JPS5857339A - Butanediol derivative, its preparation and antiulcer agent containing the same - Google Patents

Abstract

NEW MATERIAL:The 2,3-butanediol diester of formulaI[A is single bond, 1- 4C alkylene, 1-4C alkyleneoxy, propenylene, or group of formula II (R1 is H and R2 is 1-4C alkyl or phenyl, or R2 is H and R1 is halogen or phenyl); R is phenyl which may have substituent group (halogen, lower alkyl, or lower alkoxy); m is integer of 4-9]. USE:An antiulcer agent capable of strongly suppressing the formation of peptic ulcer. PROCESS:The compound of formulaIcan be prepared either by reacting the 2,3- butanediol monoester derivative of formula III with the carboxylic acid of formula CH3(CH2)mCOOH or its active derivative, or by reacting the 2,3-butanediol monoester derivative of formula IV with the carboxylic acid of formula R-A- COOH or its active derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 2,3-butanediol diester fermentation derivative and a method for producing the same.

Conventionally, 2,3-butanediol diester derivatives include:
In addition to coixenolide, which is known as an anti-tumor component of tanning seeds, there are several types of fatty acid diesters, but nothing was known about their II coral action.

As a result of intensive research on this # derivative, the present inventors found that the following general formula +11, [wherein Aij, a single bond, 01 to 4 alkylene groups, 0
1 to 4 alkylene group, propenylene R
s represents an alkyl group of 01 to 4 or a phenyl group, or R3 represents a hydrogen atom and R1 represents an atom of 10 or a phenyl group. R is a gen atom,
It has been found that a compound represented by a phenyl group (v, m is an integer from 4 to 9) which may be substituted by a lower alkyl group or a lower alkoxy group strongly suppresses the occurrence of peptic ulcer, Invention? completed.

In other words, it is an object of the present invention to provide a compound of the type 2, which is useful as an excellent prophylactic and therapeutic agent for peptic ulcers, and an antiulcer agent containing the same.

The compound of the present invention (11) can be prepared by, for example, any of the following methods.

■ 2,3-butanediol ([I K carbon aqueous CI
JJ) The active conductor Y is reacted with the active metal to give 2,3-butanediol monoester crocodile conductor 11VI, and then the active metal conductor Y is reacted with Caldene #1tV and the active metal conductor Y to obtain the target product my.

till (ill) [V+C
Hs(aillI)mcoon (y)+13 (in the formula, m and R are the same as m) ■ 2.3-butanediol (carbon i1 in II)
IVI is reacted with its active derivative to form a 2,3-butanediol monoester derivative, which is then reacted with calzenic acid (III) or an active derivative thereof to obtain the desired product.

ill! Vl (pigeon)
In this method, active derivatives of calzen 12 (1) and IVI include acid halides, acid anhydrides, mixed acid anhydrides, etc. The reaction is preferably carried out in the presence of a deoxidizing agent such as pyridine, tertiary amine, alkali carbonate, alkali hydroxide, or alkali hydride.

The results of testing the antiulcer effect and acute toxicity of the compound of the present invention thus obtained are as follows.

(11 Anti-ulcer effect Wistar male rat weighing 200g) Y24 hours i
lI! ! I did a lot of experiments. That is, indomethacin Y
1% Cal was suspended in an aqueous solution of sodium oxymethylcellulose, and 251AI/# was orally administered.

After 5 hours, 1111 ml of a 2% DeIJ Antodel-Physiological saline solution was injected into the tail vein, and 10 minutes later, the animals were sacrificed and the entire stomach was removed. Then 12 f of 1-thiformin aqueous solution
After fi/Y injection and fixation, it was spread out on a flat plate and measured at the damaged area in the stomach body, and the sum of the lengths was taken as the ulcer index.

In addition, 801 drops of polynorbate Y/JO was added to the test compound.
The solution was emulsified or suspended in 1 water of physiological saline, and subcutaneously injected into the back 1 hour before administration of indomethacin.The ulcer inhibition rate was calculated using the following formula.

Result number 1! ! It was shown to. The open compound number means those shown in Table 2. As shown in Table 1 and above, the compounds of the present invention have a strong anti-ulcer effect.

(-) Acute toxicity Compounds in Table 2 (compound number 3.5.7゜11.13
．． 14) Dissolve in Y cottonseed oil and add 1 #5 dd
It was administered intraperitoneally to Y-strain male mice at a rate of 1000 Da/Icg and kept for 7 days 11! I guessed it. Since all the mice survived and no abnormalities were observed even after 7 days had passed, it is clear that the LDaoi of any compound was 1000III9/q or more and was extremely weak in toxicity.

The anti-ulcer agent of the present invention can be administered either orally or parenterally.
Accordingly, it can also be administered according to the % dosage form,
For example, oral preparations such as powders, tablets, capsules, granules, and liquid preparations; parenteral preparations such as subcutaneous, intramuscular, or intravenous injections, liquid mixtures, and suppositories can be used.

The above formulation can be performed by a method known per se. In other words, butanediol diester, starch, lactose, mannitol, etc. binder; sodium carboxymethyl cellulose, sodium carboxypropyl cellulose, etc.;
Fan crushing of crystalline cellulose, calxoxymethylcellulose calcium, etc.; Lubricants such as talc, magnesium stearate; Fluidity improvers such as light anhydrous silicic acid, etc. Y can be formulated in appropriate combinations to form powders, tablets, capsules, etc. It can be made into granules. Mak, liquid, and injection are butanediol diester and olive oil.

The compound Y can be dissolved in peanut oil or the like to form an oil-based solution or injection, or the compound Y can be dissolved in water, physiological saline bottles, etc. using a nonionic surfactant such as polysorbate-60 or polysorbate-80. It can be produced by dissolving or suspending it in an aqueous solution or injection.

It can be manufactured by dispersing the suppository into a commonly used base such as cacao butter, synthetic oil, etc. by a conventional method and then solidifying the suppository.

The dosage of the anti-ulcer agent of the present invention thus prepared varies depending on the severity of the disease, but it is usually administered to a deceased patient at a dose of 0.1 to 1000 IIL9/匈 for oral administration, and for parenteral administration. In case 0.05~5009/9 times a day~
Needle penetration involves administering in several doses. Next, Example Y of the present invention will be described.

Example 1 (synthesis of compound 6) Sodium hydride filter, Og (0,075 mol)
Le 40111VC@turbid, ice-cooled stirring solution of 2,3-butanediol 6.3.9 (0.07 mol) in ether dQ
Dropwise. After stirring at the same temperature for 60 minutes and at room temperature for 30 minutes, it was cooled with water again and p-anisyl chloride 11.9,
! 9 (0.07 mol) of ether bath solution 40I,
After returning to room temperature and stirring for 3Q, add water χ and add ether/i#
γ fraction was collected. The mixture was washed with ether, water, 10% hydrochloric acid, water, saturated sodium bicarbonate solution, and water in this order, and dried over anhydrous sodium hydroxide. ether
Colorless liquid monoester produced using iw column chromatography (8102) 6.8,! i' (yield 46
, 4ch) Y obtained. This monoester body 2.021 (0
,009 mol) yxx-f 20ml Ic m #
L, pyridine 2, n-caproic acid under stirring under ice cooling 1.22,! A 20-liter solution of iJ (0,009 mol) in ether was added dropwise. After stirring at the same temperature for 30 minutes and then returning to room temperature for 3 hours, the water was separated and the ether layer was separated. The mixture was washed with ethereal water, 10% hydrochloric acid, water, saturated sodium bicarbonate solution, and water in this order, and dried over anhydrous sodium sulfate. The ether was distilled off under reduced pressure and the residue was subjected to column chromatography (810s) [Te! 2.7 g of the compound 6 listed in Table 1 as a colorless liquid (yield: 9
3.2) Obtained.

nθat n, So 1.492 Engineering Rh cIL-117
20(吋0)ax Example 2 (Synthesis of Compound 11) 2 g (0.03 mol) of sodium hydride was suspended in 4 Q ml of tetrahydroproalane and 2.7 g (0.03 mol) of 2.3-butanediol was added under stirring under water cooling. 03 mol) in ether! 2
014 ml was added dropwise. After stirring at the same temperature for 60 minutes and at room temperature for 60 minutes, it was cooled again on ice and a solution of 3.4.5-trimethoxybenzoic acid chloride 6.92, V (0.03 mol) in tetrahydrofuran @ 40 ml 1'1 m was added. The mixture was returned to room temperature and stirred for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. Chloroform layer! water, 10% hydrochloric acid,
Washed with water, saturated sodium bicarbonate solution, and water in that order, and dried with anhydrous sulfur and IJum. The chloroform was distilled off under reduced pressure, and the residue was subjected to Y column chromatography (810,) to obtain a colorless liquid monoester, 5.66, ? (
Yield: 43%).

Dissolve 2.84 F (0.01 mol) of this monoester in Ranithil 20111VC, add 2 ml of pyricin, and add 2.05 ml of undecanoyl chloride under stirring while cooling with water.
(0.01 mol) of ether was added dropwise to the solution in an amount of 20 d. After stirring at the same temperature for 60 minutes and then returning to room temperature for 3 hours, water
After 10 minutes, separate the ether layer. Ether #Kaishui, 1
It was washed with 0% hydrochloric acid, water, saturated sodium bicarbonate, and water, and dried over anhydrous sodium sulfate. ether v
The residue was purified by column chromatography (eloz) to give a colorless liquid with a weight of 2.04 F (yield: 50).

20' n81LtnD1.
491 EngineeringRνCrrL-” 1720(0=O)a
X Example 6 (synthesis of compound 13) 9.9 (0.1 mol) of 2.3-butanediol was added to 50 ml of ether, 1 Vcf#%I, viridi:y 10 ml
Y 770 was mixed with undecanoyl chloride 20 while stirring on ice.
．． A solution of 5.17 (0.1 mole) in 75 ml of ether was added in drops at 0.5 mL for 30 minutes, then returned to room temperature and stirred for 4 hours. Water was added thereto and the ether solution was separated. The following treatment was carried out in the same manner as in Example 1 to obtain colorless liquid monoesters 1 and 2.
,! i' (yield 51cm) was obtained.

This monoester 12.9F (0.05 mol) was added with 10 g of ether 1QQJ viridun, and while stirring under ice cooling, 8.43 g (0.05 mol) of phenylpropionic acid chloride was added.
100 d of ether solution was added dropwise. 30 minutes at the same temperature,
(After returning to room temperature and stirring for 3 hours, water was added to separate the ether layer. The ether layer was washed with water, 10% hydrochloric acid, water, saturated sodium bicarbonate solution, and water in this order, and then diluted with anhydrous sulfuric acid.)
It was dried with IJum. The ether was distilled off under reduced pressure, leaving a residue Y
Column chromatography (810,)
Compound 16 listed in Table 1 as a colorless liquid 16.2.
9 (yield 85.3 tatami) was obtained.

20 ea tnn 1.4
75 k C1rL-11720(0=O)ax Example 4 The compounds shown in Table 2 were obtained in the same manner as in Example 1.2 or 3. In the same table, the compounds used in Examples 1 to 3 are also listed = 6 Example 5 (@ agent) One tablet having the following composition was manufactured according to a conventional method.

Butanediol diester 100111
& (Compound No. 11 in Table 2) Light anhydrous silicic acid 100 ■ Crystalline cellulose 50 Dahydroxyderovil cellulose 109 Calzoxymethylcellulose calcium 25 Datalc 49 Milk [11! '
This makes the total tY350 da.

Example 6 (granules) Granules having the following composition were produced according to a conventional method.

Butanediol diester 1009 (second
Compound No. 5 in the table) Light anhydrous silicon #100 Damannite 650 Dadendene 135 Davolivinylpyrrolidone 15Iv total amount
Example 7 (injection) An oil-based injection with the following composition was prepared according to a conventional method.

Butanediol diester 100~(2nd
Compound No. 14 in the table) Total t 2000 Ikg Example 8 (Suppositories) The following group r! y, melt it, stir it, mold it, solidify it, and make one suppository.

Butanediol diester (compound number 11 in Table 2) 100II9 or more

Claims (1)

[Claims] (1) General formula % formula % [In the formula, M is a single bond, an alkylene group of 01 to 4, 0□
~4 alkyleneoxy group, propenylene group or frame-a=
a-(wherein R1 and RII are hydrogen atoms and %R
1 represents an alkyl group or phenyl group of 0□~, or R2 is a hydrogen atom and RX represents a norogen atom or a phenyl group). A 2,3-butanediol diester derivative represented by a phenyl group which may be substituted by a lower alkoxy group, where m is an integer from 4 to 9. (2) General formula % (in the formula , m and R are the same as above) to the 2,3-butanediol monoester derivative represented by the general formula OH3(OH2)mCOOH (in the formula, the same as mi prefix), the carboxylic acid or the activity thereof. The general formula (wherein, m,
R and m are the same as above) A method for producing a 2,3-butanediol diester fermentation derivative represented by: (3) 2,3-butanediol monoester crocodile conductor represented by the general formula % formula % (where m is the same as above) ] The general formula (in the formula, m, R and m
A method for producing a 2,3-butanediol diester haze conductor represented by rt (same as above). (4) An anti-ulcer agent characterized by containing a 2,5-butanediol diester derivative Y represented by the general formula % (in the formula, A, R and m are the same as the front part) (5) The anti-ulcer agent according to claim 4, which is an oral dosage form. (6) The antiulcer agent according to claim WI4, which is in a parenteral administration form.