JPH06172287A - Aminocarboxylic acid derivative and pharmaceutical composition containing the compound - Google Patents

Abstract

PURPOSE:To provide the subject new compound having low side effects, applicable over a long period and useful for the treatment of allergic diseases such as allergic rhinitis, bronchial asthma, urticaria and amyctic dermatopathy. CONSTITUTION:The compound of formula (X is H or acetyl; R is alkylene or phenylene; A is direct bond, alkylene or vinylene; (n) is 0 or 1), e.g. 2-((s)-4- benzyloxycarbonyl-4-benzyloxycarbonylamino butyrylamino)acetic acid benzyl ester. The compound of formula can be produced by reacting alpha-benzyl ester of N-benzyloxycarbonyl-L-glutamic acid with 2-aminoacetic acid benzyl ester, etc., in a solvent (e.g. methylene chloride) in the presence of triethylamine using a water-soluble carbodiimide hydrochloride.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aminocarboxylic acid compound having an antiallergic action and a pharmaceutical composition containing the derivative.

[0002]

2. Description of the Related Art Allergy is a hypersensitivity state of a living body based on an antigen-antibody reaction, and is classified into four types of type I to type IV according to the reaction mechanism. Bronchial asthma, allergic rhinitis, urticaria, etc., which are typical allergic diseases that plague many people, are caused by type I allergic reactions (immediate type, anaphylactic type). In the type I allergic reaction, when the antigen binds to IgE bound to the cell surface of mast cells or basophils, it causes a degranulation phenomenon, releases inflammatory mediators such as histamine and leukotrienes, and exhibits various allergic symptoms. . For example, allergic rhinitis, which has been increasing in number of patients in recent years, can be divided into a perennial allergy with house dust as the main antigen and a seasonal allergy (hay fever) mainly with cedar pollen.
The former requires particularly long-term treatment because it begins in childhood and the symptoms persist. Therefore, there is a need for an antiallergic agent that can be administered for a long period of time and has few side effects during treatment. As a preparation for topical administration into the nasal cavity, topical steroids such as beclomethasone, chemical mediator release inhibitors such as sodium cromoglycate are used in clinical treatment, but there are problems such as local irritation, Development of a drug that is less irritating and highly safe is desired.

The present inventors have studied on a hypoallergenic antiallergic agent capable of continuous administration for a long period of time, and as a result,
The present invention was completed by finding that the aminocarboxylic acid derivative of the present invention has an excellent antiallergic action.

[0004]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide an aminocarboxylic acid derivative having an antiallergic action, a pharmaceutically acceptable salt thereof, and an antiallergic agent containing the compound as an active ingredient. is there.

[0005]

The aminocarboxylic acid derivative of the present invention is a compound represented by the following general formula.

[Chemical 3] In the above general formula, X represents hydrogen or an acetyl group,
R is an alkylene group, preferably an alkylene group having 1 to 8 carbon atoms such as methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene,
Or represents a phenylene group, A represents a direct bond, an alkylene group, preferably an alkylene group having 1 to 8 carbon atoms such as methylene, ethylene, propylene, or a vinylene group,
n represents an integer of 0 or 1.

The aminocarboxylic acid derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the general formula (I), and examples thereof include alkali metals such as sodium and potassium, alkali metals such as calcium and magnesium. Earth metal,
Other salts with metals such as aluminum, or hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid Acid addition salts with acids such as tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, or ammonia , Salts with organic bases such as organic amines. These salts can be prepared from the free aminocarboxylic acid derivative of the present invention by a known method, or can be converted into each other. When an optical isomer is present in the compound of the present invention, the present invention includes any isomer thereof.

Next, an example of a method for producing the aminocarboxylic acid derivative of the present invention will be described. Α-benzyl ester of N-benzyloxycarbonyl-L-glutamic acid, 2-aminoacetic acid benzyl ester, 3-aminopropionic acid benzyl ester, 4-aminobutyric acid benzyl ester, 5
-Aminopentanoic acid benzyl ester, 6-aminohexanoic acid benzyl ester, 7-aminoheptanoic acid benzyl ester, 8-aminooctanoic acid benzyl ester,
Amino acid benzyl esters such as 3-aminobenzoic acid benzyl ester, 4-aminobenzoic acid benzyl ester, 4-aminomethylbenzoic acid benzyl ester and (4-aminophenyl) acetic acid benzyl ester, (3-aminophenyl) propionic acid benzyl ester Amino acid benzyl ester such as (4-aminophenyl) propionic acid benzyl ester and the like having a protecting group by a condensation reaction using water-soluble carbodiimide hydrochloride in the presence of triethylamine in a solvent such as methylene chloride that does not inhibit the reaction. Invention compounds can be prepared. Then, by catalytic reduction in the presence of a catalytic amount of palladium carbon,
The free compound of the present invention can be obtained.

As described above, the aminocarboxylic acid derivative of the present invention can be produced by a condensation reaction in peptide synthesis chemistry, and a conventional condensation method used in the art can be used. The raw material compound may appropriately have a protecting group used in peptide synthesis, and these protecting groups are subjected to catalytic reduction,
It can be removed by a usual means such as acid decomposition. The reaction temperature, time, solvent, catalyst and the like in the condensation reaction and deprotection group reaction can be set according to the reaction conditions used in ordinary peptide synthesis. The obtained compound of the present invention is purified by ordinary means such as distillation, chromatography, recrystallization, melting point, specific optical rotation, elemental analysis,
Identification was performed by NMR and the like. The specific rotation was measured using the D line of sodium.

[0009]

【Example】

Example 1.11.14 g of N-benzyloxycarbonyl-L-glutamic acid α-benzyl ester, 11.1
A solution of 3 g of 2-aminoacetic acid benzyl ester p-toluenesulfonate and 3.34 g of triethylamine in methylene chloride (150 ml) was ice-cooled, and 6.32 g of water-soluble carbodiimide hydrochloride was added. After stirring under ice-cooling for 2 hours and at room temperature for further 20 hours, the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue to separate the organic layer, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined and washed successively with a 10% aqueous citric acid solution, a saturated saline solution, a 5% aqueous sodium hydrogen carbonate solution, and a saturated saline solution. After drying over sodium sulfate, the solvent was distilled off under reduced pressure. The crystalline solid obtained was recrystallized from ethyl acetate-ether-petroleum ether and 15.23 g of 2-((S)-
4-Benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylamino) acetic acid benzyl ester was obtained. Mp: 127 - 128 ° C. [α] ^25: -1.9 ° (c1, CHCl ₃₎ NMR (CDCl ₃ , TMS): δ = 1.92-2.05 (1H, m), 2.17-2.36 (3
H, m), 3.98 (1H, dd, J = 5,18Hz), 4.08 (1H, dd, J = 5, 18H
z), 4.43-4.51 (1H, m), 5.10 (2H, s), 5.16 (2H, s), 5.15 a
nd 5.18 (2H, ABq, J = 13Hz), 5.65 (1H, d, J = 8Hz, amide), 6.
27-6.36 (1H, brs, amide), 7.28-7.40 (15H, m).

In the same manner, the following compound was obtained. 3 - ((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylamino-butyryl amino) propionic acid benzyl ester mp: 83 - 84 ° C. [α] ^25: -2.6 ° (c1, CHCl ₃₎ NMR (CDCl ₃ , TMS): δ = 1.90-2.03 (1H, m), 2.08-2.23 (3
H, m), 2.55 (2H, dd, J = 5,7Hz), 3.41-3.54 (2H, m), 4.32-
4.41 (1H, m), 5.08 (2H, s), 5.12 (2H, s), 5.13 and 5.17 (2
H, ABq, J = 12Hz), 5.71 (1H, d, J = 8Hz, amide), 6.14-6.19 (1
H, brs, amide), 7.26-7.38 (15H, m). 4-((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylamino) butyric acid benzyl ester Melting point: 106-108 ° C [α ] ²⁵ : -4.6 ° (c1, CHCl ₃ ) NMR (CDCl ₃ , TMS): δ = 1.77-1.85 (2H, m), 1.92-2.01 (1
H, m), 2.10-2.24 (3H, m), 2.28 (2H, t, J = 7Hz), 3.23 (2H, d
t, J = 6.5, 7Hz), 4.33-4.41 (1H, m), 5.08 (2H, s), 5.10 (2
H, s), 5.13 and 5.18 (2H, ABq, J = 12.5Hz), 5.70 (1H, d, J =
8Hz, amide), 5.94 (1H, t, J = 6.5Hz, amide), 7.28-7.38 (15
H, m).

5-((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylamino) pentanoic acid benzyl ester Melting point: 78-79 ° C. [α] ²⁵ : -4.3 ° (c1, CHCl ₃ ). NMR (CDCl ₃ , TMS): δ = 1.44-1.53 (2H, m), 1.59-1.68 (2
H, m), 1.91-2.04 (1H, m), 2.10-2.25 (3H, m), 2.35 (2H, t, J
= 7Hz), 3.13-3.23 (2H, m), 4.32-4.42 (1H, m), 5.09 (2H,
s), 5.10 (2H, s), 5.14 and 5.18 (2H, ABq, J = 12Hz), 5.70
(1H, d, J = 8Hz, amide), 5.76-5.83 (1H, brs, amide), 7.27-
7.38 (15H, m). 6-((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylamino) hexanoic acid benzyl ester Melting point: 85-86 ° C [α] ²⁵ : -3.6 ° (c1 , CHCl ₃ ) NMR (CDCl ₃ , TMS): δ = 1.26-1.35 (2H, m), 1.41-1.50 (2
H, m), 1.58-1.68 (2H, m), 1.91-2.03 (1H, m), 2.12-2.25 (3
H, m), 2.33 (2H, t, J = 7.5Hz), 3.12-3.22 (2H, m), 4.33-4.4
1 (1H, m), 5.08 (2H, s), 5.10 (2H, s), 5.13 and 5.18 (2H,
ABq, J = 12Hz), 5.74 (1H, d, J = 8Hz, amide), 5.77-5.84 (1H, b
rs, amide), 7.27-7.38 (15H, m).

7-((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylamino) heptanoic acid benzyl ester Melting point: 72-73 ° C. [α] ²⁵ : -3.6 ° (c1, CHCl ₃ ). NMR (CDCl ₃ , TMS): δ = 1.24-1.36 (4H, m), 1.39-1.49 (2
H, m), 1.58-1.67 (2H, m), 1.91-2.04 (1H, m), 2.12-2.25 (3
H, m), 2.34 (2H, t, J = 7Hz), 3.11-3.21 (2H, m), 4.34-4.41
(1H, m), 5.09 (2H, s), 5.10 (2H, s), 5.14 and 5.18 (2H, A
Bq, J = 12Hz), 5.69 (1H, d, J = 8Hz, amide), 5.68-5.75 (1H, br
s, amide), 7.28-7.38 (15H, m). 8-((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylamino) octanoic acid benzyl ester Melting point: 92-93 ° C [α] ^25: -3.7 ° (c1, CHCl ₃₎ NMR (CDCl ₃ , TMS): δ = 1.21-1.33 (6H, m), 1.38-1.48 (2
H, m), 1.57-1.67 (2H, m), 1.92-2.04 (1H, m), 2.10-2.25 (3
H, m), 2.33 (2H, t, J = 7.5 Hz), 3.11-3.21 (2H, m), 4.34-4.
42 (1H, m), 5.09 (2H, s), 5.10 (2H, s), 5.14 and 5.18 (2
H, ABq, J = 12Hz), 5.62-5.72 (2H, m), 7.28-7.39 (15H, m).

4-((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylamino) benzoic acid benzyl ester Melting point: 139-140 ° C. [α] ²⁵ : -16.7 ° (c1, CHCl ₃ ). NMR (CDCl ₃ , TMS): δ = 1.92-2.04 (1H, m), 2.25-2.47 (3
H, m), 4.39-4.48 (1H, m), 5.08 and 5.11 (2H, ABq, J = 12H
z), 5.14 and 5.17 (2H, ABq, J = 12Hz), 5.34 (2H, s), 5.65
(1H, d, J = 8Hz, amide), 7.26-7.45 (15H, m), 7.61 (2H, d, J =
8Hz), 8.01 (2H, d, J = 8Hz), 8.39 (1H, s, amide). 3-((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylamino) benzoic acid benzyl ester mp: 100 - 102 ° C. [α] ^25: -11.8 ° (c1, CHCl ₃₎ NMR (CDCl ₃ , TMS): δ = 1.93-2.05 (1H, m), 2.24-2.45 (3
H, m), 4.40-4.49 (1H, m), 5.06 and 5.09 (2H, ABq, J = 12H
z), 5.13 and 5.17 (2H, ABq, J = 12Hz), 5.34 (2H, s), 5.66
(1H, d, J = 8Hz, amide), 7.26-7.44 (16H, m), 7.79 (1H, d, J =
8Hz), 7.93 (1H, d, J = 8Hz), 8.04 (1H, s), 8.19 (1H, s, amid
e).

4-((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylaminomethyl) benzoic acid benzyl ester Melting point: 140-141 ° C. [α] ²⁵ : -2.0 ° (c1, CHCl ₃ ) NMR (CDCl ₃ , TMS): δ = 1.92-2.05 (1H, m), 2.14-2.31 (3
H, m), 4.35-4.50 (3H, m), 5.07 (2H, s), 5.13 and 5.18 (2
H, ABq, J = 12Hz), 5.35 (2H, s), 5.64 (1H, d, J = 8Hz, amide),
6.17-6.24 (1H, brs, amide), 7.26-7.45 (17H, m), 8.01 (2
H, d, J = 8 Hz). 2- [4-((S) -4-benzyloxycarbonyl-
4-benzyloxycarbonylaminobutyrylamino)
Phenyl] acetic acid benzyl ester mp: 146 - 147 ° C. [α] ^25: -10.6 ° (c1, CHCl ₃₎ NMR (CDCl ₃ , TMS): δ = 1.94-2.05 (1H, m), 2.24-2.42 (3
H, m), 3.61 (2H, s), 4.40-4.49 (1H, m), 5.08 and 5.10 (2
H, ABq, J = 12Hz), 5.11 (2H, s), 5.13 and 5.17 (2H, ABq, J =
12Hz), 5.65 (1H, d, J = 8Hz, amide), 7.21 (2H, d, J = 8Hz),
7.27-7.38 (15H, m), 7.47 (2H, d, J = 8Hz), 7.96 (1H, s, amid
e).

4- [3-((S) -4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyrylamino) phenyl] propionic acid benzyl ester Melting point: 110-111 ° C NMR (DMSO-d ₆ ): δ = 1.81-1.93 (1H, m), 2.05-2.16 (1H,
m), 2.42 (2H, t, J = 7.5Hz), 2.65 (2H, t, J = 7.5Hz), 2.83 (2
H, t, J = 7.5Hz), 4.13-4.20 (1H, m), 5.02 (2H, s), 6.88 (1H,
d, J = 8Hz), 7.14-7.46 (18H, m), 7.81 (1H, d, J = 8Hz), 9.84
(1H, s) 4- [4-((S) -4-benzyloxycarbonyl-
4-benzyloxycarbonylaminobutyrylamino)
Phenyl] propionic acid benzyl ester Melting point: 176-177 ° C NMR (DMSO-d ₆ ): δ = 1.82-1.94 (1H, m), 2.05-2.17 (1H,
m), 2.47 (2H, t, J = 7Hz), 4.13-4.21 (1H, m), 5.02 and 5.0
5 (2H, ABq, J = 12Hz), 5.14 (2H, s), 5.21 (2H, s), 6.57 (1H,
d, J = 16Hz), 7.25-7.69 (16H, m), 7.82 (1H, d, J = 8Hz), 10.
13 (1H, s)

Example 2.18.96 g of 2-((S)-
4-benzyloxycarbonyl-4-benzyloxycarbonylaminobutyryl) -aminoacetic acid benzyl ester as a mixed solvent of methanol, acetic acid and water (175 ml)
In addition, catalytic reduction was carried out at room temperature and atmospheric pressure in the presence of 0.5 g of 10% palladium-carbon. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure and the obtained crystalline solid was recrystallized from water-ethanol to give 5.33 g of 2-((S) -4-amino-4-carboxybutyibutyi. Rylamino) acetic acid [Compound 1]
Got Melting point: 195-196 ° C (decomposition) [α] ²⁵ : + 8.8 ° (c1, H ₂ O) NMR (0.2NNaOD, t-butanol): δ = 1.75-1.96 (2H, m), 3.
23 (2H, t, J = 8Hz), 3.24 (1H, dd, J = 6,7Hz), 3.73 (2H, s).

In the same manner, the following compound was obtained. 3 - ((S) -4-amino-4-carboxy-butyryl amino) propionic acid [Compound 2] mp: 201 - 202 ° C. (decomposition) [α] ^25: +7.6 ° (c1, H ₂ O) NMR (0.2NNaOD, t-butanol): δ = 1.71-1.92 (2H, m), 2.
25 (2H, t, J = 8Hz), 2.37 (2H, t, J = 7Hz), 3.21 (1H, dd, J = 6,
7 (Hz), 3.36 (2H, t, J = 7Hz). 4-((S) -4-amino-4-carboxybutyrylamino) butyric acid [Compound 3] Melting point: 204-206 ° C (decomposition) [α] ²⁵ : + 7.1 ° (c1, H ₂ O) NMR (0.2NNaOD, t-butanol): δ = 1.69-1.93 (4H, m), 2.
18 (2H, t, J = 7.5Hz), 2.22-2.29 (2H, m), 3.15 (2H, t, J = 7.5
Hz), 3.22 (1H, dd, J = 6, 7Hz).

5-((S) -4-amino-4-carboxybutyrylamino) pentanoic acid [Compound 4] Melting point: 186-187 ° C. (decomposition) [α] ²⁵ : + 6.3 ° (c1, H ₂ O ) NMR (0.2NNaOD, t-butanol): δ = 1.44-1.60 (4H, m), 1.
72-1.92 (2H, m), 2.17 (2H, t, J = 7Hz), 2.24 (2H, t, J = 8Hz),
3.16 (2H, t, J = 7Hz), 3.21 (1H, t, J = 6.5Hz). 6-((S) -4-amino-4-carboxybutyrylamino) hexanoic acid [Compound 5] Melting point: 193 -194 ° C [α] ²⁵ : + 8.4 ° (c1, 0.1N NaOH) NMR (0.2NNaOD, t-butanol): δ = 1.25-1.34 (2H, m), 1.
46-1.58 (4H, m), 1.73-1.92 (2H, m), 2.16 (2H, t, J = 7.5H
z), 2.24 (2H, t, J = 8Hz), 3.15 (2H, t, J = 7Hz), 3.21 (1H, d
d, J = 6,7Hz).

7-((S) -4-amino-4-carboxybutyrylamino) heptanoic acid [Compound 6] Melting point: 185-186 ° C. (decomposition) [α] ²⁵ : + 8.1 ° (c1, 0.1N NaOH) NMR (0.2NNaOD, t-butanol): δ = 1.25-1.36 (4H, m), 1.
44-1.57 (4H, m), 1.72-1.92 (2H, m), 2.15 (2H, t, J = 7Hz),
2.24 (2H, t, J = 8Hz), 3.15 (2H, t, J = 7Hz), 3.21 (1H, dd, J =
6,7Hz). 8-((S) -4-amino-4-carboxybutyrylamino) octanoic acid [Compound 7] Melting point: 194-195 ° C (decomposition) [α] ²⁵ : + 7.7 ° (c1, 0.1 NNaOH) NMR (0.2NNaOD, t-butanol): δ = 1.24-1.35 (6H, m), 1.
42-1.57 (4H, m), 1.72-1.92 (2H, m), 2.15 (2H, t, J = 7Hz),
2.24 (2H, t, J = 8Hz), 3.15 (2H, t, J = 7Hz), 3.21 (1H, dd, J =
6, 7Hz).

4-((S) -4-amino-4-carboxybutyrylamino) benzoic acid [Compound 8] Melting point: 237-238 ° C. (decomposition) [α] ²⁵ : + 15.0 ° (c1, 0.1 N NaOH) NMR (0.2NNaOD, t-butanol): δ = 1.85-2.04 (2H, m), 2.
46 (2H, t, J = 8Hz), 3.30 (1H, dd, J = 6, 7Hz), 7.48 (2H, d, J =
8Hz), 7.85 (2H, d, J = 8Hz). 3-((S) -4-amino-4-carboxybutyrylamino) benzoic acid [Compound 9] Melting point: 216-217 ° C (decomposition) [α] ²⁵ : + 12.2 ° (c1, 0.1NNaOH) NMR (0.2NNaOD, t-butanol): δ = 1.86-2.05 (2H, m), 2.
47 (2H, t, J = 8Hz), 3.30 (1H, t, J = 6Hz), 7.45 (1H, dd, J = 8,
8Hz), 7.60 (1H, ddd, J = 1, 2, 8H), 7.66 (1H, ddd, J = 1, 1.
5, 8Hz), 7.80 (1H, dd, J = 1.5, 2Hz).

4-((S) -4-amino-4-carboxybutyrylaminomethyl) benzoic acid [Compound 10] Melting point: 215-216 ° C. (decomposition) [α] ²⁵ : + 10.5 ° (c1, 0.1N NaOH) ) NMR (0.2NNaOD, t-butanol): δ = 1.78-1.97 (2H, m), 2.
34 (2H, t, J = 8 Hz), 3.24 (1H, t, J = 6.5Hz), 4.41 (2H, s),
7.35 (2H, d, J = 8Hz), 7.82 (2H, d, J = 8Hz). 2- [4-((S) -4-amino-4-carboxybutyrylamino) phenyl] acetic acid [Compound 11] Melting point: 211-212 ° C (decomposition) [α] ²⁵ : + 12.6 ° (c1, 0.1NNaOH) NMR (0.2NNaOD, t-butanol): δ = 1.84-2.03 (2H, m), 2.
44 (2H, t, J = 8Hz), 3.29 (1H, dd, J = 6, 7Hz), 3.50 (2H, s),
7.26 (2H, d, J = 9Hz), 7.35 (2H, d, J = 9Hz).

4- [3-((S) -4-amino-4-carboxybutyrylamino) phenyl] propionic acid [Compound 12] Melting point: 206-207 ° C. (decomposition) NMR (0.2NNaOD, t-butanol) : Δ = 1.84-2.03 (2H, m), 2.
44 (2H, t, J = 8Hz), 2.47 (2H, t, J = 8Hz), 2.86 (2H, t, J = 8H)
z), 3.29 (1H, t, J = 6.5Hz), 7.09-7.35 (4H, m) 4- [4-((S) -4-amino-4-carboxybutyrylamino) phenyl] propionic acid [Compound 13] Melting point: 204-205 ° C. (decomposition) NMR (0.2NNaOD, t-butanol): δ = 1.83-2.03 (2H, m), 2.
43 (2H, t, J = 8Hz), 2.46 (2H, t, J = 8Hz), 2.86 (2H, t, J = 8H)
z), 3.29 (1H, t, J = 6.5Hz), 7.26 (2H, d, J = 8.5Hz), 7.33 (2
(H, d, J = 8.5Hz)

Example 3.2.04 g of 2-((S) -4
-Amino-4-carboxybutyrylamino) acetic acid and 0.
20 g of magnesium oxide was added to 50 ml of water, and the mixture was stirred under an argon atmosphere at room temperature for 20 hours. The resulting solution was filtered through a membrane filter and freeze-dried to give 2.81 g of 2-((S) -4-amino-4-carboxybutyrylamino) acetic acid magnesium salt [Compound 1M
g] was obtained as a white amorphous powder. Hygroscopic powder [α] ²⁵ : + 1.7 ° (c1, H ₂ O) NMR (D ₂ O, TSP): δ = 2.09-2.25 (2H, m), 2.43-2.55 (2H,
m), 3.74 and 3.78 (2H, ABq, J = 17Hz), 3.79 (1H, dd, J = 5,
7Hz).

In the same manner, the following compound was obtained. 3-((S) -4-amino-4-carboxybutyrylamino) propionic acid magnesium salt [Compound 2Mg] Hygroscopic powder [α] ²⁵ : + 3.0 ° (c1, H ₂ O) NMR (D ₂ O, TSP): δ = 2.05-2.20 (2H, m), 2.35-2.47 (2H,
m), 2.40 (2H, t, J = 7Hz), 3.40 (2H, t, J = 7Hz), 3.75 (1H, dd,
J = 6, 6.5Hz). 4-((S) -4-amino-4-carboxybutyrylamino) butyric acid magnesium salt [Compound 3Mg] Hygroscopic powder [α] ²⁵ : + 3.5 ° (c1, H ₂ O ) NMR (D ₂ O, TSP): δ = 1.72-1.80 (2H, m), 2.10-2.18 (2H,
m), 2.21 (2H, t, J = 7Hz), 2.35-2.48 (2H, m), 3.20 (2H, t, J =
7Hz), 3.77 (1H, t, J = 6Hz).

5-((S) -4-amino-4-carboxybutyrylamino) pentanoic acid magnesium salt [compound 4Mg] hygroscopic powder [α] ²⁵ : + 3.6 ° (c1, H ₂ O) NMR (D ₂ O, TSP): δ = 1.46-1.62 (4H, m), 2.08-2.16 (2H,
m), 2.19 (2H, t, J = 7Hz), 2.34-2.47 (2H, m), 3.20 (2H, t, J =
6.5Hz), 3.74 (1H, t, J = 6Hz). 6-((S) -4-amino-4-carboxybutyrylamino) hexanoic acid magnesium salt [compound 5Mg] hygroscopic powder [α] ²⁵ : + 3.5 ° (c1, H ₂ O) NMR (D ₂ O, TSP): δ = 1.27-1.36 (2H, m), 1.48-1.61 (4H,
m), 2.05-2.17 (2H, m), 2.18 (2H, t, J = 7Hz), 2.33-2.47 (2
H, m), 3.19 (2H, t, J = 7Hz), 3.75 (1H, t, J = 6Hz).

7-((S) -4-amino-4-carboxybutyrylamino) heptanoic acid magnesium salt [compound 6Mg] hygroscopic powder [α] ²⁵ : + 3.6 ° (c1, H ₂ O) NMR (D ₂ O, TSP): δ = 1.26-1.38 (4H, m), 1.47-1.60 (4H,
m), 2.05-2.15 (2H, m), 2.17 (2H, t, J = 7Hz), 2.33-2.46 (2
H, m), 3.18 (2H, t, J = 7Hz), 3.71 (1H, t, J = 6Hz). 8-((S) -4-amino-4-carboxybutyrylamino) octanoic acid magnesium salt [ Compound 7 Mg] Hygroscopic powder [α] ²⁵ : + 3.3 ° (c1, H ₂ O) NMR (D ₂ O, TSP): δ = 1.26-1.35 (6H, m), 1.46-1.59 (4H,
m), 2.07-2.16 (2H, m), 2.17 (2H, t, J = 7Hz), 2.33-2.46 (2
H, m), 3.18 (2H, t, J = 7Hz), 3.75 (1H, t, J = 6Hz).

4-((S) -4-amino-4-carboxybutyrylaminomethyl) benzoic acid magnesium salt [Compound 10Mg] Hygroscopic powder [α] ²⁵ : + 4.6 ° (c1, H ₂ O) NMR (D ₂ O, TSP): δ = 2.13-2.20 (2H, m), 2.43-2.56 (2H,
m), 3.77 (1H, t, J = 6Hz), 4.43 (2H, s), 7.36 (2H, d, J = 8Hz),
7.84 (2H, d, J = 8Hz). 2- [4-((S) -4-amino-4-carboxybutyrylamino) phenyl] acetic acid magnesium salt [Compound 1
1Mg] Hygroscopic powder [α] ²⁵ : + 6.4 ° (c1, H ₂ O) NMR (D ₂ O, TSP): δ = 2.19-2.27 (2H, m), 2.55-2.68 (2H,
m), 3.52 (2H, s), 3.82 (1H, t, J = 6Hz), 7.29 (2H, d, J = 8H
z), 7.38 (2H, d, J = 8Hz).

Example 4. (1) 33.74 g of Nt-butoxycarbonyl-L
Glutamic acid α-benzyl ester, 38.37 g of 4-butyric acid benzyl ester p-toluenesulfonate and 10.62 g of triethylamine in methylene chloride (500 ml) were ice-cooled to obtain 20.12 g of water-soluble carbodiimide hydrochloride. added. After stirring under ice-cooling for 2 hours and at room temperature for further 20 hours, the solvent was distilled off under reduced pressure.
Ethyl acetate and water were added to the residue to separate the organic layer, and the aqueous layer was further extracted with ethyl acetate. Combine the organic layers, 1
It was washed successively with 0% aqueous citric acid solution, saturated saline solution, 5% aqueous sodium hydrogen carbonate solution and saturated saline solution. After drying over sodium sulfate, the solvent was distilled off under reduced pressure. The crystalline solid obtained was recrystallized from ethyl acetate-petroleum ether to give 46.72 g of 4-((S) -4-benzyloxycarbonyl-4-t-butoxycarbonylaminobutyrylamino) butyric acid benzyl ester. It was Melting point: 69-70 ° C [α] ²⁵ : -2.4 ° (c1, H ₂ O) NMR (CDCl ₃ , TMS): δ = 1.42 (9H, s), 1.84 (2H, dddd, J = 7,
7, 7, 7Hz), 1.87-1.98 (1H, m), 2.10-2.20 (3H, m), 2.4
0 (2H, t, J = 7Hz), 3.23-3.29 (2H, m), 4.25-4.34 (1H, m),
5.11 (2H, s), 5.13 and 5.19 (2H, ABq, J = 12Hz), 5.31 (1H,
d, J = 8Hz, amide), 6.04-6.12 (1H, brs, amide), 7.28-7.38
(10H, m).

(2) 15.38 g of the above product was added to 100
Stir with ml of 4N hydrochloric acid / dioxane for 1 hour at room temperature. After distilling off the solvent under reduced pressure, the residual oily substance was removed to 150
Dissolved in ml methylene chloride. Under ice cooling, 3.34 g of triethylamine and 4.71 g of N-acetoxysuccinimide were sequentially added. After stirring for 20 hours at room temperature,
The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the residue, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The solvent was distilled off under reduced pressure and the obtained white crystalline solid was purified by silica gel column chromatography to obtain 10.08 g of 4-((S) -4-acetamido-4-benzyloxycarbonylbutyrylamino). Crystals of butyric acid benzyl ester were obtained. Melting point: 129-130 ° C [α] ²⁵ : -3.5 ° (c1, CHCl ₃ ) NMR (CDCl ₃ , TMS): δ = 1.84 (2H, dddd, J = 7, 7, 7, 7Hz),
1.91-2.03 (1H, m), 2.00 (3H, s), 2.11-2.25 (3H, m), 2.4
0 (2H, t, J = 7Hz), 3.23-3.29 (2H, m), 4.52-4.59 (1H, m),
5.11 (2H, s), 5.14 and 5.17 (2H, ABq, J = 12Hz), 6.22 (1H,
t, J = 6Hz, amide), 6.69 (1H, d, J = 8Hz, amide), 7.29-7.38
(10H, m).

(3) 4.55 g of the above product was used in Example 2
And treated in the same manner as 3 and 3, and 3.00 g of 4-((S)-
4-acetylamino-4-carboxybutyrylamino)
A magnesium butyrate salt [Compound 14Mg] was obtained. Hygroscopic powder [α] ²⁵ : + 9.6 ° (c1, H ₂ O) NMR (D ₂ O, TSP): δ = 1.75 (2H, dddd, J = 7, 7, 7, 7Hz),
1.86-1.96 (1H, m), 2.04 (3H, s), 2.07-2.17 (1H, m), 2.21
(2H, t, J = 7Hz), 2.30 (2H, t, J = 7.5Hz), 3.12-3.24 (2H, m),
4.14 (1H, dd, J = 4.5, 9Hz).

Example 5. (1) 13.70 g of Nt-butoxycarbonyl-L
5. Dissolve the dicyclohexylamine salt of glutamic acid α-benzyl ester and 7.51 g of 4-aminocinnamic acid ethyl ester in 150 ml of dichloromethane,
After 32 g of water-soluble carbodiimide hydrochloride was added and reacted, the product was purified to 11.02 g of 4-((S) -4-ethoxycarbonyl-4-t-butoxycarbonylaminobutyrylamino) cinnamic acid ethyl ester. Got Melting point: 120-121 ° C NMR (DMSO-d ₆ ): δ = 1.18 (3H, t, J = 7Hz), 1.25 (3H, t, J = 7)
Hz), 1.38 (9H, s), 1.76-1.88 (1H, m), 1.97-2.09 (1H, m),
2.43 (2H, t, J = 7.5Hz), 3.98-4.01 (1H, m), 4.02-4.14 (2
H, m), 4.17 (2H, q, J = 7Hz), 6.50 (1H, d, J = 16Hz), 7.25 (1
H, d, J = 8Hz), 7.57 (1H, d, J = 16Hz), 7.60-7.67 (4H, m), 1
0.10 (1H, s)

(2) 9.87 g of the above product and 2.1
0 g of lithium hydroxide monohydrate was dissolved in a mixed solvent of 200 ml of tetrahydrofuran and 200 ml of water,
After stirring at 0 ° C. for 2 hours, the mixture was stirred at room temperature for 20 hours. After distilling off the solvent, the mixture was acidified with 6N hydrochloric acid and extracted with ethanol to obtain 7.59 g of 4-((S) -4-carboxy-4-t-butoxycarbonylaminobutyrylamino) cinnamic acid crystals. Obtained. Melting point: 223-224 ° C NMR (DMSO-d ₆ ): δ = 1.38 (9H, s), 1.76-1.88 (1H, m), 1.
99-2.10 (1H, m), 2.43 (2H, t, J = 7.5Hz), 3.89-3.97 (1H,
m), 6.40 (1H, d, J = 16Hz), 7.07 (1H, d, J = 8Hz), 7.51 (1H, d,
J = 16Hz), 7.58-7.65 (4H, m), 10.08 (1H, s), 12.10-12.60
(2H, br.s)

(3) 6.67 g of the above product in 200 m
In addition to 1 formic acid and treated at room temperature for 20 hours, the solvent was distilled off to give 4.86 g of 4-((S) -4-amino-4-carboxybutyrylamino) cinnamic acid [Compound 15]. Crystals were obtained. Melting point: 247-248 ° C (decomposition) NMR (0.2NNaOD, t-butanol): δ = 1.84-2.03 (2H, m), 2.
45 (2H, t, J = 8Hz), 3.29 (1H, t, J = 6.5Hz), 6.46 (1H, d, J = 16
Hz), 7.34 (1H, d, J = 16Hz), 7.44 (2H, d, J = 9Hz), 7.58 (2H,
(d, J = 9Hz)

[0034]

[Action]

(1) Histamine Release Inhibitory Action A rat peritoneal mast cell suspension was prepared according to the method of Omori et al. [Nippon Jakukaku, Vol. 80, pp. 441-449 (1982)]. The cells were presensitized with an anti-dinitrophenylated Ascaris extract (DNP-As), and then a test drug solution was added and incubated for 10 minutes (5 mg /
ml). Then the DNP-As solution was added and incubated for 20 minutes. Stop the reaction by cooling with ice and
e. et al. [J. Pharmac. Eep. The
r. 127, pp. 182-186 (1959), the amount of free histamine was measured. Also, anti-DNP-A
It was also carried out by a method of directly inducing histamine release using anti-rat IgE goat serum without sensitization with s.
Table 1 shows an example of the results of the histamine release-inhibitory effect of the compound of the present invention.

[0035]

[Table 1]

(2) Inhibitory action on nasal secretion 2 ml of 8-fold diluted anti-ovalbumin serum was intraperitoneally administered to the guinea pig for sensitization, and 2 days later, 50 μl of 1%
Ovalbumin was dripped into the left nasal cavity to induce nasal allergic symptoms, and 10 minutes later, the nasal discharge in the left and right nasal cavities was determined by the method of Namimatsu et al. [Int Arch A
Lergy Immunol, Vol. 95, pp. 29-34 (1991)]. Test drug is antigen induction 1
0 minute before, 50 μl of a solution containing 1 mg of the test drug was locally administered to the nasal cavity, and physiological saline was used as a control. Table 2 shows an example of the results of the nasal secretion inhibitory effect of the compound of the present invention.
Shown in.

[0037]

[Table 2]

[0038]

[Effect] As shown in Tables 1 and 2, the compound of the present invention has a significant inhibitory effect on histamine release from rat peritoneal exudate cells, and also on antigen-induced nasal secretion in guinea pigs actively sensitized with ovalbumin. It has an excellent inhibitory effect. Therefore, the compound of the present invention is very useful as a drug effective for the treatment of various diseases caused by allergy such as allergic rhinitis, bronchial asthma, allergic conjunctivitis, urticaria and pruritic skin diseases. Further, in the topical administration into the nasal cavity, the compound of the present invention has almost no irritation and few side effects, which enables continuous administration for a long period of time, and is particularly useful as a drug for the allergic disease requiring long-term treatment. Is.

The compound of the present invention can be made into a medicine by appropriately combining it with a suitable pharmaceutical carrier or diluent.
It can be formulated by any ordinary method, and can be formulated as an oral preparation such as tablets, capsules, powders and liquids, or as a parenteral preparation for subcutaneous, intravenous, intramuscular, rectal and intranasal administration. it can. Further, the fine particles of the compound of the present invention can be administered to mucous membranes of the nose, throat, trachea and the like in the form of a spray liquid, a dry powder or a liquid aerosol. In the formulation, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, the compound of the present invention can be used alone or in an appropriate combination, and a compounding agent with another pharmaceutically active ingredient can be used. May be The salts of the compound of the present invention, such as magnesium salts, are highly water-soluble, so that they can be easily formulated into various solution dosage forms, and since the pH of the solution is near neutral, a hypoallergenic drug is produced. It is particularly useful. The desired dose of the compound of the present invention is
Although it varies depending on the dosage form, administration method, administration period, etc., for example, in the case of local administration into the nasal cavity, the desired dose can be obtained by locally administering the active ingredient amount of 0.5 to 50 mg into the nasal cavity in several divided doses per day. The effect of can be obtained.

Liquids such as injections, nasal drops, eye drops and aerosols are aqueous or non-aqueous solvents such as distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, It can be formulated in the form of a solution or suspension of propylene glycol or the like. It is preferable to adjust the solution to a suitable osmotic pressure depending on the purpose of administration. The compound of the present invention in the form of a pharmaceutically acceptable salt such as a magnesium salt has high water solubility and is suitable for formulation as an aqueous solution. As an oral agent, as a tablet, a powder, a granule or a capsule, as it is or as an excipient, a binder, a disintegrating agent, a lubricant, a bulking agent, a wetting agent, a buffering agent, a preservative, a perfume or the like is appropriately combined. Can also be formulated. It may also be parenterally administered in the form of an ointment or the like. In addition, depending on the condition of the patient and the type of disease, it is possible to appropriately formulate into a dosage form other than the above-mentioned optimum for the treatment, such as a suppository or a poultice.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshiyuki Kurimoto 442-1, Kawakitayama, Kinashi, Kato-gun, Hyogo Pref.

Claims (3)

[Reference number] PC-221 [Claims] 1. An aminocarboxylic acid derivative represented by the following general formula and a pharmaceutically acceptable salt thereof. [Chemical 1] [In the formula, X represents hydrogen or an acetyl group, R represents an alkylene group or a phenylene group, A represents a direct bond, an alkylene group or a vinylene group, and n represents an integer of 0 or 1. ] 2. The aminocarboxylic acid derivative according to claim 1, which is a magnesium salt. 3. An anti-allergic agent containing, as an active ingredient, at least one of an aminocarboxylic acid derivative represented by the following general formula or a pharmaceutically acceptable salt thereof. [Chemical 2] [In the formula, X represents hydrogen or an acetyl group, R represents an alkylene group or a phenylene group, A represents a direct bond, an alkylene group or a vinylene group, and n represents an integer of 0 or 1. ]