JP2589245B2 - N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine zinc complex - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel zinc complex of N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine, a process for producing the same, an anti-ulcer agent and an anti-gastritis containing these as an active ingredient. -It relates to a duodenitis / colitis agent, an anti-stomatitis agent, an anti-hepatitis agent and a liver injury inhibitor.

[0002]

[Problems to be solved by the prior art and the invention]
It has been already reported by the present inventors that (3-methyl-2-butenyl) -4-hydroxybenzoic acid has an anti-ulcer effect and an anti-hepatitis effect (Japanese Patent Publication No. 2-28574,
Tokuhei 2-28575).

The present inventors have developed a number of N- (3) compounds to develop more excellent anti-ulcer / anti-gastritis and anti-hepatitis agents.
As a result of synthesizing -alkyl (or alkenyl) -4-hydroxybenzoyl) glycines and their complexes and examining their therapeutic effects and toxicity, they have found that these zinc complexes exhibit particularly excellent action, Through repeated research, the present invention was completed.

[0004]

According to the present invention, there is provided a compound of the general formula

Embedded image Wherein R is a C _1-10 alkyl or alkenyl group, n
Represents 1 or 2) N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine zinc complex represented by the formula (1), a process for producing the same, an anti-ulcer agent containing these as an active ingredient, an anti-gastritis / duodenitis -It relates to a colitis agent, an anti-stomatitis agent, an anti-hepatitis agent and a liver injury inhibitor.

The compound of the general formula (I) has the general formula

Embedded image (Wherein R represents a C _1-10 alkyl or alkenyl group) by reacting a compound with a zinc compound. Examples of the substituent represented by R in the general formula (II) include methyl, allyl, tert-butyl, 3-methyl-2-butenyl, n-octyl and the like.

The compound of the general formula (II) can be produced by the method shown in the following formula. That is, N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine ester is synthesized by directly reacting 3-alkyl (or alkenyl) -4-hydroxybenzoic acid with glycine or by reacting with glycine ester. And then hydrolyze it.

Embedded image (Wherein R is the same as above, R ′ is protection of the carboxyl group)

The compound of the general formula (I) can be produced, for example, by the following method. Method A: A solution prepared by dissolving 1 mol of the compound of the formula (II) in 2 mol of an alkali agent is reacted with a 1 mol solution of a zinc compound. Method B: A solution prepared by dissolving 1 mol of the compound of the formula (II) in 1 mol of an alkali agent is reacted with a 0.5 mol solution of a zinc compound.

In the general formula (I), n =
One compound is obtained, and the compound of n = 2 is obtained by the method B. Examples of the alkaline agent include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate and potassium tert.
-Alkali metal alcoholates such as butoxide are used. As the zinc compound, for example, an inorganic or organic acid salt of zinc such as zinc halide, zinc sulfate, zinc acetate or zinc carbonate or zinc hydroxide is used, but other zinc compounds may be used. The reaction is usually carried out with water, methano-
The reaction was carried out at room temperature or under heating for several minutes to several hours in a suitable solvent such as toluene or ethanol, and after the reaction, the compound of the formula (I)
Is purified by a conventional method.

The compound of the general formula (I) of the present invention has excellent antiulcer activity, antigastritis / duodenitis / colitis, antistomatitis activity, antihepatitis activity and liver injury inhibitory activity, and has low toxicity. It also has an anti-ulcer effect compared to the compound of the general formula (II).
It has better anti-gastritis and anti-hepatitis effects and lower toxicity. The compound of the general formula (I) may be mixed with an appropriate excipient, carrier, diluent, or the like, which is itself or a pharmacologically acceptable compound, and may be orally or non-orally administered in various forms such as tablets, capsules, granules, powders, and syrups. Can be used orally. Particularly superior effects can be expected by administering as a troche in the case of stomatitis and as an enteric agent in cases of duodenitis and colitis. The dosage depends on the patient's symptoms, age,
Depending on body weight, administration route, etc., the usual adult dosage is 100 mg to 200 mg once daily for oral administration.
Administered once.

Hereinafter, the present invention will be described in more detail with reference to Synthesis Examples and Test Examples of the compounds of the present invention.

[0011]

Reference Example The synthesis of the compound of the general formula (II) is as follows.

Reference Example 1 17.8 g of 3-allyl-4-hydroxybenzoic acid (0.1
Mol), 25 g (0.1 mol) of glycine ethyl ester hydrochloride, and 140 g of 4-methylmorpholine, and 140 ml of dimethylformamide.The solution obtained by dissolving 36 g of diphenylphosphoric azide in 120 ml of dimethylformamide was added thereto with stirring. It was added dropwise at 55 ° C. and stirred overnight. The solution was poured into 500 ml of saturated saline, extracted with 700 ml of ethyl acetate, and the extract was washed with 1 N hydrochloric acid, 10% saline, 10% sodium hydrogen carbonate, and 10% saline, and dried (anhydrous anhydrous). After sodium sulfate), the solvent was distilled off under reduced pressure to obtain 28.5 g of yellow oily N- (3-allyl-4-hydroxybenzoyl) glycine ethyl ester. 10% sodium hydroxide
Add 230 ml, stir at 50-60 ° C for 1 hour, cool, wash with chloroform, adjust to pH 2 with 10% hydrochloric acid, and add ethyl acetate
After extracting twice with 350 ml, the extract was washed with water and dried (anhydrous sodium sulfate), and the solvent was distilled off under reduced pressure. Toluene was added to the residue for crystallization, which was recrystallized from ethyl acetate to obtain 13.6 g of N- (3-allyl-4-hydroxybenzoyl) glycine as colorless crystals. 152-154 ° C

Elemental analysis value (%): Calculated value of C ₁₂ H ₁₃ NO ₄ C: 61.27 H: 5.57 N: 5.96 Actual value C: 61.41 H: 5.59 N: 5.93 NMR (DMSO-d ₆ ) d: 2.82 (2H , d, J = 4Hz), 4.22 (2H,
d, J = 9Hz), 4.70 -5.20 (1H, m), 5.60-6.70 (3H,
m), 7.65 (2H, s).

[0014]

Reference Examples 2 to 5 According to Reference Example 1, N- (3-alkyl (or alkenyl) -4 in the general formula (II) was prepared using the corresponding 3-substituted-4-hydroxybenzoic acid.
-Hydroxybenzoyl) glycine was obtained. Table 1 shows the melting points and elemental analysis values of the product. The products of Reference Examples 2 to 5 are all new compounds.

[Table 1]

[0015]

The synthesis of the compounds of general formula (I) is illustrated in the following examples.

[0016]

[Example 1] 4.2 g (0.1 mol) of 95% sodium hydroxide
N-[(3-methyl-2
Butenyl) -4-hydroxybenzoyl] glycine 13.
2 g (0.05 mol) was added at 10-20 ° C, stirred for 1 hour, dissolved and filtered. This filtrate was treated with zinc acetate dihydrate 13.2
g (0.06 mol) was dissolved in 100 ml of pure water, added dropwise to the filtered solution, and stirred at room temperature for 1 hour. The resulting crystals were collected by filtration, washed thoroughly with pure water, and dried at 80 ° C under reduced pressure to obtain 15.5 g of colorless crystalline zinc N- [3- (3-methyl-2-butenyl) -4-hydroxybenzoyl] glycine complex. Was. Melting point 250 ° C or higher.

Elemental analysis value (%): Calculated value for C ₁₄ H ₁₅ NO ₄ Zn C: 51.47 H: 4.63 N: 4.29 Zn: 20.02 Actual value C: 51.48 H: 4.69 N: 4.38 Zn: 20.26 IR (KBr, cm -1); 2970, 2927, 1630, 1600, 1501, 141
8, 1278, 1110, 1018,910

[0018]

Example 2 95% sodium hydroxide 2.1 g (0.05 mol)
N- [3- (3-methyl-2-butenyl) -4-hydroxybenzoyl] glycine was added to a solution of
13.2 g (0.05 mol) was added at 10-20 ° C, stirred for 1 hour, dissolved and filtered.

A solution obtained by dissolving 6.6 g (0.03 mol) of zinc acetate dihydrate in 50 ml of pure water was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. The resulting crystals are collected by filtration, washed thoroughly with pure water, and dried at 80 ° C. under reduced pressure to give colorless crystals of bis {N- [3- (3-methyl-2-butenyl) -4-hydroxybenzoyl] glycine} zinc complex 12.7 g. Melting point 250
℃ or more.

Elemental analysis value (%): Calculated value of C ₂₈ H ₃₂ N ₂ O ₈ Zn C: 57.00 H: 5.47 N: 4.75 Zn: 11.08 Actual value C: 57.14 H: 5.49 N: 4.58 Zn: 11.55 IR (KBr , cm-1); 3400, 2970, 2930, 1630, 1601, 150
0, 1420, 1280, 1113,1014, 920

[0021]

Examples 3 to 8 According to Example 1 or 2, a zinc N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine complex included in the general formula (I) was obtained. Table 2 shows the melting points and elemental analysis values of the product.

[Table 2]

[0022]

[Test example]

Experimental animals For effects on gastric secretion and anti-ulcer tests, male Spr
ague-Dawley rat (Charles-River, SPE)
A body weight of 220-240 g was used. Animals were used after a 24-hour fast before use. Water intake is free for the first 24 hours, but water is cut off 2 hours before use.

Test compound (1) Compound of the present invention 1) N- (3-allyl-4-hydroxybenzoyl) glycine zinc complex [hereinafter abbreviated as U-201] 2) N- (3-tert-butyl-4) -Hydroxybenzoyl) glycine zinc complex [hereinafter abbreviated as U-202] 3) N- [3- (3-methyl-2-butenyl) -4-hydroxybenzoyl] glycine zinc complex [hereinafter abbreviated as U-203] 4) Bis {N- [3- (3-methyl-2-butenyl) -4-hydroxybenzoyl] glycine} zinc complex [U-2
04]

(2) Compound for Comparative Test 1) 3- (3-Methyl-2-butenyl) -4-hydroxybenzoic acid [hereinafter abbreviated as B-203] 2) N- (3-allyl-4-hydroxybenzoyl) Glycine [hereinafter abbreviated as C-201] 3) N- (3-tert-butyl-4-hydroxybenzoyl) glycine [abbreviated as C-202] 4) N- [3- (3-methyl-2-) Butenyl) -4-hydroxybenzoyl] glycine [hereinafter abbreviated as C-203]

Method of Administration of Test Compound In the administration of gastric juice secretion and anti-ulcer test, the test compound was suspended in 0.5% carboxymethylcellulose and administered in a volume of 1 ml / 200 g body weight. Controls received the same volume of vehicle alone.

1. Effect on gastric juice secretion The abdomen was opened under ether anesthesia, and the pylorus was ligated. Four hours later, the animals were sacrificed by ether, the stomach was removed, and the stored gastric juice was collected. Gastric juice was spun down at 3000 rpm for 10 minutes, and gastric fluid volume and acidity (mEq / l) were measured. The acidity was titrated to pH 7.0 with 0.1 N sodium hydroxide using an automatic titrator. The acid excretion per hour (μEq / hr) was calculated from the product of the gastric fluid volume and the acidity. The test compound and the solvent were orally administered 1 hour before ligation. Intraduodenum was administered immediately after ligation. Table 3 shows the results.

U-201 has an effect on the acidity in oral administration.
Significant suppression was observed at 100 mg / Kg. In addition, in intraduodenal administration, significant suppression of acid excretion was observed at 60 mg / Kg, which was also significant for gastric juice and acidity.

[Table 3]

2. Antiulcer test (1) Gastric damage to hydrochloric acid / ethanol: 150 mM hydrochloric acid / 60% ethanol was orally administered at a volume of 1 ml / 200 g body weight. One hour later, the animals were killed by ether, the stomach and the duodenum were removed, and the contents of the stomach were removed from the duodenum. After ligation of the cardia, 2% formalin solution
8 ml of the solution was injected into the stomach from the duodenum, and after ligation of the pylorus, it was immersed in the same solution for 10 minutes to fix it slightly (hereinafter abbreviated as formalin treatment). The stomach is dissected along the greater curvature, and the length (mm) of each lesion (erosion) occurring in the glandular stomach is measured under a dissecting microscope (10x magnification). The sum was calculated. Test compound was administered with hydrochloric acid / ethanol 1
Oral administration was given hour before. Table 4 shows the results.

The compound of the present invention was found to have an extremely excellent inhibitory effect on the occurrence of gastric damage as compared with the compound of the comparative test.

[Table 4]

(2) Water Immersion Stress Stomach Injury Rats were placed in a medicinal stress box at the University of Tokyo and immersed in a water tank at 23 ° C. to the level of the xiphoid process, and subjected to stress. Eight hours later, he was raised from the water tank and killed by ether. After the stomach was removed and treated with formalin, the length (mm) of damage occurring in the glandular stomach was measured, and the total damage per animal was calculated. The test compound was orally administered immediately before the stress load.
Table 5 shows the results.

The compounds of the present invention (U-201, U-204)
At 60 mg / kg, it showed significant suppression of the occurrence of this gastric injury.

[Table 5]

(3) Acute duodenal ulcer Mepilizole ulcer Mepilizol (Daiichi Pharmaceutical, suspended in 0.5% carboxymethyl cellulose) was administered subcutaneously at 200 mg / kg, and the animals were killed with ether 24 hours later. At last, the stomach and duodenum were removed. After formalin treatment (injection of 10 ml of formalin), individual areas (mm ² ) of ulcers generated in the stomach and duodenum were measured, and the total was calculated. The test compound was mepirizo-
Oral administration was performed 1 hour before and 9 hours after administration.
Table 6 shows the results.

U-201 was found to have an extremely excellent inhibitory effect on the occurrence of duodenal ulcer.

[Table 6]

3. Acute toxicity test SLC weighing 20 g: ICR (SPE) Male mice were used in groups of five, and test compounds were administered at 1500 mg / kg, 2000 mg / kg, and 3000 mg.
A suspension of the gum arabic powder at a rate of / kg was orally administered and observed. As a result, LD _{50 of} U-203 is 1830
mg / kg. U-203 was found to be highly safe compared to the effective dose.

[0034]

The present inventors have found pharmacological activity of 3-alkyl (or alkenyl) -4-hydroxybenzoic acid, which is weak but somewhat irritating to mucous membranes. Linked to form N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl)
The use of glycine almost eliminated this irritation, but did not make any progress in efficacy. However, by using this zinc complex, the compound of the present invention has further enhanced its efficacy and has high safety.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07C 231/12 C07C 231/12 C07F 3/06 7457-4H C07F 3/06

Claims (6)

(57) [Claims] 1. A compound of the general formula (Wherein, R represents a C _1-10 alkyl or alkenyl group, and n represents 1 or 2) N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine zinc chain represented by the formula: 2. A compound of the general formula (Wherein, R represents a C _1-10 alkyl (or alkenyl group)) and a zinc compound is reacted with the compound represented by the general formula. Embedded image (Where R and n in the formula are the same as described above).
A method for producing a chain of alkyl (or alkenyl) -4-hydroxybenzoyl) glycine zinc. 3. A compound of the general formula (Wherein, R represents a C _1-10 alkyl or alkenyl group, and n represents 1 or 2) N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine zinc chain represented by An anti-ulcer agent contained as an active ingredient. 4. A compound of the general formula (Wherein R represents a C _1-10 alkyl or alkenyl group, and n represents 1 or 2), and a zinc chain of N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine is effective. An anti-gastritis, duodenitis, colitis agent contained as an ingredient. 5. A compound of the general formula (Wherein R represents a C _1-10 alkyl or alkenyl group, and n represents 1 or 2), and a zinc chain of N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine is effective. An anti-stomatitis agent contained as an ingredient. 6. A compound of the general formula (Wherein R represents a C _1-10 alkyl or alkenyl group, and n represents 1 or 2), and a zinc chain of N- (3-alkyl (or alkenyl) -4-hydroxybenzoyl) glycine is effective. An anti-hepatitis agent and a liver injury inhibitor contained as components.