JPS63215624A - Pyrrolidone derivative and use thereof - Google Patents

Abstract

NEW MATERIAL:A pyrrolidone derivative shown by formula I [R is group shown by formula II, formula III, formula IV or formula V (X is -SO2- or -CO-; R' is halogen or nitro; n is 1 or 2; with the proviso that when n=2, R' is the same and when X is -SO2-, R' is neither 4-Cl nor 3-NO2)]. EXAMPLE:N-(4'-Bromobenzenesulfonyl)-2-pyrrolidone. USE:Useful as an agent for alleviating amnesia. PREPARATION:For example, a compound shown by the formula R-Z (Z is halogen) is reacted with N-trimethylsilyl-3-pyrrolidone in the absence of a solvent or in a solvent such as benzene at 0 deg.C-150 deg.C optionally by the use of a catalyst such as triethylamine to give a compound shown by formula I.

Description

BACKGROUND OF THE INVENTION Technical Field The present invention relates to pyrrolidone derivatives and their use as anti-amnestic agents.

Nowadays, as the population ages and the problem of blurred vision in the elderly becomes more serious, it would be great if a drug could be developed that could improve the symptoms of blurred vision.
Such medicinal Qi 1 is extremely useful because it can bring great good news to society. Examples of such drugs include carunium hopantenate (Fovate), caran, aniracetam, and piracetam, but their effects are not necessarily clear, so it is necessary to develop drugs that exhibit more clearly anti-amnestic effects. This is something that is eagerly awaited.

[Summary of the invention]

With the aim of developing such a drug, the present inventors conducted various studies based on the strength of the inhibitory effect on proline-specific nidbebutidase, and found that a specific pyrrolidone compound was used as a stray substance, aniracetam. We have come to discover that it has a stronger effect.

That is, the present invention first relates to a new compound, and this new compound is a pyrrolidone derivative represented by the following formula.

The present invention also relates to the use of this new compound, and the anti-amnestic drug according to the present invention contains a pyrrolidone derivative represented by the following formula as an active ingredient.

death [Here, R is any of the following.

(where or -802- or -co-, R'
is a halogen or a nitro group, and n is 1 or 2. However, when n-2, R' is the same and X is -
302-, R' is never 4-CI or 3-No2)] Effect The pyrrolidone derivative according to the present invention has a stronger anti-amnestic effect than aniracetam, which is known as an anti-amnestic drug.

[Detailed description of the invention]

Pyrrolidone Derivatives The pyrrolidone derivatives according to the present invention are as follows: Some specific examples of the compounds represented by the above formula (1) are as follows.

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.

Production of Compound The pyrrolidone derivative (1) according to the present invention can be produced by any conventional method.

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

This method is based on M,5AKAKIBARA e,L at
:^gric, B1o1.

Cbem, 37(5), 1131 (1973).

The reaction is usually carried out using an appropriate solvent, but if the reaction rate is slow, the reaction can be carried out without a solvent to speed up the reaction.

Any inert solvent that does not participate in the reaction may be used as the solvent for the reaction. Preferably aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, ethers such as diethyl ether, dioxane and tetrahydrofuran, ketones such as acetone and methyl ethyl ketone, Esters such as ethyl acetate, acetonitrile, dimethylformamide, etc. are used alone or in combination. The amount of solvent used is not critical;
The amount used is 0 to 20 times the amount of raw materials normally used.

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

The reaction usually proceeds without the use of a catalyst, but if the reaction rate is slow, triethylamine, pyridine, N-
The process may be accelerated by adding an organic base such as methylmorpholine or dimethylaniline.

Isolation and purification of the compound produced by the reaction from the reaction solution is usually carried out by implementing techniques commonly used in the field of organic synthetic chemistry.

Production method B Another specific production method is to form a pyrrolidone moiety from a precursor of the compound of formula (1) containing a pyrrolidone moiety as its chain precursor structure by cyclizing the chain precursor structure. Specifically, R-NH
-(CH2) 3-C0OH is subjected to a condensation cyclization reaction in the presence of a suitable condensing agent.

This method can be carried out in accordance with the method described in JP-A-55-153763.

Suitable condensing agents used here include dicyclohexylcarbodiimide (DCC), chlorocarbonate esters, onium salts, and the like. In order for the reaction to proceed rapidly, triethylamine, dimethylaniline, N-methylmorpholine, pyridine, N-methylpiperidine, N-
Add an organic base such as methylpyrrolidine. The solvent used in the reaction may be any inert solvent that does not participate in the reaction and can dissolve the raw materials and reagents well. Preferably aromatic hydrocarbons such as benzene, toluene, and 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. The reaction is 11
It progresses quickly between 0℃ and 50℃, usually for 30 minutes to 24 minutes.
Finish in time. The amount of the solvent used is usually 1 to 20 times the amount of the raw material used.

Isolation of the reaction product from the reaction solution is usually achieved by implementing isolation and purification methods commonly used in the field of organic synthetic chemistry.

Uses of Compounds The pyrrolidone derivatives of formula (1) are useful as anti-amnestic agents.

In other words, this compound has an anti-amnestic effect by inhibiting the activity of proline-specific endopeptidase.
Moreover, this inhibitory effect is greater than that of aniracetam, a conventionally known anti-amnestic drug.

Note that several reports have already been made regarding the anti-amnestic effects of proline-specific endopeptidase inhibitors.

[(a) Arata Kubota, Toru Nakajima, Satoshi Okada-1 Tetsuo Hayashi, Keiji Nakamura: Abstracts of the 56th Annual Meeting of the Japanese Pharmacological Society, p. 141
(1983), (b) Tadashi Yoshimoto, Nobuhiro Koriyama, Kunio Kado, Hiroshi Oyama, Daiten Tsuru: Collection of abstracts of the 59th Biochemical Society of Japan Conference,
p, 621 (1986), (c) Tadashi Yoshimoto, Kujukuken-1
Dai Matsubara, Daiten Tsuru: Collected abstracts of the 56th Japanese Biochemical Society Conference, p. 831 (1983), (d) JP-A-61-37
Publication No. 764, etc.].

Pyrrolidone derivatives of formula (1) can be formulated and administered in the same manner as aniracetam and other anti-amnestic drugs as described above. Administration may be either oral or parenteral (for example, injection), and the preparation is usually prepared by adding an appropriate carrier or diluent (for example, pyrogen-free distilled water, starch, etc.) depending on the dosage form. It is also possible to mix and prepare compound (I) or an anti-amnestic drug consisting of the compound with physiologically active substances or medicines that are compatible with each other.

The dosage should be left to the doctor's decision for each individual patient, but in view of its proline-specific endopeptidase inhibitory effect, it can be said that the dosage may be lower than that of known aniracetam. In addition, the specific value is 0.1~10■/
Can list weight in kg.

Synthesis Example 1 2,5-dichlorobenzenesulfonyl chloride (9,82g
50.04 mol) and N-)dimethylsilyl-2-pyrrolidone (6.9 g, 0.044 mol) were dissolved in anhydrous tetrahydrofuran (50 ml) and triethylamine (0.04 mol) was dissolved in anhydrous tetrahydrofuran (50 ml).
, 2 ml) and 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 from this under reduced pressure, and a mixed solvent consisting of hexane-ethyl acetate (3:2) was added to the residue to suspend it. This suspension was mixed with silica gel (Wakogel C-200, 3).
00g) column (D40m+*XL 500m+w
) was subjected to chromatography. 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 resulting crystals were separated and dried. Tatami amount 6.14g (52
%yield).

(a) mp: 181.5-181.8°C.

3450(s), 3410(s), 3250(ν)
, 3100(v) , 3070(v) , 3000(v
), 2950(ν), 2920(v), 1930(
v), 1740(s), 1640(a+), 162
0(a), 1485(w), 1460(s), 14
40(m), 1415(ν), 1382(s), 1
355(s), 1338(v), 1320(v), 1
285(m), 1270(w), 1255(s),
1243(s), 1212(s), 1170(s)
, 1150(S), 1140(a+), 1120(s
), 1110(m), 101072(,101040
(,101015(,965(s),930(w)
, 895(m), 840(S), 820(a), 7
15(s), 698(w), 680(a+), 64
0(s), 608(s), 590(s), 525(
s), 465(w).

(c) H-NMR (100MHz.

CDC13) δ: 2.19 (qujntet,
J = 7Hzs 2H), 2-51 (ts
J-7Hzs2H), 4. 13 (t, J-7
Hz, 2H), 7.48 (m, 2H), 8.28
(m, IH).

(d) Elemental analysis: Theoretical value (as C1oH9NC1203S) C: 40.
83, H: 3.08, N: 4.76D Analysis value C: 40.92, If: 3.07, N: 4.8
3゜(E) FDMS (m/z): 294 (M)
.

Synthesis Example 2 4-bromobenzenesulfonyl chloride (10.2g, 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 was immersed in silica gel (Wakogel C-200, 150
g) Column (D40+smX L 250ss) l
I attached one piece of chromatography. The product obtained by elution with a mixed solvent of hexane-ethyl acetate (3:2) was recrystallized from a mixed solvent of chloroform-ether. Crystals (2.86 g) of N-(4'-bromobenzenesulfonyl)-2-pyrrolidone were obtained.

(a) mp: 166℃.

Br (o) IRν (cs+-'):, 3550
(m), la! 3470(s), 3420(s), 3240(W)
, 3100 (v) , 3080 (v) , 3000 (w
), 2950(v), 2900(v), 1730(
s), 1685(v), 1640(s), 1620
(g+), 1 578 (m), 1490 (v)
, 1485(w) , 1460(w) ,
1415(v), 1395(Otori), 1360
(s), 1340(v), 1320(v), 130
0(v), 1280(s)%' 1240(v), 1
220 (m), 1200 (m), 1178 (s),
1170(s), 1122(s), 101090(
,1070(II+) ,101025(,10101
0(,960(ffri),890(v),840(W
), 820(m), 750(s), 710(w),
705(w), 610(s), 595(s), 55
0(w), 540(m).

(/’) H-NMR (100MHz.

CDC13) δ: 2.10 (quintct,
J-7Hz, 2H), 2.46 (t, J-7Hz
.

2H), 3.90 (t, J-7Hz% 2H)
, 7.69 (d, J-9Hz, 2H) , 7.96
(d, J=9Hz, 2H).

(d) Elemental analysis: Theoretical value (as CHBr???03S) C: 39.4B, H: 3.31, N: 4.61 Analysis 1m 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) was added to 4-fluorobenzenesulfonyl chloride (4.28 g, 0.022 mol).

0.044 mol) was added thereto, and the mixture was stirred at 90°C for 15 minutes.

The reaction product was dissolved in chloroform (50 ml), and silica gel (Wakogel C200, 15 g) was added thereto. Chloroform was distilled off from this under reduced pressure, and the powdery residue was subjected to one column of chromatography using a silica gel (Wakogel C-200, 150 g) (7) column (D40 mm XL 250 mm). The product obtained by elution with a mixed solvent of hexane-ethyl acetate (3:2) was recrystallized from a mixed solvent of chloroform-ether.

Crystals (2.14 g) of N-(4'-fluorobenzenesulfonyl)-2-pyrrolidone were obtained.

(a) mp: 108.5 to 109.0°C.

Br (ffl) IRν (cm-'): 3420 (s)
, 11a! 3100(v), 3070(v), 3050(v),
3000(w), 2970(v), 2900(v)
, 1925(w), 1725(s), 1685(v
), 1615(w), 1600(m), 1595(
s), 1495(s), 1465(v), 1425
(w), 14l41-0(, 1363(s), 134
2(v), 1312(v), 1300(m), 12
85(w), 1230(s), 1200(s), 1
180(s), 1160(s), 1120(s),
101095(,101072(,1025(v),
1020(v), 965(s), 890(v), 8
40(s), 820(s), 720(m), 710
(w), 670(s), 645(w), 600(s)
), 562(s), 550(s), 535(m),
500(v), 460(v), 398(w).

(”) 'H-NMR (100MHz, CDC13)
δ: 2.17 (quntet, J = 7H
z, 2H), 2.46 (t, J-7Hz.

2H) 3.91 (t, J=7Hz, 2H), 7.2
2 (t, J=9Hz, 2H), 8.09 (dd,
J-5 and 9Hz, 2H).

(d) Elemental analysis: Theoretical value (as C1oH1oNFO3S) C: 49.3
7, H: 4.14, N: 5.76° Analysis value 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 Ni millimethylsilyl 2-pyrrolidone (6.9 g, 0.044 mol) were dissolved in tetrahydrofuran (50 ml), and triethylamine (0.2 mol) was dissolved in tetrahydrofuran (50 ml).
l) was added and 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-2
00,15g) was added. Chloroform was distilled off from this mixture under reduced pressure, and the powdery residue was transferred to a column of silica gel (Wakogel C-200, 150 g) (D40 mm XL25
0++s). Starting with a mixed solvent consisting of hexane-ethyl acetate (3:2), increasing the ratio of ethyl acetate in the mixed solvent,
Finally, it was eluted with ethyl acetate. The obtained product was recrystallized from chloroform to obtain crystals (1.42 g) of N-(8'-quinolinesulfonyl)-2-pyrrolidone.

(a) mp: 244.2 to 245.2°C.

Br (o) IRν (0111-'); 3550
(1), flax 3480(s), 3410(s), 325°O(m
), 3040(w), 3000(v), 2930(
w), 2900(v), 1965(w), 1910
(w), 1730(s), 1640(i), 162
0(m), 1600(m), 1560(i), 14
97(m), 1480(w), 1460(w), 1
420(v), 1383(w), 1360(i),
1 B42(s), 1325(w), 1315(v)
, 1287(v), 1240(w), 1210(s
), 1202(w), 1172(s), 1145(
s), 1120(S), 1070(v), 1010
30 (, 1020 (v), 990 (w), 960
(shoes), 930(v), 885(w), 8
40(m), 830(m), 785(s), 760
(v), 717(+a), 665(m), 630(
m), 600(s), 590(s), 560(+a
), 545(w), 525(v), 515(s)
, 423(v).

(c) H-NMR (100MHz.

CDC13) δ: 2. 16 (quntet,
J-7Hz, 2H), 2.35 (t, J-7H
z.

2H), 4.52 (t, J-7Hz, 2H), 7.
54 (ddSJ-4 and 8Hz, IH), 7.74
(d,, J=8Hz, IH), 8.10 (dd,
J-2 and 8Hz, IH), 8.26 (dd, J-
2 and 8Hz, IH), 8.69 (ddSJ-2 and 8Hz, IH), 9.03 (d, J-4Hz, I
H).

(d) Elemental analysis: Theoretical value (as C13H1°N2o3s) C: 56.5
1, H: 4.3B, N: 10.14 Analysis value C: 56.64, H: 4.42, N: 10.2
3゜(E) FDMS (m/z): 277 (M +
1) Synthesis Example 5 2-naphthalenesulfonyl chloride (5.0 g).

0.022 mol) and N-trimethylsilyl-2-pyrrolidone (6.9 g, 0.044 mol) at 85°C.
The mixture was stirred for 30 minutes. The reaction product was dissolved in chloroform (50ml
) and add silica gel (Wakogel C-200) to this.
, 15 g) was added thereto, and chloroform was distilled off from it under reduced pressure. The obtained powdery residue was passed through a column (D40 Dragon XL318) of silica gel (Wako Gel C-200, 200 g).
Chromatography was performed using The crystalline product obtained by elution 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.

3050(w), 2970(w), 2920(v)
, 1925(v), 1740(s), 1620(v)
), 1585 (V), 1500 (V), 1460 (w
), 1420(w), 1395(v), 1380(
v), 1360(S), 1350(S), 1321
(v), 1280(v), 1270(w), 1240
(v), 1 210 (+a), 1 190 (s+
), 1 170(s), 1150(v),
1130(i), 1120(s), 1075(a)
, 1.020 (w) , 962 (a+), 945 (w)
, 900(v), 890(w), 870(w),
858(v), 822(a), 755(s), 71
2(m), 660(s), 640(11), 6
10(m), 585(m), 555(11)
, 542 (m) , 530 (w), 495 (v) , 4
85(w), 475(w), 455(v).

(c) H-NMR (100MHz.

CDC13) δ: 2.08 (qufntet,
J-7Hz, 2H), 2.44 (tS J=7H
z.

2H), 4.00 (t, J=7Hz, 2H), 7.
66 (m, 2H), 7.99 (m, 4H),
8.64 (br, s, IH).

(d) Elemental analysis: Theoretical value (as C14H13NO3S) C: 61.07
, H: 4.76, N: 5.09° Analysis value C: 61.27, H: 4.8B, N: 5,20
゜(E) FDMS (m/z): 275 (M”
).

Synthesis example 6 β-Styrenesulfonyl chloride (4.5 g.

o, 022 mol) and N-trimethylsilyl-2-pyrrolidone (6.9 g, 0.044 mol).
The mixture was stirred at 90°C for 80 minutes. The reaction product was mixed with chloroform (5
0ml) and add silica gel (Wakogel C-
200.15 g) was added thereto, and chloroform was distilled off under reduced pressure. The obtained powdery residue was passed through a silica gel (Wako Gel C-200, 200 g) column (D40++ mXL
318+am). The product eluted with a mixed solvent of hexane-ethyl acetate (3:2) was further purified by silica gel (Wakogel C-2).
00,20g) column (D20m layer XL127). 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 crystallized again with the same solvent system to obtain N-(
Crystals of β-styrenesulfonyl)-2-pyrrolidone (0
, 19g) was obtained.

(a) mp: 126.5-127.0°C.

Br (o) IRν (as-'); 35
50(s+), aX 3460(s), 340'0(s), 3230(v
), 3050(v), 2990(v), 2950(
v), 2900(v), 1910(v), 17.3
8 (s), 1690 (v), 4640 (m), 1
615(s), 1610(s), 1575b), 1
490(v), 1485(w), 1450(m),
1410(w), 1380(w), 1353(s)
, 1335(11), 1320(v), 1305(ν
), 1282(w), 1240(m), 1218(m
), 1185(s), 1170(o+), 1150
(s), 1120(s), 1070(v), 102
0(v), 1010(v), 995(s), 960
(s), 930(w), 892(v), 860(m
), 830(v), 810(m), 758(s)
, 710(w), 690(a+), 630(s),
615(m), 582(y), 580(v), 55
0(g), 540(a+), 520(i), 495
(m).

(c) H-NMR (100MHz.

CDC13) δ: 2.14 (quntet,
J = 7Hz, 2H), 2.55 (t, J = 7H
z.

2H), 3.90 (tS J=7Hz, 2H),
7.07 (dS J=16Hz, IH), 7.46
(m, 5H), 7.71 (d, J=16Hz
, IH).

(d) Elemental analysis: Theoretical value (as C12H13N03S) C: 57.35
, H: 5.21, N: 5.57° Analysis value C: 57.48, H: 5.33, N: 5.68
゜(E) FDMS (m/z): 251 (M)
.

Synthesis Example 7 N-1- to 3-fluorobenzoyl chloride (6,34g)
Add dimethylsilyl-2-pyrrolidone (6.9 g),
The mixture was stirred until the reaction heat subsided. The reaction product was dissolved in chloroform (50 ml), and silica gel (Wakogel C-200, 15 g) was added thereto. Chloroform was distilled off from this under reduced pressure. The powdery residue was transferred to a column of silica gel (Wako Gel C-200, 150 g) (D4011+1).
It was subjected to chromatography using XL250 (XL250). Elution was performed with a mixed solvent consisting of hexane-ethyl acetate (3:2). The obtained crude crystals were recrystallized from a mixed solvent of chloroform and ether to obtain crystals (7.43 g) of N-(3'-fluorobenzoyl)-2-pyrrolidone.

(a) mp: 105.5-106.0°C.

Br mouth) IRν (ell-1):3550(1
), aX 3480(s), 3430(s), 3250(v)
, 3100(w), 3070(v), 3000(w)
, 2980(w), 2920(v), 1750(s
), 1670(s), 1660(sh), 1640
(w), 1620(m), 1595(+e), 15
25(w), 1490(i), 1460(v)145
0(s), 1420(v), 1388(v)1360
(m), 1345 (sh), 1325(s), 13
15 (sh), 1280 (v), 1250 (s),
1235(v), 1222(s), 1185(s)
, 1140(s), 1085(v), 1030(v)
, 1002(v), 985(v), 970(v)
, 940(v), 915(w), 900(intestine)
, 850(v), 820(v), 802(s
), 762(m), 705(v), 685(v)
, 658(w), 630(v), 620(m), 5
40(v), 523(v), 483(v), 4
10(v).

(c) H-NMR (100MHz.

CDC13) δ: 2.16 (quintot,
J = 711zs 2H), 2. 26 (t
S J-7Hz.

2H), 3.96 (t, J=7Hz, 2H), 7
．． 3 (m, 4H).

(d) Elemental analysis: Theory ffL (as C11H1oNFO2) C:63.
76, H: 4.86, N: 6.76° Analysis value C: 63.6B, 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) to give 1
Stir for hours. The reaction mixture was dissolved in chloroform (50 ml), washed with water, dried over Glauber's salt, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from a mixed solvent of chloroform and ether to obtain crystals of N-(4'-fluorobenzoyl)-2-pyrrolidone (2.02 g).
I got it.

(a) mp, 1.28.5-129.5°C.

Br (o) IRν (cm-1): 3550 (m
), ax 3450(s), 3400(s), 3250(w)
, 3080(w), 3000k), 2900(ν)
, 1920(v), 1745(s), 1660(s)
), 1640(m), 1620(s), 1605(
s), 1510 (+n), 1480 (ν), 1460
(w), 1415(w), 1383(ν), 1355
(ν), 1325(s), 1305(w), 129
5(n+), 1270(w), 1240(s), 1
225(s), 1185(s), 1180(sh),
1160 (s), 1130 (w), 1100 (v)
, 1072(v), 1020(01), 972(v
), 950(w), 905(w), 887(v)
, 850(s), 830(w), 805(v), 7
70(s), 710(ν), 680(v), 638
(v), 620(ν), 610(ν), 585(s),
522(v).

('') H-NMR (100MHz.

CD013) δ: 2. 15 (quntet,
, J -7Hz, 2H), 2-61 (ts
J-7Hz-2H), 3. 95 (t, J-
7Hz, 2H), 7, 08 (ts J-9H
z, 2H), 7.65 (dd, J-5 and 9Hz,
2H).

(d) Elemental analysis: Theoretical value (as CHNFO2) C: 63.76, H: 4.86, N: 6.76° Analysis value 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),
Stirring was continued until the exothermic reaction subsided.

The reaction product was dissolved in chloroform (50 ml), washed with water, dried over Glauber's salt, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from a mixed solvent of chloroform and ether to obtain N-(2'-fluorobenzoyl).
-2-pyrrolidone crystals (3.58 g) were obtained.

(a) mp: 90℃O t3r (b) IRν (cm-1): 3530(a)
+), IIax 3450(s), 3400(s), 3220(w)
, 3080(w), 3040(ν), 2970(ν)
, 2900(w) , 2000(w) , 1970(v
), 1940(w), 1740(s), 1660(
s), 1640(a+), 1612(s), 158
0 (Im), 1540 (m) 1.1490 (s),
1455(s), 1420(w), 1380(v)
, 1360(i+), 1327(s), 1280(v
), 1265(m), 1240(m), 1220(
s), 1185(s), 1175(m), 1150
(w), 1100(i), 11070(>, 106
0(v), 1025(s), 980(v), 955
(w), 900(m), 830(01), 775(
a+), 758(s), 708(m), 635(a
+), 610(s), 538(1), 503(1)
, 475(ν), 440(w), 400(ν).

(c) H-NMR (100MHz.

CDC13) δ: 2.13 (quntet, 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 CHNFO2) C: 63.76, H: 4.86, N: 6.76° Analysis value C: 63.92, H: 4.73, N: 6.59
゜(e) FDMS (m/z): Synthesis Example 10 4-bromobenzoyl chloride (8.78 g).

N-trimethylsilyl-2-pyrrolidone (6,90f, 0.10445 mol) was added to the mixture (0.04 mol) and stirred until the exothermic reaction subsided. The reaction product was directly recrystallized from a mixed solvent of chloroform and ether. N-(
Crystals (8.16 g) of 4'-bromobenzoyl)-2-pyrrolidone were obtained.

(a) mp: 127-128°C.

Br (Inn IRν (el+-'): 345
0(s), 118X 3470(s), 3400(s), 3240(w)
, 2980(v), 2900(v), 1733(s
), 1680(s), 1670(s), 1640(
■), 1620 (IIl), 1590 (+g), 1
480(v), 1418(v), 1399(v),
1358 (■), 1330 (s), 1328 (s)
, 1282(v), 1270(v), 1240(s)
, 1220(v), 1195(v), 1158(v)
), 1110(v), 1065(o+), 1010
45(,101010(,955(V> ,940(v
), 903(v), 888(w), 850(v)
, 830(a+), 760(11), 730(v)
, 690(v), 665(v), 638(s), 6
10(i), 52'5(v), 450(w).

(c) IH-NMR (100MHz, CDC13)
δ: 2. 15 (quntet SJ =7Hz
, 2H), 2.62 (tS J-7Hz.

2H), 3.95 (tSJ-7H2, 2H), 7.
48 (d, J=9Hz, 2H), 7.55 (d, J
-9Hz, 2H).

(d) Elemental analysis: Theoretical value (as C1, H1oNBro2) C: 49.2
7, H: 3.76, N: 5,22° Analysis value C: 49.36, H: 3.83, N: 5.19
゜(E) FDMS (m/z): 269 (M”
+1) Synthesis Example 11 N-trimethylsilyl-2-pyrrolidone (6,90
,,0,044 mol) 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 (8.08g)
I got it.

(a) mp; 126-127°C.

Br (b) IRν (cI+-'): 3450 (
S), 1ax 3250(v), 3100(v), 3080(v)
, 3000(v) , 2900(v) , 1750(s
), 1670(s), 1660(sh), 1640
(m), 1620 (m), 1602 (meal) 1
．． 1520(S), 1495(v), 1460(
v) 1412(v), 1383(v), 1355(s
) 1330(s), 1B20(s), 1300(
1245(s), 1230(v), 1190
(■) 1160 (IIc, 1108(v), 102
0(w)983(w), 91 0(v), 870
(Otori), 850(v), 830(v), 7
80(w), 740(m), 720(s), 68
3(w), 663(ν), 640(m), 610
(v).

(c) H-NMR (100MHz.

CDC13) δ: 2.19 (Qulntet SJ
= 7Hz, 2H), 2.64 Cts J”
7Hzs2H), 4.00 (t%J-7Hz, 2H
), 7.70 (dS J-8Hz, 2H), 8,
27 (d, J=8Hz, 2H).

(d) Elemental analysis: Theoretical value (as C1, H1oN204) C: 56.41
, H: 4.30, N: 11.96° Analysis value C: 56.60, H: 4.27, N: 11.7
8゜(E) FDMS (m/z): 234 (M)
.

Inhibition formula for proline-specific endopeptidase activity (1)
The inhibitory effect of the compound on proline-specific endopeptidase activity was shown by the residual activity of the same peptidase. Experimental methods: Tadashi Yoshimoto, Daisuke Tsuru, Proteins/Nucleic Acids/Enzymes, 29
(2), 127 (1984).

The results are shown in the table below. In addition, the residual activity in that case is also shown using the well-known aniracetam as a standard.

Claims (1)

[Claims] 1. A pyrrolidone derivative represented by the following formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [Here, R is one of the following. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Here, X is -SO_2- or -CO-, and R
' is a halogen or a nitro group, and n is 1 or 2. However, when n=2, R' is the same, and when X is -SO_2-, R' is 4-Cl or 3-NO_
2)] 2. An anti-amnestic drug containing a pyrrolidone derivative represented by the following formula as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [Here, R is one of the following. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Here, X is -SO_2- or -CO-, and R
' is a halogen or a nitro group, and n is 1 or 2. However, when n=2, R' is the same, and when X is -SO_2-, R' is 4-Cl or 3-NO_
It is never 2)]