JPH1067661A - Therapeutic agent for memory disorder - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare the subject therapeutic agent useful for treating memory (retention) disorder and acquiring the memory in Alzheimer type dementia by including propentofylline as an active ingredient therein. SOLUTION: This therapeutic agent for memory disorder comprises propentofylline of the formula which is 3,7-dihydro-3-methyl-1-(5-oxohexyl)-7- propyl-1H-purine-2,6-dione as an active ingredient. Since the toxicity of the compound of the formula is low, continuous administration of the therapeutic agent can be carried out and the daily dose is preferably 100-1,500mg, based on the amount of the active ingredient and intravenously, intramuscularly, perorally and intrarectally administered. In the case of the intravenous administration, intravenous drip can be performed in addition to the intravenous injection. A powdery pharmaceutical preparation can be obtained as the pharmaceutical preparation for parenteral injection by adding, e.g. a water-soluble excipient to the compound of the formula, dissolving the resultant mixture in water, distributing the resultant solution into each ampul, etc., then freeze-drying the distributed solution and hermetically sealing the ampul. A tablet, a capsule, a powder, etc., can be prepared as a peroral pharmaceutical preparation and further an enteric pharmaceutical preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for memory disorders,
More specifically, 3,7-dihydro-3-methyl-1-
(5-oxohexyl) -7-propyl-1H-purine-2,6-dione (hereinafter referred to as propentophylline) as an active ingredient, a therapeutic agent for memory impairment in Alzheimer-type dementia and a therapeutic agent for memory acquisition / retention impairment It is about.

[0002]

2. Description of the Related Art In recent years, diseases such as dementia for the elderly accompanied by memory impairment along with prolonged life expectancy have become a serious problem both medically and socially. However, to date, there are almost no drugs that can effectively treat this, and rapid development is desired.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a remedy for cerebral disorders, particularly memory disorders, in response to such a demand. The cerebral disorder referred to in the present invention means that the primary cause is in the nervous system containing glial cells and in the cerebral vascular system. The dementia referred to in the present invention means a disease which shows the following symptoms as mental and physical symptoms.

[0004] Dementia is roughly classified into two types according to the etiological classification. One is Alzheimer's dementia, a disease whose cause is unknown and in which brain nerve cells are affected. The Alzheimer's disease is progressive, with forgetfulness that worsens rapidly from the onset of the disease, disorientation of time and place, and decreased motivation. As the condition progresses further, the patient becomes highly demented, impairing language understanding and expression. The second type is cerebrovascular dementia caused by cerebrovascular disorders. As mentioned above, patients with dementia exhibit symptoms such as loss of intellectual ability, impairment of memory, impairment of abstract thinking, aphasia, apraxia, agnosia, and impairment of their basic functions are in the form or retention of memory. Have impaired ability to develop memory.

[0005] The present inventors have conducted basic studies to develop a therapeutic agent effective for memory impairment in dementia patients, and as a result, have found that propentofylline is extremely effective for memory impairment. Since no drug effective for dementia has been developed so far, propentofylline is considered to be the only drug effective for the treatment of memory impairment among various symptoms of dementia.

[0006]

SUMMARY OF THE INVENTION Propentofylline useful as an active ingredient in the therapeutic agent for memory disorders of the present invention has a chemical name of 3,7-dihydro-3-methyl-1-methylpropane.
(5-oxohexyl) -7-propyl-1H-purine-2,6-dione, having the following chemical structural formula:

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[0007] From the pharmacological studies so far, it has been known that propentofylline has 1) an action of dilating cerebral blood vessels and 2) an action of increasing cerebral blood flow. These two pharmacological actions are described in JP-B-52-33120. In recent years, several cerebral circulatory metabolism improvers have been developed, some of which have a cerebral vasodilatory effect and an increase in cerebral blood flow. However, no effective results have been obtained for dementia. The cerebral circulation metabolism improving agent is a generic name of drugs having various pharmacological actions, and includes a cerebral metabolic activator, a cerebral vasodilator, and a platelet aggregation inhibitor. For example, as a brain metabolic activator, citicoline, meclofenoxate hydrochloride,
Solcoseryl, ifenprodil tartrate, cinepatide maleate, pyritinol hydrochloride, bensicran fumarate,
There is calcium hopantenate. Known cerebral vasodilators include dihydroergotoxin, nicardipine hydrochloride, pentoxifylline, cinnarizine, and vinbocetin, in addition to the above-mentioned ifenprodil tartrate, cinepatide maleate, and bensicran fumarate described above. Aspirin, sulfinpyrazone, dipyridamole, and ticlopidine hydrochloride are used as platelet aggregation inhibitors. Neither of these drugs is effective for dementia due to memory impairment. Therefore, the therapeutic effect of propentofylline found this time on memory impairment is not due to the pharmacological action described in JP-B-52-33120, but is due to a completely different pharmacological action.

The toxicity of propentofylline used in the present invention is low, and continuous administration is possible. The acute toxicity value (LD ₅₀ ) using mice is 375 mg / kg (male) by intraperitoneal administration and 199 mg / kg (male) by intraperitoneal administration in rats.
Met. The pharmacological effect that propentofylline is effective in treating memory impairment in dementia patients will be described below in detail based on experimental results.

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS

EXPERIMENTAL EXAMPLE 1 Generally, memory is composed of the following three processes. It is conceivable that there is a retrieval process in which a memory is acquired first in which certain things are acquired by learning, then the memory is retained, and the memory appears when needed. Male IC to investigate the effect of propentofylline on memory
The experiment was conducted by passive avoidance learning using R mice. Passive avoidance learning and memory impairment due to cycloheximide administration are commonly used experimental methods (Naoki Yamazaki et al .: Ja
p. J. Psychopharmacol. 3 , 127 (1983)) describes a method of performing passive avoidance learning in mice, and describes memory impairment caused by cycloheximide. The equipment used for the experiment is a 20 cm long, 24 cm wide floor made of iron grid.
A plastic box measuring 23 cm in depth and 23 cm in depth was placed on a stand having a height of 8 cm, a width of 8 cm and a height of 1.5 cm at one corner of the floor grid. When the mouse is placed in a box and subjected to electrical stimulation at a current of about 0.3 mA for about 3 seconds, the mouse escapes on the platform. Next, an electrical stimulation for about 5 seconds was given after 8 seconds of no stimulation. By this method, the mouse acquires an aversion memory of receiving an electric stimulus when it gets off the platform, and the passive avoidance learning is established. To determine whether or not the learning was established, the mouse was placed on the platform immediately after the training under non-stimulated conditions, and the learning was established when the mouse remained on the platform for 30 seconds or longer.

[0010] This test for observing whether or not mice retain aversive memory was performed daily after training, and the memory retention was calculated according to the following equation.

(Equation 1) To induce memory impairment in mice, a cycloheximide solution dissolved in physiological saline was administered intraperitoneally 15 minutes before training to a dose of 120 mg / kg, and trained by applying electrical stimulation as described above.

The memory retention rate of the control group of 30 animals fluctuated around 40%. The control group shows a relatively stable memory retention. On the other hand, the memory retention rate of the 59 animals in the cycloheximide-administered group showed a value of 12% on the first day after training, and this value was different from the control group at a significance level of 5%. The low retention rate on the first day gradually recovered with the passage of days, and
On day 0, it returned to the control group level. These results are shown graphically in FIG. In FIG. 1, the vertical axis represents the memory retention rate (%), the horizontal axis represents the number of days after cycloheximide administration, the solid line represents the results of the control group (cycloheximide non-administration group), and the dotted line represents the results of the experimental group (cycloheximide administration group). The results are shown, and the numbers in parentheses indicate the number of mice subjected to the experiment. From FIG. 1, it is clear that administration of cycloheximide does not impair the memory acquisition and retention processes, but temporarily impairs the memory retrieval process.

The improvement effect of propentofylline in mice whose memory retrieval process was impaired by cycloheximide was examined. Memory retention test is training 24
After hours, propentofylline was administered intraperitoneally 30 minutes before the test. The experimental results are shown in Table 1. Propentofylline showed an improving effect on the memory retrieval process which was impaired even at 15 mg / kg, and a remarkable improving effect was observed even at a high dose of 30 mg / kg. This result indicates that propentofylline improves the retrieval process of impaired memory.

[0013]

[Table 1]

EXPERIMENTAL EXAMPLE 2 When propentofylline is administered before learning training,
We investigated whether the dysfunction of the search process induced by cycloheximide could be improved. Using male ICR mice as in Experimental Example 1, training for learning was performed in the same manner.
Cycloheximide was similarly administered intraperitoneally 15 minutes before the training. Propentofylline was administered intraperitoneally 30 minutes before training. The memory retention test was conducted 24 hours after training. The experimental results are shown in Table 2. Propentofylline at 15 mg / kg and 30 mg / kg ameliorated the decrease in memory retention induced by cycloheximide. The results indicate that administration of propentofylline before learning training also ameliorates the impairment of the memory retrieval process induced by cycloheximide.

[0015]

[Table 2]

Experimental Example 3 After learning and training were performed using male ICR mice in the same manner as in Experimental Example 1, on the first day, the memory improvement effect of propentofylline was observed by the following experimental plan. Mice that underwent passive avoidance learning were given ip scopolamine bromide dissolved in saline to induce memory impairment. Propentofylline was administered intraperitoneally 15 minutes before the memory retention test. In the memory retention test, the mouse was placed on a table, and the time until the mouse got off the table was measured up to 180 seconds. The statistical test is a two-sample rank test (Mannwhitney U
-Test). Scopolamine bromide 3 mg / kg significantly shortens the time it stays on the mouse platform,
This shows that scopolamine bromide induces memory impairment. This finding is well known (R. Cumin
et al: Psychopharmacology 78 , 104 (1982)). Intraperitoneal administration of 50 and 70 mg / kg of propentofylline inhibited the action of scopolamine bromide in lowering the mouse from the platform in a short time, and allowed the mouse to remain on the platform for a significantly longer time. This result indicates that propentofylline reverses the memory impairment induced by scopolamine bromide. Table 3 shows the results of this experiment.

[0017]

[Table 3]

Experimental Example 4 The effect of improving the learning and memory of propentofylline was examined using a conditional avoidance learning method. In this method, light and sound conditions are presented, and learning and memory can be observed as a response to the conditions. With this method, the degree of progress of learning and memory can be observed over time. A shuttle type condition avoidance learning method is a typical example of this method. 12 years old
The effect of propentofylline on learning and memory was investigated by using a shuttle-type conditional avoidance learning method in male SHR rats aged 5 months. The experimental apparatus used a shuttle box. The shuttle box is 26cm long, 44cm wide and 24cm deep,
The floor is lined with iron grids and can carry current. The center of the box is divided by a flat plate about 3cm in height,
In order for a rat to move from one room to another,
You have to jump over this obstacle plate.

The experimental procedure is as follows. One SHR
Rats are placed in a shuttle box and are conditioned for 7.5 seconds with sound from a speaker and light from a bulb. During this time, if the rat does not move beyond the central slab to the next room, electrical stimulation is given to the extremities for 7.5 seconds. When the rat moves to the next room during the presentation of the conditional stimulus, the rat can avoid electrical stimulation from the grid.
This operation was repeated 25 times for one rat to make one trial. A correct response was given when the rats performed an avoidance action of moving to the next room during the presentation of the sound and light conditions. The evaluation of learning memory was performed as follows: correct response rate (%) = number of correct responses / 25 times × 100 for one rat per trial. The statistical test used a two-sample rank test.

This learning was performed on rats once a day.
Five trials were performed per week. Water was orally administered at a ratio of 0.4 ml / 100 g body weight after learning to 10 control groups, and 11 mg of propentofylline was orally administered after learning to 11 experimental groups. The experimental results are shown graphically in FIG. In FIG. 2, the vertical axis indicates the correct response rate (%), the horizontal axis indicates the number of trials, the dotted line indicates the result of the control group (the group not administered with propentofylline), and the solid line indicates the result of the experimental group (the group administered with propentofylline). The results are shown, and the number in parentheses indicates the number of rats subjected to the experiment. The * mark attached to the solid line indicates a difference from the control group at a significance level of 5%, and the ** mark indicates a difference from the control group at a significance level of 1%. As is evident from FIG. 2, little improvement in learning to avoid electrical stimulation is observed in the control group. On the other hand, the correct response rate of rats receiving propentofylline gradually increased as the number of trials increased. This result indicates that propentofylline has an effect of improving learning and memory.

The above results prove that propentofylline is effective in treating memory impairment associated with dementia.
The dosage in clinical practice is usually in the range of 100 to 1,500 mg per day as propentofylline, depending on the administration method. Administration methods include intravenous, intramuscular, oral,
Rectal administration is possible. Intravenous administration is possible by intravenous drip in addition to usual intravenous injection. A preparation containing propentofylline is produced by a usual method using usual excipients and additives.

As the preparation for injection, for example, a powder preparation for injection can be used. In this case, add one or more suitable water-soluble excipients such as mannitol, sucrose, lactose, maltose, glucose, fructose and the like, dissolve in water, dispense into vials or ampoules, freeze-dry and seal. Can be used as a preparation. Oral preparations include ordinary tablets, capsules, granules, fine granules, powders, and enteric preparations.

In the case of an enteric preparation, mannitol, sucrose, lactose, maltose, starch, silicic anhydride,
Excipients such as calcium phosphate, talc, lubricants such as magnesium stearate, carboxymethyl cellulose,
Additives such as a binder such as methylcellulose, gelatin and gum arabic, and a disintegrant such as carboxymethylcellulose calcium are added as needed to make tablets, granules, fine granules, etc., and then cellulose acetate phthalate, hydroxypropyl Methylcellulose phthalate, hydroxypropylmethylcellulose acetyl succinate, polyvinyl alcohol phthalate, styrene, maleic anhydride copolymer, styrene / maleic acid copolymer, methyl methacrylate / methacrylic acid copolymer, methyl acrylate / methacrylic acid One or more of enteric bases such as copolymers and, if necessary, a coloring agent such as titanium oxide are added to form a formulation by coating, and the enteric granules or fine granules produced here Into capsules to form capsules. Can.

Also, capsules produced by a usual method can be made enteric by coating with the above-mentioned enteric base, or capsules prepared by mixing the above-mentioned enteric base alone or gelatin. Can be used as an enteric capsule. For suppositories, cacao butter,
Fatty acid monoglyceride and fatty acid diglyceride are mixed with fatty acid triglyceride in various proportions, and lipophilic base such as semi-synthetic base, and hydrophilic base such as polyethylene glycol and glycerogelatin which are heated and dissolved are added and uniformly mixed. A suppository can be formed by molding in a mold. Hereinafter, examples of the present invention will be described.

[0025]

【Example】

Example 1 20 g of propentofylline and 16 g of sodium chloride
To a total volume of 2,000 ml with distilled water for injection. This was sterile-filtered using a 0.22 micron Millipore filter, dispensed in 5 ml portions into 5 ml ampules, sealed, and autoclaved to obtain an injection.

EXAMPLE 2 Lactose (250 g), corn starch (150 g), carboxymethylcellulose calcium (150 g), talc (42 g), magnesium stearate (5 g) and silicic anhydride (3 g) were added to propentofylline (500 g), and the mixture was made into tablets in a conventional manner. Separately, hydroxypropyl methylcellulose 40
g, Macrogol 6000 2 g, titanium oxide 3.5 g, and talc 3 g were dispersed in 500 g of water, and the tablets obtained above were coated with this liquid to prepare propentofylline 11 in one tablet.
5 mg tablets were obtained.

[Brief description of the drawings]

FIG. 1 is a graph showing the memory retention of mice upon administration of cycloheximide.

FIG. 2 is a graph showing condition avoidance learning when propentofylline is administered to SHR rats.

Claims (2)

[Claims] (1) 3,7-dihydro-3-methyl-1-
An agent for treating memory impairment in Alzheimer-type dementia, comprising (5-oxohexyl) -7-propyl-1H-purine-2,6-dione as an active ingredient. (2) 3,7-dihydro-3-methyl-1-
A therapeutic agent for memory acquisition or memory retention disorder in Alzheimer-type dementia, comprising (5-oxohexyl) -7-propyl-1H-purine-2,6-dione as an active ingredient.