JPH04235162A - Novel succinamide derivative and drug containing the same - Google Patents

Abstract

PURPOSE:To provide a novel highly safe succinamide derivative which is useful as a memory, cerebral circulation and cerebral metabolism-improving agent and which has an excellent prolyl endopeptidase-inhibiting action. CONSTITUTION:A succinamide derivative of formula I (R<1> is H, halogen; R<2> is H, lower alkyl; R<3> is carboxyl, lower alkoxycarbonyl, hydroxymethyl, formyl; m is 1,2; n is 0-2; X is methylene, S), e.g. 1-[3-[N-[(R,S)-indan-1-yl) carbamoyl]propionyl]-DL-prolinol. The compound of formula I is produced by reacting a compound of formula II with a compound of formula III.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to the following general formula (I)

00
02]

[Case 2]

(In the formula, R1 represents a hydrogen atom or a halogen atom, R2 represents a hydrogen atom or a lower alkyl group, R3 represents a carboxyl group, a lower alkoxycarbonyl group, a hydroxymethyl group, or a formyl group, and m represents 1
or an integer of 2, n represents an integer of 0 to 2, and X represents a methylene group or a sulfur atom. ) Novel succinic acid amide derivatives and memory/cerebral circulation/memories containing them
Regarding a brain metabolism improving agent.

0004

[Prior Art] With the arrival of an aging society, various senile dementias caused or caused by cerebrovascular disorders, cerebral circulation disorders, cerebral metabolic disorders, memory disorders, etc. have become social problems, and there are various ways to treat these diseases. The creation of useful therapeutic and preventive agents is desired. Recent clinical reports (M.F. Mazurek et al., Neu
According to Physiology, 36, 1133 (1986)), a significant decrease in peptides involved in memory and neurotransmission is observed in the brains of senile dementia patients.

[0005] Prolyl endopeptidase is an enzyme that decomposes proline-containing peptides, and inactivates vasopressin, thyrotropin-releasing hormone, neurotensin, etc., which are involved in memory and nerve transmission. For this reason, memory and learning tests have been conducted on inhibitors of this enzyme, and it is known that compounds that inhibit prolyl endopeptidase have an anti-amnestic effect (Japanese Patent Application Laid-open No. 62-201877, Japanese Pharmacological Journal , Nanri et al., 89, 323 (1987), same magazine, Hira, 89, 243 (1987)).

[0006]

[Problem to be solved by the invention] On the other hand, as therapeutic drugs for cerebrovascular disorders, cerebral circulation improving agents, cerebral vasodilators, cerebral metabolism improving agents, etc. are used clinically, but these drugs do not cause subjective symptoms. Although improvement has been observed in neurological symptoms and disorders of activities of daily living, the improvement rate is low. Therefore, there is a need for a drug that has both an effect of improving brain metabolism and an anti-amnestic effect by inhibiting prolyl endopeptidase.

[0007]

[Means for Solving the Problems] Prior to filing the present application, the present inventors filed an application for an amino acid imide derivative having an anti-amnestic effect (Japanese Unexamined Patent Publication No. 1-250370). We have conducted intensive research to create a novel memory, cerebral circulation, and brain metabolism improving agent that has both endopeptidase inhibitory effects and cerebral circulation/brain metabolism improving effects.
The present invention has now been completed.

In the present invention, "lower alkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, sec.
- means butyl, isobutyl, t-butyl. Compound (I) of the present invention can be produced as follows.

[0009]

[Chemical formula 3]

(In the formula, R1, R2, R3, m, n
and X have the same meanings as above, and B represents a halogen atom, a hydroxyl group or a lower alkoxy group. )

That is, a compound of general formula (II) and a compound of general formula (
Compound (I) of the present invention is obtained by reacting the cyclic amino acid compound (III). Among the compounds of general formula (II),
When B is a halogen atom or a lower alkoxy group, it can be condensed with the compound of general formula (III) in the presence or absence of a base. Moreover, when B is a hydroxyl group, it is preferable to use carbodiimides as a condensing agent.

Examples of the base used in the reaction include alkali metal hydroxides or carbonates, trialkylamines, aromatic amines, etc. For example, sodium hydroxide, potassium hydroxide, etc. are preferable, and carbodiimides include 1-
Ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), and the like are preferred. Any solvent may be used as long as it does not participate in the reaction, but preferably methylene chloride, chloroform, tetrahydrofuran, dioxane, etc. are used, and the reaction temperature is -2
The temperature is 0 to 200°C, preferably -20 to 80°C, and more preferably 0 to 40°C.

Other methods, such as the acid chloride method and the mixed acid anhydride method, which are commonly used (Basics and Experiments of Peptide Synthesis, Izumiya et al., Maruzen (1985)) may also be used. Furthermore, when R3 in general formula (I) is a carboxyl group, it can also be produced by hydrolyzing the corresponding ester group with an acid or alkali, and when R3 is a formyl group, it can be produced using a corresponding hydroxymethyl group. It can also be produced by oxidizing. The oxidation method may be any conventional reaction that oxidizes alcohol to aldehyde, for example, a method using a mixture of dimethyl sulfoxide (DMSO) and its activating reagent, preferably a mixture of DMSO and a sulfur trioxide pyridine complex. A method of reacting is used. The cyclic amino acid derivative (III) of the starting compound is DL form, D
When the compound (I) of the present invention is in the DL form, D form, or L form, the corresponding DL form, D form, or L form is produced. The following compounds are representative of the compound (I) of the present invention thus obtained.

・1-{3-[N-((R,S)-indan-1-yl)carbamoyl]propionyl}-DL-
Prolinal 1-{3-[N-((R,S)-indan-1-yl)carbamoyl]propionyl}-D-prolinal
1-{3-[N-((R)-indan-1-yl)carbamoyl]propionyl}-DL-prolinal 1-
{3-[N-((S)-indan-1-yl)carbamoyl]propionyl}-L-prolinal 1-{3-
[N-((R,S)-5-chloroindan-1-yl)
Carbamoyl]propionyl}-L-prolinol 1-{3-[N-((R,S)-5-chloroindan-1-yl)carbamoyl]propionyl}-L-prolinal 1-{3-[N -Methyl-N-((R,S)-indan-1-yl)carbamoyl]propionyl}-DL-
Prolinal 3-{3-[N-((R,S)-indan-1-yl)carbamoyl]propionyl}-DL-thioprolinal 3-{3-[N-((R)-indan-1-yl) ) Carbamoyl]propionyl}-L-thioprolinal.
3-{3-[N-((R)-indan-1-yl)carbamoyl]propionyl}-DL-thioprolinal.
1-{3-[N-((R,S)-indan-1-ylmethyl)carbamoyl]propionyl}-DL-prolinol 3-{3-[N-((R)-indan-1-ylmethyl) Carbamoyl]propionyl}-L-thioprolinal 3-{3-[N-((S)-indan-1-ylmethyl)carbamoyl]propionyl}-L-thioprolinal 3-{3-[N-((R,S )-indan-1-ylmethyl)carbamoyl]propionyl}-DL-thioprolinol 3-{3-[N-methyl-N-((S)-indan-
1-ylmethyl)carbamoyl]propionyl}-L-
Prolinal・1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-L-proline・1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-DL-proline・1-{3-[N-((R,S)-5-chloroindan-2-yl)carbamoyl]propionyl}-L-prolinal 1-{3-[N-methyl-N-(indan-2- il)carbamoyl]propionyl}-L-prolinal.
3-{3-[N-(indan-2-yl)carbamoyl]propionyl}-L-thioproline 3-{3-[N
-(Indan-2-yl)carbamoyl]propionyl}-L-thioproline ethyl ester 3-{3-[N
-(Indan-2-yl)carbamoyl]propionyl}-L-thioprolinol 3-{3-[N-(indan-2-yl)carbamoyl]propionyl}-L-thioprolinal 3-{3-[N -(Indan-2-yl)carbamoyl]propionyl}-DL-thioproline 3-{3-[N-(indan-2-yl)carbamoyl]propionyl}-DL-thioproline methyl ester 3-{3-[ N-(indan-2-yl)carbamoyl]propionyl}-DL-thioprolinol 3-{
3-[N-(indan-2-yl)carbamoyl]propionyl}-DL-thioprolinal 3-{3-[N
-((R,S)-5-chloroindan-2-yl)carbamoyl]propionyl}-L-thioprolinal 1-{3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-D-prolinal 1-{
3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-DL-prolinal 1-{3-[
N-((R,S)-5-chloroindan-2-ylmethyl)carbamoyl]propionyl}-D-prolinal 1-{3-[N-((R,S)-5-chloroindan-2-ylmethyl) ) Carbamoyl]propionyl}-D
L-prolinal 3-{3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-DL-thioproline 3-
{3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-DL-thioproline ethyl ester・3-{3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-DL-thioprolinol・
3-{3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-DL-thioprolinal 3
-{3-[N-((R,S)-5-chloroindan-2
-ylmethyl)carbamoyl]propionyl}-L-thioprolinal 3-{3-[N-((R)-5-chloroindan-2
-ylmethyl)carbamoyl]propionyl}-L-thioprolinal 1-{3-[N-((R,S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-L-pro Linole 1-{3-[N-((R,S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-L-prolinal 3-{3-[N-( (R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-DL-thioprolinal 3-{3-[N-((R)-1,2,3,4-tetrahydro Naphthalen-1-ylmethyl)carbamoyl]propionyl}-L-thioprolinol 3-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)carbamoyl]propionyl}- L-thioprolinal 1-{3-[N-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-proline 1-{3-[N-( (S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-proline ethyl ester 1-{3-[N-((S)-1,2,3,4 -tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-prolinal 1-{3-[N-((R,S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl }-D-prolinal 1-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-DL-proline 1-{3-[N -((R)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-DL-proline methyl ester 1-{3-[
N-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-DL-
Prolinol 1-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-DL-prolinal 1-{3-[N-methyl- N-((S)-1,2,3
,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-prolinal 1-{3-[
N-Methyl-N-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-prolinal 1-{3-[N-methyl-N
-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-prolinol 1-{3-[N-methyl-N-((S)-1
,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-DL-prolinal 3
-{3-[N-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-thioproline 3-{3-[N-((S)-1 ,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-thioproline ethyl ester 3-{3-
[N-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-
Thioprolinol 3-{3-[N-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-thioprolinal 3-{3-[N-( (R)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-DL-thioproline 3-{3-[N-((R)-1,2,3,4-tetrahydro naphthalen-2-yl)carbamoyl]propionyl}-DL-thioproline methyl ester 3-{3
-[N-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-D
L-thioprolinol 3-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-DL-thioprolinal 3-{3-[N -((R)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-thioprolinal 1-{3-[N-((S)-1,2,3,4 -tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-DL-prolinal 1-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}- D-prolinal 1-{3-[N-methyl-N-((S)-1,2,3
,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-L-prolinal 3-{
3-[N-((S)-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-DL-thioproline 3-{3-[N-((S)-1,2 ,3,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-DL-thioproline ethyl ester 3
-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-L-thioprolinol 3-{3-[N-((R) -1,2,3,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-L-thioprolinal

The compound (I) of the present invention thus obtained is:
As described below, it has an excellent prolyl endopeptidase inhibitory effect and is highly safe, so it is useful as an agent for improving memory, cerebral circulation, and brain metabolism.

The compound (I) of the present invention can be formulated into a preparation for oral or parenteral administration by incorporating pharmaceutically acceptable adjuvants. For preparations for oral administration, the above compound may be mixed with suitable additives, such as excipients such as lactose, mannitol, corn starch, and crystalline cellulose, binders such as cellulose derivatives, gum arabic, and gelatin, and carboxymethylcellulose calcium, etc. By appropriately combining with a disintegrant, talc, a lubricant such as magnesium stearate, etc., it can be made into tablets, powders, granules, and capsules. In addition, these solid preparations are hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate,
Enteric-coated preparations can be made using coating bases such as cellulose acetate phthalate and methacrylate copolymers. As preparations for parenteral administration, for example, solutions for injection can be prepared by combining water, ethanol, glycerin, conventional surfactants, etc., and suppositories can be prepared using a base for suppositories. The dosage varies depending on age, body weight, symptoms, therapeutic effects, administration method, and administration period, but usually, in the case of oral administration, the dosage range is 1 to 2000 mg/day, preferably 10 to 200 mg/day. Administer in 3 doses.

[0017]

[Action] Brain-derived prolyl endopeptidase is Yos
The method of himoto et al. (J.Biochem., 94,
325 (1983)) from dog brain. The buffer described below was used in this measurement. Buffer A: 20mM Tris-HCl buffer (pH 7.0)
Buffer B: 0.1% gelatin, 1mM EDTA, 1
Buffer A containing mM 2-mercaptoethanol prolyl endopeptidase was diluted with Buffer B to a concentration of 0.4 units/ml to prepare an enzyme solution. Buffer A940μ
50 μl of the enzyme solution was added to the tube and heated at 37° C. for 10 minutes. 10 μl of a solution of the test compound dissolved in dimethyl sulfoxide was added, mixed with stirring, and then heated at 37° C. for 10 minutes. Add 100 μl of carbobenzoxyglycylprolyl paranitroanilide dissolved in 40% dioxane to a concentration of 2.5 mM, and react at 37° C. for 10 minutes.
100μ of 50% acetic acid containing 10% Triton X-100
1 was added to stop the reaction. In addition, as a control, the same amount (10 μl) of dimethyl sulfoxide was used instead of the test compound solution.
In addition, in a blind test, the same operation was carried out by adding the same amount of dimethyl sulfoxide instead of the test compound and the same amount of buffer B instead of the enzyme solution. The absorbance at 410 nm was measured using a spectrophotometer, and the value obtained by subtracting the blind value from each measurement value was defined as the enzyme activity. Prolyl endopeptidase inhibition strength (IC50 value) is 50% of control enzyme activity.
It was determined as the concentration (M) of each test compound that inhibits. The results are shown in Table 1 below.

[0018]

[Table 1]

As is clear from Table 1, the compound of the present invention (
I) is JP-A-62-201 used as a control compound in brain-derived prolyl endopeptidase inhibitory activity.
It was superior to the compound described in Publication No. 877.

<Toxicity test> ICR mice (Charles River), 4 to 5 weeks old, were used in groups of 10 mice. After suspending the compounds of Examples 1, 4, 5, 6, 8, 9, 10, 16 and 17 in 10% gum arabic, 3
The drug was administered intraperitoneally at a dose of 00 mg/kg and observed for 7 days. As a result, no deaths were observed under the above conditions.

[0021]

EXAMPLES The present invention will be explained in more detail below with reference to Reference Examples and Examples, but the present invention is not limited thereto. A manufacturing intermediate of the compound (I) of the present invention is shown as a reference example. Reference Example 1 3-[N-((R,S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionic acid

[0022]

[C4]

2-amino-(R,S)-1,2,3,4
-Tetrahydronaphthalene hydrochloride (1.4 g) was suspended in methylene chloride (40 ml), and triethylamine (0.85 g) was added while stirring at room temperature. After 30 minutes, succinic anhydride (0.85 g) was added, and after stirring for 3 hours, methylene chloride (20 ml) was added and washed with 10% hydrochloric acid (20 ml). After further extracting the aqueous layer with ethyl acetate (50 ml), the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from a mixture of ethyl acetate and isopropyl ether. 1.77g of the compound was obtained. Yield 94%. Melting point: 143-144℃

Reference Examples 2 to 12 Compounds of Reference Examples 2 to 12 shown in Table 2 were produced according to the method of Reference Example 1. In addition, the compound names of Reference Examples 2 to 12 are shown below.

Reference example 2 3-[N-((R,S)-indan-1-yl)carbamoyl]propionic acid Reference example 3 3-[N-(indan-2-yl)carbamoyl]propionic acid Reference example 4 3-[N-((R,S)-indan-1-ylmethyl)
Carbamoyl]propionic acid reference example 5 3-[N-(indan-2-ylmethyl)carbamoyl]propionic acid reference example 6 3-[N-((R)-tetralin-1yl)carbamoyl]propionic acid reference example 7 3- [N-((S)-tetralin-2-yl)carbamoyl]propionic acid Reference Example 8 3-[N-((R,S)-tetralin-1-ylmethyl)carbamoyl]propionic acid Reference Example 9 3-[N -((R)-tetralin-2-ylmethyl)carbamoyl]propionic acid Reference Example 10 3-[N-((S)-tetralin-2-ylmethyl)carbamoyl]propionic acid Reference Example 11 3-[N-((R ,S)-5-chloroindan-2-ylmethyl)carbamoyli]propionic acid Reference Example 12 3-[N-(N-methyl-(R,S)-indan-1-
carbamoyl]propionic acid

[0026]

[Table 2]

Example 1 1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-L-proline methyl ester

00
28]

[C5]

2.33 g of 3-[N-(indan-2-yl)carbamoyl]propionic acid was added to 30 m of methylene chloride.
2.3 g of WSC·HCl was added at room temperature and stirred for 5 minutes. Add 1.66 g of L-proline methyl ester hydrochloride and 1.52 ml of triethylamine to this solution.
was added and stirred at room temperature for 1 hour. Add 30 ml of methylene chloride to the reaction mixture, add 20 ml of 10% hydrochloric acid, and 20 ml of water.
, 20 ml of saturated sodium bicarbonate solution and 20 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Methylene chloride was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-
Hexane = 2:1) to give the title compound as an oil.
38g was obtained. Yield 69%. MS (m/z): 344 (M+) IR (neat) cm-1: 3280, 2940, 17
40,1655,1625,1550,1435,11
95,1170 NMR (CDCl3) δ: 1.90-2.74 (8H
, m), 2.75~2.83 (2H, m), 3.24~
3.33 (2H, m), 3.51-3.75 (2H, m
), 3.69 (3H, s), 4.43-4.48 (1H
, m), 4.64~4.77 (1H, m), 6.34~
6.48 (1H, br), 7.13-7.24 (4H,
m)

Example 2 1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-L-prolinol

[0031]

[C6]

1.63 g of 3-[N-(indan-2-yl)carbamoyl]propionic acid was added to 20 m of methylene chloride.
1.61 g of WSC.HCl was added at room temperature and stirred for 5 minutes. A solution of 0.71 g of L-prolinol dissolved in 5 ml of methylene chloride was added to this solution and stirred for 1 hour. After the reaction is complete, add 20 ml of methylene chloride, add 30 ml of 10% hydrochloric acid and 3 ml of saturated sodium bicarbonate solution.
0 ml and 30 ml of saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and crystallization was performed from isopropyl ether to obtain 1.63 g of colorless crystals of the title compound. Yield 74%. Melting point: 98-100°C MS (m/z): 316 (M+) IR (KBr) cm-1: 3400, 3230, 295
0,1645,1610,1550,1445,126
0,1050 NMR (CDCl3) δ: 1.54-1.66 (1H
, m), 1.80-2.07 (3H, m), 2.47 (
2H, d, J = 6Hz), 2.59 (2H, d, J = 7
Hz), 2.79 (2H, dd, J=5Hz, 16Hz
), 3.24-3.32 (2H, m), 3.44-3.
67 (4H, m), 4.03-4.15 (1H, m),
4.60-4.71 (1H, m), 4.83 (1H, d
d, J = 3Hz, 8Hz), 6.34-6.52 (1H
, br), 7.10 to 7.19 (4H, m) The compound of this example is the 1-{3-[N-(indan-2-yl)carbamoyl]propionyl}- obtained in Example 1. It can also be obtained by reducing L-proline methyl ester by a conventional method.

Example 3 1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-DL-proline methyl ester

0
034]

[C7]

3.55 g of 3-[N-(indan-2-yl)carbamoyl]propionic acid and 2.33 g of 1-hydroxybenzotriazole were suspended in 50 ml of methylene chloride, and after stirring at room temperature for 5 minutes, 2.2 g of triethylamine was added.
ml was added and dissolved. After stirring for 30 minutes, 2.52 g of DL-proline methyl ester was added and further stirred for 1 hour. After the reaction was completed, the mixture was washed successively with 30 ml of 10% hydrochloric acid, 30 ml of saturated sodium bicarbonate solution, and 30 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=19:1) to obtain 3.48 g of colorless crystals of the title compound. Yield 66%. Melting point: 128-129°C MS (m/z): 344 (M+) IR (KBr) cm-1: 3260, 1740, 162
5,1560,1435,1275 NMR (CDCl3) δ: 1.82-2.21 (4H
, m), 2.33-2.72 (4H, m), 2.79 (
2H, dd, J=5Hz, 16Hz), 3.24-3.
33 (2H, m), 3.48-3.65 (2H, m),
3.69 (3H, s), 4.40-4.46 (1H, m
), 4.60-4.72 (1H, m), 6.20-6.
40 (1H, br), 7.13-7.22 (4H, m)

Example 4 1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-DL-prolinol

[0037]

[Chemical formula 8]

1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-DL- obtained in Example 3
Dissolve 1.38 g of proline methyl ester in 6 ml of tetrahydrofuran and 6 ml of methanol, and
0.76 g of 80% methanol solution was added dropwise under ice cooling. After stirring at room temperature for 1 hour, 1 ml of acetic acid was added, and the mixture was concentrated under reduced pressure. Add 100ml of ethyl acetate to the residue, and add 20ml of 1N hydrochloric acid.
1, 30 ml of saturated sodium bicarbonate solution, and 30 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the title compound was purified by silica gel column chromatography (chloroform) and crystallized from isopropyl ether.
I got g. Yield 72%. Melting point: 111-113°C MS (m/z): 316 (M+) IR (KBr) cm-1: 3420, 3250, 164
5,1610,1545,1440 NMR (CDCl3) δ: 1.55-2.07 (4H
, m), 2.49 (2H, d, J=6Hz), 2.62
(2H, d, J = 7Hz), 2.79 (2H, dd, J
=5Hz, 21Hz), 3.25-3.33 (2H, m
), 3.42-3.70 (4H, m), 4.03-4.
19 (1H, m), 4.61-4.88 (2H, m),
5.00-6.10 (1H, m), 6.10-6.35
(1H, m), 7.10-7.22 (4H, m)

Example 5 1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-L-prolinal

[0040]

[Chemical formula 9]

0.90 g of 1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-L-prolinol obtained in Example 2 was dissolved in 6 ml of dimethyl sulfoxide, and 1.2 ml of triethylamine was added. Next, a solution of 1.36 g of sulfur trioxide/pyridine dissolved in 6 ml of dimethyl sulfoxide was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After the reaction is complete, pour into ice water and add 30 ml of ethyl acetate.
Extracted twice. The organic layer was washed successively with 30 ml of 10% citric acid solution and 30 ml of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was crystallized by adding isopropyl ether, and recrystallized from a mixture of ethyl acetate and isopropyl ether to obtain the title compound 0.
．． 47g was obtained. Yield 52%. Melting point: 135-137°C MS (m/z): 314 (M+) IR (KBr) cm-1: 3260, 2955, 173
0,1635,1550,1440,1265NMR(
CDCl3) δ: 1.90-2.04 (4H, m),
2.47-2.52 (2H, m), 2.63-2.83
(4H, m), 3.29 (2H, dd, J=7Hz, 1
6Hz), 3.53-3.64 (2H, m), 4.38
~4.42 (1H, m), 4.62 ~ 4.74 (1H,
m), 6.10~6.27 (1H, br), 7.15~
7.23 (4H, m), 9.46 (1H, d, J=2H
z)

Example 6 1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-DL-prolinal

[0043]

[Chemical formula 10]

1-{3-[N-(indan-2-yl)carbamoyl]propionyl}-DL- obtained in Example 4
1.95 g of prolinol and 12 m of dimethyl sulfoxide
1.87 g of triethylamine was added and stirred. A solution of 2.94 g of sulfur trioxide/pyridine dissolved in 12 ml of dimethyl sulfoxide was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted four times with 30 ml of ethyl acetate, and the organic layer was extracted with 30 ml of 10% citric acid solution,
It was washed successively with 30 ml of saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue to obtain 0.60 g of crystals of the title compound. Yield 31%. Melting point: 140-142°C MS (m/z): 314 (M+) IR (KBr) cm-1: 3240, 2945, 172
5,1630,1550,1435,1260NMR(
CDCl3) δ: 1.82 to 2.06 (4H, m),
2.45-2.50 (2H, m), 2.61-2.66
(2H, m), 2.78 (2H, dd, J=5Hz, 1
6Hz), 3.26 (2H, dd, J=7, 16H
z), 3.53-3.62 (2H, m), 4.28-4
．． 32 (1H, m), 4.59-4.71 (1H, m)
, 6.50-6.66 (1H, br), 7.12-7.
21 (4H, m), 9.38 (1H, d, J=2Hz)

Example 7 1-{3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-L-prolinol

0046
]

[Chemical formula 11]

3-[N-(indan-2-ylmethyl)
0.84 g of [carbamoyl]propionic acid was dissolved in 25 ml of methylene chloride, and WSC/HCl 66 was added under stirring at room temperature.
0 mg was added. A solution of 0.35 g of L-prolinol dissolved in 1 ml of methylene chloride was added under ice cooling, and the mixture was stirred for 2 hours. Add 50ml of methylene chloride and add 30ml of 10% hydrochloric acid.
1 and 30 ml of saturated sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (methylene chloride:methanol=24:1) to obtain 1.0 g of the title compound as an oil. Yield 89%. MS (m/z): 330 (M+) IR (neat) cm-1: 3300, 2925, 16
40-1610, 1525, 1440, 1260, 10
45NMR (CDCl3) δ: 1.55-1.68 (
1H, m), 1.80-2.05 (4H, m), 2.5
0-2.55 (2H, m), 2.60-2.70 (5H
, m), 3.00-3.08 (2H, m), 3.33 (
2H, t, J=6Hz), 3.45-3.70 (3H,
m), 4.06-4.20 (1H, m), 4.81-4
．． 85 (1H, m), 6.23-6.38 (1H, br
), 7.10-7.20 (4H, m)

Examples 8 to 33 Compounds of Examples 8 to 33 shown below were produced according to any of the methods of Examples 1 to 7, and by appropriately selecting the compounds of Reference Examples.

Example 8 1-{3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-L-prolinal (Example 5
method)

[0050]

[Chemical formula 12]

Yield: 50% (oil) MS (m/z): 342 (M+) IR (CHCl3) cm-1: 3450, 3320,
1730, 1650, 1620 NMR (CDCl3) δ: 1.36-1.49 (1H
, m), 1.85-2.08 (6H, m), 2.45 (
1H, dd, J=10Hz, 17Hz), 2.55~2
．． 63 (2H, m), 2.69-2.74 (2H, m)
, 2.77-2.88 (3H, m), 3.18-3.3
3 (2H, m), 4.36-4.43 (1H, m), 4
．． 52-4.68 (2H, m), 6.33-6.44 (
1H, br), 7.07 (4H, s), 9.48 (1H
, d, J=2Hz)

Example 9 3-{3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-L-thioprolinal (according to the method of Example 5)

[0053]

[Chemical formula 13]

Yield: 60% (oil) MS (m/z): 346 (M+) IR (CHCl3) cm-1: 3450, 1735,
1660-1650 NMR (CDCl3) δ: 2.40-2.68 (6H
, m), 2.70-2.80 (1H, m), 2.35-
2.95 (6H, m), 4.62 (1H, d, J=8H
z), 4.67 (1H, d, J=8Hz), 4.75~
4.87 (1H, m), 5.95-6.10 (1H, b
r), 7.11-7.20 (4H, m), 9.49 (1
H,s)

Example 10 1-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-L-prolinal (according to the method of Example 5) )

[0056]

[Chemical formula 14]

Yield: 50% (oil) MS (m/z): 342 (M+) IR (CHCl3) cm-1: 3450, 3350,
1730, 1655, 1630 NMR (CDCl3) δ: 1.32-1.49 (1H
, m), 1.85-2.08 (6H, m), 2.45 (
1H, dd, J=10Hz, 16Hz), 2.55~2
．． 63 (2H, m), 2.69-2.74 (2H, m)
, 2.77-2.88 (3H, m), 3.18-3.3
3 (2H, m), 3.52-3.68 (2H, m), 4
．． 36-4.43 (1H, m), 6.33-6.44 (
1H, br), 7.07 (4H, s), 9.48 (1H
, d, J=2Hz)

Example 11 1-{3-[N-((S)-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-L-prolinal (according to the method of Example 5) )

[0059]

[Chemical formula 15]

Yield: 50% (oil) MS (m/z): 342 (M+) IR (CHCl3) cm-1: 3450, 3300,
1730, 1655, 1630 NMR (CDCl3) δ: 1.30-1.48 (1H
, m), 1.82-2.07 (6H, m), 2.45 (
1H, dd, J=10Hz, 16Hz), 2.53~2
．． 63 (2H, m), 2.66-2.88 (5H, m)
, 3.14-3.33 (2H, m), 3.50-3.6
8 (2H, m), 4.32-4.46 (1H, m), 6
．． 22-6.36 (1H, br), 7.08 (4H, s
), 9.48 (1H, d, J = 2Hz)

Example 12 1-{3-[N-((R,S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-prolinal (method of Example 5) )

[0062]

[Chemical formula 16]

Yield: 45% (amorphous) MS (m/
z):328(M+)IR(CHCl3)cm-1:3425,1730,
1650, 1630 NMR (CDCl3) δ: 1.66-1.82 (2H
, m), 1.87~2.12 (4H, m), 2.24~
2.77 (5H, m), 2.80-2.94 (2H, m
), 3.09 (1H, dd, J=5Hz, 16Hz),
3.50-3.70 (2H, m), 4.16-4.27
(1H, m), 4.37-4.50 (1H, m), 6.
00-6.18 (1H, br), 7.03-7.13 (
4H, m), 9.47 (1H, d, J=2Hz)

Example 13 1-{3-[N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-L-prolinal (according to the method of Example 5) )

0
065]

[Chemical formula 17]

Yield: 43% Melting point: 119-121°C MS (m/z): 328 (M+) IR (KBr) cm-1: 3300, 3200, 172
0,1640,1540 NMR (CDCl3) δ: 1.50-1.60 (1H
, m), 1.63~2.05 (7H, m), 2.50~
2.62 (2H, m), 2.65-2.83 (4H, m
), 3.50-3.71 (2H, m), 4.36-4.
41 (1H, m), 5.12-5.20 (1H, m),
6.15-6.24 (1H, br), 7.00-7.2
4 (4H, m), 9.38 (1H, d, J=2Hz)

Example 14 1-{3-[N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-D-prolinal (according to the method of Example 5) )

0
068]

[Chemical formula 18]

Yield: 48% Melting point: 130-134°C MS (m/z): 328 (M+) IR (KBr) cm-1: 3300, 3200, 172
0,1630,1540 NMR (CDCl3) δ: 1.50-1.60 (1H
, m), 1.62~2.10 (7H, m), 2.56~
2.80 (6H, m), 3.55-3.70 (2H, m
), 4.40-4.52 (1H, m), 5.10-5.
20 (1H, m), 6.15-6.20 (1H, br)
, 7.10-7.24 (4H, m), 9.47 (1H,
d, J=2Hz)

Example 15 1-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-L-prolinal (according to the method of Example 5) )

0
071]

[Chemical formula 19]

Yield: 21% Melting point: 130-135°C MS (m/z): 328 (M+) IR (KBr) cm-1: 3300, 3200, 174
0,1640,1540 NMR (CDCl3) δ: 1.50-1.60 (1H
, m), 1.62~2.08 (7H, m), 2.55~
2.81 (6H, m), 3.55-3.70 (2H, m
), 4.33-4.42 (1H, m), 5.10-5.
20 (1H, m), 6.20-6.23 (1H, m),
7.05-7.24 (4H, m), 9.47 (1H, d
, J=2Hz)

Example 16 1-{3-[N-((R,S)-indan-1-ylmethyl)carbamoyl]propionyl}-L-prolinal (according to the method of Example 5)

[0074]

[C20]

Yield: 36% (amorphous) MS (m/
z):328(M+)IR(neat)cm-1:3400-3200,17
40,1640,1520 NMR (CDCl3) δ: 1.68-1.85 (1H
, m), 1.86~2.10 (4H, m), 2.15~
2.36 (1H, m), 2.42-2.70 (4H, m
), 2.74-3.02 (2H, m), 3.23-3.
42 (2H, m), 3.45-3.60 (3H, m),
4.30-4.42 (1H, m), 6.00-6.14
(1H, br), 7.15-7.26 (4H, m), 9
．． 47-9.48 (1H, m)

Example 17 1-{3-[N-((R,S)-5-chloroindan-
2-ylmethyl)carbamoyl]propionyl}-L-
Prolinal (according to the method of Example 5)

[0077]

[C21]

Yield: 67% Melting point: 94-97°C MS (m/z): 362 (M+) IR (KBr) cm-1: 3500-3100,174
0,1610,1580 NMR (CDCl3) δ: 1.90-2.12 (4H
, m), 2.48~2.75 (7H, m), 2.90~
3.10 (2H, m), 3.25-3.33 (2H, m
), 3.55-3.64 (2H, m), 4.38-4.
45 (1H, m), 6.20-6.34 (1H, br)
, 7.08-7.15 (3H, m), 9.45 (1H,
d, J=2Hz)

Example 18 1-{3-[N-((R,S)-indan-1-yl)
Carbamoyl]propionyl}-L-prolinal (according to the method of Example 5)

[0080]

[C22]

Yield: 17% (amorphous) MS (m/
z): 314 (M+) IR (KBr) cm-1: 3280, 2930, 173
0,1630,1540,1440 NMR (CDCl3) δ: 1.70-2.10 (5H
, m), 2.50~3.05 (7H, m), 3.45~
3.62 (2H, m), 4.30-4.40 (1H, m
), 5.43 (1H, m), 6.45-6.55 (1H
, m), 7.15~7.30 (4H, m), 9.38~
9.59 (1H, m)

Example 19 1-{3-[N-((R,S)-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)carbamoyl]
propionyl}-L-prolinal (according to the method of Example 5)

[0083]

[C23]

Yield: 42% (oil) MS (m/z): 342 (M+) IR (neat) cm-1: 3320, 2930, 17
25,1625,1540,1435 NMR (CDCl3) δ: 1.69-2.28 (8H
, m), 2.55~2.74 (6H, m), 2.90~
3.05 (1H, m), 3.35-3.58 (4H, m
), 4.30-4.50 (1H, m), 6.45-6.
69 (1H, m), 7.10-7.22 (4H, m),
9.43 (1H, s)

Example 20 1-{3-[N-methyl-N-((R,S)-indan-1-yl)carbamoyl]propionyl}-L-prolinal (according to the method of Example 5)

[0086]

[C24]

Yield: 36% (oil) MS (m/z): 328 (M+) IR (neat) cm-1: 2940, 1725, 16
35,1435,745 NMR (CDCl3) δ: 1.88-2.44 (6H
, m), 2.61~3.01 (9H, m), 3.64~
3.73 (2H, m), 4.40-4.65 (1H, m
), 5.56 (0.5H, t, J=8Hz), 6.27
(0.5H, t, J=8Hz), 7.09~7.28(
4H, m), 9.51 (1H, s)

Example 21 3-{3-[N-(indan-2-ylmethyl)carbamoyl]propionyl}-L-thioprolinol (according to the method of Example 2)

[0089]

[C25]

Yield: 86% (oil) MS (m/z): 348 (M+) IR (CHCl3) cm-1: 3450, 3350,
1660-1640, 1520, 1420 NMR (CDCl3) δ: 2.40-2.74 (6H
, m), 2.88~3.20 (4H, m), 3.20~
3.39 (2H, m), 3.57-3.77 (2H, m
), 4.20-4.86 (3H, m), 6.30-6.
57 (1H, br), 7.08-7.23 (4H, m)

Example 22 1-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-L-prolinol (using the method of Example 2) Compliant)

[0092]

[C26]

Yield: 88% (oil) MS (m/z): 344 (M+) IR (CHCl3) cm-1: 3320, 1650,
1620, 1440 NMR (CDCl3) δ: 1.32-1.48 (1H
, m), 1.55-1.68 (1H, m), 1.79-
2.07 (5H, m), 2.38-2.61 (3H, m
), 2.62-2.70 (2H, m), 2.75-2.
90 (3H, m), 3.21-3.30 (2H, m),
3.45-3.71 (4H, m), 4.10-4.22
(1H, m), 6.32-6.44 (1H, br), 7
．． 07 (4H, s)

Example 23 1-{3-[N-((S)-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)carbamoyl]propionyl}-L-prolinol (using the method of Example 2) Compliant)

[0095]

[C27]

Yield: 60% (oil) MS (m/z): 344 (M+) IR (neat) cm-1: 3400, 3300, 16
40,1620 NMR (CDCl3) δ: 1.34-1.49 (1H
, m), 1.57~1.70 (1H, m), 1.79~
2.09 (5H, m), 2.38-2.61 (3H, m
), 2.61-2.73 (2H, m), 2.75-2.
90 (3H, m), 3.20-3.37 (2H, m),
3.43-3.72 (5H, m), 4.11-4.23
(1H, m), 6.32-6.48 (1H, br), 7
．． 07 (4H, s)

Example 24 1-{3-[N-((R,S)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl]propionyl}-L-prolinol (of Example 2) method)

[0098]

[C28]

Yield: 85% (amorphous) MS (m/
z): 330 (M+) IR (CHCl3) cm-1: 3425, 1650,
1610,1510 NMR (CDCl3) δ: 1.58-2.09 (6H
, m), 2.49~2.56 (2H, m), 2.62~
2.75 (3H, m), 2.88 (2H, t, J=6H
z), 3.06-3.13 (1H, m), 3.48-3
．． 61 (3H, m), 3.63-3.72 (1H, m)
, 4.13-4.31 (2H, m), 4.83-4.8
8 (1H, m), 6.00-6.12 (1H, br),
7.01-7.14 (4H, m)

Example 2
5 1-{3-[N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-L-prolinol (according to the method of Example 2)

0
101]

[C29]

Yield: 60% (amorphous) MS (m/
z): 330 (M+) IR (neat) cm-1: 3400, 3200, 16
20,1520 NMR (CDCl3) δ: 1.50-1.60 (1H
, m), 1.62~2.08 (7H, m), 2.52~
2.78 (4H, m), 2.79-2.83 (2H, m
), 3.50-3.70 (4H, m), 4.16-4.
20 (1H, m), 4.89-4.93 (1H, m),
5.10-5.20 (1H, m), 6.15-6.24
(1H, br), 7.05-7.24 (4H, m)

Example 26 1-{3-[N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-D-prolinol (using the method of Example 2) Compliant)

0
104]

[C30]

Yield: 67% (amorphous) MS (m/
z): 330 (M+) IR (neat) cm-1: 3400, 3200, 16
20,1520 NMR (CDCl3) δ: 1.50-1.60 (1H
, m), 1.62~2.08 (7H, m), 2.52~
2.78 (4H, m), 2.79-2.83 (2H, m
), 3.50-3.71 (4H, m), 4.17-4.
18 (1H, m), 4.90-4.93 (1H, m),
5.10-5.15 (1H, m), 6.15-6.24
(1H, br), 7.05-7.24 (4H, m)

Example 27 1-{3-[N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-L-prolinol (using the method of Example 2) Compliant)

0
107]

[Chemical formula 31]

Yield: 71% Melting point: 128-130°C MS (m/z): 330 (M+) IR (KBr) cm-1: 3400, 3250, 162
0,1520 NMR (CDCl3) δ: 1.50-1.62 (1H
, m), 1.63~2.08 (7H, m), 2.50~
2.60 (2H, m), 2.65-2.75 (4H, m
), 3.45-3.72 (4H, m), 4.10-4.
24 (1H, m), 4.85-4.90 (1H, m),
5.10-5.22 (1H, m), 6.10-6.20
(1H, br), 7.05-7.24 (4H, m)

Example 28 3-{3-[N-((R,S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]propionyl}-L-thioprolinol (Example 2 method)

[0110]

[C32]

Yield: 32% (amorphous) MS (m/
z): 348 (M+) IR (neat) cm-1: 3500-3200,16
10,1510 NMR (CDCl3) δ: 1.65-2.03 (4H
, m), 2.40~2.83 (6H, m), 2.86~
3.12 (2H, m), 3.40-3.45 (1H, m
), 3.60-3.83 (2H, m), 4.20-4.
85 (3H, m), 5.05-5.16 (1H, m),
6.08-6.12 (1H, br), 7.05-7.2
4 (4H, m)

Example 29 1-{3-[N-((R,S)-indan-1-ylmethyl)carbamoyl]propionyl}-L-prolinol (according to the method of Example 2)

[0113]

[Chemical formula 33]

Yield: 83% (amorphous) MS (m/
z): 330 (M+) IR (neat) cm-1: 3600-3100,16
30,1550 NMR (CDCl3) δ: 1.45-2.32 (6H
, m), 2.40~2.70 (4H, m), 2.72~
3.00 (2H, m), 3.25-3.72 (7H, m
), 4.05-4.21 (1H, m), 4.80-4.
90 (1H, m), 6.00-6.14 (1H, br)
, 7.15-7.26 (4H, m)

Example 30 1-{3-[N-((R,S)-5-chloroindan-
2-ylmethyl)carbamoyl]propionyl}-L-
Prolinol (according to the method of Example 2)

[0116]

[C34]

Yield: 88% (oil) MS (m/z): 364 (M+) IR (neat) cm-1: 3600-3100,16
10,1550 NMR (CDCl3) δ: 1.58-1.65 (1H
, M), 1.85-2.08 (3H, m), 2.50-
2.72 (7H, m), 2.97-3.04 (2H, m
), 3.29-3.35 (2H, m), 3.46-3.
68 (4H, m), 4.16-4.18 (1H, m),
4.85 (1H, dd, J=3Hz, 8Hz), 6.2
4-6.28 (1H, br), 7.09-7.16 (3
H, m)

Example 31 1-{3-[N-((R,S)-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)carbamoyl]
propionyl}-L-prolinol (according to the method of Example 2)

[0119]

[C35]

Yield: 61% (amorphous) MS (m/
z): 344 (M+) IR (neat) cm-1: 3300, 2920, 16
15,1445,745 NMR (CDCl3) δ: 1.60-2.06 (8H
, m), 2.46~2.75 (6H, m), 2.90~
3.05 (1H, m), 3.35-3.70 (6H, m
), 4.08-4.16 (1H, m), 4.85-4.
95 (1H, m), 6.25-6.40 (1H, m),
7.08-7.23 (4H, m)

Example 3
2 1-{3-[N-methyl-N-((R,S)-indan-1-yl)carbamoyl]propionyl}-L-prolinol (according to the method of Example 2)

[0122]

[C36]

Yield: 41% (oil) MS (m/z): 330 (M+) IR (neat) cm-1: 3400, 2930, 16
25,1435,745 NMR (CDCl3) δ: 1.65-2.11 (5H
, m), 2.38~2.50 (1H, m), 2.61~
3.02 (9H, m), 3.54-3.72 (4H, m
), 4.18-4.28 (1H, m), 4.95-5.
03 (1H, m), 5.58 (0.5H, t, J = 8H
z), 6.28 (0.5H, t, J=8Hz), 7.0
9-7.29 (4H, m)

Example 33 1-{3-[N-((R,S)-indan-1-yl)
Carbamoyl]propionyl}-L-prolinol (according to the method of Example 2)

[0125]

[C37]

Yield: 61% (amorphous) MS (m/
z): 316 (M+) IR (KBr) cm-1: 3280, 2950, 161
0,1540,1440 NMR (CDCl3) δ: 1.59-1.68 (1H
, m), 1.73~2.06 (4H, m), 2.50~
2.69 (5H, m), 2.78-3.03 (2H, m
), 3.48-3.69 (4H, m), 4.05-4.
20 (1H, m), 4.82-4.90 (1H, m),
5.44 (1H, dd, J=8Hz, 16Hz), 6.
34 (1H, d, J = 8Hz), 7.10-7.28 (
4H, m)

Formulation Example 1 Compound of Example 2
50g lactose
315g corn starch
125g crystalline cellulose
Mix 25g of the above components uniformly, add 200ml of a 7.5% hydroxypropylcellulose aqueous solution, and use an extrusion granulator to make particles with a diameter of 0.
The mixture was made into granules using a 5 mm screen, immediately rolled into balls using a marmerizer, and then dried to give granules. Film coating liquid 1 of the following composition is applied to this dry granule.
．． 9 kg was coated using a fluidized bed granulator to form enteric-coated granules. Coating liquid composition: Hydroxypropyl methylcellulose phthalate
5.0 (w/w)% stearic acid

0.25 (w/w)% methylene chloride
50.0 (w/
w)% ethanol
44.7
5 (w/w)%

Formulation Example 2 Compound of Example 5
20g lactose

100g corn starch
36g crystalline cellulose
3
0g carboxymethylcellulose calcium
10g magnesium stearate
4g The ingredients of the above composition were mixed uniformly, and one tablet was made into 200 tablets using a punch with a diameter of 7.5 mm using a single-shot tablet machine.
It was made into a mg tablet. Next, the tablets were spray-coated with a coating liquid having the following composition, and each tablet was coated with a coating solution of 10 m
g was applied to form an enteric film-coated tablet. Coating liquid composition: Hydroxypropyl methylcellulose phthalate
8.0 (w/w)% glycerin fatty acid ester
0.4 (w/w)% methylene chloride

50.0 (w/w)% white beeswax

0.1 (w/w)% isopropanol

41.5 (w/w)%

[0129]

Effects of the Invention As mentioned above, the compound of the present invention has a prolyl endopeptidase inhibitory effect, so it has both the memory-improving effect and the cerebral circulation/cerebral metabolism-improving effect, and is highly safe. As a treatment for cerebral infarction sequelae, cerebral arteriosclerosis, subarachnoid hemorrhage sequelae, head trauma sequelae, brain surgery sequelae, cerebrovascular dementia, Parkinson's disease, Alzheimer's disease, Pick's disease, hypoxic toxicity sequelae, alcohol encephalopathy, etc. Useful.

Claims (3)

[Claims] Claim 1: General formula (I) [Formula 1] (wherein, R1 represents a hydrogen atom or a halogen atom, and R
2 represents a hydrogen atom or a lower alkyl group, R3 represents a carboxyl group, lower alkoxycarbonyl group, hydroxymethyl group or formyl group, m represents an integer of 1 or 2, n represents an integer of 0 to 2, X represents a methylene group or a sulfur atom. ) A succinic acid amide derivative represented by 2. The succinamide derivative according to claim 1, which is an optical isomer. 3. A memory/cerebral circulation/brain metabolism improving agent comprising the succinic acid amide derivative according to claim 1 or 2 as an active ingredient.