Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-02
2001-08-28
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06281242
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to medicaments. More specifically, the present invention relates to medicaments which comprises as an active ingredient 2-(1-pyrrolidinyl) acetamide derivatives, whose typical example includes neifracetam, and is useful for preventive and/or therapeutic treatment of amnesia caused by general anesthesia and the like.
2. Discussion of the Background Information
In emergency anesthesia, which accounts for 70% of all anesthesia used for surgical operations, certain and rapid recovery from anesthesia is desired for safety of a patient (Korttila, K., et al., Acta Anaesthesiol. Scand., 34, pp. 400-403, 1990; Ogg, T. W., Brit, Med. J., 281, pp. 212-214, 1980; Noble, J., et al., Postgrad. Med., J., 61, pp. 103-104, 1985). Progress has been made in development of anesthetic agents that are rapidly metabolized and leave only slight hangover effects. However, there still remains a problem of significant cognitive disorders immediately after operations.
For example, propofol (diisopropylphenol; Diprivan) is a short-time acting intravenous anesthetic agent that has been preferably used because of its fast and smooth anesthesia induction and rapid recovery. However, it has been suggested that propofol may possibly cause amnesia at wakening from anesthesia. Effects of propofol on memory formation have not fully revealed to date. In rodents, subanesthetic doses of propofol were demonstrated to induce anterograde amnesia as for avoidance tasks, whilst similar dose ranges failed to induce retrograde amnesia (Pang, R. et al., Pharmacol. Biochem. Behva., 44, pp. 145-151, 1993; a possible interpretation of these results is that retrograde amnesia was not observed because of the maximum dose of 100 mg/kg after training). Contrary to these results, the inventors of the present invention found that retrograde amnesia was also induced by administration of a higher dose of propofol (see, examples given in the present specification).
As for amnesia in human, propofol has been suggested to induce anterograde amnesia of intraoperative events (Steib, A. et al., Acta Anaesthesiol. Scand., 34, pp. 632-635, 1990). However, there is still debate as to whether it affects cryptomnesia (Bethune, D. W., et al., Brit. J. Anaesthesia, 69, pp. 197-199, 1992; and Cork, R. C., et al., Br. J. Anaesthesia, 76, pp. 492-498, 1996). In addition, it has also been reported that cognitive functions associated with learning, language, reasoning, and planning remain suppressed for at least 3 hours after cessation of propofol administration (Sanou, J., et al., Neuro Report, 7, pp.
1130-1132, 1996).
Agents that assist recovery from the cognitive disorders associated with propofol-induced anesthesia are expected as clinically useful; however, only a few agents have so far been known (Ogg, T. W., et al., Anaesthesia, 34, pp. 783-789, 1979; Ghouri, A., Anesthesiology, 81, pp. 333-339, 1994). For example, doxapram and flumazenil have been investigated. However, these medicaments have not been generally used due to a possible risk of re-sedation arising from the short acting nature of these agents.
2-(1-Pyrrolindinyl)acetamide derivatives have been known to exhibit improving effects on cerebral function (Japanese Patent Application Unexamined Publication (Kokai) No. 56-2960/1981). In particular, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (generic name: nefiracetam) has been revealed to have clinical usefulness as a cerebral function improving agent. Nefiracetam has been known to preserve memory formation in various animals models of learning disability (Yamada, K., et al., CNS Drug Reviews, 2, pp. 322-342, 1996).
The class of cognition-enhancing agents including nefiracetam as a typical example require 16 to 24 hours before their memory improving effects are exhibited (Mondadori, C., et al., Proc. Natl. Acad. Sci., USA, 91, pp. 2041-2045, 1994). Since these agents are ineffective in adrenalectomised animals, it has been suggested that they regulate gene transcription in such a manner that formation of long term memory trace is facilitated (Mondodori, C., et al., Brain Res., 435, pp. 310-314, 1987). The regulatory ability has been demonstrated in adult rats by evaluating the ability of nefiracetam to protect scopolamine-compromised learning-dependent modifications of nerve cell adhesive molecule (NCAM) in a polysialylation state, which occur in the memory fixation period 10 to 12 hours after training in a certain population of granular cells at the boundary hilus of dentate gyrus granule cell layer (Doyle, E., et al., J. Neurochem., 61, pp. 266-272, 1993; Fox, G. B. et al., J. Neurochem., 65, pp. 2796-2799, 1995; and Murphy, K. J., et al., J. Neurochem., 67, pp. 1268, 1274, 1996).
A similar effect has been observed in an in vitro experiment using a PC-12 pheochromocytoma cell model. Pre-exposure to Nefiracetam of sensitized PC-12 cells significantly enhances subsequent nerve growth factor-induced neuritogenesis and NCAM polysialylation (Odumeru, O., et al., Behav. Brain Res., 83, pp. 173-178, 1997). While this action is not apparent dose-dependent, it is considered that nefiracetam enhances time-dependent regulation of neuroplasticization events after training, and thereby contributes to the synaptic rearrangements underlying the memory fixation (Bailey, C. H., Annu. Rev. Physiol., 55, pp. 397-426, 1993).
SUMMARY OF THE INVENTION
An object of the present invention is to provide a medicament for preventive and/or therapeutic treatment of amnesia. More specifically, the object of the present invention is to provide a medicament for preventive and/or therapeutic treatment of amnesia that is caused by general anesthesia induced by use of an anesthetic agent such as propofol, and onsets after awaking from the general anesthesia.
The inventors of the present invention conducted various studies to achieve the foregoing object, and as a result, they found that 2-(1-pyrrolidinyl)acetamide derivatives known as useful agents for cerebral function improvement, in particular nefiracetam, remarkably suppressed amnesia after awaking from general anesthesia. The present invention was achieved on the basis of these findings.
The present invention thus provides a medicament for preventive and/or therapeutic treatment of amnesia, which comprises as an active ingredient a compound represented by the following formula (I): R
2
—CH
2
CONH—R
1
(I) wherein R
1
represents pyridyl group, a substituted pyridyl group, phenyl group, or a substituted phenyl group; and R
2
represents a 2-oxo-I-pyrrolidinyl group which may be substituted, preferably comprises nefiracetam.
According to preferred embodiments of the present invention, there are provided the aforementioned medicament for preventive and/or therapeutic treatment, which is used for amnesia caused by general anesthesia; the aforementioned medicament for preventive and/or therapeutic treatment, which is used for amnesia that occurs after awaking from general anesthesia; the aforementioned medicament for preventive and/or therapeutic treatment, wherein the amnesia is anterograde amnesia; the aforementioned medicament for preventive and/or therapeutic treatment, wherein the amnesia is retrograde amnesia; the aforementioned medicament of preventive and/or therapeutic treatment, wherein the general anesthesia is produced by an anesthetic agent for intravenous administration; and the aforementioned medicament for preventive and/or therapeutic treatment, which is in the form of a pharmaceutical composition comprising a compound of formula (I) as an active ingredient, preferably nefiracetam, together with an additive for pharmaceutical preparations. As further aspects of the present invention, there are provided a use of a compound of the formula (I), preferably, nefiracetam, for the manufacture of the aforementioned medicament for preventive and/or therapeutic treatment; and a method for prevention and/or therapeutic treatment of amnesia, which comprises the step of administering a preventively and/or therapeutical
O'Connell Alan
O'Gorman David
Regan Ciaran
Shiotani Tadashi
Daiichi Pharmaceutical Co. Ltd.
Greenblum & Bernstein P.L.C.
Reamer James H.
LandOfFree
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