sieve. Next, these particles are filled into one capsule with a capsule filling machine containing 190 9
It was filled. Formulation Example 2 Oral Soft Capsules 50 parts of decaprenyl methyl acetate and 130 parts of fractionated coconut oil are mixed to form a homogeneous solution.

Separately, a gelatin solution consisting of 93 parts of gelatin, 19 parts of glycerin, 10 parts of D-sorbitol, 0.2 parts of propyl paraoxybenzoate and 0.4 parts of titanium oxide was prepared, and this was used as a capsule coating agent by manual plate punching. Soft capsules containing 180 female contents were purified by. Formulation Example 3 Injection 5 parts of decaprenyl ethyl acetate, an appropriate amount of peanut oil, and 1 part of pendyl alcohol are mixed, and the total volume is made up to 100 cc using peanut oil.

Claims (1)

[Scope of Claims] 1. A novel acetic acid derivative represented by the general formula R^1-CH_2COOR^2 (wherein R^1 represents a decaprenyl group, and R^2 represents a hydrogen atom and a lower alkyl group). 2 The general formula R^1X (wherein R^1 represents a decaprenyl group and X represents a halogen atom) represents a decaprenyl group, a ride and the general formula CH_2(COOR)_2 (wherein R represents a lower alkyl group) ) is reacted with malonic acid dialkyl ester represented by the general formula R^1-
Decaprenylmalonic acid dialkyl ester represented by CH(COOR)_2 (wherein R^1 and R have the same meanings as above) was obtained, and then this was hydrolyzed to give the general formula R^1-CH(C
OOH)_2 (R^1 in the formula has the same meaning as above)
The general formula R^1-CH_ is characterized by obtaining decaprenylmalonic acid represented by and further decarboxylating it.
A method for producing an acetic acid derivative represented by 2COOH (wherein R^1 has the same meaning as above). 3 An acetic acid derivative represented by the general formula R^1-CH_2COOH (in the formula R^1 represents a decaprenyl group) and a lower acetic acid derivative represented by the general formula R^2-OH (in the formula R^2 represents a lower alkyl group) A method for producing an acetic acid derivative represented by the general formula R^1CH_2COOR^2 (wherein R^1 represents a decaprenyl group and R^2 represents a lower alkyl group), which comprises reacting with an alcohol. 4. An ulcer therapeutic agent containing an acetic acid derivative represented by the general formula R^1-CH_2COOR^2 (wherein R^1 represents a decaprenyl group and R^2 represents a hydrogen atom and a lower alkyl group) as an active ingredient.