JPH0169A - Novel prolinal derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to prolyl endopeptidase 7'-F-dase (prolyl
lyl endopeptidass) inhibitory activity.

More specifically, the present invention provides: 1) a novel prolinal derivative represented by the following general formula having prolyl endopeptidase inhibitory activity (in the formula, all symbols have the meanings as shown below); ) their production methods and illusions Containing them as active ingredients (yi, 111'
Concerning amnesia drugs.

Conventional technology Recent research is gradually elucidating the true nature of the push transmitters in the body, substances that have a deep connection with memory, and many of these are thought to be neuropeptides containing proline. .

It has been reported that when these proline-containing pP peptides are administered to rats with experimental amnesia, memory is restored (see 5science 211, 601 (1981)).

On the other hand, these neuropeptide hormones are estimated to be metabolized by peptidase injected into the brain, and especially prolyl endopeptidase (prolyl endopeptidase).
peptidass: EC, 3, 4, 21, 26)
is thought to be deeply involved in metabolism (
J. Biochsm 94, 1179 (1983
).

From these things, by inhibiting prolyl endopeptidase? Research guidelines are being directed towards suppressing the metabolism of the 141st generation of proboscis shells and preventing or treating amnesia (proteins, nuclei, enzymes 2).
5 (Su, 513 (1980): Japan 1ka Kajikai u 5
8(11), 1147 (1984): J.

Neurochem, 41.69 (1983):
42.237 (1984)).

There are several compounds that have been synthesized for these purposes, including N-benzyloxycarbonyl-glycyl-j
It has been shown that loryluchloromethane E and N-benzyloxycarbonyl-t,-floryl-chloromethane potently inhibit prolyl endopeptidase (J.

Neurochem, 41, 69 (1983
) reference).

In addition, recently, a prolinal brocade conductor (see JP-A-60-188317 , (1υ -mosquito formula [where nb represents a number from 1 to 4, and Hb represents a lower alkyl ester group, -CH, OH group, or aldehyde group.

N-acylpyrrolidine conductor represented by
-37764; by amendment, compounds with n = 5 are also disclosed) and (phantom general formula [wherein Ac represents a methyl group or a benzyloxy group, and Be has the same meaning in one formula] is an isopropyl group or an isobutyl group, and ne represents 2 or 3.'' Compound 9B (JP-A No. 61-183297-10 has been disclosed to be used for M for the above purpose. ing.

Furthermore, recently, the anti-amnestic and anti-amnesiac Chikyo Dian-hyeon, which has a prolinal skeleton, was released.

(1v) Compound represented by the general formula (see JP-A-61-238775)
, (V) General formula: In the formula, R represents a lower alkyloxycarbonyl group, hydroxymethyl group, or formyl group, R16 represents a hydrogen atom or a lower alkyl group, and R2@ represents a phenyl group or a group of the following formula (wherein where R represents a hydrogen atom, a halogen atom or a lower alkoxy group, Rs6 represents a hydrogen atom or a lower alkyl group, ne represents 0 or 1, A@ represents an oxygen atom, a methylene group, a hydroxymethylene group,
Phenylmethyleno group or carbonyl41. or R1@ and R2@ together represent an aromatic ring T1 or an unsubstituted benzylidene group. ”
N-acylpyrrolidine conjugate (Japanese Patent Application Laid-Open No. 1989-1992)
1-238776).

(No. V) -ff formula (wherein nf indicates the number of O~2, Rlf is a saturated or unsaturated 1I of carbon chains 5 to 25)
If represents an organic group, where the unsaturated carbon chain is
(may contain a double bond of 1161, or -cn,
R3f represents a lower alkyl ester group, -CH, OH group, or aldehyde group. ) (see JP-A-61-238799).

(v+i) General formula (wherein, ng represents an integer of 1 or more, R1 represents a J!2! sum or unsaturated straight-chain hydrocarbon group having carbon chains from 5 to 25, where unsaturated The carbon chain consists of multiple 231
In the following formula -COORC, R4 represents a lower alkyl group. )g represents a lower alkyl ester group, droxymethyl group, or formyl group, and 82g represents a methyl group, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group, carboxyl group, formyl group, amine group, hydroxyl group, hydroxyl group, It represents an alkyl group, a thiol group, a methylthio group, or a guanidi7 group, and these six groups may be substituted, and when R5 represents a hydrogen atom or ng represents the number of 3, R and 86g together can also represent the -X introduction between g carbon and nitrogen. ) Compound 'II (see JP-A-62-84058).

(vm) General formula (in the formula, mh represents an integer of 1 to 8, nh is 1 to 6
Rlh represents a hydrogen atom, R2h represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group, a hydroxyphenyl group, an indolyl group, an imitazolyl group, or a methylthio group, or Rth and R2h together represent a bond between carbon and nitrogen, and R
represents a lower alkyl ester group, hydroxymethyl group or formyl group. Dipeptide derivatives with (%)
See No. 62-148467.

Furthermore, prior to filing the present application, the present inventors have developed a prolinal enzyme that has anti-amnestic effects.

That is, (IX) General formula ε In the formula, Aj is an alkylene or alkenylene group having 1 to 8 carbon atoms, or I! having 3 to 7 carbon atoms. i! Represents a Japanese hydrocarbon, lj is a hydrogen atom, phenyl group, benzyl group, carbon 15E
represents an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, Bj represents an alkylene group having 1 to 8 carbon atoms optionally substituted with a phenyl group or benzyl group, or a single bond; Dj represents a halogen group; Alkyl or alkoxy group having 1 atom and 1 to 4 carbon atoms, nitro group or trifluoromethyl &
1 to 3 carbon rings or ambiguous rings with ml or no f1. ] It is a prolinal fatty acid represented by
See No. 90631.

Purpose of the Invention The present inventors have devoted themselves to research to find a novel compound useful as an anti-amnestic agent, and have discovered that the prolinal cast conductor represented by the general formula (1) above achieves the purpose. Completed the invention.

The compound of the present invention represented by the general formula (1) is as described above (
Compounds represented by the general formulas A) to (J) *i3yohi literature,
(J, Neurochem, 41), the compound of the present invention has a prolyl endopeptidase inhibitory activity (having a pyrrolidine-2-Alf skeleton).However, the compound of the present invention has a structural difference from these compounds. It is a new compound with different characteristics.

In other words, the modification of adding an oxo group to the alkylene chain between the benzene ring and prolinal is known (see section (V) of the prior art; Jikai 11fi 61-238776), but in that modification, the oxo group is added to the alkylene chain between the benzene ring and prolinal. is directly bonded to the benzene ring.

The compounds of the present invention are compounds in which an alkylene chain is further inserted between the benzene ring and the oxo group of the compound represented by the general formula (E) described in the prior art. It was found that it has lyluendopeptidase inhibitory activity.

Furthermore, we attempted 5IiI+ in several compounds, such as (1) converting the alkylene moiety of A to a saturated orohydrocarbon, (2) adding a substituent to the benzene ring, and (2) converting the benzene ring to a naphthalene ring. It was also discovered that all of the modified compounds have prolyl endopeptidase inhibitory activity.

In addition, the present inventors made several modifications, particularly to the group represented by D, in the earlier application (compound represented by general formula (J)), and as a result, the benzene ring was replaced with another aromatic ring (
Also includes heterocycles and saturated compounds: ? It has been confirmed that the prolyl endopeptidase inhibitory activity is maintained even in compounds substituted with lj, t-hanaphthalene, fluorene, and 7-ranol.

Among the compounds of the present invention, which are compounds of the compound represented by general formula It is not difficult to predict that the activity will be maintained even if the compound is replaced by a compound.

DISCLOSURE OF THE INVENTION The present invention provides 1) a general formula in which A is alkylene having 1 to 4 carbon atoms or 3 carbon atoms;
-7 saturated aqueous hydrocarbon base, n represents 2.3 or 4, D is a halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms, trifluoromethyl, 44 or a nitro group 1
(represents a carbocyclic or heterocyclic ring directly connected by three atoms from ia or unsubstituted.) 1nPA prolinal inhibitors, 2) their production history, ε, and 3) their active ingredients. Contains amnesia.

In general formula (1), the alkylene end of carbon eil to 4 represented by A refers to methylene, ethylene, trimethylene, tetramethylene groups, and isomers thereof.

The saturated hydrocarbon ring having 3 to 7 carbon atoms represented by A and A of general formula (1) refers to cyclobutane, cyclobutane, cyclobencune, cyclohexane ε, and cyclohebutane.

In the general formula (1), the halogen atom DA refers to fluorine, chlorine, bromine and iodine atoms. Also carbon ex1~4
The alkyl group refers to methyl, ethyl, propyl, and butyl groups, and isomers thereof, and the alkoxy group having 1 to 4 carbon atoms refers to methoxy, ethoxy, propoxy, butyl, and isomers thereof.

In the general formula (1), the charcoal represented by D refers to a monocyclic, bicyclic or tricyclic aromatic ring having 15 or less carbon atoms, which may be partially or completely saturated.

These materials include, for example, benzene, naphthalene,
Examples include indene, azure, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene, and their -S or all-saturated cages.

The heterocycle represented by general formula (1)
8yohi S term refers to a slope where the number of atoms is 15 or less.

Among these monkeys, those with one or two heterozygous babies are preferred.

Examples of these substances include furan, thiophene, virol, oxazole, inoxazole, thiazole,
Inthiazole, imitazole, pyrazole, furazane, bira/, pyridine, pyridazine, pyrimidine, pyrazine, indole, inindole, benzofuran, benzothiophene, indolizine, chromene, quinoline,
Examples include isoquinoline, quinolidine, purine, indazole, quinazoline, cinnoline, quinoxaline, phthalazine, pteridine, carbazole, acridine, phenanthrene, xannan, phenazine, fetchazide/lodge, and moths saturated in part or in whole.

Particularly preferable examples of D in general formula (1) include benzene,
Naphthalene and some of these are abut.

It is a source of knowledge.

Among these monkeys, substituted benzene Kaede is preferred as a compound further added with a substituent group.

%f/f In this specification, including drying, the steric r
Stereoisomer S produced by t (Ogura carbon etc.) and carbon X
All of the Senzō military techniques that arise due to branching of occupations, etc. are included in non-invention.

For example, those skilled in the art will readily understand that the alkylene S or alkenylene group referred to in the present invention includes not only one-order but also those having a branched chain.

The position where the ``cough'' in the groups 8 and D shown in humans can be bonded to the adjacent group may be any position.

The uninvented compound represented by the general formula (1) is defined by Ao) Sobatake to represent a general formula ring, ARK represents 7 γ-rukyle groups having 1 to 4 carbon atoms, and other symbols have the same meanings as above. represent. ] It can be divided into two groups of compounds shown below.

According to the present invention, the compound of the present invention represented by the general formula (1) is represented by the general formula (1), in which all symbols have the same meanings as above. ] It can be constructed by molding the prolinol prayer body shown in ] under mild conditions.

The [forming reaction] under mild conditions is known, for example,
Inert static medium (DMSO% methylene chloride, chloroform, benzene, etc.) A, tertiary amine (triethylamine,
oxidizing agents (sulfur trioxide-pyridine series, chromium trioxide-pyridine complexes,
t-butyl chloroformate, oxalyl chloride, etc.) at a temperature of 0°C to 50°C.

# of intermediates! Prolinol #s represented by the general formula (... or (1)
4 can be produced according to a series of reactions in the reaction scheme CAJ shown below.

Reaction scheme LAJ A, each symbol represents the laziness of f,
or has the same meaning as above.

B - Alkenyl or alkynyl group having 2 to 4 carbon atoms, m -1,2,3f: or 4° The valley reaction in the reaction scheme CAJ is carried out by a known method, and the starting materials used in each reaction and All reagents are known or can be prepared by known methods.

The reaction product can be purified by conventional purification means, such as vaporization under normal or reduced pressure, rapid liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing.
It can be purified by methods such as recrystallization. Purification may be performed for each reaction or after completion of several reactions.

Pharmacological activity of the inventive compound The compound of the present invention represented by the general formula (1) has prolyl endopeptidase inhibitory activity, as described above, and has been used, for example, in laboratory J1. In the experiment, ft Ws
I got the result.

(Prolyl endopeptidase inhibitory activity 2 in an in vitro system) The compounds of the present invention exhibited the activities shown in 1 one after another in the experimental system described below.

Table 1 Prolyl endobeptita in inma 1tro threads.

-ze inhibitory activity was determined by the following experimental system.

20 mM Tris-HCl buffer, (pH 7,5: 10
Contains mMEDTA and 10mM mercaptoethanol. ) 935 μL 1 DMSO bath solution of the compound of the present invention
Tris@IJ of prolyl endopeptidase purified from μt and orchid brain! ings solution (0,13 units/-
;J,Bioah@m,, 94, 1179 (19
83) method. ) 15μL of the mixture at 37℃
I brain-baited for 15 minutes. Add 5mM to this
N-benzyloxycarbonyl-glycyl-prolyl-
p-nitroanilide (40% dioxane aqueous solution) 40μ
After adding t and inking and baking at the same temperature for 1 minute,
The absorbance (a,) at 405 nm was measured. Further, this reaction solution was incubated at 37° C. for 30 minutes, and then the absorbance (a,) at 405 nm was measured.

At the same time, an experiment was conducted using the above-mentioned yarn in which the al bath solution of the compound of the present invention was replaced with DMSO, and the absorbance K b and S were measured in the same manner.

The inhibition rate was calculated using the following formula, and the concentration required for 50'A inhibition (IC, -
(Protein/Nucleic acid/# element 25(6), 513゜(
1980).

On the other hand, the toxicity of the compound of the present invention is extremely low, and it can be judged that it is sufficiently safe for use in medical practice.

Adaptation to pharmaceuticals In animals including humans, especially in humans, 1fiW of zorolyl endobeptidase is thought to be involved in neurotransmission in the brain and memory, as mentioned above. It is useful for the prevention and/or treatment of amnesia because it prevents the metabolism of substances (all peptides) that are present in the brain.

Since the compounds of the present invention have prolyl endopeptidase inhibitory activity, as evidenced by the results of in vitro experiments, they are expected to be useful in the prevention and/or treatment of amnesia.

To use the compounds of the invention for the above-mentioned purposes, they may be administered systemically or topically, orally or parenterally.

The dosage varies depending on the age of the animal, symptoms, therapeutic effects, administration method, processing time, etc., but it is usually in the range of 1 to 500 M per adult, once to several times a day. Orally administered or adults - 1q to 100 per person at a time
'90 is administered parenterally (preferably intravenously) once to several times a day.

Of course, as mentioned in f41, the dose t varies depending on various conditions, so there are cases where it is sufficient to use fewer children than before the above administration, and there are cases where it is necessary to administer the drug beyond the range.

When administering the compound of the present invention, it is used as a solid composition for oral administration, a liquid composition 'oJ' and other compositions, an injection for non-oral administration, an external preparation, a suppository, etc.

Solid compositions for oral administration include tablets, pills, capsules, powders, granules, and the like.

In such solid compositions, one or more active substances are present in a small amount (at least one inert diluent).
Milk shield, mannitol, glucose, hydroxypropyl cellulose, tie crystal cellulose, starch, polyand'-
t-lepyrolide/, magnesium aluminate metasilicate, etc.).

These compositions can be prepared using additives other than inert diluents, such as lubricants (such as magnesium stearate), disintegrants (such as fibrous gluconate modified calcium), and solubilizing agents (glutamic acid, asparagine, etc.). Acids and stabilizers (
It may contain lactose, etc.

Tablets or pills may, if necessary, be ruptured with a film of ampholytic or enteric bath additives (sucrose, seratin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc.).

Capsules include hard capsules and soft capsules.

Liquid compositions for oral administration include solutions, emulsions, suspensions, syrups, and elixirs.

Such liquid compositions include commonly used inert diluents (purified water, ethanol, etc.).

These compositions v! J includes, in addition to inert diluents, adjuvants such as moisturizers and suspending agents, sweeteners, flavoring agents, aromatics,
11/FMi agent may be contained.

Compositions thereof for oral administration include sprays containing one or more active substances and formulated in conventional manner. The spray may contain, in addition to an inert diluent, a stabilizer (sulfite, sodium hydroxide, etc.) and a buffering agent (sodium chloride, sodium citrate, citric acid, etc.) to impart chronicity. spray agent a
For example, US Patent Nos. 2,868,691 and 309
The method described in No. 5355 can be used.

Injections for parenteral administration include sterile aqueous or nonaqueous #4 solutions, suspensions, and emulsions.

In such injections, one or more active substances may be present in a small amount (and one inert aqueous diluent (distilled water for injection, physiological saline, etc.) or an inert non-aqueous diluent ( Propylene glycol, polyethylene glycol, olive oil, ethanol, polysorbate 80 (
:it recording m) is used in combination with one.

These injections may also contain adjuvants such as anti-deception agents, wetting agents, emulsifiers, dispersants, stabilizers (lactose, etc.), and solubilizing agents (glutamine, aspartic acid, etc.). good.

These are usually filtered (such as bacterial filters)
It is sterilized by adding a porcelain or by irradiation, or after these treatments, it is made into a solid composition by a method such as freezing and drying, and immediately before use, it is mixed with sterile water or a sterile injectable diluent. used in addition.

Other compositions for non-oral administration include external preparations, such as liniments, and suppositories for rectal administration, which contain one or more active substances and are formulated in a conventional manner. , pessaries for administration of Nyen, etc.

Reference t? EXAMPLES The present invention will be described in detail with reference examples and examples below.
The present invention is not limited to these.

rTLcJ, FNMRJ, and "EngR" in the old reference examples and examples refer to "IS layer chromatography" respectively.
, [nuclear magnetic resonance spectrum] and 1 infrared absorption spectrum]. The m medium in parentheses described in the chromatographic separation section indicates the bathing solvent or developing solvent used, and the proportions indicate volume. Unless otherwise specified, IR is measured by the liquid film method, and NMR is measured by the liquid film method.
Measured using Arashi chloroform (CDCA).

Reference Example 1 Synthesis of 7-phenyl-4-oxoheptanoic acid Acetone (6I@g) of 7-phenylhebutane-1,4-diol (630'W)! Fi to Jeans' trial music (3, 4d:
2.6N) was added for about 1 hour.

The reaction solution was diluted with ethyl ether, and diluted with water and saturated saline.
- After washing and drying, - thinning, Ii with the following va value! A compound (contains a lactone equivalent to part of 580q) is added to JI4111 (clam).

TLC: RfO, 14 and 0.43 (Hexane:EtOAc = 1:1).

Reference Example 2 Synthesis of N-(7-phenyl-4-okynehebutanoyl-L-prolinol) In an argon atmosphere, methylene chloride (6 ml) #d9.
Diisopropylcarbodiimide (0.5 ml) was added to the solution and stirred for 30 minutes. Due to the reaction, L-prolinal (
0.31d), stirred for 1 hour, and heated to 18°C at -5°C.
I left it for a while. Mix the reaction solution with 'M, EE, m tfii
The iodine was loaded with silica gel column chromatography (hex-7-EtOAc) and the title compound (219 cape) with 1 column at the bottom was obtained.

TLC:RfO,20(1;tOAc):NM
R: δ 7.1-7.35 (5H, m), 4.05-
4.25 (LH.

m), 3.40-3.75 (4H, m), 2.40-2
．． 80 (8H.

m), 1.82.2 (6H, m).

Reference Example 3 Synthesis of 2-[3-(2-nitrophenyl)furovir]tetrahydrofuran-5-one 2-(3-phenylpropyl)tetrahydrofuran-5
-one (230 wI) was dissolved in acetic anhydride (1-) in a bath, cooled on ice, and 70 μt of concentrated water was added thereto. After standing for 20 minutes, the mixture was stirred at room temperature for 30 minutes.

Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and then subjected to silica gel column chromatography (EtOAc:
Purification was performed using 1:1 hexane to obtain the title compound (255Iff) having the following physical properties.

TLC: Rf O,21 and 0.24 (EtOAe
:hexane=1:1).

Reference Example 4 Synthesis of N-L4-hydroxy-7-(2-nitrophenyl)heptanoyl-L-prolinol The lactone (250~) synthesized in Reference Example 3 was dissolved in THF (5-),
L-prolinol (163 μt) was added and cooled on ice. Because of the reaction, sodium hydride (45M9) was added and stirred at the same temperature for 30 minutes.

The reaction solution was acidified with IN hydrochloric acid, and ethyl vinegar was added. The organic layer was dried and concentrated under reduced pressure to obtain the title compound having the raw value of 1 below.

TLC: Rf O, 14I E bottle; OAc:
OH, OH = 95 2 5 ;).

Example I N-(7-phenyl-4-oxoheptanoyl)-L-
Synthesis of Prolinal Prolinol (105#) synthesized in CHO Silkworm Study 2 was dissolved in dry DMSO (11Rt), and triethylamine (0.32mj) was added to this solution #. A DMSO (1 m) bath solution of sulfur trioxide-pyridine complex (185 η) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into ice water, stirred, and then ethyl acetate was added. The organic layer was washed with saturated brine overnight, and washed with saturated saline solution overnight.
i. After searching, it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EtOAc:hexane=8:2)
The title compound (69,4■) purified by
I got it.

TLC: Rf O,31 (EtOAc nihexane=,
8: 2):IR Niji 2900, 1705, 1
700,1630,1420°735.680-.

'j! , Flow Example 1 (a) -1 (E) Example 1.28 Using the same procedure as in Example 1, a compound having the physical properties shown in the following example was obtained. Example 1
For (j), use the compound of Example 4! J? 3 Monoga.

(nυ Formulation Example) The following ingredients were mixed in a conventional manner and tableted to form 100 tablets containing 50 m9 of an oily component in charcoal.

0N-(7-phenyl-4-oxoheptanoyl)-L
-7' Lolinal... 5fO cellulose calcium gluconate (disintegrant)... 0.2F O magnesium stearate (+144 lubricant)...
...0.1t OdM crystalline cellulose ...4.7 Patent applicant: Ono Awashina Koryo Kaisha Co., Ltd. Patent attorney Kunihisa Oya

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, A represents an alkylene group having 1 to 4 carbon atoms or a saturated hydrocarbon ring having 3 to 7 carbon atoms; , n is 2, 3 or 4
D represents a halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms, a trifluoromethyl group, or an unsubstituted carbocyclic or heterocyclic ring substituted with 1 to 3 nitro groups. 2) D is a halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms, a trifluoromethyl group or a nitro group 1
The compound according to claim 1, which is a phenyl or naphthyl group substituted with 3 to 3 or unsubstituted. 3) The compound has a general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I a) [In the formula, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ has 3 carbons.
-7 represents a saturated hydrocarbon ring, and the other symbols have the same meanings as above. ] The compound according to claim 1, which is a prolinal derivative represented by: 4) The compound is N-[trans-2-(3-phenylpropanoyl)cyclopentanecarbonyl]-L-prolinal or N-[trans-2-(3-phenylpropanoyl)cyclohexanecarbonyl]-L-prolinal A compound according to claim 1 or 3. 5) The compound has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I b) [In the formula, AlK represents an alkylene group having 1 to 4 carbon atoms, and the other symbols have the same meanings as above. ] Claim 1 is a novel prolinal derivative represented by
Compounds described in Section. 6) Claim 5 in which D is an unsubstituted naphthyl group
Compounds described in Section. 7) The compound is N-[6-(1-naphthyl)-4-oxohexanoyl]-L-prolinal or N-[6-(
7. The compound according to claim 1 or 6, which is 2-naphthyl)-4-oxohexanoyl]-L-prolinal. 8) Claim 5 in which D is an unsubstituted phenyl group
Compounds described in Section. 9) The compound is N-(6-phenyl-4-oxohexanoyl)-L-
Prolinal, N-(7-phenyl-4-(8-phenyl-4-oxooctanoyl)-L-prolinal or N-(2RS-isopropyl-3-oxo-7-phenylheptanoyl)-L-prolinal) The compound according to claim 1 or 8. 10) The compound according to claim 5, wherein D is a phenyl group substituted with a substituent. 11) The compound is N-[6-(4-methylphenyl)-4-oxohexanoyl]-L-prolinal, N-[6-(4-methoxyphenyl)-4-oxohexanoyl]-L-prolinal , N-[6-(4-chlorophenyl)-4-oxohexanoyl]-L-prolinal, N-[6-(3-chlorophenyl)-4-oxohexanoyl]-L-prolinal, N-[7- Claim 1 which is (2-nitrophenyl)-4-oxoheptanoyl]-L-prolinal or N-[4-oxo-6-(p-trifluoromethylphenyl)hexanoyl]-L-prolinal A compound according to item 1 or item 10. 12) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) [In each formula, A is an alkylene group with 1 to 4 carbon atoms or an alkylene group with 3 carbon atoms ~7 saturated hydrocarbon ring, n represents 2, 3 or 4, D is substituted with a halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms, a trifluoromethyl group or 1 to 3 nitro groups represents a substituted or unsubstituted carbocycle or heterocycle. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by oxidizing the prolinol derivative shown under mild conditions ▼ (I) [In the formula, all symbols have the same meanings as above. ] A method for producing a prolinal derivative. 13) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, A represents an alkylene group having 1 to 4 carbon atoms or a saturated hydrocarbon ring having 3 to 7 carbon atoms, and n is 2 or 3. or 4
and D represents a halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms, a trifluoromethyl group, or an unsubstituted carbocyclic or heterocyclic ring substituted with 1 to 3 nitro groups. ] An anti-amnestic agent containing the novel prolinal shown as an active ingredient.