JPS6350352B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following general formula () (In the formula, R is a lower alkyl group having 1 to 6 carbon atoms, a phenyl group, or an aralkyl group having 7 to 9 carbon atoms,
n represents a positive integer from 1 to 3. However, when n is 1, the case where R is a methyl group is excluded. The present invention relates to a method for producing an aluminum salt of N-[β-(N'-acylamino)propionyl]histidine represented by: The present inventors have conducted intensive research to find pharmaceuticals, especially substances for treating diseases of the digestive system, and have found that N-
The present invention was completed based on the discovery that the aluminum salt of [β-(N'-acylamino)propionyl]histidine has an excellent therapeutic effect on peptic ulcers. Therefore, an object of the present invention is to provide a method for producing a compound represented by the general formula (). Examples of the lower alkyl group having 1 to 6 carbon atoms for R in the general formula () of the present invention include methyl, ethyl, propyl, butyl, and hexyl groups, and examples of the aralkyl group having 7 to 9 carbon atoms include methyl. Includes benzyl group, phenethyl group, etc. The compound represented by the general formula () of the present invention can be produced by any of the following methods. Method (1): By reacting N-[β-(N'-acylamino)propionyl]histidine with aluminum alkoxide, N of the general formula () is
−[β-(N′-acylamino)propionyl]
An aluminum salt of histidine is produced. The reaction solvent may be water, a water-containing organic solvent, or a non-aqueous organic solvent. There are no particular limitations on the aluminum alkoxide, and aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum t-butyroxide, aluminum cyclohexyl oxide, and the like can be used. If the aluminum alkoxide used contains impurities such as aluminum hydroxide or its polymer, the aluminum alkoxide is distilled or dissolved before use, and the impurities are removed separately using a solvent that does not dissolve the impurities. This is desirable. The reaction temperature is not particularly limited, but ranges from room temperature to 80°C.
Temperatures up to °C are commonly applied. After the reaction, the desired product can be isolated by removing the reaction solvent and alcohols produced by the reaction. Method (2): The aluminum salt of N-[β-(N′-acylamino)propionyl]histidine is
[β-(N′-acylamino)propionyl] It is produced by passing a mixed aqueous solution of histidine and a mineral acid salt of aluminum such as aluminum sulfate, aluminum nitrate or aluminum chloride through an anion exchange resin. As the anion exchange resin, any of weakly basic, medium basic, and strongly basic resins can be used, but it is preferable to use a weakly basic anion exchange resin such as Amberlite IR-45. The amount of resin used is determined by the amount and type of mineral acid ions in the mixed solution, but if it is too small, mineral acid ions will mix into the effluent, which is undesirable, and if it is too large, N-[β-( Since the adsorption amount of N'-acylamino)propionyl]histidine increases, which is undesirable, it is appropriate to use 2 to 3 equivalents. Although there is no particular restriction on the concentration of the column liquid, it is preferable that the mineral acid ion concentration is maintained at about 0.5 to 1 equivalent. Appropriate tower passing speed is about SV0.5 to 2. By concentrating the aqueous solution thus discharged to dryness under reduced pressure, the target compound of general formula () can be obtained. In both methods (1) and (2), the molar ratio of the raw material compound to N-[β-(N'-acylamino)propionyl]histidine and aluminum alkoxide or aluminum mineral acid salt is 1: 1, 2:1, 3:1, N-[β-(N'-acylamino)propionyl]histidine monoaluminum, bis{N
-[β-(N'-acylamino)propionyl]histidine}monoaluminum or tris{N
A desired aluminum salt of -[β-(N'-acylamino)propionyl]histidine monoaluminum can be produced. The raw material compound N-[β-(N'-acylamino)propionyl]histidine is obtained by reacting histidine or its ester with β-N-acylalanine or its reactive derivative, and then eliminating the ester residue. It is produced by acylating the β-amino group of N-(β-aminopropionyl)histidine. The compound of the present invention represented by the general formula () obtained as described above has an excellent peptic ulcer therapeutic action. That is, it exhibits excellent ulcer-inhibiting effects on various experimental ulcer models. For example, 300 for pylorus ligation ulcer, stress ulcer, aspirin ulcer, indomethacin ulcer and histamine ulcer in rats.
Shows excellent inhibitory effect at mg/Kg to 1000mg/Kg. Therefore, the compounds of the present invention are useful as therapeutic agents for acute and chronic peptic ulcers. Furthermore, when the acute toxicity of the compound of the present invention in rats was investigated, there were no deaths after oral administration of 10 g/Kg, and no changes were observed in other general symptoms. Note that these experimental methods and results will be described later as reference examples. As described above, the compound of the present invention has very low toxicity and is useful as an extremely safe and excellent medicine. When administering the compound of the present invention to adults, the preferred route of administration is oral, and the dosage varies depending on age, symptoms, etc., but is generally 500 mg to 5000 mg/day.
The day is appropriate. The dosage form for oral administration can be tablets, capsules, granules, etc. Next, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. Reference example 1 Effect on pylorus ligation ulcer One group of male rats weighing 210 to 230 g
The number was 10. Shay et al. (Gastroenterology 5, 43
After fasting for 48 hours and removing the stomach under ether anesthesia and collecting gastric juice, the area (mm ² ) of the ulcer occurring in the forestomach was measured under a dissecting microscope (10
It was measured at 100% (fold) and expressed as an ulcer index. Drugs were administered orally immediately after pyloric ligation. The results are shown in Table 1.

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[Table] Reference example 2 Effect on stress ulcers One group of male rats weighing 240 to 260 g
Takagi et al. (Jap.J.Pharmac.18(9), 9-
18, 1968) and placed in a restrained stress cage and immersed in water up to the xiphoid process in a 23°C water tank to apply stress. Seven hours later, the fish was removed from the tank, immediately beaten to death, and its stomach was removed. After injecting 1% formalin into the stomach and immersing it in 1% formalin for 10 minutes, the stomach was incised along the greater curvature and the length (mm) of the mucosal ulcer occurring in the glandular stomach was measured. It was measured and expressed as ulcer index. Drugs were orally administered 10 minutes before stress loading. The results are shown in Table 2.

[Table] Reference Example 3 Effect of aspirin on ulcers One male Donriyu rat weighing 220 to 230 g was
Group 10 animals, Okabe et al. (Jap.J.Pharmac.24, 357~
After fasting for 24 hours, the pylorus is ligated under ether anesthesia according to the method of 361, 1974). After closing the abdomen,
Administer aspirin 100mg/Kg orally. After 7 hours, the stomach was instilled under ether anesthesia and gastric juice was collected.
% formalin treatment, the length (mm) of ulcers occurring in the glandular stomach was measured, and the total per animal was taken as the ulcer index. The test drug was orally administered immediately after pylorus ligation. The results are shown in Table 3.

[Table] Reference example 4 Effect on indomethacin ulcer One group of male rats weighing 200 to 215 g
10 animals, indomethacin 25mg/Kg after 24 hours fasting
was administered subcutaneously. After 7 hours, the animals were sacrificed with ether and the stomachs were immersed in 1% formalin solution for 10 minutes. The semi-fixed stomach was incised along the greater curvature, and the length (mm) of ulcers occurring in the mucosal area was measured and expressed as an ulcer index. The drug is indomethacin administration.
Administered orally 10 minutes prior. The results are shown in Table 4.

[Table] Reference example 5 Effect on histamine ulcer One group of male rats weighing 210 to 230 g
10 animals, histamine phosphate 300mg after 48 hours fasting
mg/Kg was administered intraperitoneally. After 4 hours, the animals were sacrificed with ether and the stomachs were immersed in 1% formalin solution for 10 minutes. The semi-fixed stomach was incised along the greater curvature, and the length (mm) of ulcers occurring in the mucosal area was measured and expressed as an ulcer index. Drugs were administered orally 10 minutes before histamine administration. The results are shown in Table 5.

[Table] Reference Example 6 Acute Toxicity Test The compound of the present invention was orally administered to male and female Wistar rats weighing 150 to 200 g, each group containing 10 rats. The observation period was 7 days. The results are shown in Table 6.

[Table] Reference compounds are the same as above.
Reference Example 7 N-[β-(N'-acetylamino)propionyl]histidine aluminum salt: Dissolve 5.36g of N-[β-(N'-acetylamino)propionyl]histidine in 100ml of water and add it. The mixture was heated to a hot solution of about 40° C., and 90 ml of isopropyl alcohol solution containing 4.08 g of aluminum isopropoxide was gradually added dropwise with vigorous stirring. After the dropwise addition was completed, the mixture was stirred at 40°C for 10 minutes, then insoluble matter was separated, and the solvent was distilled off under reduced pressure. Isopropyl alcohol was added to the obtained oily residue to solidify it. The solid was powdered and then collected and washed thoroughly with isopropyl alcohol. 60℃ under reduced pressure
A colorless powder of N-[β-
6.5 g (quantitative) of (N'-acetylamino)propionyl]histidine aluminum salt was obtained. The infrared absorption spectrum chart of the obtained product is shown in FIG. 1, and the differential thermal analysis chart is shown in FIG. NMR (D ₂ O) δ: 2.00 (3H, s, COC H ₃ ) 2.55 (2H, m, -CH ₂ C H ₂ NHCOCH ₃ ) 3.40 (4H, m, -COC H ₂ CH ₂ N- and -C H ₂ CH
) 4.20 (1H, m, methine proton) 7.30, 8.50 (1H x 2, s x 2, imidazole ring proton) Elemental analysis C ₁₁ H ₁₇ N ₄ O ₆ Calculated value (%) as Al C: 40.25 H: 5.22 N :17.07 Analysis value (%) C: 40.18 H: 5.58 N: 16.76 Example 1 2.76 g of N-acetyl-L-carnosine was added to 20 ml of isopropyl alcohol containing 0.70 g of aluminum isopropoxide at 60°C, and after stirring for 1 hour. ,
10 ml of water was added and stirred for 30 minutes to obtain a homogeneous solution. Thereafter, insoluble matter was separated, isopropyl alcohol was distilled off under reduced pressure, and the remaining aqueous solution was freeze-dried to obtain 2.8 g (quantitative) of N-acetyl-L-carnosine aluminum salt as a colorless powder. Melting point: 220℃ (decomposition) [α] ²⁵ _D : +22.8゜ (C = 5%, water) IRν ^KBr _nax cm ^-1 : 3400 (OH), 1630 (C=O), 1390,
1300 NMR (D ₂ O) δ: 1.63 (3H, s, CH ₃ CO-) 2.21 (2H, t, -COC H ₂ CH ₂ NH-) 2.96 (2H, m,

[Formula]) 3.16 (2H, t, -COCH ₂ C H ₂ NH-) 4.44 (1H, m,

[Formula] 7.41, 8.81 (1H x 2, s x 2, imidazole ring proton) Elemental analysis (C ₁₁ H ₁₅ N ₄ O ₄ ) ₃ As Al Calculated value (%) C: 47.82, H: 5.48, N: 20.28 Analysis value (%) C: 47.58, H: 5.24, N: 20.08 Example 2 2.73 g of N-acetyl-L-carnosine was added to 20 ml of isopropyl alcohol containing 1.04 g of aluminum isopropoxide at 60°C and treated in the same manner as in Example 1 to obtain N-acetyl-L-carnosine as a colorless powder. 2.9 g (quantitative) of aluminum salt was obtained. Melting point: 218 (decomposed) [α] ²⁵ _D : +19.6° (C = 5%, water) IRν ^KBr _nax cm ^-1 : 3400 (OH), 1630 (C=O), 1390,
1300 NMR (D ₂ O) δ: 1.91 (3H, s, CH ₃ CO) 2.42 (2H, t, -COC H ₂ CH ₂ NH-) 3.10 (2H, m,

[Formula]) 3.32 (2H, t, -COCH ₂ C H ₂ NH-) 4.44 (1H, m,

[Formula] 7.09, 8.32 (1H x 2, s x 2, imidazole ring proton) Elemental analysis (C ₁₁ H ₁₅ N ₄ O ₄ ) ₂ As AlOH Calculated value (%) C: 45.67, H: 5.41, N: 19.37 Analysis value (%) C: 45.84, H: 5.12, N: 19.45 Example 3 1.11 g of N-propionyl-L-carnosine was added to 11 ml of isopropyl alcohol containing 0.80 g of aluminum isopropoxide at 60°C, and after stirring for 1 hour, 10 ml of water was added and stirred for 30 minutes to form a homogeneous solution. . Thereafter, insoluble matter was separated, the isopropyl alcohol was distilled off under reduced pressure, and the remaining aqueous solution was freeze-dried to obtain 1.3 g (quantitative) of N-propionyl-L-carnosine aluminum salt as a colorless powder. Melting point: 228℃ (decomposition) [α] ²⁵ _D : +11.4゜ (C = 3%, water) IRν ^KBr _nax cm ^-1 : 3400 (OH), 1640 (C=O), 1540,
1400 NMR (D ₂ O) δ: 1.02 (3H, t, CH ₃ CH ₂ CO−) 2.11 (2H, q, −CH ₃ C H ₂ CO−) 2.40 (2H, t, −COC H ₂ NH− ) 3.08 (2H, m,

[Formula]) 3.28 (2H, t, -COCH ₂ C H ₂ NH-) 4.44 (1H, m,

[Formula]) 7.07, 8.26 (1H x 2, s x 2, imidazole ring proton) Elemental analysis (C ₁₂ H ₁₇ N ₄ O ₄ ) Al (OH) ₂ Calculated value (%) C: 42.10, H: 5.61 , N: 16.37 Analysis value (%) C: 41.88, H: 5.83, N: 16.12 Example 4 N-heptanoyl was added to 15 ml of isopropyl alcohol containing 0.68 g of aluminum isopropoxide.
1.13 g of L-carnosine was added and the same procedure as in Example 3 was carried out to obtain 1.3 g (quantitative) of colorless powder of N-heptanoyl-L-carnosine aluminum salt. Melting point: 280°C or higher [α] ²⁵ _D +0.4° (C = 1%, water) IRν ^KBr _nax cm ^-1 : 3400 (OH), 2930, 2860 (alkyl)
,
1640, (C=O), 1540 NMR (D ₂ O) δ: 0.80 (3H, t, CH ₃ −CH ₂ −) 1.20 (8H, m, −CH ₂ −×4) 2.12 (2H, t, -CH ₂ C H ₂ CO-) 2.40 (2H, t, -COC H ₂ CH ₂ NH-) 3.07 (2H, m,

[Formula] 3.31 (2H, t, -COCH ₂ C H ₂ NH-) 4.44 (1H, m,

[Formula]) 7.06, 8.28 (1H x 2, s x 2, imidazole ring proton) Example 5 N-benzoyl-L in 15 ml of isopropyl alcohol containing 0.8 g of aluminum isopropoxide
- 1.27 g of carnosine was added and treated in the same manner as in Example 3 to obtain 1.5 g (quantitative) of colorless powder of N-benzoyl-L-carnosine aluminum salt. Melting point: 280°C or higher [α] ²⁵ _D : +6.2° (C=1%, H ₂ O) IRν ^KBr _nax cm ^-1 : 3400 (OH), 1630 (C=O), 1540,
1400 NMR (D ₂ O) δ: 2.55 (2H, t, -COC H
₂ CH ₂ NH−) 3.07 (2H, m,

[Formula] 3.55 (2H, t, -COCH ₂ C H ₂ NH-) 4.44 (1H, m,

[Formula] 6.99 [1H, s, imidazole ring proton (5
position)] 7.44 (5H, m, benzene ring proton) 8.08 [1H, s, imidazole ring proton (2
)] Elemental analysis (C ₁₆ H ₁₇ N ₄ O ₄ ) Al(OH) ₂ Calculated value (%) C: 49.23, H: 4.92, N: 14.36 Analysis value (%) C: 49.18, H: 4.86, N: 14.18

[Brief explanation of drawings]

FIG. 1 is an infrared absorption spectrum of N-[β-(N'-acetylamino)propionyl]histidine aluminum salt. Figure 2 shows N-[β-
This is a differential thermal analysis of (N'-acetylamino)propionyl]histidine aluminum salt.

Claims (1)

[Claims] 1. General formula (In the formula, R represents a lower alkyl group having 1 to 6 carbon atoms, a phenyl group, or an aralkyl group having 7 to 9 carbon atoms.) Or the general formula () characterized by dissolving in an organic solvent and reacting with aluminum alkoxide at room temperature to 80℃ (In the formula, n represents a positive integer of 1 to 3, and R is the same as above, except when n is 1 and R is a methyl group.) A method for producing an aluminum salt of ′-acylamino)propionyl]histidine.