JPS6284058A - Novel compound having peptidase-inhibiting action, its preparation and use - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (n is integer of 1 or more; R1 is 5-25C-saturated or unsaturated straight-chain hydrocarbon group; R3 is lower alkyl ester, hydroxymethyl, formyl; R2 is methyl, phenyl, indolyl, amino, hydroxy, methylthio; R5 is H, or when n is 3, R2 incorporates to R5 to represent the single bond between C and N atoms). USE:Antiamnesic. PREPARATION:The reaction of a carboxylic acid of formula II, its anhydride or chloride with the peptide of formula III, which has lower alkyl-esterified carboxyl groups and contains proline residues, gives the compound of formula I.

Description

[Detailed description of the invention] (Industrial application field) The present invention uses prolyl endo(butidase (EC).

3, 4, 2 1, 2 6, Fro
This invention relates to a novel compound that exhibits enzyme inhibitory activity against G'/1-endopepttdasa), its chemical synthesis method, and prolyl endopeptidase activity inhibitors and drugs containing it as an active ingredient, especially as an anti-amnestic agent. It is related to the use of.

(Prior art) Prolyl entobutidase is a neurotransmitter, substance P%TRH (thyroid stimulating hormone).
It is known to act on and inactivate neurotensin and vanpressin, which is thought to be related to memory. On the other hand, Dr. Tsuru and Dr. Yoshimoto of the Nagasaki University School of Pharmaceutical Sciences found that a compound that inhibits prolyl entobutidase activity prevents experimental amnesia caused by scopolamine in rats, and they infer that prolyl endopeptidase inhibitors are involved in memory consolidation. did. The results also suggest that prolyl endopeptidase inhibitors may be used to prevent and treat amnesia.

(Technical Problems to be Solved by the Invention) Based on the above findings, the present inventors conducted research to find a compound that has strong prolyl entobutidase inhibitory activity and also has anti-amnestic activity. Furthermore, in order to find a new compound with sufficiently low toxicity, we synthesized a compound similar to a natural product by combining fatty acids, amino acids, and iptide compounds, which are highly safe as natural compounds. We have completed the present invention by discovering that a new compound having anti-prolyl endopeptidase activity has an extremely excellent effect on amnesia.

(Structure of the Invention) The N-acylpyrrolidine derivative of the present invention has the general formula (I) Rt and 3 (wherein R represents an integer of 1 or more, and E represents a saturated or unsaturated compound having 5 to 25 carbon atoms). represents a straight-chain hydrocarbon group, where the unsaturated carbon chain may contain multiple double bonds, and Rs is of the formula: C0OR.

(In the formula, 84 represents a lower alkyl group.) represents a lower alkyl ester group, hydroxymethyl group, or formyl group, and R2 is a methyl group, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group, carboxyl group, formyl group. group, amino group, hydroxy group, hydroxyalkyl group, thiol group, methylthio group, or guanidino group, and each of these groups may be substituted,
R3 represents a hydrogen atom, or when #'in represents the number 3, R2 and 85 together can also represent a single bond between carbon and nitrogen. ).

In the formula, 3 as an integer of 1 or more is preferably from 1 to 30, more preferably from 1 to 12.

A compound in which Rt and R, together in Formula I form a single bond between carbon and nitrogen, has the following structure:

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

Among the compounds of formula (I), the following compounds are preferred in terms of high anti-prolyl endopeptidase activity.

Hereafter, these compounds may be referred to by the numbers in parentheses.

(SUAM1166) (SUAM1212) (SUAM1217) (SUAM1215) The compounds of the present invention can be synthesized by general peptide synthesis methods, but are conveniently synthesized by the synthesis method of the present invention described below. In addition, each abbreviation represents the following meaning.

Z: penzyloxycarbonyl group Boa: tertiary butyloxycarbonyl group pro nibroline residue CH, OH orLeu: norleucine residue Phe: phenylalanine residue Mgt: methionine residue 1, is: lysine residue Li2 (Z): #'-Benzyloxycarbonyllysine residue Glu (Bzl): Glutamic acid-γ-benzyl ester residue CH,OH OMa: Methyl ester group WSCD: N-ethyl-N',N'-dimethylaminopropylcarbodiimide TEA:) Ethylamine The compound of general formula (1) of the present invention can be synthesized as follows.

(1) First, the general formula (in IF, R1 is -COOR
The synthesis of the compound represented by the general formula (Ic) or (Id) which is the lower alkyl ester group of 4 is carried out by combining a carboxylic acid arid, carboxylic acid anhydride or carboxylic acid represented by the general formula: and the general formula (11cL ) or (116): It can be easily synthesized by a conventional method from a peptide containing a proline residue whose carboxyl terminus is esterified with a lower alkyl ester, represented by R-abundance.

(2) Next, in order to obtain a compound represented by the formula (I6) or (I/'') in which R1 is a 10H,OH group in the general formula (Ic) or i
To reduce the compound represented by lm ([d),
For example, methanol may be added dropwise to a suspension of these compounds together with sodium borohydride in tertiary butyl alcohol or tetrahydrofuran.

(3) Furthermore, the compound of the present invention represented by the general formula (Ig) or (I) is prepared from the metal compound represented by the general formula (Ic) or (1f) using, for example, a sulfur trioxide-pyridine complex as an oxidizing agent. Synthesize. Dimethyl sulfoxide is used as the solvent, the reaction temperature is room temperature, and the reaction time is about 1 hour.

Next, the present invention will be explained in more detail based on Examples and Reference Examples.

Reference example Synthesis (a) of starting material represented by formula (Ill)
H-Phg-Pro-OMgZ-Pha-OH
(1 eq.), Pro-0Mg hydrochloride (1 eq.) and T
EA (1 eq.) is dissolved in dry methylene chloride and WSCD (1 eq.) is added under water cooling. After stirring at room temperature for 20 hours, the reaction solution was washed with IN hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure is purified by medium pressure column chromatography using silica gel. Obtained Z
-Alla-Pro-OMg (1 equivalent t) was dissolved in ethanol, and boron trifluoride-ether complex (1 equivalent) and para/rum carbon (medium value) were separated and 2
The group is removed and the solvent is distilled off under reduced pressure to obtain the desired product.

In the above (α), instead of Z -Phg -OH, @;l-
Met-OH, (a) Z-norLgu-OH1j
, - by using (a') H-Me, respectively
t -Pro-OMg, (i')H-norLelL
-Pro-OMg can be obtained (oil compound).

(b) H-L! /5(Z) -Pro-OMg-)
Refluorinated Boc-Lys(Z)-OH (1 equivalent), Pro-0Mg hydrochloride (1 equivalent) and TEA (1 equivalent)
t) in dry methylene chloride and WSCD under water cooling.
(1 equivalent) is added. After stirring at room temperature for 20 hours, the reaction solution was washed with IN hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure is purified by medium pressure column chromatography using silica gel.

The obtained Boa-L9s(1)-Pro-OMa
J) (1 eq.) Dissolve in dry methylene chloride, add excess trifluoroacetic acid and stir (approximately 6 hours). The solvent is distilled off under reduced pressure to obtain the desired product (oil compound).

In (b) above, Boc -L'/ 8 (?) -O
By using Eoc-Glw(Bzl)-OHf instead of H, H-Glu(Bzl)-Pro-
0 Mg .) Lifluoroacetate is obtained (oil compound).

(CI H-Pro -Pro -OMgZ-Pr
o -OH (1 eq.) and H-Pro-OMg-hydrochloride (1 eq. and TEA (1 eq. fk) are dissolved in dry methylene chloride and WSCD (1 eq.) is added under water cooling. Stir at room temperature for 20 hours. After that, the reaction solution was washed with IN hydrochloric acid, water, saturated water, water, and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure, and the resulting residue was passed through a medium-pressure column using silica gel. Purify by chromatography.

The obtained Z -Pro -Pro-OMg (1 equivalent)
Dissolved in ethanol, boron trifluoride-ether complex (
1 equivalent) and palladium on carbon (a small amount) are added, the Z group is removed by catalytic reduction in a hydrogen atmosphere, and the solvent is distilled off under reduced pressure to obtain the desired product as an oily compound.

All of the target compounds can be obtained in oil form.

As a result of investigating the efficacy of this compound in inhibiting the decomposition of Z-glycyl-prolyl-β-naphthylamide by prolyl endopeptidase, it was found that it exhibited very strong anti-prolyl endopeptidase activity, as shown in the test example below. It showed no inhibitory activity against proteinases such as , papain, promelain, trypsin, chymotoribusi/, thermolysin, and ebucin.

Furthermore, the present compound thus obtained is novel and has anti-amnestic effects as shown in the Examples.

Example 1 a) N-oleoyl-Phe-Pro-OMe
(S UAMH-Phe, -Pro -OMgZ,
, 1 equivalent) and TE:A (1 equivalent) were dissolved in dry tetrahydrofuran, and oleic acid chloride (1 equivalent) was dissolved under water cooling.
8 drops were added. The mixture was stirred at room temperature for 6 hours, and the precipitated TEA hydrochloride was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was dissolved in a small amount of ether, washed with IN hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, an ether solution of diazomethane was added (excess) to methyl esterify unreacted oleic acid. The residue obtained by distilling off the solvent under reduced pressure was subjected to medium pressure column chromatography using silica gel to obtain the target compound. (
Oily compound) In the above (α), H-Phe-Pro
-OMg (7) instead of (7) H-Met-Pr
By using o-OMg (a') oleoyl-
Met-Pro-OMtt (SUAM1198)
(a) H-norLttrb -Pro
By using -OMg (a') oleoyl-n
orLaw-Pro-OMe(SUAMll 64
), and in the above (α), H-Pha -Pro-
Instead of OMg (1 eq.) and TEA (1 eq.), (
'A H-L'/5(Z) -Pro -Oleoyl-Z,ys(f)- by using 0Mg trifluoroacetate (1 equivalent) and TEA (2 equivalents)
Pra-QMg (SUAMll 97), (1)H
-Glw(Hz l ) -Pro -OMg .) By using lifluoroacetate (1 eq.) and TEA (2 eq.), (bi')oleoyl-Glu(Ezl) -
Pro-OMg (SUAM1196) can be obtained respectively.

(bI N-oleoyl-pro-Pro-OM
tt (SU AMH-Pro-Pro-OMt
t (1 equivalent) and TA'A (1 equivalent) were dissolved in dry tetrahydrofuran, and oleic acid chloride (1 equivalent) was added under water cooling.
was dripped. The mixture was stirred at room temperature for 6 hours, and the precipitated TEA hydrochloride was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was dissolved in a small amount of ether, washed with IN hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, an ether solution of diazomethane was added (
Excess) unreacted oleic acid was methyl esterified. The residue obtained by distilling off the solvent under reduced pressure was purified by medium pressure column chromatography using silica gel to obtain the target compound. (Oil compound) Example 2 (α) Oleoyl-Phi-Pro-CH,OH(
Oleoyl-Pha-P obtained in SU A M Example 1
ro-OMe (SUAMl194) (2g) and sodium borohydride (600 ml) are dissolved in tertiary Budel alcohol (60rR1) and heated and stirred (80°C).

Then, anhydrous methanol (5ON) was added dropwise under reflux, and after the dropwise addition was completed, the mixture was heated under reflux and stirred for 2 hours. The reaction solution was returned to room temperature, and water (several M) was added while cooling with water to inactivate unreacted sodium borohydride. After methanol and tert-butyl alcohol were distilled off under reduced pressure, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by medium pressure column chromatography using silica gel to obtain the target compound (
1 g) was obtained. (Oil compound) In the above (α), oleoyl-Ph is used as a raw material compound.
By using (a) oleoyl-Met-Pro-OMg instead of a-Pro-OMtt, (a') oleoyl-Met-Pro-CH,OH
(SUAMl206), (a) oleoyl-nor
By using Leu-Pro-OMe (Ilioleoyl-norLtsu-Pro-CH,OH
(SUAM 1165), (one) oleoyl-
By using L'/5 (1) -Pro -OM g (1') oleoi# -r,ys(z) -Pro
-cH,oH (SUAMl207) is converted into (2')oleoyl-Ghb(CH20
H) -Pro -CH,OH (SUAMl209) were obtained, respectively.

(b) Oleoyl-Pro -Pro -CH,OH (
, S' U A M Oleoyl-Pro obtained in Example 1
-Pro -ON g (SUAM1 engineering 95) (2g)
and sodium borohydride (600y) are dissolved in tertiary butyl alcohol (60rILe) and heated and stirred (8
0℃).

Next, flowing anhydrous methanol (50M) was added dropwise to No. 1, and after the addition was completed, the mixture was heated under reflux and stirred for 2 hours. The reaction filtrate was returned to room temperature, and unreacted sodium borohydride was inactivated by adding water (several ILt) while cooling with water. After removing methanol and tertiary butyl alcohol under reduced pressure, extraction with ethyl acetate,
The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by medium pressure column chromatography using silica gel to obtain the target compound (1 g) (oil compound).

Example 3 (α) Oreoi-Phtt-Pro-CHO(
Oleoyl-Phe-Pr'' obtained in S UAM Example 2
o-CH20H(SUAMl205) (1,!i'
) and TEA (800 m9) were dissolved in anhydrous dimethyl sulfoxide (8N), and sulfur trioxide-pyridine complex (700 m) was dissolved in dimethyl sulfoxide (811 m9) with stirring.
t) Added solution. Stir bag for about 1 hour at room temperature, ice water (10
0M), extracted with ethyl acetate, and extracted with IO% citric acid@
After washing with liquid, saturated brine, saturated J water, and saturated brine, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to medium pressure column chromatography using silica gel to obtain the target compound. (700■)(
Oily compound) In the above (a), oleoyl-P is used as a raw material compound.
By using (a) oleoyl-Me t -pro -CH20H instead of he -Pro -CH,OH, (a') oleoyl-Mtxt -Pro
-CHO (S U AM1214) to (a) oleoyl-norLeu -Pr.

By using -CH,OR (a') oleoyl-
norLeu-Pro-CHO (S U AM 116
6), (one) oleoi k -Lys(Z) -Pr
By using o -CH20Hf (T')oleoyl-L'1s(Z) -Pro-CHO(SUAMl
216), (1) oleoyl-Glw(CH,OH
) -Pro -CH,OH (2'
) Oleoyl-Glw(CHO) -Pro -CHO
(SUAM1217) can be obtained.

(bl Oleoyl-Pro-Pro-CHO (SU
Oleoyl obtained in AM Example 2 -Pro -Era-
cg, oH (svAwx 204) (1g) and TEA
(800~) was dissolved in anhydrous dimethyl sulf7oxide (81), and the sulfur dioxide-pyridine complex (700
IIv; A dimethyl sulfoxide (8M) solution was added. After stirring at room temperature for about 1 hour, the mixture was poured into ice water (100μ), extracted with ethyl acetate, washed with 10% citric acid solution, saturated brine, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The bath medium was distilled off under reduced pressure, and the resulting residue was purified by medium-pressure column chromatography using silica gel to obtain the target compound (700 cm) (oil compound).

The physicochemical data of the obtained compound are shown in Table 1. The compounds in Table 1 are all oily, and include CCZ, ether, CHCII, CH2Cl12, A:OB.
t.

and QJ soluble in Mg0H, and SUAM11
It is also soluble in 94t'i benzene.

Compound Molecular formula SUAM 1194 SUAM 1198 SUAM 1164 IEνfr,, (m-” H-N
MR(δ)330.3250.2920, 0.9(3
H, 倶), l-0~2.4 (34g.

740.1630.1600 inertia), 8.70 (2H
, always), 8.76420.1370.1200 (
3H, It), 4.50 (If, Tsumugi), 80.840.
770, 5.00 (IH, fi), 5.35
(2H, m), 0 6.4
0 (IH, d, J = 9.0), 7.24 (5H, 8) 920.2850.1740 0.90 (3H, m
), 1.1-2.4 (32H.

530.1440.1360 m), 8.12 (3
ff, s), 2. ．． 58 (2H.

190.1170.950 Regular), B, 73C3H
, a), 8.75 (2H.

Om), Shizu, 54 (111, m), 4.94 (IH
.

inertia), 5.34C2H, tn), 6.32 (IH*as
,y=8. o) 0.8-1.0 (6H, tn), 1.0-2.4 (3
8H, m), 8.70 (2H, m), 8.72 (3H,
s included 4.50 (IH, m), 4.76 (1#, m), 5
．． 32 (2H, m), 6.28 (IH, d, J = 8.0
) SUAM 1197 SUAM 1196 SUAM 1195 2850.1740 0.90C3H,m), 1.1
~2.4 (38H.

1530.1450 m), 3.22 (2H, r
n), 8.66 (3#.

1170.730 g), 8.72 (2B, apprehension)
, +, 5o (IH.

), 4.80 (lH, fA), 5.10 (2H.

m), 5.35C2H, m>, 6.34 (IH.

d, J=8.0n,'! , 35 (5H, 5) 285
0.1730 0.90 (3H, m), 1.0-2.
8 (36#.

1170.730 m), 8.70C2H, m)
, 8.72<3H.

8), 4.50 (IH, m), +, 9o (xH.

γ1, ), 5.14 (2H, dd, J=15.0n,
5.35 (2H, m), 6.38 (H, d, J=9.
0) 2850.1740 0.90 (3H, m), 1.2~
2.4C36H.

1320.1190 m), 14-4.0 (4H,
m), 3.72C3H, 8), 4.5-4.8 (2H,
m), 5.35 (2H, m) ] SUAM 1205 ] SUAM 1206 :850.1610 0.88 (3H, m), 1.
0-2.4 (32H.

040.690 m), 8.00 (2H, m)
, 8.2-8.8C4H, m), 4.20 (2H, m
), 4.96 (IH, m), 5.34 (2H, m),
6.28 (IH, d, J=8.0), 7.26 (5H.

:850.1620 0.90 (3H, m), 1.
0-2.4 (34H.

050.730 m), 2.10 (3H, s)
, 2.54 (2H.

t, J=7.0), 8.6-4.0 (4H, 倶)
, 4.28 (2H, m), 4.94 (LH, m), 5
．． 34 (2H, m), 6.28 (LH, d.

J=8.0) 0.84 (6H, groove), 1.0-2.3 (38H.

m), 8.56 (3H, m), 8.80 (IH.

爲), 4゜12(LH, η, 4.70(2H.

m], 5.38 (2H, m), 6.46 (IH.

d, J=8.0) SUAM 1207 SUAM 1209 SUAM 1204 3300.2925.2850.1700 0.8
8 (3B, m), 1.0-2.3 (38H.

1620.1530.1450.1250 m),
8.18 (2H, tn), 3.4-8.81050.7
30.700 (3H, m), 4.
30 (2H, m), 4.6-5.2 (3i9m), 5
．． 08 (2H,s), 5.32 (2H,m), 6.
38 (lB, d.

J=8.0), 7.34 (5H, a) 3300.29
20.2850.1720 0.82 (3H, mJ
, 1.0-2.2 (36B.

1610.1530.1450.1180 m),
8.2-8.9 (7H, m), 4.12720.59
0 (IH, m), 4.7
6 (2H, m), 5.28 (2H1 regular), 7. υ4(
lH, a,, r 8.0) 3400.2920.2850.1620 0.86
(3j7.m), 1.0-2.4 (36B.

1430.1320.1140.920 m),
8.60 (5ff, m), 8.80-4.40720
(2H, m), 4.
70 (IB, groove), 5.15 (IB9), 5.3o (
2B, Ina〕 3300. 1620. 740.7 SUAM 1212 3300. 1620. 1110, SUAM 1214 3300. 1620. 990.7 2920.2850.1730 0.88 (3H, m
), 1.0-2.4 (32H.

1530.1450.1loo frL), 8.08
(2B,,), 8.60 (2H.

:) Otn), 4.38 (IH, m), 5.00 (IH
.

love), 5.32 (2,77, door), 8.24 (lH.

d, J=8.0), 7.26 (5H,s),
9.3z (xH・d, J=8.0)2920.2
850.1730 0.88C3H, m), 1.0~
2.3 (34H.

1530.1440.1340 m), 2.12(
3H, a), 2.58 (2H.

750 m), 8.74 (
2H, m), 4.54 (IH.

m), 4.96 (Hf, mJ, 5.33 (2H.

groove), 6.26 (LH, d, J = 8.0) 9.50 (I
H, d, J = 2.0) 2920.2850.1730 0.84 (6H, m
), 1.0-2.3 (38H.

1540.1450.1110 m), 3.70 (
2H, m), 4.50 (IH.

20 m
), 477 (IH, m), 5-30 (2H.

m), 6.40 (1i, t, , r=s, o)
9.47 (1#, d, J = 2.0) SUAM 1216 SUAM 1217 SUAM 1215 2930.2850.171 (J O, 88 (3H
, m), 1.0-2.4 (38H.

1530.1450.1340rn), 3.20
(2H, m), 4.54 (LH.

1130, l 020.740 m), 4.82
(2H, m), 5.08 (2#.

8), 5.32 (27f, m), 6.26 (LH.

d, J=8.0), 7.33 (5#, s), 9.
48 (LH, d, J=1.5) 2920.28
50,1720 0.86 (3#, m), 1.0~
2.6 (36H.

1530.1440.1 (,180m), 8.70 (
2H, m), 4.60 (IH.

m), 4.84 (IH, m), 5.32 (2H.

m), 6.34 (1#, d, J=8.0),
9.50<xi, tt, J=3.0. ．．
7=1.0) 9.78 (1M, d, J=2.0) 2920.2850.1720 0.86 (3#, m
), 1.0-2.4 (36B.

1430.1320.1200 m), 8.60<
4B, m), 4.60 (2H.

m), 5.32 (2H, m), 9.50 (1, H.

d, J=2.0) Example 4 Measurement of anti-prolyl endopeptidase activity Measurement of anti-prolyl endopeptidase activity was carried out by Yoshimoto (T.
moto and Tori, Tsurrb, Agr, Biol.

Chem, 42.2417.1978). That is, 0.0025M Z-glycyl-proline-β-naphthylamide 0.25rILt, O, 1M
0.99 ml of phosphate buffer (pH 7.0) and 0.99 ml of a solution of the anti-prolyl entobutidase compound of the invention.
After heating the mixture containing 0.01g in a test tube at 37°C for 3 minutes, add prolyl entbutidase solution (0.2 units/
WLt) was added at 0.1 d710 and reacted at 35° C. for 10 minutes. Thereafter, Triton X-100 in 1M acetate buffer (pH 4,0) @ solution 2. Q
ml was added so that the final concentration of surfactant was 10%, and after being left at room temperature for 15 minutes, the absorbance (α) at 410 nm VC was measured.

At the same time, the blind absorbance (b+) was measured using only a buffer solution instead of the anti-prolyl iptidase compound solution, and the prolyl entbutidase inhibition rate was calculated using the following formula: % formula %, 50% inhibition. The required amount [IC, .] was determined. The test results are shown in Table 2.

Table 2 Example 5 Measurement of the preventive effect of experimental amnesia by scopolamine using rats ([intracavitary administration]) Examining the effect of the anti-prolyl endo (petitase compound of the present invention) on preventing long-term memory consolidation inhibition by scopolamine That is, 9% of the compound of the present invention was added to 1 /
O-25mq/g, 0.1~/g, 0.025■/
9.0.010 m? / Wistar (Wistar) after adjusting the size to correspond to the size of the
ster) strain male rats (100-120p) once into the peritoneal cavity, and 1 hour after administration, electric shock (1.7rn
Passive avoidance learning according to A) was performed, and immediately thereafter, an amount equivalent to scopolamine 3m91IC9 was intraperitoneally administered.

Effects were determined by passive avoidance tests 24 hours and 48 hours later.A control group of animals in which scopolamine and physiological saline were intraperitoneally administered without administration of the test compound, and a control group in which scopolamine and saline were administered intraperitoneally without administration of the test compound and administration of scopolamine. This was done by comparing the number of amnestic and non-amnestic rats in each group of animals that were tested together. Test results 8 are shown in Table 3.

Claims (9)

[Claims] (1) General formula (1): ▲Mathematical formulas, chemical formulas, tables, etc.▼(1) (In the formula, n represents an integer of 1 or more, and R_1 is a saturated or unsaturated straight line with 5 to 25 carbon atoms. Represents a chain hydrocarbon group, where the unsaturated carbon chain may contain multiple double bonds, and R_3 is a lower alkyl ester of the following formula: -COOR_4, where R_4 represents a lower alkyl group. basis,
Represents a hydroxymethyl group or formyl group, R_2
is a methyl group, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group, carboxyl group, formyl group, amino group, hydroxy group, hydroxyalkyl group,
It represents a thiol group, a methylthio group, a guanidino group, etc., each of these groups may be substituted, and when R_5 represents a hydrogen atom or n represents the number of 3,
R_2 and R_5 together can also represent a single bond between carbon and nitrogen. ) A compound represented by (2) General formula (Ia): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ia) (In the formula, n, R_1 and R_3 are the first claims
R_2 represents a methyl group, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group, carboxyl group, formyl group, amino group, hydroxy group, hydroxyalkyl group, thiol group, methylthio group, or It represents a guanidino group, etc., and each of these groups may be substituted. ) The compound according to claim 1, which is represented by: (3) General formula (Ib) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ib) (In the formula, R_1 and R_3 represent the meanings given in claim 1.) Represented by , a compound according to claim 1. (4) The compound according to claim 1 or 2, wherein n represents a number from 1 to 30. (5) The compound according to claim 4, wherein n represents a number from 1 to 12. (6) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 represents the meaning given by the following formula (I)) A carboxylic acid, carboxylic acid anhydride, or carboxylic acid chloride represented by General formula (II) ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, n, R_2, R_3 and R_5 are the following formulas (
I) has the meaning given by ), the carboxyl group is reacted with a peptide containing a lower alkyl esterified proline residue to form the general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (where n is 1 or more, R_1 represents a saturated or unsaturated linear hydrocarbon group having from 5 to 25 carbon atoms, where the unsaturated carbon chain may contain multiple double bonds, and R_3 represents A lower alkyl ester group of the following formula: -COOR_4 (in the formula, R_4 represents a lower alkyl group),
Represents a hydroxymethyl group or formyl group, R_2
is a methyl group, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group, carboxyl group, formyl group, amino group, hydroxy group, hydroxyalkyl group,
It represents a thiol group, a methylthio group, a guanidino group, etc., each of these groups may be substituted, and when R_5 represents a hydrogen atom or n represents the number of 3,
R_2 and R_5 together can also represent a single bond between carbon and nitrogen. ) A method for producing an N-acylpyrrolidine derivative represented by: (7) General formulas: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas,
There are tables, etc.▼ (In the formula, R_1 represents the meaning given by the following formula (I).) Carboxylic acid, carboxylic acid anhydride, or carboxylic acid chloride represented by the general formula (II) ▲Mathematical formula, chemical formula , tables, etc.▼(II) (In the formula, n, R_2 and R_3 represent the meaning given by the following formula (I), and R_5 is the following formula: -COOR_
4 (in the formula, R_4 represents a lower alkyl group). ), the carboxyl group is reacted with a peptide containing a lower alkyl esterified proline residue to form the general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (where n is represents an integer of 1 or more, R_1 represents a saturated or unsaturated linear hydrocarbon group having from 5 to 25 carbon atoms, where the unsaturated carbon chain may contain multiple double bonds, R_3 is a lower alkyl ester group of the following formula: -COOR_4 (in the formula, R_4 represents a lower alkyl group),
Represents a hydroxymethyl group or formyl group, R_2
is a methyl group, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group, carboxyl group, formyl group, amino group, hydroxy group, hydroxyalkyl group,
It represents a thiol group, a methylthio group, a guanidino group, etc., each of these groups may be substituted, and when R_5 represents a hydrogen atom or n represents the number of 3,
R_2 and R_5 together can also represent a single bond between carbon and nitrogen. ) is obtained and reduced to form an N-acylpyrrolidine derivative represented by formula (I) in which R_3 is -CH_2O
A compound with H is obtained, and this is further oxidized to give the general formula (
A method for producing an N-acylpyrrolidine derivative in which R_3 is -CHO in I). (8) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, n represents an integer of 1 or more, and R_1 is a saturated or unsaturated straight line with a carbon number of 5 to 25. Represents a chain hydrocarbon group, where the unsaturated carbon chain may contain multiple double bonds, and R_3 is a lower alkyl ester of the following formula: -COOR_4, where R_4 represents a lower alkyl group. basis,
Represents a hydroxymethyl group or formyl group, R_2
is a methyl group, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group, carboxyl group, formyl group, amino group, hydroxy group, hydroxyalkyl group,
It represents a thiol group, a methylthio group, a guanidino group, etc., each of these groups may be substituted, and when R_5 represents a hydrogen atom or n represents the number of 3,
R_2 and R_5 together can also represent a single bond between carbon and nitrogen. ) A prolyl endopeptidase activity inhibitor comprising an N-acylpyrrolidine derivative represented by: (9) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, n represents an integer of 1 or more, and R_1 is a saturated or unsaturated straight line with a carbon number of 5 to 25. Represents a chain hydrocarbon group, where the unsaturated carbon chain may contain multiple double bonds, and R_3 is a lower alkyl ester of the following formula: -COOR_4, where R_4 represents a lower alkyl group. basis,
Represents a hydroxymethyl group or formyl group, R_2
is a methyl group, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group, carboxyl group, formyl group, amino group, hydroxy group, hydroxyalkyl group,
It represents a thiol group, a methylthio group, a guanidino group, etc., each of these groups may be substituted, and when R_5 represents a hydrogen atom or n represents the number of 3,
R_2 and R_5 together can also represent a single bond between carbon and nitrogen. ) An anti-amnestic agent containing an N-acylpyrrolidine derivative represented by the following as an active ingredient.