JPH0651677B2 - Dipeptide derivative, production method and use thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention has the general formula (1): (In the formula, m represents an integer of 1 to 8, n represents an integer of 1 to 6, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, and a phenyl group. Or a methylthio group, or R ¹ and R ² always represent a bond between carbon and nitrogen, and R ³ represents a lower alkyl ester group, a hydroxymethyl group or a formyl group) , Its manufacturing method and its use.

More specifically, the compound of the present invention having the general formula (1) is a prolyl endopeptidase (EC, 3.4.21.2).
6, Prolyl-andopeptidase), not only shows enzyme inhibitory activity, but is also an effective compound for ameliorating and treating symptoms due to organic disorders in the brain.

Here, "organic disorder in the brain" is a cerebral infarction sequelae, sequelae of cerebral hemorrhage, various symptoms derived from cerebral ischemic disorders such as sequela of arteriosclerosis and senile dementia, presenile dementia, amnesia, sequelae of head trauma, It means various organic disorders caused by aftereffects of brain surgery.

(Prior Art) Prolyl endopeptidases are substance P and TRH (thyroid stimulating hormone), which are considered to be neurotransmitters.
It is also known to act on and inactivate vanpressin, which is thought to be related to neurotensin and memory. On the other hand, Dr. Tsuru and Mr. Yoshimoto of Nagasaki University found that compounds that inhibit prolyl endopeptidase activity prevent experimental amnesia caused by rat scopolamine, and reasoned that prolyl endopeptidase inhibitors are involved in memory consolidation. . The results also suggest that prolyl endopeptidase inhibitors could be used for the prevention and treatment of amnesia.

In fact, the novel peptide derivative represented by the general formula (1) of the present invention was confirmed to have an effect on amnesia by experiments using experimental animals.

Brain cells maintain an intracellular environment that is completely different from the surrounding environment (extracellular fluid), maintain the difference and live, but in order to do so, they must continually generate and supply energy . Most of the energy required by the nerve cells in the brain is supplied by oxygen and glucose, and these energy sources are scarcely stored in the brain, so they are constantly supplied from blood.

If the brain is damaged and the supply of oxygen and glucose is cut off, the energy metabolism disorder generally progresses in stages, and the cells lose their function over time and eventually collapse organically. However, the function cannot be normally performed.

Therefore, in order to stably supply the energy source of the brain tissue and keep the external environment of the cerebral nerve cells constant, a mechanism for adjusting the cerebral blood flow of the cerebral blood vessels themselves is well developed.

When treating cerebrovascular disorders medically, various cerebral circulation improving agents, cerebral vasodilators, cerebral metabolism improving agents and the like have been used so far. However, although these drugs improve the subjective symptoms, they hardly improve the neurological symptoms at present.

(Problems to be Solved by the Invention) The inventors of the present invention have a prolyl endopeptidase inhibitory activity which is considered to be closely involved in the improvement / treatment of symptoms caused by various disorders in the brain. We have conducted intensive research to find compounds having antiamnestic activity. Furthermore, in order to find a novel compound having sufficiently low toxicity, a compound similar to a natural product is synthesized by combining a highly safe fatty acid, an amino acid, and a peptide compound as a natural compound, and is represented by the above general formula (I). It was found to have anti-prolyl endopeptidase activity.

(Means for Solving Problems) As a result of earnest research by the present inventors, the novel dipeptide derivative represented by the general formula (I) has antiproline endopeptidase activity, and the novel dipeptide derivative is an experimental model animal. On the other hand, a completely new finding that it also has an antiamnestic effect was obtained, and the present invention was completed.

That is, the novel dipeptide derivative represented by the formula (1) of the present invention is effective for ameliorating and / or treating mental functional symptoms caused by organic disorders in the brain, and is particularly effective for amnesia.

The compound of formula (1) of the present invention is proline residue, and in that it contains a straight-chain type fatty chain, is significantly different from the conventionally well-known anti-amnestic agent of the piracetam derivative system, further amino acid or Since it is a peptide derivative, its toxicity to the living body is extremely low.

Among the compounds of formula (1), the following compounds are preferable because of their high anti-prolyl endopeptidase activity. In the following, these compounds may be referred to by the numbers in the cutlet.

The compound of the present invention can be synthesized by a general peptide synthesis method, but is conveniently synthesized by the synthetic method of the present invention described below. The abbreviations have the following meanings.

Z: benzyloxycarbonyl group Boc: tertiary butyloxycarbonyl group Pro: proline residue -Pro-OMe: -Pro-CH ₂ OH: -Pro-CHO: norLeu: norleucine residue Phe: phenylalanine residue Met: methionine residue OMe: methyl ester group WSCD: N-ethyl-N ', N'-dimethylaminopropylcarbodiimide TEA: triethylamine of the general formula (1) of the present invention The compound can be synthesized as follows.

(1) First, in the general formula (1), R ₃ is a lower alkyl ester group of —COOB. (Wherein m, n, R ¹ and R ² have the same meanings as described above, and B represents a lower alkyl group) and can be synthesized by the following method.

That is, the general formula (2) (Wherein n, R ¹ , R ² and B have the same meanings as defined above) and the general formula (3): [In the formula, m represents the same meaning as described above, and A represents a hydroxyl group, a halogen atom or a group: (Wherein, m has the same meaning as defined above) and is obtained by reacting a carboxylic acid, an acid halide or an acid anhydride in the presence of a base.

This synthetic method is an acylation reaction of an amino group which is generally used, and a reagent such as a base used is different depending on whether the starting component having the formula (3) is a carboxylic acid, an acid halide or an acid anhydride. For example, when using an acid halide, a trialkylamine such as triethylamine is preferable as a base, but an aqueous solution of an alkali metal hydroxide,
Alkali metal carbonate or the like may be used.

When using an acid anhydride, an aqueous solution of the above-mentioned alkali metal hydroxide, for example, sodium hydroxide, potassium hydroxide or the like, or an alkali metal carbonate, such as sodium carbonate,
Examples include potassium carbonate.

When a carboxylic acid is used, a condensing agent such as WSCD or dicyclohexylcarbodiimide is used in an organic solvent that does not participate in the reaction.

General formula (1b): The compound having the formula (wherein m, n, R ¹ and R ² are as described above) can be easily obtained by treating the compound (1a) with a reducing agent. For example, a third compound containing these compounds (1a) together with sodium borohydride
In a suspension of butyl alcohol or tetrahydrofuran,
The compound (1
Alcohols with b) are obtained.

As a general method including the method exemplified here, a reducing agent such as sodium borohydride, lithium borohydride, zinc borohydride, potassium borohydride and the like is used as a compound (1
The alcohol compound (1b) can also be obtained by adding it to the alcohol solution of a).

Formula (1c): (Wherein, m, n, R ¹ and R ² have the same meanings as described above), the prolinal derivative can be obtained by treating the compound (1b) with an oxidizing agent in an organic solvent.

The solvent used in this reaction may be one that does not participate in the reaction, but dimethyl sulfoxide is the best. Examples of the oxidizing agent include sulfur trioxide-pyridine complex, dimethyl sulfoxide, dimethyl sulfoxide-dicyclohexylcarbodiimide-phosphoric acid, silver oxide, manganese dioxide and the like.

The present invention is further described in detail by the following preparation examples and examples. Preparative examples illustrate the methods of synthesizing the starting compounds used in Examples 1-3.

Preparation Example (a) H-Phe-Pro-OMe Z-Phe-OH (1 equivalent), Pro-OMe hydrochloride (1 equivalent) and T
EA (1 eq) is dissolved in dry methylene chloride and WSCD (1 eq) is added under ice cooling. After stirring at room temperature for 20 hours, the reaction mixture was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water, and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography using silica gel. The obtained Z-Ala-
Pro-OMe was dissolved in ethanol (1 equivalent), boron trifluoride-ether complex (1 equivalent) and palladium carbon (small amount) were added, the Z group was removed by catalytic reduction, and the solvent was distilled off under reduced pressure. I got a thing.

Instead of Z-Phe-OH in (a) above, (A) Z-Met-OH, (B) Z-norLe
By using u-OH, (a ′) H-Met-Pro-OM
e, (i ′) H-norLeu-Pro-OMe could be obtained (oil compound).

(b) H-Pro-Pro-OMe Z-Pro-OH (1 equivalent) and H-Pro-OMe · hydrochloride (1 equivalent)
And TEA (1 eq) were dissolved in dry methylene chloride and WSCD (1 eq) was added under ice cooling. After stirring at room temperature for 20 hours, the reaction mixture was treated with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water,
The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography using silica gel. Obtained Z-
Pro-Pro-OMe (1 equivalent) was dissolved in ethanol, boron trifluoride-ether complex (1 equivalent) and palladium carbon (small amount) were added, and Z group was removed by catalytic reduction under hydrogen atmosphere, and the solvent was depressurized. The target substance was obtained as an oily compound by evaporation. All the target compounds could be obtained in the form of oil.

Example 1. a) N- (4-phenylbutanoyl-Phe-Pro-OMe (SUAM1232) H-Phe-Pro-OMe (1 eq) and TEA (1 eq) were dissolved in dry tetrahydrofuran and cooled under ice-cold 4-fu. Enylbutanoyl chloride (1 equivalent) was added dropwise, and the mixture was stirred at room temperature for 6 hours to remove the precipitated hydrochloride of TEA.The solvent was distilled off under reduced pressure and the residue was dissolved in a small amount of ether to dissolve in 1N hydrochloric acid and saturated saline. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and added with an ether solution of diazomethane (excess) unreacted 4-phenyl-n.
-Butyric acid was methyl esterified. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography using silica gel to obtain the target compound. (Oil compound) Instead of H-Phe-Pro-OMe in (a) above, (A) H-Met-P
By using ro-OMe, (A ′) N- (4-phenylbutanoyl) -Met-Pro-OMe (SUAM 1343)
(A) By using H-norLeu-Pro-OMe, (a ') N- (4
-Phenylbutanoyl) -norLeu-Pro-OMe (SUAM1)
235) could be obtained respectively.

(b) N- (4-phenylbutanoyl) -Pro-Pro-OMe (S
UAM1229) H-Pro-Pro-OMe (1 equivalent) and TEA (1 equivalent) were dissolved in dry tetrahydrofuran, and 4-phenylbutanoyl chloride (1 equivalent) was added dropwise under ice cooling. After stirring at room temperature for 6 hours, the precipitated hydrochloride of TEA was excessively removed. The solvent was evaporated under reduced pressure, the residue was dissolved in a small amount of ether, washed with 1N hydrochloric acid, saturated saline, saturated sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, an ether solution of diazomethane was added to it (excessive) unreacted 4-phenyl-
N-butyric acid was methyl esterified. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography using silica gel to obtain the target compound. (Oil compound) In the above (b), by using (a) 2-phenylacetyl chloride instead of 4-phenylbutanoyl chloride, (a ') N- (2-phenylacetyl) -Pro -
By using Pro-OMe (SUAM1334) with (i) 3-phenylpropionyl chloride, (i ') N- (3
-Phenylpropionyl) -Pro-Pro-OMe (SUAM13
By using (u) 5-phenylpentanoyl chloride in (37), (u ') N- (5-phenylpentanoyl) -Pro-Pro-OMe (SUAM1340) could be obtained.

Example 2. (a) N- (4- phenylalanine butanoyl) -Phe-Pro-CH ₂ OH
(SUAM1233) N- (4-phenylbutanoyl) -Phe-P obtained in Example 1
ro-OMe (SUAM1232) (1.3 g) and sodium borohydride (460 mg) were added to tert-butyl alcohol (20 g).
ml) and heat and stir (80 ° C.). Then, anhydrous methanol (3.4 ml) was added dropwise under reflux, and after completion of the addition, the mixture was heated under reflux with stirring for 2 hours. The reaction solution was returned to room temperature, and water (several ml) was added under ice cooling to inactivate unreacted sodium borohydride. After distilling off methanol and tert-butyl alcohol under reduced pressure, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography using silica gel to obtain the target compound (1.2 g).
(Oil Compound) Instead of N- (4-phenylbutanoyl) -Phe-Pro-OMe as the starting compound in (a) above, (A) N- (4-
Phenylbutanoyl) -Met-Pro-OMe
(A ') N- (4-phenylbutanoyl) -Met-Pro-CH ₂ OH
(SU ′ 1344) was converted to (I ′) N- by using (I) N- (4-phenylbutanoyl) -norLeu-Pro-OMe.
(4-phenylbutanoyl) -norLeu-Pro-CH ₂ OH (SU
AM 1236), respectively.

(b) N- (4- phenylalanine butanoyl) -Pro-Pro-CH ₂ OH
(SUAM1230) N- (4-phenylbutanoyl) -Pro-P obtained in Example 1
ro-OMe (SUAM1229) (1.3 g) and sodium borohydride (510 mg) were added to tertiary butyl alcohol (20 g).
ml) and heat and stir (80 ° C.). Next, anhydrous methanol (3.8 ml) was added dropwise under reflux, and after completion of dropping, the mixture was heated under reflux with stirring for 2 hours. The reaction solution was returned to room temperature, and water (several ml) was added under ice cooling to inactivate unreacted sodium borohydride. After distilling off methanol and tert-butyl alcohol under reduced pressure, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography using silica gel to obtain the target compound (1.2 g) (oil compound).

In the above (b), N- (4-phenylbutanoyl) -Pr
By using (a) N- (2-phenylacetyl) -Pro-Pro-OMe instead of o-Pro-OMe, (a ′) N- (2
- phenylalanine _{acetyl) -Pro-Pro-CH 2 OH} (SUAM133
5) to (i) N- (3-phenylpropionyl) -Pro-Pr
By using o-OMe, (i ′) N- (3-phenylpropionyl) -Pro-Pro-CH ₂ OH (SUAM1338)
By using (U) N- (5-phenylpentanoyl) -Pro-Pro-OMe, (U ') N- (5-phenylpentanoyl) -Pro-Pro-CH ₂ OH (SUAM1341) is obtained. I was able to get each.

Example 3. (a) N- (4-phenylbutanoyl) -Phe-Pro-CHO (S
UAM1234) N- (4-phenylbutanoyl) -Phe-P obtained in Example 2
ro-CH ₂ OH (SUAM1233) (1.2 g) and TEA (1.6
ml) in anhydrous dimethyl sulfoxide (8 ml),
A solution of sulfur trioxide-pyridine complex (1.9 g) in dimethylsulfoxide (8 ml) was added with stirring. About 2 at room temperature
After stirring for 0 minutes, the mixture was poured into ice water (100 ml), extracted with ethyl acetate, washed with 10% citric acid solution, saturated saline solution, saturated sodium bicarbonate solution and saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography using silica gel to obtain the target compound. (800 mg) (oil compound) In the above (a), instead of N- (4-phenylbutanoyl) -Phe-Pro-CH ₂ OH as a raw material compound, (a) N-
By using (4-phenylbutanoyl) -Met-Pro-CH ₂ OH, (A ′) N- (4-phenylbutanoyl) -Met-Pr
By using o-CHO (SUAM1345) with (a) N- (4-phenylbutanoyl) -norLeu-Pro-CH ₂ OH
(I ') N- (4-phenylbutanoyl) -norLeu-Pro-CHO
(SUAM1333) could be obtained respectively.

(b) N- (4-phenylbutanoyl) -Pro-Pro-CHO (S
UAM1231) N- (4-phenylbutanoyl) -Pro-P obtained in Example 2
ro-CH ₂ OH (SUAM1230) (1.3g) and TEA (2.0
ml) in anhydrous dimethyl sulfoxide (8 ml),
A solution of sulfur trioxide-pyridine complex (2.3 g) in dimethylsulfoxide (8 ml) was added with stirring. About 2 at room temperature
After stirring for 0 minutes, the mixture was poured into ice water (100 ml), extracted with ethyl acetate, washed with 10% citric acid solution, saturated saline solution, saturated sodium bicarbonate solution and saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography using silica gel to obtain the target compound (700 mg) (oil compound).

In the above (b), N- (4-phenylbutanoyl) -Pr
instead of o-Pro-CH ₂ OH, by using (A) _{N-(2-phenylpropyl-acetyl) -Pro-Pro-CH 2 OH} (SUAM1335), ( A ') N-(2-phenyl Acetyl) -Pro-Pro-
By using CHO (SUAM1336) with (a) N- (3-phenylpropionyl) -Pro-Pro-CH ₂ OH,
(I ') N- (3-phenylpropionyl) -Pro-Pro-CHO
By using (SUAM1339) with (U) N- (5-phenylpentanoyl) -Pro-Pro-CH ₂ OH, (U ′)
N- (5-phenylpentanoyl) -Pro-Pro-CHO (SU
AM 1342) was obtained respectively.

Physicochemical data of the obtained compound are shown in Table 1. Each of the compounds shown in Table 1 was oily, carbon tetrachloride,
It is soluble in ether, chloroform, methylene chloride, ethyl acetate and methanol.

As a result of investigating the efficacy of the present compound for inhibiting the decomposition of Z-glycyl-prolyl-β-naphthylamide by prolyl endopeptidase, it showed a very strong anti-prolyl endopeptidase activity as shown in Example 4 below. It showed no inhibitory activity against proteinases such as papain, proline, trypsin, chymotrypsin, thermolysin and pepsin.

Further, the present compound thus obtained is novel and has an antiamnestic effect as shown in Example 5.

Example 4. Measurement of anti-prolyl endopeptidase activity The anti-prolyl endopeptidase activity was measured by Yoshimoto (T.
Yoshimoto and D. Tsuru, Agr. Biol. Chem. 42, 241
7, 1978) and the like. That is, 0.0025
M Z-glycyl-proline-β-naphthylamide 0.
A mixture containing 25 ml, 0.99 ml of 0.1 M phosphate buffer (pH 7.0) and 0.01 ml of the solution of the anti-prolyl endopeptidase compound of the present invention was heated in a test tube at 37 ° C. for 32 minutes, and then, 0.1 ml of prolyl endopeptidase solution (0.2 unit / ml) was added and reacted at 35 ° C. for 10 minutes.
Then Triton X-1 in 1M acetate buffer (pH 4.0)
2.0 ml of 00 (Triton X-100) solution was added so that the final concentration of the surfactant would be 10%, and the mixture was allowed to stand at room temperature for 15 minutes, and then the absorbance (a) at 410 nm was measured.

At the same time, the blind absorbance (b) was measured using only the buffer solution instead of the solution of the anti-prolyl peptidase compound, and the prolyl endopeptidase inhibition rate was calculated by the following formula: [(ba) / b] × 100. The amount required for 50% inhibition [IC ₅₀ ] was calculated. The test results are shown in Table 2.

Example 5. Measurement of Experimental Amnesia Preventive Effect of Scopolamine Using Rat (Intraperitoneal Administration) The antiprolyl endopeptidase compound of the present invention was examined for its effect of preventing long-term memory fixation inhibition by scopolamine. That is, physiological saline containing 20 μg / kg of the compound of the present invention was administered once to the abdominal cavity of each Wistar male rat (100 to 120 g).
After a while, perform passive avoidance learning by electric shock,
Immediately after that, 3 mg / kg of scopolamine was intraperitoneally administered.

The effect was determined by a passive avoidance test after 24 hours, in which a control animal group that was intraperitoneally administered with scopolamine and physiological saline without administration of the test compound was administered together with the test compound and scopolamine. For each animal group, the number of amnestic rats and non-amnestic rats was compared. The test results are shown in Table 3.

Example 6. Acute toxicity test with mouse CDF-1 male mouse (body weight 27.2 to 30.1 g)
(Purchased from abalone experimental animal) was used to examine the acute toxicity of the compound of the present invention.

As the drug solution, each compound was dissolved in DMSO, and 0.1 ml was intraperitoneally administered per mouse. Five mice were used for each administration group and observed at 24 hours and 48 hours after administration. The average dose of each compound is shown in Table 4.

As a result, with the above dose, after 24 and 48 hours,
All groups were healthy and no toxicity was observed.

The present invention also includes a pharmaceutical composition containing the compound of the present invention which is effective for ameliorating / treating the symptoms of organic disorders in the brain and a pharmaceutically acceptable adjuvant.

These active ingredients and pharmaceutical compositions are orally administered in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions. It is also used parenterally, for example as an injection and a suppository.

Auxiliary agents for solid dosage contained in the pharmaceutical composition include, for example, solid powder carriers, lactose, sucrose, dextrose, mannitol, sorbit, cellulose,
Examples include glycine.

Examples of lubricants include silicon dioxide, talc, magnesium stearate, polyethylene glycol, and binders such as starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone. Disintegrators include starch and agar.

The compound of the present invention is orally administered to an adult at a daily dose of usually 10 to 4000 mg, preferably 100 to 1000 mg, or parenterally at a dose of 1 to 2000 mg, preferably 50 to 500 mg. Administer. It is clear that the dose varies depending on the type of disease to be administered, the age of the patient, the body weight, the degree of symptoms, and the administration form.

Formulation Example 1. Active substance 10 parts Lactose 75 parts Heavy magnesium oxide 15 parts were uniformly mixed to give tablets and capsules.

Formulation example 2. Active substance 45 parts Starch 15 parts Lactose 40 parts were uniformly mixed to obtain powder and granules.

Formulation example 3. Active substance 1 part Surfactant 5 parts Physiological saline solution 94 parts were mixed by heating and sterilized to obtain an injection.

(Effects of the Invention) As described above, the compound according to the present invention exhibits remarkable anti-endoprolyl peptidase activity and anti-amnestic effect.
Further, the results of the acute toxicity test showed that even 500 mg / kg / mouse was not toxic, and the safety margin was sufficiently wide, and it is useful as a drug for the prevention and treatment of amnesia.

Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI technical display location // C12N 9/99 9161-4B (72) Inventor Ryuji Tanaka 1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka Prefecture No. 1 Suntory Co., Ltd. Applied Microbiology Laboratory (56) Reference JP-A-60-188317 (JP, A) JP-A-56-59714 (JP, A) JP-A-61-238776 (JP, A)

Claims (11)

[Claims] 1. A general formula: (In the formula, m represents an integer of 1 to 8, n represents an integer of 1 to 6, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, and a phenyl group. Or represents a methylthio group, or R ¹ and R ² together form a carbon
Represents a bond between nitrogens, R ³ is a lower alkyl ester group,
A dipeptide derivative having a hydroxymethyl group or a formyl group). 2. A general formula: (In the formula, m represents an integer of 1 to 8, n represents an integer of 1 to 6, R ⁴ represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group or a methylthio group, and R ³ Represents a lower alkyl ester group, a hydroxymethyl group or a formyl group). 3. A general formula: (Wherein, m represents an integer of 1 to 8 and R ³ represents a lower alkyl ester group, a hydroxymethyl group or a formyl group). 4. The compound according to claim 2, wherein R ⁴ is a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group or a methylthio group. 5. A patent in which R ³ is a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonyl group, a hydroxymethyl group or a formyl group. Claim 1st
The compound according to any one of items 1 to 3. 6. A general formula: [In the formula, m represents an integer of 1 to 8, A is a hydroxyl group, a halogen atom or a group: (Wherein m represents the same meaning as described above)] and a general formula: (In the formula, n represents an integer of 1 to 6, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms,
Represents a phenyl group or a methylthio group, or R ¹ and R
² together represents a carbon-nitrogen bond, and B represents a lower alkyl group) and is reacted in the presence of a base to give a compound of the general formula: (Wherein, m, n, R ¹ , R ² and B are as defined above) or an acyl peptide ester derivative, or is reacted in the presence of a base, then reduced and further oxidized. General formula to do: (Wherein m, n, R ¹ and R ² have the same meanings as described above, and R ³ represents a lower alkyl ester group, a hydroxymethyl group or a formyl group). 7. The dipeptide derivative has the general formula: (In the formula, m represents an integer of 1 to 8, n represents an integer of 1 to 6, R ⁴ represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group or a methylthio group, and R ³ Represents a lower alkyl ester group, a hydroxymethyl group or a formyl group). 8. The dipeptide derivative has the general formula: (In the formula, m represents an integer of 1 to 8 and R ³ represents a lower alkyl ester group, a hydroxymethyl group or a formyl group). 9. The method according to claim 6, wherein the base is a trialkylamine, an alkali metal hydroxide or an alkali metal carbonate. 10. A general formula: (In the formula, m represents an integer of 1 to 8, n represents an integer of 1 to 6, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, and a phenyl group. Or represents a methylthio group, or R ¹ and R ² together form a carbon
Represents a bond between nitrogens, R ³ is a lower alkyl ester group,
A prolyl endopeptidase activity inhibitor comprising a dipeptide derivative having a hydroxymethyl group or a formyl group) as an active ingredient. 11. A general formula: (In the formula, m represents an integer of 1 to 8, n represents an integer of 1 to 6, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, and a phenyl group. Or represents a methylthio group, or R ¹ and R ² together form a carbon
Represents a bond between nitrogens, R ³ is a lower alkyl ester group,
An antiamnestic agent containing a dipeptide derivative having a hydroxymethyl group or a formyl group) as an active ingredient.