JPH01242526A - Carbamate compound - Google Patents

Abstract

PURPOSE:To obtain a medicine formulation containing a specific carbamate compound and salt thereof, useful as a medicine, especially useful as a nervous function improving medicine in senile dementia, etc., having long duration time of action and low side effects and toxicity and capable of bringing out choline esterase inhibiting activity. CONSTITUTION:The carbamate compound expressed by formula I [X is -o-,-(R4)N-(R4 is H or hydrocarbon residue); R1-R3 are H or hydrocarbon residue] and salt thereof are contained. The compound expressed by formula I is obtained, e. g., by reacting a compound expressed by formula IV obtained by subjecting a compound expressed by formula II (R5 is 1-3C hydrocarbon residue) to cyclocondensation with a compound expressed by formula III and salt thereof with a compound expressed by formula V (Y is halogen). The compound expressed by formula I can be orally or parenterally administered to a mammal containing human. In the case of the oral administration, the dose is 0. 1mg-500mg, preferably 1mg-50mg.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a pharmaceutical preparation that exhibits cholinesterase inhibitory activity and is useful as a drug, particularly as a brain function improving drug in senile dementia, Alzheimer's disease, and the like.

BACKGROUND OF THE INVENTION As society continues to age, various compounds that have brain function-improving effects have been proposed. As one of these, physostigmine, a cholinesterase inhibitor, has been found to have an effect on improving brain function.

Also, some techniques related to carbamate compounds have been published [JP-A-61-225158. Unexamined Japanese Patent Publication 1986-
103876, Arch,
Exp, Patho! , Pharmakol,)
150.1 (1930), U.S. Patent No. 190599
No. 0.

On the other hand, British Patent No. 681376, US Patent No. 2681
915 and West German Patent Application No. 181276, etc., it is disclosed that compounds related to the compound represented by the following formula (1) are useful as insecticides or fungicides. There is no teaching regarding improvement effects, etc.

Problems to be Solved by the Invention In addition to the above-mentioned physostigmine, alkyl phosphates and neostigmine are also known to have a cholinesterase inhibitory effect, but all of them have a short duration of action, are highly toxic, and have a high toxicity against peripheral nerves. It has drawbacks such as significant side effects, and is not necessarily satisfactory for therapeutic or prophylactic use in humans. On the other hand, there is a strong demand for a drug that acts on the central nervous system, especially a drug that can be used as a brain function improving agent for senile dementia and Alzheimer's disease, but no satisfactory compound has yet been found. Thus, the main object of the present invention is to provide a pharmaceutical composition that exhibits a cholinesterase inhibitory effect and can be used as a brain function improving agent with fewer side effects and toxicity.

Means for Solving the Problems The present inventors have made extensive efforts to search for a compound useful as a brain function improving drug that acts on the central nervous system, particularly acetylcholinesterase. The present inventors have discovered that a brain function improving agent containing a carbamate compound or a salt thereof has a long duration of action and low side effects and toxicity, and after further studies, they have completed the present invention.

That is, the present invention Formula (1) [Wherein, X is 10- or -R, N-, R7, Rt].

R3 and R4 each represent a hydrogen atom or a hydrocarbon residue,] A carbamate compound [hereinafter sometimes simply referred to as compound (1)]. The present invention relates to a pharmaceutical preparation that exhibits cholinesterase inhibitory activity characterized by containing cholinesterase or a salt thereof, and a preparation thereof that is a brain function improving agent.

In the formula (1), RI, Rt, R3 and R
The "hydrocarbon residue" represented by 4 has 1 to 3 carbon atoms.
alkyl groups (e.g. methyl, ethyl, propyl).

A phenyl group or an aralkyl group having 7 to 9 carbon atoms (eg, benzyl, phenethyl, phenylpropyl) can be mentioned.

Among the compounds represented by formula (1), especially Rt.

Compounds in which at least one of R5 is a hydrocarbon residue are preferred. A more preferred compound is one in which R1 is an alkyl group.
．． , at least one of R3 is an alkyl group, and X is -R4
This is a compound in which R4 is a hydrocarbon residue in N-.

More specifically, in the compound represented by the formula (1), R, , R, 11, is preferably an alkyl group having 1 to 3 carbon atoms, and more preferably an alkyl group having 1 to 2 carbon atoms. X is preferably -R,N-, and R4 is an aralkyl group having 7 to 9 carbon atoms.

Methyl group is preferred.

The compound (1) of the present invention may form acid addition salts, especially physiologically acceptable acid addition salts, such as inorganic acids (e.g. hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or organic acids (e.g. acetic acid,
Propionic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid).

Compound (1) is, for example, disclosed in the above-mentioned US Pat. No. 2,68191.
It can be produced by a known method such as the method described in No. 5. Further, the compound (1) may be, for example, a compound of formula (II) RICCIItCORi (II)
[In the formula, R5 has the same meaning as above, and R6 represents a hydrocarbon residue having 1 to 3 carbon atoms (eg, lower alkyl such as methyl, ethyl, propyl, phenyl group, benzyl group, etc.). ]
For example, a compound represented by the formula % formula % ([[) U in the formula, R4 has the same meaning as above. ] or a salt thereof, and formula (IV) obtained by condensation rationalization [wherein R,, r (, are the same meanings as above)] or a salt thereof and formula (V) [wherein, It t , Rs has the same meaning as above, Y represents halogen (e.g. chloro, bromine, iodine), or formula (VI) zt, N=c=o (Vl) [wherein, R8 has the same meaning as Rt, Rs It can be produced by reacting with a compound represented by .].

Further, the compound (1) is a compound represented by the formula (■) obtained by condensing and cyclizing the compound represented by the formula (II) and hydroxylamine or a salt thereof, where R is the same as defined above. It can also be produced by reacting a compound represented by formula (V) or formula (Vl) with a compound represented by formula (V) or formula (Vl).

The condensation cyclization reaction between the compound represented by formula (■) and the compound represented by formula (III) or hydroxylamine or a salt thereof can be carried out by a method known per se. More specifically, the following method can also be used, for example. That is, a compound represented by formula (II) and a compound represented by formula (
This can be carried out by reacting the compound represented by I[I), hydroxylamine, or a salt thereof, usually in a solvent, if necessary, in the presence of a base or the like. Examples of the base include organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylamine, triethylenediamine, and tetramethylethylenediamine; examples include sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide;
Examples include inorganic bases such as potassium hydroxide, sodium hydride, potassium hydride, n-butyllithium, and the like.

Examples of solvents include alcohol solvents (e.g. methanol, ethanol, propatool, butanol, hexanol), hydrocarbon solvents (e.g. benzene, toluene, hexane, pentane), halogenated hydrocarbon solvents (e.g. dichloromethane, chloroform). , dichloroethane, carbon tetrachloride), ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane), amide solvents (e.g., dimethylformamide, hexamethylphosphonotriamide), and dimethyl sulfoxide. It is better. Formula (n
), the compound of formula (III) or hydroxylamine or a salt thereof is added in an amount of approximately equal to 3 moles.
It is preferable to use molar amounts, preferably equimolar amounts. The reaction is carried out at a temperature of about 10°C to 200°C, preferably about 25°C to 1
It can be carried out at 20°C. The reaction time is the compound (n
) and the reaction temperature, it is usually open for about 30 minutes to 24 hours, preferably 2 hours to 10 hours.

A compound represented by formula (IV) or formula (■) and formula (V)
Alternatively, the reaction with a compound represented by formula (V[) can also be carried out by a known method. For example, such reactions may be carried out in any commonly used solvent, such as water, methanol, ethanol, propatool, chloroform, dichloromethane, benzene, toluene, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, etc. For example, it can be carried out at a temperature of about -100 to 120°C, preferably about 20' to 50°C. Furthermore, this reaction can be carried out as necessary, for example,
Organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, triethyleneamine, tetramethylethylenediamine, and e.g. sodium bicarbonate,
The reaction can be carried out in the presence of an inorganic base such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, n-butyllithium, or the like. Formula (IV) or formula (
Formula (V) is also used in an equivalent molar amount per mole of the compound represented by (2). The reaction time is usually about 1 minute to 20 hours, preferably about 30 minutes to 2 hours. The salts of the compound of formula (I[), compound of formula (IV), hydroxylamine, etc., and the intermediate compound and the intermediate compound used in the above-mentioned method for producing the compound of the present invention are as follows for compound (I). Examples include acid addition salts such as those mentioned above.

Compound (1) thus obtained can be converted into its salt as described above according to a conventional method, and when obtained as a salt of the compound of Bunmu (1), it can also be converted into a free compound according to a conventional method. .

The compound of formula (1) or a salt thereof produced as described above can be prepared by known means such as filtration, chromatography,
It can be isolated and purified by means such as recrystallization.

Effects of the Invention As shown in the following experimental examples, the compound (1) of the present invention or a salt thereof acts on the central nervous system of mammals, has a strong inhibitory ability against acedercholinesterase, and has various effects on mice. In contrast to amnesia-inducing effects, anti-amnestic effects were observed.

Furthermore, as shown in the experimental examples below, the compound (1) of the present invention has an extremely good separation of effects on the central nervous system and peripheral nerves, compared to the above-mentioned known acetylcholinesterase inhibitors, and is highly effective in mice. At doses that exhibit anti-amnestic effects (0.03 mg to 10 mg/body), peripheral nerve effects such as mydriasis, flow effects, and diarrhea are absent or very slight, and oral administration is effective. It is useful as a brain function improving drug for mammals including humans.

Examples of useful target diseases for the compounds of the present invention include senile dementia, Alzheimer's disease, Huntington's disease,
Examples include hyperexertion disease and chronic illness, and it can be used to prevent or treat these diseases.

When using the compound of the present invention as a brain function improving drug as described above, for example, according to a method known per se,
It can be administered orally or parenterally to mammals including humans in various dosage forms such as tablets, granules, capsules, injections, and whole tablets. The dosage varies depending on the type of disease, symptoms, etc.

- For adults fishing on boats, for oral administration - 0.1 mg to 500+ ng per day, preferably 1 mg to 50 m
It is g.

EXAMPLES The present invention will be explained in more detail with reference to Examples, Formulation Examples, and Experimental Examples.

In the following description of Examples, "%" represents "% by weight" unless otherwise specified. Further, "room temperature" means approximately 5°C to 25°C, and φ represents a phenyl group.

Example 1 1.3-dimethyl-5-dimethylaminocarbonyloxypyrazole hydrochloride 5.20 g of ethyl acetoacetate and 2.1 g of methylhydrazine
4-zo was dissolved in ethanol (50-zo) and stirred at 80°C for 3 hours, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 3.3 g of 1,3-dimethyl-5-hydroxypyrazole. Obtained. 1.12 g of this 1°3-dimethyl-5-hydroxypyrazole was added to dimethylformamide (lo
d) 0.44 g of 60% oily sodium hydride dissolved in
was added, and after stirring at room temperature for 30 minutes, 0.92 d of dimethylcarbamyl chloride was added, and the mixture was further stirred at room temperature for 30 minutes.

After the solvent was distilled off under reduced pressure, it was dissolved in dichloromethane (50d), washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The remaining oil was dissolved in dioxane (50d), a 3N hydrogen chloride solution in ethanol (4d) was added thereto, and the solvent was concentrated to precipitate a solid. This was collected by filtration to obtain 1.8 g of colorless crystals with a melting point of 122-127°C.

Elemental analysis value Calculated value as CeH+4CLN so t C43,74II 6.42 N 19.12 Experimental value C43,72116,45N 18.77 Example 2 7.69 g of ethyl benzoyl acetate and 3.94 d of phenylhydrazine were added to ethanol (50 d) Melt at 80°C
After stirring for 1 hour, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 4.6 g of 1,3-diphenyl-5-hydroxypyrazole. This 1,3-diphenyl-
1.18 g of 5-hydroxypyrazole was added to dioxane (2
0 precepts) dissolved in 60% oily sodium hydride 0.22
After stirring at 80° C. for 30 molecules, 0.46 d of dimethylcarbamyl chloride was added and the mixture was further stirred at 80° C. for 30 minutes.

The solvent was distilled off, and the residue was dissolved in ethyl acetate (501n1.), washed with water, and dried over anhydrous magnesium sulfate.
)] to give 1.0 colorless crystals with a melting point of 81-82°C.
I got g.

Elemental analysis value C, s Calculated value as H17N 30 t C70,33115,57N 13.67 Experimental value C
70,38115,54N 13.711 Example 3 5.20 g of ethyl acetoacetate and phenylhydrazine3.
Dissolve 94d in xylene (50*=ffi) +30°
After stirring for 3 hours at C, the solvent was distilled off, and the residue was dissolved in ethyl ether for $! ! 5-Hydroxy-3-methyl-
4.3 g of 1-phenylpyrazole was obtained.

0.87 g of this 5-hydroxy-3-methyl-1-phenylpyrazole was dissolved in dimethylformamide (10d), 0.22 g of 60% oily sodium hydride was added thereto, and after stirring at 80°C for 30 minutes, 0.46 d of carbamyl was added and the mixture was further stirred at 80°C for 30 minutes. After distilling off the solvent, the oil was dissolved in ethyl acetate (50%), washed with water, dried over anhydrous magnesium sulfate, the solvent was removed, and the remaining oily compound was transferred to a silica gel column [developing solvent, methanol/dichloromethane (1/99)]. V/V)) was separated to obtain 0.5 g of the desired colorless oily compound.

Elemental analysis value C+5I (calculated value C as 1sN30t)
63,66II 8.16 N 17.13 Experimental value
C63,6386,14N 17.21 Example 4 7.69 g of ethyl benzoylacetate and methylhydrazine 2
．． 14M1. and 5.3 g of 5-hydroxy-1-methyl-3-phenylpyrazole in the same manner as in Example 2.
I got it. 1.74 g of this 5-hydroxy-1-methyl-3-phenylpyrazole was added to dimethylformamide (10
d), add 0.44 g of 60% sodium hydride, stir at 80°C for 30 minutes, and dimethylcarbamyl chloride 0.
．． 92- was added, and after further stirring at 80°C for 30 minutes, the solvent was distilled off, the remaining oily compound was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solution was added with 3N hydrogen chloride in methanol. After adding the solution (3 precepts), the solvent was distilled off, and the residue was recrystallized from ethyl acetate to give a melting point of 88-
1.5 g of colorless crystals at 105°C were obtained.

Elemental analysis value C,, H,, C1, N, O, calculated value C55,42115,72N 14.91 Experimental value C
55,51H5,67N 15.15 Example 5 Ethyl acetoacetate 5.20g, benzylhydrazine 2
7.80 g of hydrochloride and 10 g of anhydrous sodium bicarbonate were suspended in xylene (100Tn1. ), washed with water, dried over anhydrous magnesium sulfate, removed the solvent, and transferred the residue to a silica gel column [developing solvent: methanol/dichloromethane (5
/95 (V/V))] for 9 minutes, the solvent of the fraction containing the target product was distilled off, the residue was suspended in ethyl ether and collected by filtration to obtain l-benzyl-5-hydroxy- 1.8 g of 3-methylpyrazole was obtained. This l-benzyl-5-hydroxy-3-methylpyrazole 1.0
Dissolve 6g in dimethylformamide (10d) and add 60
After adding 0.22 g of sodium hydride and stirring at room temperature for 30 minutes, 0.46M1 of dimethylcarbamyl chloride was added, and after further stirring at room temperature for 30 minutes, the solvent was distilled off and the remaining oily compound was dissolved in dichloromethane (50y4). After dissolving in water and washing with water,
After drying over anhydrous magnesium sulfate, the solvent was distilled off and the remaining oil was separated using a silica gel column [developing solvent: methanol/dichloromethane (5/95 (V/V))]. By distilling off, 1.1 g of colorless crystals with a melting point of 32-35°C were obtained.

Elemental analysis value Calculated value as CI4H17N 3o t
CB4.85116.61 N 16.21 Experimental value
C64,75It 6.59 N ia, 12 Example 6 7.69 g of ethyl benzoyl acetate, 2.8 g of hydroxylamine hydrochloride, and 5.1 g of anhydrous sodium bicarbonate were suspended in ethanol (50 ml) and heated at 80°C. After stirring for 3 hours, insoluble materials were filtered off, the solvent was distilled off, and the residue was recrystallized from ethanol/ethyl ether [1/4 (V/V)].
5-Hydroxy-3-phenylisoxazole 5.2
I got g. 1.61 g of this 5-hydroxy-3-phenylisoxazole was dissolved in dimethylformamide (10d).
and add 0.44g of 60% sodium hydride.
After stirring at 80°C for 30 minutes, dimethylcarbamyl chloride 0.9
2d was added, and the mixture was further stirred at 80°C for 1 hour. The solvent was distilled off, the residue was dissolved in ethyl acetate (50d), washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was transferred to a silica gel column [developing solvent: methanol/dichloromethane (5/95 (V/ V))] for 9 minutes, the solvent of the fraction containing the target product was removed, and recrystallization was performed from n-hexane to obtain 0.5 g of colorless crystals with a melting point of 62°C.

Elemental analysis value: C, -3-Methylpyrazole IOg(2) Lactose
198 g (3) Corn starch 50 g (4) Magnesium stearate 2 g (+) (2) and 20 g of corn starch were mixed together and granulated with a paste made from 15 g of corn starch and 25- of water; Corn starch and (4) were added and the mixture was compressed to produce 2000 tablets of 3 mm diameter containing 5 mg of (1) per tablet.

Formulation Example 2 (1) 5-dimethylaminocarbonyloxy-3-methyl-1-phenylpyrazole 20g (2) Lactose
198 g (3) Corn starch 40 g (4) Magnesium stearate 2 g (1), (2) and 20 g of corn starch were mixed together and granulated with a paste made from 15 g of corn starch and 25 d of water; Add corn starch and (4) and compress the mixture in a compression tablet machine to give (+) l per tablet.
2000 tablets with a diameter of 5+n+++ containing γ-mg were produced.

[Experimental example] Cholinesterase inhibitory effect The cholinesterase inhibitory effect of the compound of the present invention was
An investigation was conducted using tyl-[3H])-acetylcholine. That is, as a cholinesterase source, Wis
Using the S1 fraction of tar male rat cerebral cortex homogenate, adding (acetyl-[3H])-acetylcholine as a substrate and the compound of the present invention as a test substance,
After incubation for 30 minutes, the reaction was stopped, a toluene-based scintillator was added and shaken, and the [3H]-hyperacid produced by the reaction was transferred to the toluene layer and counted with a liquid scintillation counter to inhibit cholinesterase. Activity was determined.

The cholinesterase inhibitory activity of the test compound was expressed as 50% inhibitory concentration (IC,.). The cholinesterase inhibitory effect of physostigmine was also measured by the same method.

The results are shown in Table 1.

Table 1 Compounds Acetylcholinesterase (Example No.) Inhibitory Activity ICs. (μM)1
0.36 2 >to.

3 0.68 5 0.15 G 12 Physostigmine 0.22 It can be seen that the compound of the present invention exhibits the same acetylcholinesterase inhibitory effect as physostigmine, a known acetylcholinesterase inhibitor.

Biological test a) Effect on carbon dioxide-induced amnesia The nootropic effect of the compound (1) of the present invention was investigated by a passive avoidance test. That is, a 5-week-old male mouse is first placed in a light room of a passive avoidance learning device consisting of two light and dark rooms. Mice naturally move quickly to dark rooms.

When moved, a 0.6 milliamp current is applied to the mouse from the floor of the dark room for 3 seconds under conditions of no escape. The mice remember the electric shock for several weeks. Impairing the formation of this memory by the following types of operations,
The effect of the compound (1) of the present invention on this memory disorder was investigated. That is, immediately after receiving the electric shock, the mouse was placed in a 4f2 glass container filled with carbon dioxide gas, and when breathing stopped, the mouse was removed and natural breathing was restored by artificial respiration.

This action causes the mouse to forget that it received an electric shock.

Therefore, we conducted a memory recovery test the next day. That is,
The mouse was placed back into the light and dark room of the passive avoidance learning device, and the time taken to move to the dark room was measured.

The mice forgot that they had received the electric shock and returned to the dark room after 10 to 20 seconds. On the other hand, the mice administered with the compound (1) of the present invention recovered their memory and either did not try to move to the dark room or took a long time to move even if they did. Therefore, the effect of the test compound is determined by comparing the average value of the time the mice remain in the light room (latency time) during this test (8 mice in the - group) with the control n (5% gum arabic suspension m solution not containing the test compound). This study was conducted by comparing the results with the group administered only with The performance is 100% higher than the average value in the control group.
It is expressed as a percentage change when (Table 2). The test compound was dissolved in 5% gum arabic suspension and administered intraperitoneally (i, p) 30 minutes before the test.

b) Effect on scopolamine-induced amnesia The effect on scopolamine-induced amnesia was investigated by a trial passive avoidance experiment using C57BL/6 mice. The learning procedure is basically based on Burbach et al.
), 22 + , I 310-+312 (19
It was carried out according to the method of [1983].

The apparatus used in the experiment consists of a dark room with a grid floor and a light room connected to it.When a mouse is placed in the light room,
They are allowed to move freely to the darkroom.

Using this device, once the mouse enters the dark room, a single electric shock (CO, 4 mA, 3 seconds) is applied. Scopolamine (1 mg/kg), used to induce amnesia, is administered intraperitoneally (i,p,) 15 minutes before administering the electric shock. Then, 24 hours later, I received an electric shock, IC! A memory retention test was conducted. Retention of passive avoidance behavior was measured by the time taken by the mouse placed in the light room to enter the dark room (latency).

The test compound was dissolved in physiological saline or administered as a gum arabic suspension intraperitoneally (i,p) 30 minutes before the test. Mice in the control group that received saline alone generally exhibited avoidance times of 20 seconds or less and developed amnesia.

The median latency in the group administered with the compound of the present invention was expressed as a percentage corresponding to that in the control group, and the Mann-Vhitney U test was used for significance testing. The number of mice used for testing each group is between 9 and 12.

The results are shown in Table 2.

Table 2 Compound Administration m CO2 Scopolamine (Example number) (mg/kg i, p,) Induced amnesia Induced amnesia 91 0, 10 122 135
”3 0.03 162 173
″5 0.10 382″ +6
4'0.30 282" 2+7 Physostigmine 0.03 285 990.1
0 406" 1240.30
397"""I)<0.05 U test against control""P<0.01 U test against control""P<0.002 U test against controlP is bqa in Mann-Whitney test:
Indicates I<(probabNity).

From the above, it can be seen that the compound of the present invention exhibits an excellent anti-amnestic effect similar to that of physostigmine.

, General Symptoms (Adverse Effects) Using 4 mice per group, the mice were placed in a stainless steel observation cage measuring 13 x IEj x 25 cm, and after acclimating to the cage for about 1 hour, the test compound was administered. Symptoms (side effects) of mice after administration of each compound 2-4 days after administration
Observations and records were made over time until hours later. Peripheral autonomic nervous symptoms observed during administration of cholinesterase inhibitors include tremor, hypothermia, and sedation as effects on the central nervous system, and the frequency of occurrence and type of symptoms. was used as an index for evaluation.

Water-soluble compounds are dissolved in physiological saline, and insoluble compounds are dissolved in saline.
It was administered intraperitoneally (i, p,) or orally (p, o,) as a suspension of gum arabic.

The results are shown in Table 3. The ratings are as follows.

t: Marked: Moderate +: Mild m: Not observed Compounds in Table 3 Administration m Administration example number (mg/kg) Method Sedation Hypothermia Tremor Lyrics Diarrhea Mydriasis I to i, p, +
−+ ---1001), 0. ↑
↑ -1-12 100 i, p
, −−−−−1(10p, o, −”−−− 330p, o, −+ −−−−430p,
o, ------- 100I), 0. 10 廿 ---15
10 p, o ↓ ---1-6IoO
i, p, ------- 1009, o, ------- Physostigmine 0.5 i, p, + -------0,7°
i, p, +l+-廿 +1++1+ 廿
-1 p, o, + 4" p, o, +l+s + 2 out of 4 died. There were no other deaths. From 2.
It can be seen that the compound of the present invention has extremely minor side effects compared to physostigmine.

LD 5° value using mice Using 10 mice per group, half of the mice died before the drug was administered (mg/kg, intraperitoneally (i, p)) or orally (p, o,) Administration) (L D 50) was determined. The results are shown in Table 4.

Table 4 Compound LDso value Example number i, p, p, o.

1　　　　　　　＞　10　　　＞to.

2 > 100 > 1003
N, D, > 304
N, D, >1005
N, D, > 106
> 100 > 100 Physostigmine 0.73 N, D,: Not yet studied From the above, it can be seen that the compound of the present invention has extremely low toxicity and is safe compared to physostigmine.

Claims (2)

[Claims] (1) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X is -O- or -R_4N-, R_1, R_
2, R_3 and R_4 each represent a hydrogen or hydrocarbon residue. ] A pharmaceutical preparation that exhibits cholinesterase inhibitory activity, characterized by containing a carbamate compound or a salt thereof. (2) The preparation according to claim 1, which is a brain function improving agent.