JPWO1999003466A1 - Preventive and therapeutic drugs for amnesia - Google Patents

Abstract

( ⁵⁷ ) [Abstract] A pharmaceutical useful for the prevention and/or treatment of amnesia caused by intravenously administered anesthetics such as propofol, comprising as an active ingredient a compound (e.g., ^N- ( _2,6 -dimethylphenyl)-2-(2-oxo- ¹ -pyrrolidinyl)acetamide) represented by the following formula: R2-CH2CONH-R1 ( ^R1 represents a pyridyl group, a substituted pyridyl group, a phenyl group, or a substituted phenyl group; R2 represents a 2-oxo-pyrrolidinyl group which may have a substituent).

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical invention. More specifically, the present invention relates to a pharmaceutical containing a 2-(1-pyrrolidinyl)acetamide derivative, of which nefiracetam is a representative compound, as an active ingredient, which is useful for preventing and/or treating amnesia caused by general anesthesia, etc.

BACKGROUND ART In emergency anesthesia, which accounts for 70% of all surgeries, reliable and rapid recovery from anesthesia is necessary for patient safety (Korttjla, K., et al.
l. , Acta Anaesthesiol. Scand. , 34, pp. 40
0-403, 1990; 0gg, T. W. , Brit. Med. J. ,281,
pp. 212-214, 1980; Noble, J. , et al. , Post
Grad. Med., J., 61, pp. 103-104, 1985.) Although progress has been made in developing anesthetics with rapid metabolism and minimal residual effects, the problem of significant cognitive impairment immediately after surgery remains.

For example, propofol (diisopropylphenol; Diprivan) is a short-acting intravenous anesthetic that is highly valued for its rapid onset and smooth induction with rapid recovery, but it has been suggested that it may cause amnesia upon awakening from anesthesia. Although the effects of propofol on memory formation have not yet been fully elucidated, it has been shown that non-anesthetic doses of propofol induce anterograde amnesia in an avoidance task in rodents, whereas no reversed isotropic amnesia occurs in the same dose range (Pang, R. et al., Pharmacol. Bioc.
Hem. Behva., 44, pp. 145-151, 1993: It is thought that retrograde amnesia could not be observed because the maximum dose after training was 100 mg/kg.) Contrary to this finding, the present inventors found that retrograde amnesia also occurred at higher doses (see Examples).

Regarding amnesia in humans, it has been suggested that propofol induces anterograde amnesia for intraoperative events (Steib, A, et al., Act.
a Anaesthesiol, Scand. , 34, pp. 632-635,
1990), and there is some debate as to whether it has an effect on implicit memory (Bethune, D.W., et al., Brit. J, Anaesth
esia, 69, pp. 197-199, 1992; and Cork, R. C. ，
et al. , Br. J. Anaesthesia, 76, pp. 492-49
8, 1996). It has also been reported that cognitive functions related to learning, language, thinking, and planning remain depressed for at least 3 hours after propofol administration is stopped (Sanou, J., et al., Neuro Report, 7, pp. 1
130-1132, 1996).

Drugs that facilitate recovery from cognitive impairment induced after propofol anesthesia are expected to be clinically useful, but few have been found to date (Ogg,
T. W. , et al. , Anaesthesia, 34, pp. 784-78
9, 1979; Ghouri, A. , Anesthesiology, 81, p.
p. 333-339, 1994). For example, doxapram
and flumazenil have been studied, but these drugs have not been widely used due to the potential risk of re-sedation resulting from their short acting characteristics.

On the other hand, 2-(1-pyrrolidinyl)acetamide derivatives having brain function improving effects are known (Japanese Patent Laid-Open Publication No. 56-2960), and in particular, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (generic name "nefiracetam") has been confirmed to be clinically useful as a brain function improving agent. Nefiracetam is known to maintain memory formation in various learning disability animal models (Yamada, K., et al.
, CNS Drug Reviews, 2, pp. 322-342, 1996)
.

Cognitive enhancers, such as nefiracetam, have been shown to improve memory.
It takes 6 to 24 hours (Mondadori, C., et al., Proc. N
atl. Acad. Sci, USA, 91, pp. 2041-2045, 19
94), and their lack of effect in adrenalectomized animals suggests that these drugs regulate gene transcription to facilitate the formation of long-term memory traces (M
ondodori, C. , et al. , Brain Res. , 435, pp.
310-314, 1987). This regulatory ability was observed after learning-dependent modification of the polysialylation state of neural cell adhesion molecule (NOAM) in a given number of granular cells in the dentate gyrus granule cell layer junction, which was impaired by scopolamine in adult rats (10-12 training sessions).
This has been demonstrated by assessing the protective effect of nefiracetam on memory consolidation (appearing during the memory consolidation phase hours later) (Doyle, E., et al., J. Neurol. 2002, 144:145-146).
rochem. , 61, pp. 266-272, 1993; Fox, G. B. ，
et al. , J. Neurochem. , 65, pp. 2796-2799,
1995; and Murphy, K. J. , et al., J. et al. Neuroc
hem. , 67, pp. 1268, 1274, 1996).

Similar effects were observed in vivo using the PC-12 pheochromocytoma cell model.
This has also been observed in in vitro studies. Pretreatment of sensitized PC-12 cells with nefiracetam significantly enhances subsequent nerve growth factor-induced neurite outgrowth and NOAM polysialylation (Odumeru, O., et al., Behav.
v. Brain Res., 83, pp. 173-178, 1997). Although this effect is not clearly dose-dependent, it is believed that nefiracetam enhances the time-dependent regulation of neuroplasticity after training and contributes to synaptic reorganization underlying memory consolidation (Bailey, C. H., Annu.
Rev, Physiol. , 55, pp. 397-426, 1993).

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a drug for preventing and/or treating amnesia. More specifically, an object of the present invention is to provide a drug for preventing and/or treating amnesia that is caused by general anesthesia using an anesthetic such as propofol and that develops after awakening from general anesthesia.

As a result of intensive efforts to solve the above problems, the present inventors have found that 2-(1-pyrrolidinyl)acetamide derivatives, particularly nefiracetam, which have been useful as brain function improvers, can significantly suppress amnesia after awakening from general anesthesia. The present invention was completed based on the above findings.

That is, the present invention provides a compound represented by the following formula (I): R ² —CH ₂ CONH—R ¹ (wherein R
¹ represents a pyridyl group, a substituted pyridyl group, a phenyl group, or a substituted phenyl group; R
The present invention provides a drug for the prophylaxis and/or treatment of amnesia, which contains, as an active ingredient, a compound represented by the formula (2) (wherein ² represents a 2-oxo-1-pyrrolidinyl group which may have a substituent), preferably nefiracetam.

According to a preferred embodiment of the present invention, the above-mentioned prophylactic and/or therapeutic agent is applied to amnesia caused by general anesthesia; the above-mentioned prophylactic and/or therapeutic agent is applied to amnesia after awakening from general anesthesia; the above-mentioned prophylactic and/or therapeutic agent is applied when the amnesia is anterograde amnesia;
The above preventive and/or therapeutic agent, wherein the amnesia is reversed homozygous amnesia; the above preventive and/or therapeutic agent, wherein general anesthesia is administered by intravenous administration; and
The present invention also provides the above-mentioned prophylactic and/or therapeutic agent in the form of a pharmaceutical composition comprising a compound of formula (I), preferably nefiracetam, and a formulation additive. In addition, another aspect of the present invention provides use of the compound of formula (I), preferably nefiracetam, for the manufacture of the above-mentioned prophylactic and/or therapeutic agent, and a method for the prophylaxis and/or treatment of amnesia, which comprises the step of administering to a patient a prophylactically and/or therapeutically effective amount of the compound of formula (I), preferably nefiracetam.

BEST MODE FOR CARRYING OUT THE INVENTION The above-mentioned 2-(1-pyrrolidinyl)acetamide derivative, which is the active ingredient of the pharmaceutical of the present invention, is a compound described in JP-A-56-2960 as a compound useful for improving brain function. ^R represents a pyridyl group, a substituted pyridyl group, a phenyl group, or a substituted phenyl group, and examples of the substituent on the ring present in the substituted pyridyl group or the substituted phenyl group include a halogen atom, a trifluoromethyl group, a nitro group, an acetyl group, an alkyl group, an alkoxy group, an alkylmercapto group, an amino group, a sulfonyl group, and an aminoethoxycarbonyl group.

^R2 represents a 2-oxo-1-pyrrolidinyl group which may have a substituent, and the substituent may be a hydroxyl group or the like. The above compound can be easily produced by the method described in, for example, JP-A-56-2960 or JP-A-6-65197. The most preferred compound among the above compounds is
N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (generic name: nefiracetam, used clinically).

The medicament of the present invention can be used for the prevention and/or treatment of amnesia. Examples of amnesia include anterograde amnesia and retrograde amnesia, and either or both of these are suitable targets for the medicament of the present invention. As used herein, "anterograde amnesia" refers to memory impairment for events occurring in the future relative to the time of involvement of an amnesia-inducing factor (e.g., administration of a general anesthetic), and "reverse homoeopathic amnesia" refers to memory recall impairment for events occurring in the past relative to the time of involvement of an amnesia-inducing factor. However, the target targets for the medicament of the present invention are not limited to these specific amnesias.

Since general anesthesia is known to induce amnesia, the medicament of the present invention can preferably be used for the prevention and/or treatment of amnesia caused by general anesthesia. The type of general anesthesia is not particularly limited, and any anesthesia that may induce amnesia can be used. Examples include inhalation anesthesia such as halothane or methoxyflurane; intravenous anesthesia such as thiopental sodium, ketamine, or propofol; induction anesthesia used in inhalation anesthesia, or an appropriate combination thereof. Among these, short-acting intravenous anesthetics, such as anesthesia with propofol, are preferred applications of the medicament of the present invention.

The dosage form of the above-mentioned medicament of the present invention is not particularly limited, and can be administered orally or parenterally to humans. As the medicament of the present invention, the compound of the above formula, which is the active ingredient, may be used as it is, but it is usually preferable to prepare a formulation in a form well known to those skilled in the art by appropriately using one or more pharmacologically and pharmaceutically acceptable additives together with the active ingredient compound, and use it orally or parenterally. As the active ingredient, a physiologically acceptable salt of the compound of formula (I), a solvate or hydrate of the free compound or a physiologically acceptable salt may also be used.

Examples of preparations suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups, and examples of preparations suitable for parenteral administration include injections for subcutaneous, intravenous, or intramuscular injection, drip infusions, suppositories, inhalants, transdermal absorbents, transmucosal absorbents, and patches. Pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments, diluents, bases,
Solubilizers or solubilizing agents, isotonicity adjusting agents, pH adjusting agents, stabilizers, propellants, adhesives, etc. may be used.

For example, formulations suitable for oral administration or transdermal or transmucosal administration may contain, as pharmacologically and pharmaceutically acceptable additives, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrants or disintegration aids such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium; hydroxypropylcellulose, hydroxypropylmethylcellulose,
Binders such as polyvinylpyrrolidone or gelatin; lubricants such as magnesium stearate or talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol or titanium oxide; petrolatum, liquid paraffin,
Bases such as polyethylene glycol, gelatin, kaolin, glycerin, refined ice, or hard fat can be used.
or propellants such as compressed gas; sodium polyacrylate, polyvinyl alcohol,
The formulation may be prepared using additives for formulations such as adhesives such as methylcellulose, polyisobutylene, polybutene, etc.; and base fabrics such as cotton cloth or plastic sheets.

Preparations suitable for injection or infusion include, for example, distilled water for injection, physiological saline,
Additives for formulations may be added, such as solubilizers or solubilizing aids such as propylene glycol that can constitute aqueous or ready-to-use injections; isotonicity agents such as glucose, sodium chloride, D-mannitol, and glycerin; and pH adjusters such as inorganic acids, organic acids, inorganic bases, and organic bases.

The dosage of the medicament of the present invention is not particularly limited and may be appropriately selected depending on the dosage form, the degree of amnesia, the purpose of administration such as preventive or therapeutic administration, the age and body weight of the patient, etc. For example, the amount of the active ingredient is 200 to 2,000 mg per day.
The daily dose is preferably about 300 to 900 mg, and the above-mentioned daily dose can be administered in divided doses. The timing of administration of the medicament of the present invention can also be selected appropriately. It has been confirmed that a preventive effect against amnesia can be obtained when the medicament of the present invention is administered before anesthesia (Examples, Tables 3 and 4 described below), and similar effects can be expected when the medicament of the present invention is administered after anesthesia.

EXAMPLES The present invention will be explained in more detail below with reference to examples, but the scope of the present invention is not limited to the following examples.

In the examples, N-(2,6-dimethylphenyl)-2-(2
-oxo-1-pyrrolidinyl)acetamide [generic name: nefiracetam (nef
Nefiracetam (hereinafter referred to as "nefiracetam" in the examples) was used to investigate the effect of propofol (diisopropylphenol), a short-acting intravenous anesthetic, on amnesia induced by the drug. More specifically, the anterograde and retrograde amnesia induced by non-anesthetic and anesthetic doses of propofol were investigated in combination with modulation of NCAM polysialylation and memory retrieval in a passive avoidance task in rats, and the effects of nefiracetam on these two parameters were evaluated.

(1) Experimental Method (a) Passive Avoidance Training Eighty-day-old male Wistar rats (300-350 g) were individually housed in cages under standard conditions with no food or water restrictions. These experimental animals were placed in the test environment three days before the start of the test and kept under those conditions. A one-trial step-through light-dark task was used for the passive avoidance test. After the training, the behavior of each animal was evaluated.
A rat was placed in the light compartment of a passive avoidance response apparatus, and the latency to enter the dark compartment was recorded.
Immediately after the animals entered the dark compartment, they received a 5-second mild foot shock at 0.75 mA, and were forced to immediately return to the light compartment to avoid the stimulus. To test the memory recall ability of each animal, the animals were placed in the light compartment 12 hours after training, and the latency to enter the dark compartment was recorded. This value was used as a measure of the animals' ability to remember the inhibitory stimulus (foot shock). 600 seconds was used as the evaluation criterion time.

Propofol (Aldrich) was diluted in 0 mL of 10% Tween-20 (Sigma).
The propofol was dissolved in 9% saline and administered intraperitoneally 15 minutes before training. In separate experiments, it was administered at different times after training. The depth of propofol anesthesia achieved in animals receiving propofol alone or in combination with nefiracetam was determined by the loss of tail pinch response and the time to paw withdrawal. The time to righting reflex was used as a measure of recovery time from anesthesia. Nefiracetam (Daiichi Pharmaceutical) was administered intraperitoneally 1 hour before training. All experimental procedures were approved by the Biomedical Sciences Review Board of University College Dublin and performed by personnel holding appropriate licenses issued by the Department of Health.

(b) Quantification of hippocampal polysialylated neurons To detect hippocampal polysialylated neurons, the method of Fox et al. (Fox,
G. B. , et al. , J. Neurochem, 65, pp. 2796-2
799, 1995) was used to carry out PSA (polysialic acid) immunocytoassay.
Cryopreserved axial sections of 2 μm were fixed in 70% (v/v) ethanol and stained with anti-polysialic acid, ascites fluid 1:500 dilution (kindly provided by Prof. G. Rougon; Rougon,
G. et al. , J. Cell. , Biol. , 103, pp. 2429-2
The sections were then incubated overnight with fluorescein-conjugated goat anti-mouse IgM (Calbiochem) at a 1:100 dilution for 3 hours, followed by incubation in Citifluor® fluorescence-enhancing medium.
(agar) was inoculated.

The sections were briefly exposed (60 seconds) to propidium iodine (40 ng/ml PBS; Sigma Chemical Co., UK) to fluorescently counterstain the nuclei.
The total number of PSA-immunopositive neurons in the granule cell layer and hilus marginalis was counted from -5.6 mm from bregma using ten 12-μm sections, avoiding double counting of the 0-μm perikarya (perinuclear area). The cell count was divided by the total area of the granule cell layer, multiplied by the average granule cell layer area (0.15±0.01 ^mm2 at this level), and the mean±standard error was calculated to express the number of PSA-positive cells per unit area. Area measurements were performed using a Quantimet 500 image analysis system (Quantimet 50
The analysis was performed using a 3D image analysis system (Image Analysis System).

(c) Statistical analysis All values are expressed as mean ± standard error, and their statistical significance was determined using the Mann-Whitney U test for behavioral data.
st), and for immunohistochemical data, Student's t test
t t-test) was used, and a value of p<0.05 was considered significant.

(2) Results To determine whether propofol induces anterograde amnesia, the anesthetic was administered 15 minutes before passive avoidance training. All control animals were judged to have fully mastered the task based on their escape latencies before sacrifice 12 hours after training. However, animals given 75 mg/kg of propofol showed a shortened latency to enter the dark compartment, clearly demonstrating significant amnesia. This state of amnesia persisted for 10 minutes.
Since there was no significant reduction in latency at the low dose of 100 mg/kg, it was concluded that the effect was dose-dependent. The results are shown in Table 1. Latency is shown as the mean ± standard error (n = 6), and those with significant differences compared to control animals (p < 0.05) are marked with *.
Marked.

No difference was observed in ambulatory activity (exploratory behavior) in the open field 5 minutes before training between animals in which amnesia was induced with 75 mg/kg propofol and control animals (number of crossings within 5 minutes in the treatment group and control group was 144.0±6.5 and 135.0±24.2, respectively).
No difference was observed even just before the memory recall test 2 hours later (the number of mice that crossed the line within 5 minutes in the treatment group and the control group was 110.6±4.9, respectively).
119.3±13.0). Therefore, it was thought that the amnesic state described above was not due to a decline in attention or movement.

Retrograde amnesia was induced by administering propofol 3 hours after training.
A larger dose of propofol was required to induce retrograde amnesia (150 mg/kg
), this dose resulted in complete loss of consciousness. Although the animals were fully conscious just prior to the memory recall test 12 hours later (no attentional or motor deficits were observed in the open field: 5-minute line crossings were 158.0±25.8 and 163.0±13.5 for the treated and control groups, respectively), they were unable to recall memory 12 hours after training (Table 1).

These results clearly demonstrate that the anesthetic effects of propofol exhibit two distinct properties regarding the consolidation of short-term memories into long-term storage: anterograde amnesia can be induced at relatively low concentrations, whereas reversed amnesia requires twice the dose, indicating that the memory trace is initially unstable and strengthens over time.

Furthermore, since memory recovery was not impaired even when an effective anesthetic dose was administered 4 hours after training, it was determined that the induction of retrograde amnesia by propofol is time-dependent. The results are shown in Table 2. In the table, the values are shown as mean ± standard error (n = 6). The fact that retrograde amnesia is induced only within 3 hours after training indicates that the memory then enters the process of finally being stored for a long period of time.
Animals given 1 mg/kg propofol did not show any deficits in attention or motor activity during memory recall 12 hours later (number of crossings at 5 minutes in the treated and control groups was 88.7±9.4 and 92.3±13.1, respectively).

Administration of nefiracetam (9 mg/kg) 1 hour before training completely prevented the anterograde amnesia induced by propofol (75 mg/kg) treatment 15 minutes before training. Furthermore, no significant differences in response latency were observed between the propofol and nefiracetam combination group, the nefiracetam monotherapy group, and the control group. Similar results were obtained in animals in which reverse homotypic amnesia was induced with a high dose of propofol (150 mg/kg). The results are shown in Table 3. * indicates a significant difference compared to propofol alone (p<0.05), and values are expressed as mean ± standard error (n=6).

In the propofol monotherapy group and the propofol and nefiracetam combination therapy group,
The quality of anesthesia was not affected. Animals in both groups showed similar latency times for loss of tail pinch response and paw withdrawal reflex (199.0±6.2 and 181.0±1.0 for propofol alone and in combination with nefiracetam, respectively).
Duration of action, as judged by the return of the righting reflex, was also similar in both groups (96.3±12.7 and 90.3±10.5 minutes for the propofol alone and nefiracetam combination groups, respectively).

Next, we investigated whether nefiracetam protects against learning-dependent modification of the polysialylated state of neurons in the dentate gyrus of the hippocampus. As a control, we examined the frequency of PSA-positive neurons in the dentate gyrus after propofol-induced anterograde amnesia. As shown in Table 4-1, in animals that underwent passive avoidance training, the frequency of immune-reactive positive neurons increased significantly 12 hours after training, and the number of polysialylated cells was significantly increased (Fox, G.B., et al., 2014).
J. Neurochem. , 65, pp. 2796-2799, 1995; Mu
rphy, K. J. , J. Neurochem, 67, pp. 1268-127
4, 1996). In addition, in animals in which amnesia was induced by the administration of propofol (75 mg/kg) 15 min before training, the number of polysialylated neurons was not different from that in untreated, untrained animals or immediately after training.

On the other hand, in the combined treatment group (animals in which anterograde amnesia induced by propofol administration 15 minutes before training was prevented by administration of nefiracetam 1 hour before training), an increase in polysialylated neurons was observed to the same extent as that observed in the control group. Furthermore, the learning-dependent increase in polysialylation in hippocampal dentate gyrus neurons was preserved in the group of animals in which propofol-induced retrograde amnesia was prevented by administration of nefiracetam. The results are shown in Table 4.

One hour after administration of nefiracetam (9 mg/kg), there was no significant difference in PSA-positive dentate gyrus neurons between untrained animals and untrained controls (69 ± 3 and 64.5 ± 2.3, respectively), confirming that the increase in expression of these polysialylated neurons was not solely due to nefiracetam administration.

INDUSTRIAL APPLICABILITY The medicament of the present invention is useful for the prevention and/or treatment of amnesia, and is particularly useful for the prevention and/or treatment of anterograde amnesia and/or retrograde amnesia caused by general anesthetics.

──────────────────────────────────────────────────── Continuation of front page (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP(GH, GM, K E, LS, MW, SD, SZ, UG, ZW), UA (AM , AZ, BY, KG, KZ, MD, RU, TJ, TM) , AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, D K, EE, ES, FI, GB, GE, GH, GM, HR ,HU,ID,IL,IS,JP,KE,KG,KR, KZ, LC, LK, LR, LS, LT, LU, LV, M D, MG, MK, MN, MW, MX, NO, NZ, PL , PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, U Z, VN, YU, ZW (72) Inventor Tadashi Shioya 1-16-13 Kitakasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center (Note) This publication is based on the publication published internationally by the International Bureau of Patents (WIPO). The effect of the international publication of the Japanese patent application (Japanese utility model registration application) related to this publication arises pursuant to Article 184-10, Paragraph 1 of the Patent Act (Article 48-13, Paragraph 2 of the Utility Model Act) and is unrelated to this publication.

Claims (10)

[Claims] [Claim 1] A drug for the prevention and/or treatment of amnesia, comprising as an active ingredient a compound represented by the following formula (I): ^R2 - _CH2CONH - ^R1 (wherein ^R1 represents a pyridyl group, a substituted pyridyl group, a phenyl group, or a substituted phenyl group; and ^R2 represents a 2-oxo-1-pyrrolidinyl group which may have a substituent). 2. The preventive and/or therapeutic drug according to claim 1, which is used for amnesia caused by general anesthesia. 3. The preventive and/or therapeutic drug according to claim 2, which is applied to amnesia after awakening from general anesthesia. 4. The preventive and/or therapeutic agent according to claim 2 or 3, wherein the amnesia is anterograde amnesia. 5. The preventive and/or therapeutic agent according to claim 2 or 3, wherein the amnesia is retrograde amnesia. 6. The preventive and/or therapeutic agent according to any one of claims 2 to 5, wherein the general anesthesia is administered by intravenous administration or inhalation anesthesia. 7. The prophylactic and/or therapeutic drug according to any one of claims 1 to 6, which is in the form of a pharmaceutical composition containing the compound of formula (I) as an active ingredient and pharmaceutical additives. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the active ingredient is N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide. 9. The preventive and/or therapeutic agent according to any one of claims 1 to 8.
Or use of a compound represented by the following formula: ^R2 - _CH2CONH - ^R1 (wherein ^R1 represents a pyridyl group, a substituted pyridyl group, a phenyl group, or a substituted phenyl group; and ^R2 represents a 2-oxo-1-pyrrolidinyl group which may have a substituent) for the manufacture of a therapeutic agent. [Claim 10] A method for preventing and/or treating amnesia, comprising the step of administering to a patient an effective amount of a compound represented by the following formula: ^R2 - _CH2CONH - ^R1 (wherein ^R1 represents a pyridyl group, a substituted pyridyl group, a phenyl group, or a substituted phenyl group; and ^R2 represents a 2-oxo-1-pyrrolidinyl group which may have a substituent).