JP2627262B2 - New tripeptide compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel peptide compound, a pharmaceutically acceptable salt thereof, and a method for producing the same.

[0002]

2. Description of the Related Art Peptides are used in vivo for chemicals.
It is known that it plays an important role as a physiologically active substance such as a mediator or a hormone. Accordingly, various peptides and their derivatives have been synthesized, and their effects on living organisms have been studied. The present inventors have conducted intensive studies,
The present inventors have found a novel peptide compound of the present invention having a central nervous activity, and have completed the present invention.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel peptide compound useful as a medicine and the like and a method for producing the same.

[0004]

Means for Solving the Problems The peptide compound of the present invention is a compound represented by the following general formula (I).

Embedded image [Wherein A is Glu, γ-Glu, Asp or β-As
p and X are Gly, Ala, Val, Leu, Ile, P
he, Pro, Ser, Tyr, Hyp, Lys, Hi
Y represents an amino acid residue selected from s, Asp, Glu and 5-HTP, and represents an alkylene group having 2 to 6 carbon atoms or an alkylene group having 2 to 6 carbon atoms having a hydroxyl group. ]

In the present invention, peptides and amino acids are obtained from the International Union of Pure and Applied Chemistry (IUPAC) and the International Union of Biochemistry (IUAC).
B) It is represented by the abbreviation of adoption and the abbreviation commonly used in this field. For example, the following abbreviations are used. Gly: glycine, Ala: alanine, Val: valine, Le
u: leucine, Ile: isoleucine, Phe: phenylalanine, Pro: proline, Ser: serine, Thr: threonine, Tyr: tyrosine, Lys: lysine, Hyp: hydroxyproline, His: histidine, Asp: aspartic acid, Arg: arginine, Glu: glutamic acid, Trp: tryptophan, 5-HTP: 5-hydroxytryptophan, Cys: cysteine, Met: methionine, β-Ala:
β-alanine, Pyr: pyroglutamic acid, GABA: γ-aminobutyric acid, GABOB: β-hydroxy-γ-aminobutyric acid,
EACA: ε-aminocaproic acid

[0006] The amino acid residue in the present invention is a D-form,
Any of L-form and DL-form may be used. In the general formula (I), Y represents an alkylene group having 2 to 6 carbon atoms such as ethylene, propylene, butylene, pentylene, hexylene, or an alkylene group having 2 to 6 carbon atoms having preferably one hydroxyl group. That is, as the carboxyl-terminal amino acid residue containing Y, preferably β-Ala, GABA,
GABOB, EACA and the like.

[0007] Particularly preferred compounds in the present invention are as follows. γ-Glu-Gly-GABA, γ-Glu-Ala-GAB
A, γ-Glu-Val-GABA, γ-Glu-Leu-GABA, γ
-Glu-Ile-GABA, γ-Glu-Phe-GABA, γ-Glu
-Pro-GABA, γ-Glu-Ser-GABA, γ-Glu-Tyr
-GABA, γ-Glu-Hyp-GABA, γ-Glu-Lys-GAB
A, γ-Glu-His-GABA, γ-Glu-Asp-GABA, γ
-Glu-Glu-GABA, γ-Glu-5-HTP-GABA, γ-
Glu-Phe-β-Ala, γ-Glu-Phe-GABOB, γ-
Glu-Phe-EACA, Glu-Phe-GABA, Glu-Phe-β
-Ala, Glu-Phe-GABOB, Glu-Phe-EACA, Asp
-Phe-EACA, Asp-Phe-β-Ala, Asp-Phe-GA
BOB, Asp-Phe-EACA, β-Asp-Phe-GABA, β-
Asp-Phe-β-Ala, β-Asp-Phe-GABOB, β-
Asp-Phe-EACA, D-Asp-Phe-GABA, D-Asp-
Phe-β-Ala, D-Asp-Phe-GABOB, D-Asp-
Phe-EACA, D-β-Asp-Phe-GABA, D-β-Asp
-Phe-β-Ala, D-β-Asp-Phe-GABOB, D-
β-Asp-Phe-EACA, γ-Glu-Pro-β-Ala, γ
-Glu-Pro-GABOB, γ-Glu-Pro-EACA, Glu-
Pro-GABA, Glu-Pro-β-Ala, Glu-Pro-GABO
B, Glu-Pro-EACA, Asp-Pro-GABA, Asp-Pro
-Β-Ala, Asp-Pro-GABOB, Asp-Pro-EACA,
β-Asp-Pro-GABA, β-Asp-Pro-β-Ala, β
-Asp-Pro-GABOB, β-Asp-Pro-EACA, DA
sp-Pro-GABA, D-Asp-Pro-β-Ala, D-Asp
-Pro-GABOB, D-Asp-Pro-EACA, D-β-Asp
-Pro-GABA, D-β-Asp-Pro-β-Ala, D-β
-Asp-Pro-GABOB, D-β-Asp-Pro-EACA.

The peptide compound of the present invention includes a pharmaceutically acceptable salt of the compound represented by formula (I), for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid,
Inorganic acids such as perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid,
Fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p
-Acid addition salts with organic acids such as toluenesulfonic acid, naphthalenesulfonic acid and sulfanilic acid, or alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium and magnesium, or metals such as aluminum. Salt. The peptide compound of the present invention
Including its metal complex compounds, for example, zinc, nickel,
Complex compounds with cobalt, copper, iron and the like can be mentioned. These salts or metal complex compounds can be produced from the free peptide compound of the present invention or can be mutually converted by a known method.

The peptide compound of the present invention can be produced by a usual method in peptide chemistry. That is, the peptide compound of the present invention can be synthesized by a liquid phase method or a solid phase method. As a condensation method for forming a peptide bond, there are an azide method, an active ester method, a mixed acid anhydride method, an acid chloride method, a method using a condensing agent, and the like. Can be used. In the condensation reaction, the amino acid or peptide used as a raw material may be one having a substituent constituting the peptide compound of the present invention and / or a protecting group usually used in peptide chemistry, and a carboxyl group which does not participate in the reaction. , An amino group and a side chain functional group may be protected by a known method, or a carboxyl group or an amino group involved in the reaction may be activated.

The method for producing the peptide compound of the present invention will be described below. The abbreviations of the substituents and reagents are as follows. Z: benzyloxycarbonyl, Boc: t-butoxycarbonyl, Bzl: benzyl, OBzl: benzyloxy, H
ONSu: N-hydroxysuccinylimide, ONSu: N-hydroxysuccinylimide ester, HONB: N-hydroxy-5-norbornene-2,3-dicarboximide,
ONB: N-hydroxy-5-norbornene-2,3-dicarboximide ester, DSC: disuccinimidyl carbonate, DCC: dicyclohexylcarbodiimide, DCU
rea: dicyclohexylurea, DCHA: dicyclohexylamine, WSCD: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, ECF: ethyloxycarbonyl chloride, NMM: N-methylmorpholine, TosOH: p-toluenesulfonic acid, THF : Tetrahydrofuran, TEA: Triethylamine, DMF: Dimethylformamide

I. Method for producing tripeptide

Embedded image

[0012]

Embedded image

[0013]

Embedded image

[0014]

Embedded image

[0015]

Embedded image

The above scheme shows an example of each method, and each N-terminal can be similarly carried out using any of α, β and γ-amino acids. Production methods I (1) to (3) are based on the use of an active ester such as N-hydroxysuccinylimide ester (ONSu) or N-hydroxy-5-norbornene-2,3-dicarboximide ester (ONB) to prepare the peptide compound of the present invention. This is an example in which is manufactured. ONSu conversion is similar to ONB conversion.
N-hydroxysuccinylimide (HONSu) instead of SC
And DCC.

As the protecting group for the amino group of the N-terminal and side chain functional groups, as in benzyloxycarbonyl (Z), o
-Chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl and the like can be used. In addition, t-pentoxycarbonyl, p- similar to t-butoxycarbonyl (Boc)
It is possible to use methoxybenzyloxycarbonyl and the like. As the protecting group for the carboxyl group of the C-terminal and side chain functional groups, p-nitrobenzyloxy, 4-pyridyloxy and the like can be used similarly to benzyloxy (OBzl), but it is not always necessary to protect depending on the type of reaction. [Production methods I (2) and (3)]. Further, the hydroxyl group of the side chain functional group may be protected with benzyl or the like.

These substituents can be removed selectively or entirely by ordinary means such as catalytic reduction and acid decomposition during the synthesis process of the peptide compound of the present invention or at the final stage. Other substituents can be introduced by a usual method.

In the production method I (1), the constituent amino acids are
In contrast to the method of sequentially condensing to the terminal, the method I (1) is a method of extending in the reverse direction from the N-terminus to the C-terminus. Can also be synthesized. Instead of sequentially condensing constituent amino acids, it is also possible to produce a tripeptide using a synthesized dipeptide, for example, Leu-GABA [Production method I (2)].

DCC can be used not only for forming an active ester such as ONB as in Production Method I (3), but also as a condensing agent for directly forming a peptide bond [Production Method I (4)]. As a condensing agent similar to DCC, 1-ethyl-3- (3-dimethylaminopropyl)-having excellent water solubility is used.
And water-soluble carbodiimides such as carbodiimide hydrochloride.

The peptide compound of the present invention can also be produced by a mixed acid anhydride method [Production method I (5)]. Examples of the acid component of the acid compound anhydride include ethyloxycarbonyl chloride and isobutyloxycarbonyl chloride, and examples of the base include triethylamine and N-methylmorpholinone. As the solvent that can be used in the above reaction, any solvent may be used as long as it is inert to the raw materials and the product, and preferably can dissolve both, and may be in a suspended state, such as tetrahydrofuran, ethyl acetate, and dioxane. , Acetonitrile, chloroform, dichloromethane,
Examples thereof include dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, benzene, ether, water, and the like, and mixtures thereof, which can be appropriately selected depending on the type of reaction.

The purpose can be achieved by conducting the condensation reaction at -15 ° C to room temperature for 1 hour to several days, preferably at 0 ° C to room temperature for 1 hour to 1 day. Further, regarding the elimination reaction of the protecting group, in the case of catalytic reduction using palladium-carbon or the like,-
The objective can be achieved by conducting the reaction at 15 ° C. to room temperature for 1 hour to several days, preferably at 0 ° C. to room temperature for 1 hour to 1 day. When a strong acid such as hydrochloric acid is used, the peptide is kept in the presence of the strong acid for a long time. Therefore, a reaction time of 1 hour to several hours is appropriate.

[0023]

The production examples of the peptide compound of the present invention are specifically shown below by way of examples. In each example, the L-form was used for amino acids unless otherwise specified. NMR was measured using t-butanol (δ = 1.23 ppm) as an internal standard and expressed as a δ value. All the specific rotations were measured using the D line of sodium.

Embodiment 1 FIG. (I) 3.5 g of Boc-Gly-OH and 5.12 g of DSC were suspended in 80 ml of acetonitrile. To the suspension was added a 20 ml solution of acetonitrile containing 1.58 g of pyridine, and the mixture was stirred at room temperature for 4 hours.
oc-Gly-ONSu was obtained. Without purifying Boc-Gly-ONSu, 7.31 g of TosOH.GABA-OBzl and 2.02 g of TEA were added to the solution at room temperature and stirred for 20 hours. The solvent was distilled off under reduced pressure, and the obtained oil was dissolved in 100 ml of ethyl acetate. The solution was diluted with water, 5% aqueous sodium bicarbonate, saturated saline, 10%
The organic layer was washed successively with a citric acid aqueous solution and a saturated saline solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The oily product was solidified by adding petroleum ether and recrystallized from ethyl acetate / ether / petroleum ether to obtain Boc-G
5.54 g of ly-GABA-OBzl was obtained. (79% yield) Melting point: 94.0-94.5 ° C

(Ii) 5.26 g of Boc-Gly-GABA-OBzl was treated with 4N hydrochloric acid / 75 ml of dioxane at room temperature for 1.5 hours.
The solvent was distilled off under reduced pressure, and ether was added to the oily product to solidify. The crystalline residue was collected by filtration, washed with ether, and dried over sodium hydroxide under reduced pressure to obtain HCl.
4.21 g of Gly-GABA-OBzl were obtained. The obtained product was used for the next reaction without purification. (iii) Dissolve 3.15 g of HCl.Gly-GABA-OBzl and 1.11 g of TEA in 100 ml of acetonitrile, and add Z-Glu (ONSu) -OBzl.
4.68 g were added at room temperature. After stirring for 20 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. Solution in water, 5%
The extract was washed sequentially with an aqueous sodium hydrogen carbonate solution, a saturated saline solution, a 10% aqueous citric acid solution and a saturated saline solution, dried over anhydrous sodium sulfate, and then evaporated to dryness under reduced pressure. The obtained crystalline residue was recrystallized from ethyl acetate / ether to give Z-Glu (G
5.62 g of ly-GABA-OBzl) -OBzl were obtained. Melting point: 107.5-109.5 ° C [α] ²⁴ = -7.5 (C = 1.0, DMF)

The following compounds were obtained in the same manner. Z-Glu (Ala-GABA-OBzl) -OBzl Melting point: 165.5-166.5 ° C [α] ²⁴ = -8.8 (C = 1.0, DMF) Z-Glu (Ile-GABA-OBzl) -OBzl Melting point: 166-170 ° C (Α) ²⁴ = −5.3 (C = 1.1, DMF) Z-Glu (Phe-GABA-OBzl) -OBzl Melting point: 154−156 ° C. (α) ²⁴ = −9.8 (C = 1.0, DMF) Z-Glu ( Tyr (OBzl) -GABA-OBzl) -OBzl Melting point: 169-170.5 ° C (α) ²⁴ = -11.0 (C = 1.0, DMF)

Z-Glu (Pro-GABA-OBzl) -OBzl Melting point: 99-100.5 ° C [α] ²⁴ = -36.0 (C = 1.0, DMF) Z-Glu (Ser (OBzl) -GABA-OBzl) -OBzl Melting point: 120-123 ° C [α] ²⁴ = -2.3 (C = 1.1, DMF) Z-Glu (Asp (OBzl) -GABA-OBzl) -OBzl Melting point: 129-131 ° C [α] ²⁴ = -17.3 (C = 1.0, DMF) Z-Glu (Glu (OBzl) -GABA-OBzl) -OBzl Melting point: 144-145.5 ° C (α) ²⁴ = -7.5 (C = 1.0, DMF) Z-Glu (Lys (Z) -GABA -OBzl) -OBzl Melting point: Decomposes gradually from 140 ° C (α) ²⁴ = -8.7 (C = 1.1, DMF)

(Iv) Z-Glu (Gly-GABA-OBzl) -OBzl
4.34 g was dissolved in a mixed solvent of 40 ml of methanol, 40 ml of acetic acid and 5 ml of water, 1.0 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature under normal pressure of hydrogen for 2 days. The catalyst was removed by filtration, and the solvent was distilled off from the reaction solution under reduced pressure. 50 ml of toluene was added to the residue, and the remaining acetic acid was azeotropically removed with the solvent. After repeating this operation three times, the white precipitate was collected by filtration and recrystallized from water / ethanol to obtain Glu (Gly-GABA), that is, γ-Glu-Gly-GABA.
(Compound 1) 1.89 g was obtained. Melting point: 225-226 ° C [α] ²⁵ = +7.6 (C = 0.5, 0.1NNaOH) NMR (0.1NDCl / D ₂ O): δ = 1.79 (tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0
Hz), 2.16-2.31 (m, 2H), 2.39 (t, 2H, J = 7.0Hz), 2.55 (dt, 1
H, J ₁ = 7.0Hz, J ₂ = 16.0Hz), 2.60 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 16.0
Hz), 3.24 (t, 2H, J = 7.0Hz), 3.86 (s, 2H), 4.09 (t, 1H, J =
6.5Hz)

The following compounds were obtained in the same manner. γ-Glu-Ala-GABA (compound 2) Melting point: 187-188 ° C. [α] ²² = −26.5 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.34 (d, 3H , J = 7.0Hz), 1.77 (t
t, 2H, J ₁ = 7.0Hz, J ₂ = 7.0Hz), 2.10-2.25 (m, 2H), 2.37 (t, 2
H, J = 7.0Hz), 2.49 (dt, 1H, J 1 = 7.0Hz, J 2 = 15.0Hz), 2.54 (d
t, 1H, J ₁ = 7.0Hz, J ₂ = 15.0Hz), 3.20 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 1
4.0Hz), 3.24 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 14.0Hz), 4.00 (t, 1H,
J = 7.0Hz), 4.18 (q, 1H, J = 7.0Hz)

Γ-Glu-Ile-GABA (compound 3) Melting point: 187-190 ° C. (decomposition) [α] ²⁴ = −21.7 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 0.86 (t, 3H, J = 7.5Hz), 0.90
(d, 3H, J = 7.0Hz), 1.13-1.22 (m, 1H), 1.41-1.52 (m, 1H),
1.75-1.86 (m, 3H), 2.12-2.26 (m, 2H), 2.39 (t, 2H, J = 7.0H
z), 2.52 (dt, 1H, J ₁ = 8.0Hz, J ₂ = 16.0Hz), 2.58 (dt, 1H, J ₁ =
_{8.0Hz, J 2 = 16.0Hz),} 3.22 (dt, 1H, J 1 = 7.0Hz, J 2 = 14.0Hz),
3.26 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 14.0Hz), 4.02 (t, 1H, J = 6.5H
z), 4.05 (d, 1H, J = 8.0Hz)

Γ-Glu-Phe-GABA.H ₂ O (compound 4) Melting point: 174-175 ° C. (decomposition) [α] ²⁴ = + 4.1 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.50-1.62 (m, 2H), 2.00-2.18
(m, 4H), 2.48 (t, 2H, J = 7.5Hz), 2.97-3.05 (m, 1H), 3.02
(d, 2H, J = 8.0Hz ), 3.20 (dt, 1H, J 1 = 7.0Hz, J 2 = 14.0Hz), 3.
98 (t, 1H, J = 6.5Hz), 4.47 (t, 1H, J = 8.0Hz), 7.24-7.38 (m,
5H)

Γ-Glu-Pro-GABA (Compound 5) Melting point: Decomposed gradually from 55 ° C. [α] ²⁵ = −60.2 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.79 (tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0
Hz), 1.89-2.03 (m, 3H), 2.13-2.29 (m, 3H), 2.39 (t, 2H, J =
7.0Hz), 2.65 (t, 2H, J = 7.0Hz), 3.17-3.29 (m, 2H), 3.55-
3.69 (m, 2H), 3.91 (t, 1H, J = 7.0Hz), 4.33 (dd, 1H, J ₁ = 7.0H
(z, J ₂ = 8.0Hz)

Γ-Glu-Ser-GABA (compound 6) Melting point: 175-177 ° C. (decomposition) [α] ²² = -15.6 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.79 (tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0
Hz), 2.20 (dddd, 1H, J ₁ = 7.0Hz, J ₂ = 7.0Hz, J ₃ = 7.0Hz, J ₄ = 1
4.0Hz), 2.26 (dddd, 1H, J ₁ = 7.0Hz, J ₂ = 7.0Hz, J ₃ = 7.0Hz, J ₄
= 14.0Hz), 2.39 (t, 2H, J = 7.0Hz), 2.57 (ddd, 1H, J ₁ = 7.0H
z, J ₂ = 7.0Hz, J ₃ = 15.0Hz), 2.62 (ddd, 1H, J ₁ = 7.0Hz, J ₂ = 7.0
Hz, J ₃ = 15.0Hz), 3.23 (ddd, 1H, J ₁ = 7.0Hz, J ₂ = 7.0Hz, J ₃ = 1
3.0Hz), 3.28 (ddd, 1H , J 1 = 7.0Hz, J 2 = 7.0Hz, J 3 = 13.0Hz),
3.82 (d, 1H, J = 5.5Hz), 4.08 (t, 1H, J = 7.0Hz), 4.35 (t, 1H,
(J = 5.5Hz)

Γ-Glu-Tyr-GABA (compound 7) Melting point: 185-186 ° C. [α] ²² = + 6.3 (C = 1.0, AcOH) NMR (0.1NDCl / D ₂ O): δ = 1.50-1.61 (m, 2H), 2.01-2.21
(m, 4H), 2.49 (t, 1H, J = 8.0Hz), 2.50 (t, 1H, J = 8.0Hz), 2.
91 (dd, 1H, J ₁ = 8.0Hz, J ₂ = 13.0Hz), 2.96 (dd, 1H, J ₁ = 8.0Hz,
J ₂ = 13.0Hz), 2.95-3.03 (m, 1H), 3.21 (dt, 1H, J ₁ = 6.5Hz, J
₂ = 14.0Hz), 4.01 (t, 1H, J = 6.5Hz), 4.40 (t, 1H, J = 8.0Hz),
6.82 (d, 2H, J = 8.0Hz), 7.12 (d, 2H, J = 8.0Hz)

Γ-Glu-Asp-GABA (compound 8) Melting point: 217-218 ° C. (decomposition) [α] ²² = + 1.0 (C = 0.5, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O): δ = 1.78 (tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0
Hz), 2.15-2.29 (m, 2H), 2.38 (t, 2H, J = 7.0Hz), 2.54 (dt, 1
H, J ₁ = 7.5Hz, J ₂ = 15.0Hz), 2.58 (dt, 1H, J ₁ = 7.5Hz, J ₂ = 15.0
Hz), 2.81 (dd, 1H, J ₁ = 8.0Hz, J ₂ = 16.5Hz), 2.89 (dd, 1H, J ₁
= 6.0Hz, J ₂ = 16.5Hz), 3.25 (t, 2H, J = 7.0Hz), 4.09 (t, 1H, J
= 7.0Hz), 4.64 (dd, 1H, J ₁ = 6.0Hz, J ₂ = 8.0Hz)

Γ-Glu-Glu-GABA (compound 9) Melting point: 179-183 ° C. (decomposition) [α] ²² = -11.2 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.79 (tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0
Hz), 1.96 (ddt, 1H, J ₁ = 7.0Hz, J ₂ = 9.0Hz, J ₃ = 15.0Hz), 2.0
9 (ddt, 1H, J ₁ = 6.0Hz, J ₂ = 7.0Hz, J ₃ = 15.0Hz), 2.14-2.25
(m, 2H), 2.39 (t, 2H, J = 7.0Hz), 2.47 (t, 2H, J = 7.0Hz), 2.
48-2.60 (m, 2H), 3.22 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 14.0Hz), 3.2
5 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 14.0Hz), 3.97 (t, 1H, J = 6.5Hz),
4.26 (dd, 1H, J ₁ = 6.0Hz, J ₂ = 9.0Hz)

Γ-Glu-Lys-GABA (compound 10) Melting point: 277-278 ° C. (decomposition) [α] ²² = -10.1 (C = 1.0, AcOH) NMR (0.1NDCl / D ₂ O): δ = 1.33 -1.50 (m, 2H), 1.63-1.79
(m, 4H), 1.79 (tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0Hz), 2.18 (dddd, 1
H, J ₁ = 7.0Hz, J ₂ = 7.0Hz, J ₃ = 7.0Hz, J ₄ = 15.0Hz), 2.22 (ddd
d, 1H, J ₁ = 7.0Hz, J ₂ = 7.0Hz, J ₃ = 7.0Hz, J ₄ = 15.0Hz), 2.38
(t, 2H, J = 7.0Hz ), 2.53 (ddd, 1H, J 1 = 7.0Hz, J 2 = 7.0Hz, J 3 = 1
5.0Hz), 2.58 (ddd, 1H, J ₁ = 7.0Hz, J ₂ = 7.0Hz, J ₃ = 15.0Hz),
2.98 (br.t, 2H, J = 7.5Hz), 3.22 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 13.0
Hz), 3.26 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 13.0Hz), 4.04 (t, 1H, J =
7.0Hz), 4.18 (dd, 1H, J ₁ = 6.0Hz, J ₂ = 8.0Hz)

Embodiment 2 FIG. (i) 1.62 g of Leu-GABA and 0.76 g of TEA were dissolved in a mixed solvent of 30 ml of acetonitrile and 15 ml of water, and Z-Glu (ONSu)-
3.28 g of OBzl and 20 ml of acetonitrile were added. After stirring for 20 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in a mixed solvent of 50 ml of 1N hydrochloric acid and 100 ml of chloroform. The organic layer was separated, washed with water, and then dried over anhydrous sodium sulfate.
After evaporating the solvent under reduced pressure, the crystalline residue was recrystallized from chloroform / hexane to give Z-Glu (Leu-GABA-OH) -OBzl 3.8
8 g were obtained. (Yield 97%) Melting point: 127.5-129 ° C [α] ²⁴ = -14.9 (C = 1.0, DMF)

The following compounds were obtained in the same manner. Z-Glu (Val-GABA-OH) -OBzl Melting point: 197-198 ° C [α] ²⁴ = −5.2 (C = 1.0, DMF) Z-Glu (Hyp-GABA-OH) -OBzl Melting point: 92-94 ° C [Α] ²⁴ = −28.9 (C = 1.0, DMF)

(Ii) Z-Glu (Leu-GABA-OH) -OBzl 4.34
g was subjected to catalytic reduction in the same manner as in Example 1 (iv),
Glu (Leu-GABA), that is, γ-Glu-L
1.25 g of eu-GABA (compound 11) was obtained. (Yield 60%) Melting point: 180-181 ° C [α] ²⁴ = -22.3 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 0.87 (d, 3H, J = 6.0 Hz) ), 0.92
(d, 3H, J = 6.0Hz), 1.50-1.67 (m, 3H), 1.78 (tt, 2H, J ₁ = 7.0
Hz, J ₂ = 7.0Hz), 2.13-2.27 (m, 2H), 2.38 (t, 2H, J = 7.0Hz),
2.52 (dt, 1H, J ₁ = 7.5Hz, J ₂ = 15.0Hz), 2.58 (dt, 1H, J ₁ = 7.5
_{Hz, J 2 = 15.0Hz),} 3.20 (dt, 1H, J 1 = 7.0Hz, J 2 = 14.0Hz), 3.2
6 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 14.0Hz), 4.06 (t, 1H, J = 6.5Hz),
4.22 (dd, 1H, J ₁ = 5.5Hz, J ₂ = 9.5Hz)

The following compounds were obtained in the same manner. γ-Glu-Val-GABA (compound 12) Melting point: 204-206 ° C. (decomposition) [α] ²⁵ = −23.8 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 0.92 ( d, 3H, J = 7.0Hz), 0.94
(d, 3H, J = 7.0Hz), 1.80 (tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0Hz), 2.0
4 (dqq, 1H, J ₁ = 7.0Hz, J ₂ = 7.0Hz, J ₃ = 7.0Hz), 2.12-2.26 (m,
2H), 2.40 (t, 2H, J = 7.0Hz), 2.52 (dt, 1H, J ₁ = 7.5Hz, J ₂ = 1
6.0Hz), 2.59 (ddd, 1H, J ₁ = 7.0Hz, J ₂ = 8.0Hz, J ₃ = 16.0Hz),
3.22 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 13.5Hz), 3.27 (dt, 1H, J ₁ = 7.0H
z, J ₂ = 13.5Hz), 3.99 (d, 1H, J = 7.0Hz), 4.00 (t, 1H, J = 7.0H
z)

Γ-Glu-Hyp-GABA (Compound 13) Melting point: Decomposed gradually from 88 ° C. [α] ²⁵ = -50.3 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.80 (tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0
Hz), 2.02-2.09 (m, 1H), 2.13-2.36 (m, 3H), 2.41 (t, 2H, J =
7.0Hz), 2.55-2.77 (m, 2H), 3.18-3.30 (m, 2H), 3.62 (dd,
1H, J ₁ = 2.0Hz, J ₂ = 11.0Hz), 3.79 (dd, 1H, J ₁ = 4.0Hz, J ₂ = 11.
0Hz), 4.09 (t, 1H , J = 7.5Hz), 4.43 (dd, 1H, J 1 = 8.0Hz, J 2 =
8.5Hz), 4.55-4.60 (m, 1H)

Example 3. (i) His.H ₂ O.HCl 3.98 was added to a mixed solvent of 25 ml of DMF and 50 ml of water.
g and sodium hydrogen carbonate (2.01 g), and Z-Glu (ONSu) -OBzl (7.27 g) dissolved in acetonitrile (25 ml) was added thereto with stirring at room temperature. After stirring for 20 hours, the solvent is distilled off,
The residue was neutralized by adding 20 ml of 1N hydrochloric acid at 5 ° C. The precipitated oil was extracted with 100 ml of chloroform to give a crystalline product as a precipitate. After washing with water, recrystallization from an aqueous methanol solution gave 6.34 g of Z-Glu (His-OH) -OBzl. (Yield 80
%) Melting point: 134-136 ℃ [α] ²⁴ = -7.2 (C = 1.0, DMF)

(Ii) Z-Glu (His-OH) -OBzl 5.09 g, Tos
4.02 g of OH.GABA-OBzl, 1.11 g of NMM and 2.15 g of HONB were dissolved in 100 ml of dichloromethane. 2.47 g of DCC dissolved in 50 ml of dichloromethane was added to the mixed solution at 0 ° C., and the mixture was stirred for 2 hours. After further stirring at room temperature for 20 hours, the deposited DC
Urea and TosOH.NMM were removed by filtration, and the filtrate was concentrated under reduced pressure. The oily residue was dissolved in chloroform (100 ml), washed successively with water, 5% aqueous sodium hydrogen carbonate, water, 10% aqueous citric acid, and water, and then the solvent was distilled off. After recrystallization of the oily product from ether, the crude product was purified by silica gel column chromatography to give Z-Glu (His-GABA-OBzl).
4.87 g of -OBzl were obtained. (Yield 71%) Melting point: 139-141 ° C [α] ²⁴ = -10.8 (C = 1.1, DMF)

(Iii) Z-Glu (His-GABA-OBzl) -OBzl 4.
1 g was subjected to catalytic reduction in the same manner as in Example 1 (iv),
Glu (His-GABA), that is, γ-Glu-His
1.57 g of -GABA (compound 14) was obtained. Melting point: 146-149 ° C (decomposition) (α) ²⁵ = -3.0 (C = 1.0, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.73 (tt, 2H, J ₁ = 7.5Hz, J ₂ = 7.5
Hz), 2.14-2.27 (m, 2H), 2.32 (t, 2H, J = 7.5Hz), 2.48 (t, 2
H, J = 8.0Hz), 3.14 (dd, 1H, J 1 = 8.0Hz, J 2 = 15.0Hz), 3.17-3.
27 (m, 3H), 3.87 (t, 1H, J = 6.5Hz), 4.60 (dd, 1H, J 1 = 7.0Hz,
J ₂ = 8.0Hz), 7.32 (s, 1H), 8.65 (s, 1H)

Example 4. (i) 5.84 g of Boc-Phe-OH, TosOH.β-Ala-OBzl
7.03 g was dissolved in 80 ml of dichloromethane, and 2.03 g of TEA was added. At 0 ° C., 4.54 g of DCC was added, and the mixture was stirred at 0 ° C. for 3 hours and at room temperature overnight. The precipitated DCUrea was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed sequentially with 10% citric acid, water, 4% sodium bicarbonate, and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain 8.36 g of Boc-Phe-β-Ala-OBzl. (Yield 98
%)

(Ii) Boc-Phe-β-Ala-OBzl 4.26
g in 16 ml of dioxane and 6N hydrochloric acid / dioxane 33
ml was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, and the mixture was neutralized by adding ice-cooled saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted three times with chloroform, and the chloroform layers were combined and washed with half-saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 80 ml of dichloromethyl, and 3.71 g of Z-Glu-OBzl was added. DC at 0 ° C
2.06 g of C was added, and the mixture was stirred at 0 ° C. for 3 hours and at room temperature overnight.
The precipitated DCUrea was removed by filtration, and the filtrate was concentrated under reduced pressure to give Z-G
5.37 g of lu (Phe-β-Ala-OBzl) -OBzl were obtained. (Yield 77%) Melting point: 161.0-162.5 ° C [α] ²² = -12.0 (C = 1.0, CHCl ₃ )

The following compounds were obtained in the same manner. Z-Glu (Phe-GABOB-OBzl) -OBzl Melting point: 142.5-143.5 ° C [α] ²² = -7.2 (C = 1.0, CHCl ₃ ) Z-Glu (Phe-EACA-OBzl) -OBzl Melting point: 145-146 ° C [α] ²² = -10.8 (C = 1.4, CHCl ₃ ) Z-Glu (Pro-β-Ala-OBzl) -OBzl Melting point: 109-110.5 ° C [α] ²² = -57.2 (C = 1.2, CHCl ₃ ) Z-Glu (Pro-GABOB-OBzl) -OBzl Melting point: Oily substance [α] ²⁶ = -44.9 (C = 1.2, CHCl ₃ ) Z-Glu (Pro-EACA-OBzl) -OBzl Melting point: Oily substance [α ] ^{22 = -40.4 (C = 2.0,} CHCl 3)

Z-Glu (OBzl) -Phe-β-Ala-OBzl Melting point: 157-158 ° C [α] ²² = -20.1 (C = 1.0, CHCl ₃ ) Z-Glu (OBzl) -Pro-GABA-OBzl Melting point: 142.5-143.5 ° C. Z-Glu (OBzl) -Pro-EACA-OBzl Melting point: Oily substance Z-Asp (Phe-β-Ala-OBzl) -OBzl Melting point: 158-159 ° C. [α] ²² = + 2.2 (C = 1.0, CHCl ₃ ) Z-Asp (Phe-EACA-OBzl) -OBzl Melting point: 133-133.5 ° C. [α] ²² = + 18.9 (C = 1.1, CHCl ₃ ) Z-Asp (OBzl) -Phe -Β-Ala-OBzl Melting point: 144-145 ° C [α] ²² = +10.7 (C = 1.0, CHCl ₃ )

(Iii) Z-Glu (Phe-β-Ala-OBzl) -OBz
l 2.50 g was subjected to catalytic reduction in the same manner as in Example 1 (iv), and the protecting group was removed to remove Glu (Phe-β-Ala), that is, γ.
1.30 g of -Glu-Phe-β-Ala (compound 15) was obtained.
(99% yield) NMR (0.1NDCl / D ₂ O): δ = 2.07 (dt, 1H, J ₁ = 7.0 Hz, J ₂ = 14.
5Hz), 2.14 (dt, 1H, J ₁ = 7.0Hz, J ₂ = 14.5Hz), 2.36 (ddd, 1H,
J ₁ = 5.5Hz, J ₂ = 8.0Hz, J ₃ = 17.5Hz), 2.45 (ddd, 1H, J ₁ = 5.5H
z, J ₂ = 6.0Hz, J ₃ = 17.5Hz), 2.52 (t, 2H, J = 7.0Hz), 2.99 (d
d, 1H, J ₁ = 8.0Hz, J ₂ = 13.5Hz), 3.03 (dd, 1H, J ₁ = 8.0Hz, J ₂ = 1
3.5Hz), 3.27 (ddd, 1H , J 1 = 5.5Hz, J 2 = 8.0Hz, J 3 = 14.0Hz),
3.40 (ddd, 1H, J ₁ = 5.5Hz, J ₂ = 6.5Hz, J ₃ = 14.0Hz), 3.97 (t, 1
H, J = 6.5Hz), 4.49 (t, 1H, J = 8.0Hz), 7.24 (dt, 2H, J ₁ = 1.5H
z, J ₂ = 7.0Hz), 7.30 (tt, 1H, J ₁ = 1.5Hz, J ₂ = 7.0Hz), 7.35 (t
(t, 2H, J ₁ = 1.5Hz, J ₂ = 7.0Hz)

The following compounds were obtained in the same manner. γ-Glu-Phe-GABOB (compound 16) Melting point: 163-165 ° C. (decomposition) [α] ²⁶ = + 21.3 (C = 1.0, 0.1NHCl) NMR (0.1NDCl / D ₂ O): δ = 2.09- 2.19 (m, 2H), 2.19-2.27
(m, 1H), 2.31-2.33 (m, 1H), 2.30 (br.t, 2H, J = 6.5Hz), 3.
00-3.14 (m, 2H), 3.14-3.35 (m, 2H), 3.91-4.03 (m, 2H),
4.51-4.55 (m, 1H), 7.20-7.39 (m, 5H)

Γ-Glu-Phe-EACA (compound 17) Melting point: 184-185 ° C. (decomposition) [α] ²⁶ = + 14.1 (C = 1.1, 0.1NHCl) NMR (0.1NDCl / D ₂ O): δ = 1.07 (br.tt, 2H, J ₁ = 7.0Hz, J ₂ =
7.0Hz), 1.27 (br.tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0Hz), 1.50 (br.
tt, 2H, J ₁ = 7.0Hz, J ₂ = 7.0Hz), 2.12 (dt, 2H, J ₁ = 6.5Hz, J ₂ =
7.5Hz), 2.33 (t, 2H, J = 7.5Hz), 2.49 (br.t, 2H, J = 7.5Hz),
2.99 (ddd, 1H, J ₁ = 6.5Hz, J ₂ = 7.0Hz, J ₃ = 13.5Hz), 3.01 (d,
2H, J = 8.0Hz), 3.14 (ddd, 1H, J ₁ = 6.5Hz, J ₂ = 7.0Hz, J ₃ = 13.5
Hz), 4.00 (t, 1H, J = 6.5Hz), 4.48 (t, 1H, J = 8.0Hz), 7.26
(br.d, 2H, J = 7.0Hz), 7.30 (br.t, 1H, J = 7.0Hz), 7.37 (br.
(t, 2H, J = 7.0Hz)

Γ-Glu-Pro-β-Ala (compound 18) Melting point: 91-93 ° C. [α] ²⁶ = -50.1 (C = 1.1, 0.1NHCl) NMR (0.1NDCl / D ₂ O): δ = 1.85 -2.05 (m, 4H), 2.15-2.30
(m, 3H), 2.62 (t, 1H, J = 6.5Hz), 2.68 (br.t, 1H, J = 7.5Hz),
3.39-3.53 (m, 4H), 3.55-3.70 (m, 4H), 4.10 (t, 1H, J = 6.5
Hz), 4.32 (dd, 1H, J ₁ = 4.5Hz, J ₂ = 8.0Hz)

Γ-Glu-Pro-GABOB (compound 19) Melting point: 66-68 ° C. [α] ²⁶ = -32.0 (C = 1.2, 0.1NHCl) NMR (0.1NDCl / D ₂ O): δ = 1.90-2.04 (m, 3H), 2.15-2.33
(m, 3H), 2.42-2.51 (m, 1H), 2.57-2.64 (m, 1H), 2.69 (br.
(t, 2H, J = 7.0Hz), 3.31-3.35 (m, 2H), 3.59-3.68 (m, 2H),
4.08-4.20 (m, 2H), 4.15 (dd, 1H, J ₁ = 5.0Hz, J ₂ = 9.0Hz)

Γ-Glu-Pro-EACA (compound 20) Melting point: 62-63 ° C. [α] ²⁶ = -40.5 (C = 1.1, 0.1NHCl) NMR (0.1NDCl / D ₂ O): δ = 1.27–1.39 (m, 2H), 1.46-1.65
(m, 4H), 1.86-2.03 (m, 3H), 2.15-2.30 (m, 3H), 2.38 (t, 2
H, J = 7.5Hz), 2.68 (dt, 2H, J 1 = 3.0Hz, J 2 = 8.0Hz), 3.11-3.
26 (m, 2H), 3.58-3.68 (m, 2H), 4.13 (t, 1H, J = 7.0Hz), 4.3
2 (dd, 1H, J ₁ = 5.0Hz, J ₂ = 8.5Hz)

Glu-Phe-β-Ala (compound 21) Melting point: 154.5-155.5 ° C. [α] ²⁶ = + 35.6 (C = 0.9, 0.1NHCl) NMR (0.1NDCl / D ₂ O): δ = 2.15 ( dt, 2H, J ₁ = 7.5Hz, J ₂ = 8.0
Hz), 2.28 (ddd, 1H, J ₁ = 5.5Hz, J ₂ = 8.0Hz, J ₃ = 17.0Hz), 2.4
1 (ddd, 1H, J ₁ = 5.5Hz, J ₂ = 6.5Hz, J ₃ = 17.0Hz), 2.51 (t, 2H, J
= 7.5Hz), 2.99 (dd, 1H, J ₁ = 9.0Hz, J ₂ = 13.0Hz), 3.12 (dd, 1
H, J ₁ = 7.0Hz, J ₂ = 13.0Hz), 3.20 (ddd, 1H, J ₁ = 5.5Hz, J ₂ = 8.0
Hz, J ₃ = 13.5Hz), 3.39 (ddd, 1H, J ₁ = 5.5Hz, J ₂ = 6.5Hz, J ₃ = 1
3.5Hz), 4.07 (t, 1H , J = 6.5Hz), 4.52 (dd, 1H, J 1 = 7.0Hz, J 2
= 9.0Hz), 7.26 (br.t, 2H, J = 7.2Hz), 7.30 (br.t, 1H, J = 7.2H)
z), 7.37 (br.t, 2H, J = 7.2Hz)

Glu-Pro-GABA (compound 22) Melting point: 157-158 ° C [α] ²⁶ = -60.1 (C = 1.0, H ₂ O) Glu-Pro-EACA (compound 23) Melting point: 76-78 ° C ( Decomposition) [α] ²⁶ = −62.8 (C = 1.0, 0.1NHCl) NMR (0.1NDCl / D ₂ O): δ = 1.23-1.33 (m, 2H), 1.42-1.65
(m, 4H), 1.79-2.07 (m, 3H), 2.17-2.31 (m, 2H), 2.14 (dd,
1H, J ₁ = 7.0Hz, J ₂ = 14.5Hz), 2.34 (t, 2H, J = 7.5Hz), 2.58 (t,
2H, J = 7.5Hz), 3.10 (dd, 1H, J 1 = 6.5Hz, J 2 = 14.0Hz), 3.24
(dd, 1H, J ₁ = 7.0Hz, J ₂ = 14.0Hz), 3.55-3.65 (m, 1H), 3.65-
3.75 (m, 1H), 4.36 (dd, 1H, J ₁ = 7.0Hz, J ₂ = 8.0Hz), 4.41 (d
(d, 1H, J ₁ = 5.0Hz, J ₂ = 7.0Hz)

Β-Asp-Phe-β-Ala (compound 24) Melting point: 158-160 ° C. (decomposition) [α] ²⁶ = + 13.4 (C = 1.2, 0.1NHCl) NMR (0.1NDCl / D ₂ O) : δ = 2.35 (ddd, 1H, J ₁ = 5.5Hz, J ₂ = 8.
0Hz, J ₃ = 17.0Hz), 2.44 (ddd, 1H, J ₁ = 5.5Hz, J ₂ = 6.0Hz, J ₃ = 1
7.0Hz), 3.00 (dd, 1H, J ₁ = 5.5Hz, J ₂ = 9.5Hz), 3.02 (d, 2H, J
= 8.0Hz), 3.04 (dd, 1H, J ₁ = 5.5Hz, J ₂ = 9.5Hz), 3.27 (ddd, 1
H, J ₁ = 5.5Hz, J ₂ = 8.0Hz, J ₃ = 14.0Hz), 3.40 (ddd, 1H, J ₁ = 5.5
Hz, J ₂ = 6.0Hz, J ₃ = 14.0Hz), 4.33 (t, 1H, J = 5.5Hz), 4.49
(t, 1H, J = 8.0Hz ), 7.23 (dt, 2H, J 1 = 1.5Hz, J 2 = 6.5Hz), 7.3
2 (tt, 1H, J ₁ = 1.5Hz, J ₂ = 6.5Hz), 7.36 (tt, 2H, J ₁ = 1.5Hz, J ₂
= 6.5Hz)

Β-Asp-Phe-EACA (Compound 25) Melting point: 178-180 ° C. (decomposition) [α] ²⁶ = + 10.0 (C = 1.1, 0.1NHCl) NMR (0.1NDCl / D ₂ O): δ = 0.97-1.10 (m, 2H), 1.20-1.35
(m, 2H), 1.49 (tt, 2H, J ₁ = 7.5Hz, J ₂ = 7.5Hz), 2.32 (br.t, 2
H, J = 7.5Hz), 2.94 (dd, 1H, J 1 = 13.0Hz, J 2 = 14.0Hz), 2.99 (d
d, 1H, J ₁ = 8.0Hz, J ₂ = 18.0Hz), 3.00 (dd, 1H, J ₁ = 9.0Hz, J ₂ = 1
3.5Hz), 3.07 (dd, 1H, J ₁ = 5.5Hz, J ₂ = 18.0Hz), 3.10 (dd, 1
H, J ₁ = 7.0Hz, J ₂ = 13.5Hz), 3.12 (dd, 1H, J ₁ = 13.0Hz, J ₂ = 14.
0Hz), 4.34 (dd, 1H, J ₁ = 5.5Hz, J ₂ = 8.0Hz), 4.52 (dd, 1H, J ₁
= 7.0Hz, J ₂ = 9.0Hz), 7.27 (br.d, 2H, J = 7.0Hz), 7.31 (br.t,
1H, J = 7.0Hz), 7.37 (br.t, 2H, J = 7.0Hz)

Asp-Phe-β-Ala (compound 26) Melting point: 168-171 ° C. (decomposition) [α] ²⁶ = + 14.9 (C = 1.0, 0.1NHCl) NMR (0.1NDCl / D ₂ O): δ = 2.31 (ddd, 1H, J ₁ = 5.5Hz, J ₂ = 8.
_{0Hz, J 3 = 17.0Hz),} 2.41 (td, 1H, J 1 = 5.5Hz, J 2 = 17.0Hz), 2.
99 (dd, 1H, J ₁ = 7.2Hz, J ₂ = 18.0Hz), 3.01 (dd, 1H, J ₁ = 8.0Hz,
_{J 2 = 16.0Hz), 3.07 (} dd, 1H, J 1 = 5.0Hz, J 2 = 18.0Hz), 3.10 (d
d, 1H, J ₁ = 7.0Hz, J ₂ = 16.0Hz), 3.22 (ddd, 1H, J ₁ = 5.5Hz, J ₂ =
_{8.0Hz, J 3 = 14.0Hz),} 3.39 (dt, 1H, J 1 = 5.5Hz, J 2 = 14.0Hz),
_{4.33 (dd, 1H, J 1} = 5.0Hz, J 2 = 7.2Hz), 4.53 (br.t, 1H, J = 8.0H
z), 7.25 (d, 2H, J = 7.0Hz), 7.31 (t, 1H, J = 7.0Hz), 7.37
(t, 2H, J = 7.0Hz)

Embodiment 5 FIG. (i) 10.76 g of Boc-Pro-OH and 5.06 g of TEA were added in 250 m of THF.
After cooling, 5.43 g of ECF was added dropwise at -15 ° C, and the mixture was stirred for 15 minutes. TosOH. GABA-OBzl 20.1 g, TEA
A mixed solution of 5.57 g dissolved in 100 ml of chloroform was added at 0 ° C.
Added in. After stirring the reaction solution at 0 ° C. for 2 hours and at room temperature for 20 hours, the solvent was distilled off. The residue was dissolved in 150 ml of ethyl acetate, and washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution, a saturated saline solution, a 10% aqueous citric acid solution, and a saturated saline solution.
After dehydrating the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain oily Boc-Pro-GABA-OBzl. Boc
-Pro-GABA-OBzl was treated with 250 ml of 4N hydrochloric acid / dioxane and the solvent and hydrochloric acid were distilled off under reduced pressure. The residue was dissolved in 100 ml of dioxane and the residual hydrochloric acid was re-evaporated with the solvent. The resulting oil was crystallized from ether / petroleum ether to give 15.48 g of HCl.Pro-GABA-OBzl. (Yield 95
%)

(Ii) HCl.Pro-GABA-OBzl and Z-Glu (ON
Using Su) -OBzl, the same condensation reaction and catalytic reduction operation as in Examples 1 (iii) and (iv) were performed to obtain γ-Glu-Pro
-GABA (compound 5) was obtained.

Embodiment 6 FIG. (I) HCl.Phe-GABA-OBzl was prepared according to Examples 4 (i) and (i).
Obtained in a similar manner to i). 3.57 g of Z-Asp (OBzl) -OH, HC
Dissolve 4.15 g of l.Phe-GABA-OBzl and 1.11 g of TEA in 50 ml of dichloromethane, and add 2.11 g of WSCD.HCl under ice-cooling.
The mixture was stirred at 0 ° C. for 2 hours and at room temperature for another 20 hours. The reaction mixture was sequentially washed with water, a 10% aqueous citric acid solution, water, a 5% aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration from ether and Z-Asp (OBzl) -Phe-GABA
5.31 g of -OBzl were obtained. (Yield 78%) Melting point: 128-130 ° C [α] ²⁵ = -30.2 (C = 1.0, DMF)

The following compounds were obtained in the same manner. Z-Asp (Phe-GABA-OBzl) -OBzl Melting point: 163-165 ° C [α] ²⁵ = -55.4 (C = 1.0, DMF) Z-Glu (OBzl) -Phe-GABA-OBzl Melting point: 129-131 ° C [Α] ²⁵ = -16.7 (C = 1.0, DMF) ZD-Asp (Phe-GABA-OBzl) -OBzl (NO ₂ ) Melting point: 149-151 ° C [α] ²⁴ = -8.1 (C = 1.0, DMF) DMF) Z-Asp (Pro-GABA-OBzl) -OBzl Melting point: oil Z-Asp (OBzl) -Pro-GABA-OBzl Melting point: oil

Z-Glu (OBzl) -Pro-β-Ala-OBzl Melting point: oily substance Z-Asp (OBzl) -Phe-GABOB-OBzl Melting point: 109-111 ° C. [α] ²⁴ = -19.5 (C = 1.1 , DMF) Z-Asp (Phe-GABOB-OBzl) -OBzl Melting point: 143-145 ° C [α] ²⁴ = -9.9 (C = 1.1, DMF) Z-D-Asp (Phe-GABOB-OBzl) -OBzl ( NO ₂ ) Melting point: 154-156 ° C [α] ²⁴ = -1.5 (C = 1.0, DMF) Z-Glu (OBzl) -Phe-GABOB-OBzl Melting point: 137-139 ° C [α] ²⁴ = -16.4 (C = 1.0, DMF)

Z-Asp (OBzl) -Pro-GABOB-OBzl Melting point: oily substance Z-Asp (Pro-GABOB-OBzl) -OBzl Melting point: oily substance ZD-Asp (Pro-GABOB-OBzl) -OBzl ( NO ₂ ) Melting point: oily substance Z-Glu (OBzl) -Pro-GABOB-OBzl Melting point: oily substance Z-Asp (OBzl) -Phe-EACA-OBzl Melting point: 131-133 ° C [α] ²⁴ = -20.3 (C = 1.0, DMF)

ZD-Asp (Phe-EACA-OBzl) -OBzl (N
O ₂ ) Melting point: 156-158 ° C [α] ²⁴ = -2.3 (C = 1.5, DMF) Z-Glu (OBzl) -Phe-EACA-OBzl Melting point: 142-143 ° C [α] ²⁴ = -15.4 (C = 1.4, DMF) Z-Asp (OBzl) -Pro-EACA-OBzl Melting point: oily substance Z-Asp (Pro-EACA-OBzl) -OBzl Melting point: oily substance ZD-Asp (Pro-EACA-OBzl)- OBzl (NO ₂ ) Melting point: oil Boc-D-Asp (OBzl) -Phe-GABA-OBzl Melting point: 96-97 ° C [α] ²⁵ = -10.9 (C = 1.0, DMF)

(Ii) Z-Asp (OBzl) -Phe-GABA-OBzl
3.74 g was subjected to catalytic reduction in the same manner as in Example 1 (iv), and the protecting group was removed to remove Asp-Phe-GABA (compound 27).
39 g were obtained. (Yield: 69%) Melting point: 217-218 ° C (decomposition) [α] ²⁵ = +16.0 (C = 1.0, H ₂ O)

The following compounds were obtained in the same manner. β-Asp-Phe-GABA (compound 28) Melting point: 216-217 ° C. (decomposition) [α] ²⁵ = −22.1 (C = 0.5, 0.1 N NaOH) Glu-Phe-GABA (compound 29) Melting point: 196-198 ° C. (Decomposition) [α] ²⁵ = -15.2 (C = 0.5, 0.05NNaOH) β-D-Asp-Phe-GABA (compound 30) Melting point: 190-192 ° C (decomposition) [α] ²⁴ = -3.2 (C = 1.0, H ₂ O)

Β-Asp-Pro-GABA (compound 31) Melting point: 85-87 ° C. (decomposition) [α] ²⁴ = −66.8 (C = 1.0, H ₂ O) Asp-Pro-GABA (compound 32) Melting point: Softened from 55 ° C (amorphous solid) [α] ²⁴ = −63.8 (C = 1.0, H ₂ O) Glu-Pro-β-Ala (compound 33) Melting point: 69-70 ° C. (amorphous solid) [α] ²⁴ = −61.1 (C = 1.0, H ₂ O)

Asp-Phe-GABOB (compound 34) Melting point: 198-200 ° C. (decomposition) [α] ²⁴ = + 2.6 (C = 0.6, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O): δ = 2.06 -2.30 (m, 2H), 2.95-3.10
(m, 2H), 2.95-3.30 (m, 2H), 3.06-3.17 (m, 1H), 3.20-3.3
0 (m, 1H), 3.86-3.96 (m, 1H), 4.30-4.37 (m, 1H), 4.54-4.
62 (m, 1H), 7.2-7.4 (m, 5H)

Β-Asp-Phe-GABOB (compound 35) Melting point: 168-170 ° C. (decomposition) [α] ²⁴ = −15.6 (C = 0.7, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O): δ = 2.12-2.33 (m, 2H), 2.87-2.99
(m, 2H), 3.00-3.06 (m, 2H), 3.05-3.30 (m, 2H), 3.90-4.0
0 (m, 1H), 4.17 (t, 1H, J = 5.8Hz), 4.49-4.57 (m, 1H), 7.2-
7.4 (m, 5H)

Β-D-Asp-Phe-GABOB (Compound 36) Melting point: 98-100 ° C. (decomposition) [α] ²⁴ = + 5.2 (C = 1.5, H ₂ O) NMR (0.1NDCl / D ₂ O) ): δ = 2.12-2.24 (m, 1H), 2.27-2.35
(m, 1H), 2.89-2.96 (m, 2H), 2.99-3.06 (m, 2H), 3.05-3.1
6 (m, 1H), 3.16-3.25 (m, 1H), 3.90-3.99 (m, 1H), 4.10-4.
16 (m, 1H), 4.48-4.57 (m, 1H), 7.2-7.4 (m, 5H)

Glu-Phe-GABOB (compound 37) Melting point: 220-222 ° C. (decomposition) [α] ²⁴ = + 9.1 (C = 0.6, 0.1NNaOH) NMR (0.1NDCl / D ₂ O): δ = 2.03 -2.29 (m, 2H), 2.10-2.18
(m, 2H), 2.46-2.54 (m, 2H), 2.98-3.08 (m, 1H), 3.10-3.1
8 (m, 1H), 3.10-3.30 (m, 2H), 3.84-3.95 (m, 1H), 4.04-4.
10 (m, 1H), 4.52-4.61 (m, 1H), 7.25-7.45 (m, 5H)

Asp-Pro-GABOB (compound 38) Melting point: oil [α] ²⁴ = -58.6 (C = 1.3, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.89-2.00 (m, 1H), 2.00-2.12
(m, 2H), 2.28-2.39 (m, 1H), 2.42-2.52 (m, 1H), 2.57-2.6
5 (m, 1H), 2.94 (dd, 1H, J ₁ = 8.8Hz, J ₂ = 18.0Hz), 3.14 (dd, 1
(H, J ₁ = 4.0Hz, J ₂ = 18.0Hz), 3.24-3.41 (m, 2H), 3.61-3.71
(m, 1H), 3.71-3.80 (m, 1H), 4.10-4.21 (m, 1H), 4.45 (dd,
1H, J ₁ = 6.6Hz, J ₂ = 8.1Hz), 4.65 (dd, 1H, J ₁ = 4.0Hz, J ₂ = 8.8H
z)

Β-Asp-Pro-GABOB (compound 39) Melting point: oil [α] ²⁴ = -70.5 (C = 1.1, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.90-2.07 ( m, 3H), 2.23-2.34
(m, 1H), 2.42-2.52 (m, 1H), 2.57-2.66 (m, 1H), 3.17 (dd,
_{1H, J 1 = 3.9Hz, J} 2 = 18.1Hz), 3.26 (dd, 1H, J 1 = 5.8Hz, J 2 = 18.
1Hz), 3.30-3.38 (m, 2H), 3.58-3.68 (m, 2H), 4.11-4.21
(m, 1H), 4.34 (dd, 1H, J ₁ = 3.9Hz, J ₂ = 5.8Hz), 4.39 (dd, 1H,
(J ₁ = 4.9Hz, J ₂ = 8.9Hz)

Β-D-Asp-Pro-GABOB (compound 40) Melting point: oil [α] ²⁴ = -64.8 (C = 1.1, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.90- 2.06 (m, 3H), 2.22-2.33
(m, 1H), 2.42-2.53 (m, 3H), 2.57-2.65 (m, 1H), 3.20 (d, 2
(H, J = 4.9Hz), 3.28-3.40 (m, 2H), 3.55-3.70 (m, 2H), 4.10
-4.22 (m, 1H), 4.39 (t, 1H, J = 4.9Hz), 4.40 (dd, 1H, J ₁ = 4.4
Hz, J ₂ = 8.1Hz)

Glu-Pro-GABOB (Compound 41) Melting point: oil [α] ²⁴ = -47.1 (C = 1.3, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.87-2.13 (m, 3H), 2.13-2.29
(m, 2H), 2.29-2.40 (m, 1H), 2.40-2.53 (m, 1H), 2.57-2.5
6 (m, 1H), 2.58-2.65 (m, 2H), 3.26-3.42 (m, 2H), 3.60-3.
69 (m, 1H), 3.73-3.81 (m, 1H), 4.12-4.21 (m, 1H), 4.43-
4.50 (m, 1H; Prounit), 4.43-4.50 (m, 1H; Glu unit)

Asp-Phe-EACA (compound 42) Melting point: 179-181 ° C. (decomposition) [α] ²⁴ = + 3.3 (C = 0.7, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O): δ = 0.95 -1.09 (m, 2H), 1.20-1.32
(m, 2H), 1.42-1.53 (m, 2H), 2.30 (t, 2H, J = 7.2Hz), 2.89-
3.18 (m, 2H), 2.93-3.18 (m, 2H; Phe unit), 2.93-3.18 (m,
2H; Asp unit), 4.33 (t, 1H, J = 6.3Hz), 4.51 (t, 1H, J = 7.9H
z), 7.2-7.4 (m, 5H)

Β-D-Asp-Phe-EACA (compound 43) Melting point: 181-183 ° C. (decomposition) [α] ²⁴ = + 1.6 (C = 0.6, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O) : δ = 0.98-1.10 (m, 2H), 1.22-1.33
(m, 2H), 1.43-1.53 (m, 2H), 2.31 (t, 2H, J = 7.4Hz), 2.91-
3.00 (m, 1H), 2.95-3.00 (m, 2H), 3.00-3.05 (m, 2H), 3.12
(ddd, 1H, J ₁ = 6.8Hz, J ₂ = 6.8Hz, J ₃ = 13.5Hz), 4.25 (t, 1H, J =
5.6Hz), 4.47 (t, 1H, J = 8.0Hz), 7.2-7.4 (m, 5H)

Glu-Phe-EACA (compound 44) Melting point: 100-102 ° C. [α] ²⁴ = + 8.8 (C = 0.7, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O): δ = 0.96-1.06 ( m, 2H), 1.20-1.31
(m, 2H), 1.41-1.52 (m, 2H), 2.09-2.21 (m, 2H). 2.30 (t, 2
H, J = 7.5Hz), 2.51 (t, 2H, J = 7.2Hz), 2.94 (ddd, 1H, J ₁ = 6.8
Hz, J ₂ = 6.8Hz, J ₃ = 13.7Hz), 2.98 (dd, 1H, J ₁ = 9.3Hz, J ₂ = 13.
4Hz), 3.11 (ddd, 1H, J ₁ = 6.8Hz, J ₂ = 6.8Hz, J ₃ = 13.7Hz; EACA
unit), 3.11 (dd, 1H, J ₁ = 6.8Hz, J ₂ = 6.8Hz; Phe unit), 4.
08 (t, 1H, J = 6.6Hz), 4.51 (dd, 1H, J 1 = 6.8Hz, J 2 = 9.3Hz),
7.2-7.4 (m, 5H)

Asp-Pro-EACA (compound 45) Melting point: 141-143 ° C. (decomposition) [α] ²⁴ = −60.9 (C = 0.6, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O): δ = 1.26 1.36 (m, 2H), 1.45-1.55
(m, 2H), 1.55-1.65 (m, 2H), 1.86-1.96 (m, 1H). 1.96-2.1
0 (m, 2H), 2.26-2.36 (m, 1H), 2.37 (t, 2H, J = 7.4Hz), 2.94
(dd, 1H, J ₁ = 8.8Hz, J ₂ = 20.2Hz), 3.13 (ddd, 1H, J ₁ = 6.7Hz, J
₂ = 6.7Hz, J ₃ = 13.5Hz), 3.16 (dd, 1H, J ₁ = 4.3Hz, J ₂ = 20.0H
z), 3.26 (ddd, 1H, J ₁ = 6.8Hz, J ₂ = 6.8Hz, J ₃ = 13.5Hz), 3.63
-3.71 (m, 1H), 3.71-3.79 (m, 1H), 4.65 (dd, 1H, J ₁ = 4.3Hz,
(J ₂ = 8.8Hz)

Β-Asp-Pro-EACA (Compound 46) Melting point: oil [α] ²⁴ = -99.9 (C = 1.4, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.27.37 ( m, 2H), 1.47-1.56
(m, 2H), 1.56-1.65 (m, 2H), 1.87-1.97 (m, 1H). 1.97-2.0
4 (m, 2H), 2.21-2.33 (m, 1H), 2.38 (t, 2H, J = 7.3Hz), 3.11
-3.28 (m, 2H). 3.16-3.24 (m, 2H), 3.54-3.69 (m, 2H), 4.3
4 (dd, 1H, J ₁ = 4.4Hz, J ₂ = 8.7Hz) .4.34-4.38 (m, 1H)

Β-D-Asp-Pro-EACA (compound 47) Melting point: oil [α] ²⁴ = −62.1 (C = 1.3, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.26 1.37 (m, 2H), 1.46-1.56
(m, 2H), 1.56-1.65 (m, 2H), 1.87-1.97 (m, 1H). 1.97-2.0
4 (m, 2H), 2.21-2.32 (m, 1H), 2.38 (t, 2H, J = 7.3Hz), 3.10
-3.28 (m, 2H). 3.16-3.23 (m, 2H), 3.53-3.70 (m, 2H), 4.3
5 (dd, 1H, J ₁ = 4.3Hz, J ₂ = 8.9Hz) .4.35-4.40 (m, 1H)

D-Asp-Phe-GABA (compound 48) Melting point: 187-189 ° C. (decomposition) [α] ²⁵ = -19.3 (C = 0.5, 0.1 N NaOH)

The following compounds were obtained in the same manner. D-Asp-Pro-GABA (Compound 49) Melting point: 155-156 ° C [α] ²⁴ = -67.9 (C = 1.0, H ₂ O)

D-Asp-Phe-GABOB (Compound 50) Melting point: 177-179 ° C. (decomposition) [α] ²⁴ = -16.7 (C = 0.6, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O): δ = 2.28-2.46 (m, 2H), 2.73 (dd, 1
H, J ₁ = 5.9Hz, J ₂ = 15.4Hz), 2.78 (dd, 1H, J ₁ = 5.9Hz, J ₂ = 15.4H
z), 2.92-3.03 (m, 1H), 3.10-3.20 (m, 1H), 3.15-3.34 (m,
2H), 3.98-4.07 (m, 1H), 4.29 (t, 1H, J = 5.9Hz), 4.61-4.6
9 (m, 1H), 7.2-7.4 (m, 5H)

D-Asp-Pro-GABOB (compound 51) Melting point: oily substance [α] ²⁴ = -64.1 (C = 1.3, H ₂ O) NMR (0.1NDCl / D ₂ O): δ = 1.90-2.10 ( m, 3H), 2.24-2.37
(m, 1H), 2.43-2.53 (m, 1H), 2.63 (dd, 1H, J ₁ = 4.2Hz, J ₂ = 1
6.0Hz), 2.92 (dd, 1H, J ₁ = 8.4Hz, J ₂ = 17.8Hz), 3.09 (dd, 1
(H, J ₁ = 4.5Hz, J ₂ = 17.8Hz), 3.28-3.38 (m, 2H), 3.64-3.73
(m, 1H), 3.73-3.82 (m, 1H), 4.13-4.22 (m, 1H), 4.43 (dd,
1H, J ₁ = 4.3Hz, J ₂ = 8.9Hz), 4.66 (dd, 1H, J ₁ = 4.5Hz, J ₂ = 8.4H
z)

D-Asp-Phe-EACA (compound 52) Melting point: 167-169 ° C. (decomposition) [α] ²⁴ = -16.3 (C = 0.6, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O): δ = 1.07-1.18 (m, 2H), 1.30-1.41
(m, 2H), 1.45-1.57 (m, 2H), 2.32 (t, 2H, J = 7.6Hz), 2.80
(d, 2H, J = 6.0Hz), 2.93-3.15 (m, 2H), 2.93-3.22 (m, 2H),
4.30 (t, 1H, J = 6.0Hz), 4.57 (t, 1H, J = 8.4Hz), 7.2-7.4 (m,
5H)

D-Asp-Pro-EACA (compound 53) Melting point: 155-157 ° C. (decomposition) [α] ²⁴ = -100.6 (C = 0.6, 0.1 N NaOH) NMR (0.1NDCl / D ₂ O): δ = 1.28-1.39 (m, 2H), 1.47-1.56
(m, 2H), 1.56-1.66 (m, 2H), 1.90-1.99 (m, 1H), 1.99-2.0
8 (m, 2H), 2.24-2.36 (m, 1H), 2.39 (t, 2H, J = 7.4Hz), 2.91
(dd, 1H, J ₁ = 8.6Hz, J ₂ = 16.0Hz), 3.08 (dd, 1H, J ₁ = 3.8Hz, J ₂
= 16.0Hz), 3.13-3.28 (m, 2H), 3.63-3.72 (m, 1H), 3.73-
3.81 (m, 1H), 4.38 (dd, 1H, J ₁ = 4.4Hz, J ₂ = 8.6Hz), 4.65 (d
(d, 1H, J ₁ = 3.8Hz, J ₂ = 8.6Hz)

Example 7. γ was obtained in the same manner as in Example 3.
-Glu-5-HTP-GABA (compound 54) was obtained. Melting point:
120-123 ° C (decomposition) [α] ²⁴ = +12.8 (C = 1.0, H ₂ O)

[0092]

Next, the pharmacological action of the compound of the present invention will be described. (I) The central nervous action of the compound of the present invention was determined by the Chemitorode method [Maria-S. Oitzl and J. P. Huston, Brain Researc.
h, vol. 308 (1984) 33-42]. Weight 20
0-300 g of Wistar rats are pentobarbital (50 m
(g / kg, intraperitoneal administration) Under anesthesia, the top of the head was shaved and the head was fixed to a rat brain fixing device. Make an incision in the scalp, one in the frontal bone, one in each of the left and right parietal regions, 1 to 1.2 mm in diameter
Holes were drilled. A brass screw-insensitive electrode with a diameter of 1.2 mm and a length of 2.5 mm was attached to the hole in the frontal bone.

Among the holes drilled at the top of the head, the Chemi
A torode (a recording electrode was adhered to a drug injection cannula) was implanted on the right side with a stainless steel recording electrode, and was fixed together with an electrode pin socket with dental cement. Each recording electrode was symmetrically inserted into the brain. Refer to the Atlas of Paxions and Watson for the position of the electrode tip,
The coordinates of the hippocampus (Bregma -2.7mm, outer 2.5mm, depth 2.8mm) were chosen.

The rats were reared for about one week as a healing period after the electrodes were implanted, and subjected to the experiment. After recording the electroencephalogram before administration of the test drug for several tens minutes as a subject, 100 ng to 10 μg of the test drug dissolved in 2 μl of physiological saline was intracerebrally administered from the injection electrode, and recording of the electroencephalogram was started immediately. As a control, only physiological saline was injected.

When the neurotrophic effect was observed by spikes of the electroencephalogram in the rat at rest, the compound of the present invention showed a characteristic spike from about 8 minutes after administration and continued from 40 to 60 minutes after administration. On the other hand, γ-aminobutyric acid (GABA), which is known to have cerebral metabolic activation and sedation as an inhibitory neurotransmitter, showed a similar spike from 2 to 3 minutes after administration and continued until about 25 minutes after administration . FIG. 1 shows spikes of the electroencephalogram of the compound of the present invention and GABA.

The dose at which spikes can be sufficiently observed is GA
BA was 10 μg, whereas the compound of the present invention was 100 ng to 1 μg. During the observation of the behavior of the test animals during this period, a sedative state was observed, which was not a cataplesy-like immobilization but a natural physiological response that immediately resulted in an arousal state to an external stimulus.

(II) The analgesic effect of the compound of the present invention was examined by using a modified Landart-Cerit method (tail pressure method). 10 per group
Stimulation was applied to the ridge of male ddY strain mice (body weight: 24-30 g) using a Randall-Cerrit type pressure stimulus measuring device, and the pressure was increased until an escape response was exhibited. 0.1 μmole
/ The average value of the pressurized weight 5 minutes after administration of the test drug of the mouse in the large tank was divided by the value before administration, and this value was expressed as an analgesic coefficient.

An example of the results is shown in Table 1.

[Table 1]

[0099]

[Effect] As is clear from the above pharmacological experiments, the compound of the present invention has a significant effect on the central nervous system at a dose of 1/10 to 1/100 of GABA, and the action time is longer than that of GABA. did. In addition, an excellent analgesic effect was exhibited by administration in the large tank. Since spikes of brain waves and sedation / analgesic action similar to GABA are observed, the compound of the present invention
It is considered to have GABA-like central nervous activity, and therefore, it is expected to be useful as a drug for the purpose of, for example, amelioration of mental symptoms, activation of brain metabolism, sedation, analgesia, and the like.

[Brief description of the drawings]

FIG. 1 shows an example of an electroencephalographic spike observed when the compound of the present invention and GABA are administered into the hippocampus.

Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication // C07K 1/06 A61K 37/02 AAB

Claims (5)

(57) [Claims] 1. A compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof. Embedded image [Wherein A is Glu, γ-Glu, Asp or β-As
p and X are Gly, Ala, Val, Leu, Ile, P
he, Pro, Ser, Tyr, Hyp, Lys, Hi
Y represents an amino acid residue selected from s, Asp, Glu and 5-HTP, and represents an alkylene group having 2 to 6 carbon atoms or an alkylene group having 2 to 6 carbon atoms having a hydroxyl group. ] 2. The compound according to claim 1, wherein A is γ-Glu and Y is alkylene having 3 carbon atoms, and a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein X is Phe, and a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, wherein X is Pro, and a pharmaceutically acceptable salt thereof. 5. A central nervous system drug comprising as an active ingredient at least one peptide compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image [Wherein A is Glu, γ-Glu, Asp or β-As
p and X are Gly, Ala, Val, Leu, Ile, P
he, Pro, Ser, Tyr, Hyp, Lys, Hi
Y represents an amino acid residue selected from s, Asp, Glu and 5-HTP, and represents an alkylene group having 2 to 6 carbon atoms or an alkylene group having 2 to 6 carbon atoms having a hydroxyl group. ]