JP2517582B2 - Pyrrolidone derivative and its use - Google Patents

Description

Description: BACKGROUND OF THE INVENTION Technical Field The present invention relates to a pyrrolidone derivative and its use as an anti-amnestic drug. With the progress of artificial aging, the problem of blurring of the elderly has become more serious. If a drug capable of improving bokeh symptoms can be developed, it can bring great gospel to society, and such a drug is extremely useful. Examples of such drugs include calcium hopanthenate (hopate), caran, aniracetam, and piracetam, but their effects are not always clear, and therefore, drugs that more clearly show anti-amnestic effects will be developed. Is awaited.

[Outline of Invention]

For the purpose of developing such a drug, the present inventors have conducted various studies using the strength of the inhibitory action of proline-specific endopeptidase as an index, and as a result, a specific pyrrolidone compound is stronger than aniracetam used as a standard substance. It came to discover that it has an effect.

That is, the present invention firstly relates to a novel compound, which is a pyrrolidone derivative represented by the following formula.

[Here, R is any of the following.

(Wherein, X is -SO ₂ - is or -CO-, R 'is a halogen or nitro group, n is 1 or 2.
However, when n = 2, R ′ is the same and X is —SO ₂
- the 'never is 4-C1, or 3-NO _2, X is when the -CO- R' R is 2-halogen, is not a 4-halogen or 2-NO ₂ when) The present invention also relates to the use of the pyrrolidone derivative related to the above compound, wherein the antiamnestic drug according to the present invention comprises the pyrrolidone derivative represented by the above formula (I) as an active ingredient (provided that , in formula (I), R and X are as defined above, X is -SO ₂ - is not R 'is 4-Cl or 3-nO ₂ when the).

Effect The pyrrolidone derivative according to the present invention has a stronger antiamnestic action than aniracetam, which is known as an antiamnestic drug.

[Specific Description of the Invention]

Pyrrolidone Derivative The pyrrolidone derivative according to the present invention is represented by the above formula (I).

Some specific examples of the compound represented by the formula (I) are shown below.

N- (8'-quinolinesulfonyl) -2-pyrrolidone, N- (2'-naphthalenesulfonyl) -2-pyrrolidone, N- (β-styrenesulfonyl) -2-pyrrolidone, N- (2 ', 5'- Dichlorobenzenesulfonyl)-
2-pyrrolidone, N- (4'-bromobenzenesulfonyl) -2-pyrrolidone, N- (4'-fluorobenzenesulfonyl) -2-pyrrolidone, N- (2'-fluorobenzoyl) -2-pyrrolidone, N- (3'-Fluorobenzoyl) -2-pyrrolidone, N- (4'-fluorobenzoyl) -2-pyrrolidone, N- (4'-bromobenzoyl) -2-pyrrolidone, and N- (4'-nitrobenzoyl) -2-Pyrrolidone.

Preparation of Compounds The pyrrolidone derivative (I) according to the present invention can be prepared by any purposeful method.

Production Method A One of the specific production methods comprises supplying the R-moiety and the pyrrolidone moiety of the compound of the formula (I) from separate compounds and combining them. -Z
(Z represents a halogen atom) and N-trimethylsilyl-
Some are due to reaction with 2-pyrrolidone.

This method is described by M. SAKAKIBARA et al: Agric.Biol.Chem.,
37 (5), 1131 (1973).

The reaction is usually carried out using a suitable solvent, but when the reaction rate is slow, the reaction can be carried out rapidly by carrying out the reaction in the absence of solvent. The solvent used in the reaction may be any inert solvent that does not participate in the reaction. Preferably, benzene, toluene, aromatic hydrocarbons such as xylene, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, diethyl ether, dioxane, ethers such as tetrahydrofuran, acetone, ketones such as methyl ethyl ketone, Esters such as ethyl acetate, acetonitrile, dimethylformamide and the like are used alone or in combination.
The amount of solvent used is not critical and is used in an amount of 0 to 20 times the amount of the starting materials normally used.

The reaction temperature is not critical and is usually in the range of 0 ° C to 150 ° C, and the reaction usually ends in 30 minutes to 24 hours, but unreacted raw materials may be recovered even if the reaction time is further extended. is there.

The reaction usually proceeds without using a catalyst, but when the reaction rate is slow, triethylamine, pyridine, N
-It may progress rapidly by adding an organic base such as methylmorpholine or dimethylaniline.

The compound produced by the reaction is usually isolated and purified from the reaction solution by carrying out a method generally used in the field of synthetic organic chemistry.

Production Method B Another specific production method is to form a pyrrolidone moiety from a precursor of a compound of formula (I) containing a pyrrolidone moiety as its chain precursor structure by cyclization of the chain precursor structure. Specifically, R-NH
This is due to a condensation cyclization reaction of a compound of — (CH ₂ ) ₃ —COOH in the presence of a suitable condensing agent.

This method can be carried out according to the method described in JP-A-55-153763.

As the condensing agent used here, dicyclohexylcarbodiimide (DCC), chlorocarbonic acid esters, onium salts and the like are suitable. In order to proceed the reaction rapidly, triethylamine, dimethylaniline, N-methylmorpholine, pyridine, N-methylpiperidine, N-
Add an organic base such as methylpyrrolidine. The solvent used in the reaction may be an inert solvent which does not participate in the reaction and can dissolve the raw material and the reagent well. Preferably, benzene, toluene, aromatic hydrocarbons such as xylene,
Halogenated hydrocarbons such as methylene chloride, chloroform, ethane dichloride and carbon tetrachloride, esters such as ethyl acetate and the like are used alone or in combination. Reaction is -10
It progresses rapidly between ℃ and 50 ℃, and usually ends within 30 minutes to 24 hours. The solvent used is usually 1 to 20 with respect to the raw materials used.
Used twice.

Isolation of the reaction product from the reaction solution can be achieved by carrying out isolation and purification methods that are generally performed in the field of synthetic organic chemistry.

Uses of Compounds Pyrrolidone derivatives of formula (I) are useful as antiamnestic agents.

That is, this compound has an anti-amnestic action because it inhibits the activity of proline-specific endopeptidase, and this inhibitory action is greater than that of aniracetam, which is a conventionally known anti-amnestic drug.

Several reports have already been made on the antiamnestic effect of proline-specific endopeptidase inhibitors. [(B) Shin Kubota, Toru Nakajima, Toshikazu Okada, Tetsuo Hayashi, Keiji Nakamura; Proc. Of the 56th Annual Meeting of the Japanese Pharmacological Society, p.141 (1
983), (b) Tadashi Yoshimoto, Nobuhiro Koriyama, Kunio Kakudo, Hiroshi Oyama, Daisuke Tsuru: Proceedings of the 59th Annual Meeting of the Biochemical Society of Japan, p.621 (198)
6), (c) Tadashi Yoshimoto, Kenichi Kumo, Dai Matsubara, Daisuke Tsuru: No. 5
6th Annual Meeting of the Biochemical Society of Japan, p.831 (1983),
(D) JP-A-61-37764, etc.].

The pyrrolidone derivative of formula (I) can be formulated and administered in the same manner as aniracetam and other antiamnestic agents as described above. Administration may be oral or parenteral (eg, injection), and it is usual to prepare a suitable carrier or diluent depending on the dosage form (eg, pyrogen-free distilled water, starch, etc.). Compound (I), or an antiamnestic agent comprising the compound,
It is also possible to mix compatible physiologically active substances or drugs.

The dosage should be left to the discretion of the physician for the individual patient, but due to its proline-specific endopeptidase inhibitory effect, it can be said that it may be smaller than the known aniracetam. In addition, specific numerical values may include 0.1 to 10 mg / kg body weight.

Synthesis Example 1 2,5-Dichlorobenzsulfonyl chloride (9.82 g, 0.04 mol) and N-trimethylsilyl-2-pyrrolidone (6.9
g, 0.04 mol) was dissolved in anhydrous tetrahydrofuran (50 ml), triethylamine (0.2 ml) was added, and the mixture was stirred at reflux temperature for 18.5 hours. The solvent was distilled off from the reaction solution under reduced pressure. The residue was dissolved in chloroform (50 ml), and silica gel (Wakogel C-200, 15 g) was added to this solution. Chloroform was distilled off under reduced pressure, and the residue was suspended by adding a mixed solvent of hexane-ethyl acetate (3: 2). This suspension was added to silica gel (Wako Gel C-20
Chromatography on a column (0,300 g) (D40 mm × L500 mm). Elution with a mixed solvent consisting of hexane-ethyl acetate (3: 2) gave the product (6: 4 g). This was dissolved in a small amount of chloroform, ether was added thereto, and the mixture was left at room temperature. The crystals that formed were separated and dried.
Yield 6.14 g (52% yield).

(A) mp: 181.5-181.8 ° C.

3550 (s), 3450 (s), 3410 (s), 3250 (w), 31
00 (w), 3070 (w), 3000 (w), 2950 (w), 2920
(W), 1930 (w), 1740 (s), 1640 (m), 1620
(M), 1485 (w), 1460 (s), 1440 (m), 1415
(W), 1382 (s), 1355 (s), 1338 (w), 1320
(W), 1285 (m), 1270 (w), 1255 (s), 1243
(S), 1212 (s), 1170 (s), 1150 (s), 1140
(M), 1120 (s), 1110 (m), 1072 (m), 1040
(M), 1015 (m), 965 (s), 930 (w), 895
(M), 840 (s), 820 (m), 715 (s), 698
(W), 680 (m), 640 (s), 608 (s), 590
(S), 525 (s), 465 (w).

(C) ¹ H-NMR (100 MHz, CDCl ₃ ) δ: 2.19 (quintet,
J = 7Hz, 2H), 2.51 (t, J = 7Hz, 2H), 4.13 (t,
J = 7Hz, 2H), 7.48 (m, 2H), 8.28 (m, 1H).

(D) Elemental analysis: theoretical value (as C ₁₀ H ₉ NCl ₂ O ₃ S) C: 40.83, H: 3.08, N: 4.76.

Analytical values C: 40.92, H3.07, N: 4.83.

(E) FDMS (m / z): 294 (M ⁺ ).

Synthesis Example 2 4-Bromobenzesulfonyl chloride (10.2 g, 0.04 mol) and N-trimethylsilyl-2-pyrrolidone (6.9 g,
0.044 mol) was stirred at room temperature for 18 hours. The reaction solution is a column (D40mm × L2) of silica gel (Wakogel C-200, 150g).
50 mm). The product obtained by eluting with a mixed solvent of hexane-ethyl acetate (3: 2) was recrystallized from a mixed solvent of chloroform-ether. Crystals of N- (4'-bromobenzenesulfonyl) -2-pyrrolidone (2.86 g) were obtained.

(A) mp: 166 ° C.

3505 (m), 3470 (s), 3420 (s), 3240 (W), 31
00 (w), 3080 (w), 3000 (w), 2950 (w), 2900
(W), 1730 (s), 1685 (w), 1640 (m), 1620
(M), 1578 (m), 1490 (w), 1485 (w), 1460
(W), 1415 (w), 1395 (m), 1360 (s), 1340
(W), 1320 (w), 1300 (w), 1280 (m), 1240
(W), 1220 (m), 1200 (m), 1178 (s), 1170
(S), 1122 (s), 1090 (m), 1070 (m), 1025
(W), 1010 (w), 960 (m), 890 (w), 840
(W), 820 (m), 750 (s), 710 (w), 705
(W), 610 (s), 595 (s), 550 (w), 540
(M).

(C) ¹ H-NMR (100 MHz, CDCl ₃ ) δ: 2.10 (quintet,
J = 7Hz, 2H), 2.46 (t, J = 7Hz, 2H), 3.90 (t,
J = 7Hz, 2H), 7.69 (d, J = 9Hz, 2H), 7.96 (dJ
= 9Hz, 2H).

(D) Elemental analysis: theoretical value (as C ₁₀ H ₁₀ BrNO ₃ S) C: 39.48, H: 3.31, N: 4.61 Analytical value C: 39.56, H: 3.36, N: 4.73.

(E) FDMS (m / z): 304 (M ⁺ ).

Synthesis Example 3 N-trimethylsilyl-2-pyrrolidone (6.9 g, 0.044 mol) was added to 4-fluorobenzenesulfonyl chloride (4.28 g, 0.022 mol), and the mixture was stirred at 90 ° C for 15 minutes. The reaction product was dissolved in chloroform (50 ml), and silica gel (Wako gel C200, 15 g) was added thereto. Chloroform was distilled off from this under reduced pressure, and the powdery residue was passed through a column of silica gel (Wakogel C-200, 150 g) (D40 mm x
L250 mm) for chromatography. Hexane-
The product obtained by eluting with a mixed solvent of ethyl acetate (3: 2) was recrystallized from a mixed solvent of chloroform-ether. Crystals of N- (4′-fluorobenzsulfonyl) -2-pyrrolidone (2.14 g) were obtained.

(A) mp: 108.5-109.0 ° C.

3420 (s), 3100 (m), 3070 (w), 3050 (w), 30
00 (w), 2970 (w), 2900 (w), 1925 (w), 1725
(S), 1685 (w), 1615 (w), 1600 (m), 1595
(S), 1495 (s), 1465 (w), 1425 (w), 1410
(M), 1363 (s), 1342 (w), 1312 (w), 1300
(M), 1285 (w), 1230 (s), 1200 (s), 1180
(S), 1160 (s), 1120 (s), 1095 (m), 1072
(W), 1025 (w), 1020 (w), 965 (s), 890
(W), 840 (s), 820 (m), 720 (m), 710
(W), 670 (s), 645 (w), 600 (s), 562
(S), 550 (s), 535 (m), 500 (w), 460
(W), 398 (w).

(C) ¹ H-NMR (100 MHz, CDCl ₃ ) δ: 2.17 (quintet,
J = 7Hz, 2H), 2.46 (t, J = 7Hz, 2H) 3.91 (t, J
= 7Hz, 2H), 7.22 (t, J = 9Hz, 2H), 8.09 (dd, J
= 5 and 9 Hz, 2H).

(D) Elemental analysis: theoretical value (as C ₁₀ H ₁₀ NFO ₃ S) C: 49.37, H: 4.14, N: 5.76.

Analytical values C: 49.46, H: 4.22, N: 5.79.

(E) FDMS (m / z): 244 (M ⁺ +1) Synthesis Example 4 8-quinolinesulfonyl chloride (5.0 g, 0.022 mol) and N-trimethylsilyl-2-pyrrolidone (6.9 g, 0.044)
Mol) and tetrahydrofuran (50 ml), triethylamine (0.2 ml) was added, and the mixture was stirred at reflux temperature for 141.5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform (50 ml), and silica gel (Wakogel C-200, 15 g) was added. Chloroform was distilled off from this mixture under reduced pressure, and the powdery residue was subjected to chromatography on a silica gel (Wakogel C-200, 150 g) column (D40 mm × L250 mm). Hexane-ethyl acetate (3: 2)
Starting from the mixed solvent consisting of, the ratio of ethyl acetate in the mixed solvent was increased, and finally it was eluted with ethyl acetate. The obtained product was recrystallized from chloroform to give N- (8'-quinolinesulfonyl) -2-pyrrolidone crystals (1.42 g).

(A) mp: 244.2-245.2 ° C.

3550 (m), 3480 (s), 3410 (s), 3250 (m), 30
40 (w), 3000 (w), 2930 (w), 2900 (w), 1965
(W), 1910 (w), 1730 (s), 1640 (m), 1620
(M), 1600 (m), 1560 (m), 1497 (m), 1480
(W), 1460 (w), 1420 (w), 1383 (w), 1360
(M), 1342 (s), 1325 (w), 1315 (w), 1287
(W), 1240 (w), 1210 (s), 1202 (w), 1172
(S), 1145 (s), 1120 (s), 1070 (w), 1030
(W), 1020 (w), 990 (w), 960 (m), 930
(W), 885 (w), 840 (m), 830 (m), 785
(S), 760 (w), 717 (m), 665 (m), 630
(M), 600 (s), 590 (s), 560 (m), 545
(W), 525 (w), 515 (s), 423 (w).

(C) ¹ H-NMR (100 MHz, CDCl ₃ ) δ: 2.16 (quintet,
J = 7Hz, 2H), 2.35 (t, J = 7Hz, 2H), 4.52 (t,
J = 7Hz, 2H), 7.54 (dd, J = 4 and 8Hz, 1H), 7.
74 (dd, J = 8Hz, 1H), 8.10 (dd, J = 2 and 8Hz,
1H), 8.26 (dd, J = 2 and 8Hz, 1H), 8.69 (dd,
J = 2 and 8Hz, 1H), 9.03 (d, J = 4Hz, 1H).

(D) elemental analysis: Calculated (as _{C 13 H 12 N 2 O 3} S) C: 56.51, H: 4.38, N: 10.14 analysis C: 56.64, H: 4.42, N: 10.23.

(E) FDMS (m / z): 277 (M ⁺ +1) Synthesis example 5 2-naphthalenesulfonyl chloride (5.0 g, 0.022 mol)
And N-trimethylsilyl-2-pyrrolidone (6.9g, 0.04
4 mol) was stirred at 85 ° C. for 30 minutes. The reaction product was dissolved in chloroform (50 ml), silica gel (Wakogel C-200, 15 g) was added thereto, and chloroform was distilled off under reduced pressure. The resulting powdery residue was applied to a silica gel (Wakogel C-200, 200 g) column (D40 mm × L318 m).
m). The crystalline product obtained by eluting with a mixed solvent of hexane-ethyl acetate (3: 2) was recrystallized from a mixed solvent of chloroform-ether to give N- (2'-naphthalenesulfonyl) -2- Crystals of pyrrolidone (1.81 g) were obtained.

(A) mp: 121.5-122.5 ° C.

3430 (s), 3050 (w), 2970 (w), 2920 (w), 19
25 (w), 1740 (s), 1620 (w), 1585 (w), 1500
(W), 1460 (w), 1420 (w), 1395 (w), 1380
(W), 1360 (s), 1350 (s), 1321 (w), 1280
(W), 1270 (w), 1240 (w), 1210 (m), 1190
(M), 1170 (s), 1150 (w), 1130 (m), 1120
(S), 1075 (m), 1020 (w), 962 (m), 945
(W), 900 (w), 890 (w), 870 (w), 858
(W), 822 (m), 755 (s), 712 (m), 660
(S), 640 (m), 610 (m), 585 (m), 555
(M), 542 (m), 530 (w), 495 (w), 485
(W), 475 (w), 455 (w).

(C) ¹ H-NMR (100 MHz, CDCl ₃ ) δ: 2.08 (quintet,
J = 7Hz, 2H), 2.44 (t, J = 7Hz, 2H), 4.00 (t,
J = 7Hz, 2H), 7.66 (m, 2H), 7.99 (m, 4H), 8.6
4 (br.s, 1H).

(D) Elemental analysis: theoretical value (as C ₁₄ H ₁₃ NO ₃ S) C: 61.07, H: 4.76, N: 5.09.

Analytical values C: 61.27, H: 4.83, N: 5.20.

(E) FDMS (m / z): 275 (M ⁺ ).

Synthesis Example 6 β-styrenesulfonyl chloride (4.5 g, 0.022 mol) and N-trimethylsilyl-2-pyrrolidone (6.9 g, 0.044)
Mol) was stirred at 80-90 ° C for 80 minutes. The reaction product was dissolved in chloroform (50 ml), silica gel (Wakogel C-200, 15 g) was added thereto, and chloroform was distilled off under reduced pressure. The resulting powdery residue was applied to a silica gel (Wakogel C-200, 200 g) column (D40 mm × L318 m).
m). The product eluted with a mixed solvent of hexane-ethyl acetate (3: 2) was further chromatographed on a column of silica gel (Wakogel C-200, 20 g) (D20 mm x L127 mm).
The product eluted with a mixed solvent of hexane-ethyl acetate (3: 2) was recrystallized with a mixed solvent of chloroform-ether, and the obtained crystals were recrystallized in the same solvent system to give N- ( Crystals of β-styrenesulfonyl) -2-pyrrolidone (0.19 g) were obtained.

(A) mp: 126.5-127.0 ° C.

3550 (m), 3460 (s), 3400 (s), 3230 (w), 30
50 (w), 2990 (w), 2950 (w), 2900 (w), 1910
(W), 1738 (s), 1690 (w), 1640 (m), 1615
(S), 1610 (s), 1575 (w), 1490 (w), 1485
(W), 1450 (m), 1410 (w), 1380 (w), 1353
(S), 1335 (m), 1320 (w), 1305 (w), 1282
(W), 1240 (m), 1218 (m), 1185 (s), 1170
(M), 1150 (s), 1120 (s), 1070 (w), 1020
(W), 1010 (w), 995 (s), 960 (s), 930
(W), 892 (w), 860 (m), 830 (w), 810
(M), 758 (s), 710 (w), 690 (m), 630
(S), 615 (m), 582 (w), 580 (w), 550
(M), 540 (m), 520 (m), 495 (m).

(C) ¹ H-NMR (100 MHz, CDCl ₃ ) δ: 2.14 (quintet,
J = 7Hz, 2H), 2.55 (t, J = 7Hz, 2H), 3.90 (t,
J = 7Hz, 2H), 7.07 (d, J = 16Hz, 1H), 7.46
(M, 5H), 7.71 (d, J = 16Hz, 1H).

(D) Elemental analysis: theoretical value (as C ₁₂ H ₁₃ NO ₃ S) C: 57.35, H: 5.21, N: 5.57.

Analytical values C: 57.48, H: 5.33, N: 5.68.

(E) FDMS (m / z): 251 (M ⁺ ).

Synthesis Example 7 N-Trimethylsilyl-2-pyrrolidone (6.9 g) was added to 3-fluorobenzoyl chloride (6.34 g), and the mixture was stirred until the heat of reaction subsided. Chloroform the reaction product (50 ml)
Melt and add silica gel (Wako Gel C-200, 15
g) was added. Chloroform was distilled off from this under reduced pressure. The powdery residue was treated with silica gel (Wakogel C-200, 150
g) column chromatography (D40 mm x L250 mm). Elution was performed with a mixed solvent of hexane-ethyl acetate (3: 2). The obtained crude crystals were recrystallized with a mixed solvent of chloroform and ether to give N- (3'-
Fluorobezoyl) -2-pyrrolidone crystals (7.43g)
I got

(A) mp: 105.5-106.0 ℃.

3550 (m), 3480 (s), 3430 (s), 3250 (w), 31
00 (w), 3070 (w), 3000 (w), 2980 (w), 2920
(W), 1750 (s), 1670 (s), 1660 (sh), 1640
(W), 1620 (m), 1595 (m), 1525 (w), 1490
(M), 1460 (w), 1450 (s), 1420 (w), 1388
(W), 1360 (m), 1345 (sh), 1325 (s), 1315
(Sh), 1280 (w), 1250 (s), 1235 (w), 1222
(M), 1185 (s), 1140 (m), 1085 (w), 1030
(W), 1002 (w), 985 (w), 970 (w), 940
(W), 915 (w), 900 (m), 850 (w), 820
(W), 802 (m), 762 (m), 705 (w), 685
(W), 658 (w), 630 (w), 620 (m), 540
(W), 523 (w), 483 (w), 410 (w).

(C) ¹ H-NMR (100 MHz), CDCl ₃ ) δ: 2.16 (quinte
t, J = 7Hz, 2H), 2.26 (t, J = 7Hz, 2H), 3.96
(T, J = 7Hz, 2H), 7.3 (m, 4H).

(D) Elemental analysis: theoretical value (as C ₁₁ H ₁₀ NFO ₂ ) C: 63.76, H: 4.86, N: 6.76.

Analytical value C: 63.63, H: 4.82, N: 6.85.

(E) FDMS (m / z): 207 (M ⁺ ).

Synthesis Example 8 N-Trimethylsilyl-2-pyrrolidone (6.9 g) was added to 4-fluorobenzoyl chloride (6.34 g), and the mixture was stirred for 1 hour. The reaction product was dissolved in chloroform (50 ml), which was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from a mixed solvent of chloroform and ether to give N- (4'-fluorobenzoyl).
A crystal of 2-pyrrolidone (2.02 g) was obtained.

(A) mp. 128.5-129.5 ° C.

3550 (m), 3450 (s), 3400 (s), 3250 (w), 30
80 (w), 3000 (w), 2900 (w), 1920 (w), 1745
(S), 1660 (s), 1640 (m), 1620 (s), 1605
(S), 1510 (m), 1480 (w), 1460 (w), 1415
(W), 1383 (w), 1355 (w), 1325 (s), 1305
(W), 1295 (m), 1270 (w), 1240 (s), 1225
(S), 1185 (s), 1180 (sh), 1160 (s), 1130
(W), 1100 (w), 1072 (w), 1020 (m), 972
(W), 950 (w), 905 (w), 887 (w), 850
(S), 830 (w), 805 (w), 770 (s), 710
(W), 680 (w), 638 (w), 620 (w), 610
(W), 585 (s), 522 (w).

(C) ¹ H-NMR (100 MHz, CDCl ₃ ) δ: 2.15 (quintet,
J = 7Hz, 2H), 2.61 (t, J = 7Hz, 2H, 3.95 (t, J
= 7Hz, 2H), 7.08 (t, J = 9Hz, 2H), 7.65 (dd, J
= 5 and 9 Hz, 2H).

(D) Elemental analysis: theoretical value (as C ₁₁ H ₁₀ NFO ₂ ) C: 63.76, H: 4.86, N: 6.76.

Analytical values C: 63.56, H: 4.81, N: 6.73.

(E) FDMS (m / z): 207 (M ⁺ ).

Synthesis Example 9 N-Trimethylsilyl-2-pyrrolidone (6.9 g) was added to 2-fluorobenzoyl chloride (6.34 g), and the mixture was stirred until the exothermic reaction was stopped. Chloroform (50
ml), washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crude crystals obtained were recrystallized from a mixed solution of chloroform and ether to give N- (2'-fluorobenzoyl) -2-pyrrolidone crystals (3.58 g).
I got

(A) mp: 90 ° C.

3530 (m), 3450 (s), 3400 (s), 3220 (w), 30
80 (w), 3040 (w), 2970 (w), 2900 (w), 2000
(W), 1970 (w), 1940 (w), 1740 (s), 1660
(S), 1940 (m), 1612 (s), 1580 (m), 1540
(M), 1490 (s), 1455 (s), 1420 (w), 1380
(W), 1360 (m), 1327 (s), 1280 (w), 1265
(M), 1240 (m), 1220 (s), 1185 (s), 1175
(M), 1150 (w), 1100 (m), 1070 (w), 1060
(W), 1025 (s), 980 (w), 955 (w), 900
(M), 830 (m), 775 (m), 758 (s), 708
(M), 635 (m), 610 (s), 538 (m), 503
(M), 475 (w), 440 (w), 400 (w).

(C) ¹ H-NMR (100 MHz, CDCl ₃ ) δ: 2.13 (quintet,
J = 7Hz, 2H), 2.60 (t, J = 7Hz, 2H), 3.99 (t,
J = 7Hz, 2H), 7.3 (m, 4H).

(D) Elemental analysis: theoretical value (as C ₁₁ H ₁₀ NFO) C: 63.76, H: 4.86, N: 6.76.

Analytical value C: 63.92, H: 4.73, N: 6.59.

(E) FDMS (m / z): Synthesis Example 10 4-Bromobenzoyl chloride (8.78 g, 0.04 mol) with N
-Trimethylsilyl-2-pyrrolidone (6.90 g, 0.044 mol) was added and stirred until the exothermic reaction subsided. The reaction was directly recrystallized with a mixed solvent consisting of chloroform and ether. N- (4'-bromobenzoyl) -2-
Crystals of pyrrolidone (8.16 g) were obtained.

(A) mp: 127-128 ℃.

3450 (m), 3470 (s), 3400 (s), 3240 (w), 29
80 (w), 2900 (w), 1733 (s), 1680 (s), 1670
(S), 1640 (m), 1620 (m), 1590 (m), 1480
(W), 1418 (w), 1399 (w), 1358 (m), 1330
(S), 1328 (s), 1282 (w), 1270 (w), 1240
(S), 1220 (w), 1195 (w), 1158 (w), 1110
(W), 1065 (m), 1045 (w), 1010 (m), 955
(W), 940 (w), 903 (w), 888 (w), 850
(W), 830 (m), 760 (m), 730 (w), 690
(W), 665 (w), 638 (m), 610 (m), 525
(W), 450 (w).

(C) ¹ H-NMR (100 MHz, CDCl ₃ ) δ: 2.15 (quintet,
J = 7Hz, 2H), 2.62 (t, J = 7Hz, 2H), 3.95 (T,
J = 7Hz, 2H), 7.48 (d, J = 9Hz, 2H), 7.55 (d,
J = 9Hz, 2H).

(D) Elemental analysis: theoretical value (as C ₁₁ H ₁₀ NBrO ₂ ) C: 49.27, H: 3.76, N: 5.22.

Analytical value C: 49.36, H: 3.83, N: 5.19.

(E) FDMS (m / z): 269 (M ⁺ +1) Synthesis Example 11 4-nitrobenzoyl chloride (7.40 g, 0.04 mol) in N
-Trimethylsilyl-2-pyrrolidone (6.90 g, 0.044 mol) was added and stirred until the exothermic reaction subsided. The reaction product was directly recrystallized from a mixed solvent of chloroform and ether. Crystals of N- (4'-nitrobenzoyl) -2-pyrrolidone (8.08 g) were obtained.

(A) mp: 126-127 ° C.

3450 (s), 3250 (w), 3100 (w), 3080 (w), 30
00 (w), 2900 (w), 1750 (s), 1670 (s), 1660
(Sh), 1640 (m), 1620 (m), 1602 (m), 1520
(S), 1495 (w), 1460 (w), 1412 (w), 1383
(W), 1355 (s), 1330 (s), 1320 (s), 1300
(M), 1245 (s), 1230 (w), 1190 (m), 1160
(W), 1108 (w), 1020 (w), 983 (w), 910
(W), 870 (m), 850 (w), 830 (w), 780
(W), 740 (m), 720 (m), 683 (w), 663
(W), 640 (m), 610 (w).

(C) ¹ H-NMR (100 MHz, CDCl ₃ δ: 2.19 (quintet, J
= 7Hz, 2H), 2.64 (t, J = 7Hz, 2H), 4.00 (t, J
= 7Hz, 2H), 7.70 (d, J = 8Hz, 2H), 8.27 (d, J
= 8Hz, 2H).

(D) Elemental analysis: theoretical value (as C ₁₁ H ₁₀ N ₂ O ₄ ) C: 56.41, H: 4.30, N: 11.96.

Analytical value C: 56.60, H: 4.27, N: 11.78.

(E) FDMS (m / z): 234 (M ⁺ ).

Inhibition of Proline-Specific Endopeptidase Activity The inhibitory effect of the compound of formula (I) on the proline-specific endopeptidase activity was shown by the residual activity of the same peptidase. The experimental method is based on Tadashi Yoshimoto, Daisuke Tsuru, Proteins / Nucleic Acids / Enzymes, 29 (2) .127 (1984).

The results are shown in the table below. It should be noted that the known activity of aniracetam was used as a standard, and the residual activity in that case is also shown.

Claims (2)

(57) [Claims] 1. A pyrrolidone derivative represented by the following formula. [Where R is any of the following: (Wherein, X is -SO ₂ - is or -CO-, R 'is a halogen or nitro group, n is 1 or 2.
However, when n = 2, R ′ is the same and X is —SO ₂
When-, R'is not 4-Cl or 3-NO ₂ , and when X is -CO-, R'is not 2-halogen, 4-halogen, or 2-NO _2. . ) 2. An anti-amnestic drug containing a pyrrolidone derivative represented by the following formula as an active ingredient. [Where R is any of the following: (Wherein, X is -SO ₂ - is or -CO-, R 'is a halogen or nitro group, n is 1 or 2.
However, when n = 2, R ′ is the same and X is —SO ₂
When-, R'is not 4-Cl or 3-NO ₂ )]