JP2784921B2 - Carbamate compounds - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a medicament, particularly a pharmaceutical agent having a cholinesterase inhibitory activity, which is useful as a brain function improving agent for senile dementia, Alzheimer's disease and the like.

2. Description of the Related Art With the aging of society, various compounds having various cerebral function improving effects have been proposed. As one of them, physostigmine, a cholinesterase inhibitor, has been found to have a brain function improving effect. In addition, techniques relating to some carbamate compounds have also been published [Japanese Patent Application Laid-Open No. 61-1986].
225158, Japanese Patent Application Laid-Open No. 61-103876, Archie-Future Experiment Telepathology und Pharmacology (Arch. Exp. Pathol. Pharmakol.) 150 , 1 (1930), US Patent No. 1905990].

On the other hand, British Patent No. 681376, U.S. Patent No. 2,681,915 and West German Patent Application No. 181276 disclose that compounds related to the compound represented by the following formula (I) are useful as insecticides or fungicides. However, there is no teaching about the medicinal effect, especially the cerebral function improving effect and the like.

Problems to be Solved by the Invention In addition to the above physostigmine, alkyl phosphates and neostigmine are also known to have a cholinesterase inhibitory action, but all have a short duration of action, strong toxicity, side effects on peripheral nerves However, it is not always satisfactory for therapeutic and prophylactic use in humans. On the other hand, there is a strong demand for the emergence of a drug acting on the central nervous system, particularly a drug for improving cerebral function against senile dementia and Alzheimer's disease, but no satisfactory compound has yet been found. Thus, a main object of the present invention is to provide a pharmaceutical composition which exhibits a cholinesterase inhibitory action and has less side effects and toxicity than can be used as a brain function improving agent.

Means for Solving the Problems The present inventors have made intensive efforts to search for a compound useful as a brain function improving agent that acts on the central nervous system, particularly acetylcholinesterase, and as a result, the compound is represented by the following formula (I). The inventors have found that a carbamate compound or a salt thereof exhibits an excellent cerebral function-improving action, has a long duration of action, has low side effects and low toxicity, and has further studied to complete the present invention.

That is, the present invention relates to formula (I) [Wherein, X represents -O- or -R ₄ N-, R ₁ , R ₂ , R ₃ and R
₄ represents a hydrogen atom or a hydrocarbon residue, respectively. [Hereinafter simply referred to as compound (I)
May be referred to. Or a salt thereof, which provides a cholinesterase inhibitory activity, and a preparation thereof which is a brain function improving agent.

In the formula (I), the “hydrocarbon residue” represented by R ₁ , R ₂ , R ₃ and R ₄ includes an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl), a phenyl group ,
Or an aralkyl group having 7 to 9 carbon atoms (for example, benzyl,
Phenethyl, phenylpropyl).

Among the compounds represented by the formula (I), a compound in which at least one of R ₂ and R ₃ is a hydrocarbon residue is particularly preferable. Further preferred compounds are those in which R ₁ is an alkyl group, at least one of R ₂ and R ₃ is an alkyl group, X is —R ₄ N— and R ₄ is a hydrocarbon residue.

More specifically, in the compound represented by the formula (I), R ₁ , R ₂ and R ₃ are preferably an alkyl group having 1 to 3 carbon atoms, more preferably an alkyl group having 1 to 2 carbon atoms. . X is -R ₄ N-are preferred as the R _4,. 7 to carbon atoms
Nine aralkyl groups and methyl groups are preferred.

The compound (I) of the present invention may form an acid addition salt, especially a physiologically acceptable acid addition salt, and these salts include, for example, inorganic acids (for example, hydrochloric acid, nitric acid,
Phosphoric acid, hydrobromic acid) or salts with organic acids (eg, acetic acid, propionic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) Is mentioned.

Compound (I) can be produced, for example, by a known method such as the method described in the aforementioned US Pat. No. 2,681,915.
Further, the compound (I) is, for example, a compound of the formula (II) [Wherein, R ₁ has the same meaning as described above, and R ₅ represents a hydrocarbon residue having 1 to 3 carbon atoms (eg, lower alkyl such as methyl, ethyl, propyl, a phenyl group or a benzyl group). With a compound represented by the formula (III) Wherein R ₄ is as defined above. Or a salt of the formula (IV) obtained by condensed cyclization with a salt thereof. [Wherein, R ₁ and R ₄ are as defined above. Or a salt thereof and a compound of the formula (V) [Wherein, R ₂ and R ₃ have the same meanings as above, and Y represents halogen (eg, chloro, bromo, iodine). Or a formula (VI) R ₆ N = C = O (VI) wherein R ₆ is the same as R ₂ and R ₃ . And a compound represented by the formula:

Further, the compound (I) is obtained by condensing a compound represented by the formula (II) with hydroxylamine or a salt thereof to obtain a compound represented by the formula (VII) [Wherein, R ₁ is as defined above. And a compound represented by the formula (V) or (VI).

The condensation cyclization reaction between the compound represented by the formula (II) and the compound represented by the formula (III) or hydroxylamine or a salt thereof can be carried out by a method known per se. More specifically, for example, the following method can be used. That is, the compound represented by the formula (II) and the compound represented by the formula (II)
The reaction can be carried out by reacting the compound represented by I) or 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-methylaminopyridine, triethylamine, diisopropylamine, triethylenediamine, and tetramethylethylenediamine;
Examples thereof include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium potassium, sodium hydroxide, potassium hydroxide, and the like, sodium hydride, potassium hydride, n-butyllithium, and the like. Examples of the solvent include alcohol solvents (eg, methanol, ethanol, propanol, butanol, hexanol), and hydrocarbon solvents (eg, benzene, toluene,
Hexane, pentane), halogen-based hydrocarbon solvents (eg, dichloromethane, chloroform, dichloroethane, carbon tetrachloride), ether-based solvents (eg, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane), amide-based solvents (eg, dimethylformamide) , Hexamethylphosphonotriamide) and dimethyl sulfoxide. Formula (II)
It is preferable to use the compound of the formula (III) or hydroxylamine or a salt thereof in an amount of about 1 to 3 mol, preferably about 1 mol, per 1 mol of the compound of the formula (I). The reaction can be carried out at about 10 ° C to 200 ° C, preferably at about 25 ° C to 120 ° C. The reaction time depends on the type of compound (II) and the reaction temperature, but is usually about 30 minutes to 24 hours, preferably about 2 hours to 10 hours.

The reaction between the compound represented by the formula (IV) or the formula (VII) and the compound represented by the formula (V) or the formula (VI) can also be performed by a known method. For example, such a reaction may be any commonly used solvent, for example, in a solvent such as water, methanol, ethanol, propanol, chloroform, dichloromethane, benzene, toluene, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, etc. -10 ° to 120 ° C
Temperature, preferably at a temperature of about 20 ° to 50 ° C. Further, this reaction may be carried out, if necessary, for example, with an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, triethyleneamine, tetramethylethylenediamine, or the like, for example, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, water. The reaction can be carried out in the presence of an organic base such as sodium oxide and potassium hydroxide, sodium hydride, potassium hydride, n-butyllithium and the like. Formula (IV) or Formula (VI
The compound represented by the formula (V) or (VI) is usually used in an amount of about 1/2 to 3 mol per mol of the compound represented by I).
Preferably, about equimolar amounts are used. The reaction time is generally about 1 minute to 20 hours, preferably about 30 minutes to 2 hours.
The formula (II) used in the method for producing the compound of the present invention described above.
Examples of the respective salts of the compound of the formula (I), the compound of the formula (IV), the starting compound such as hydroxylamine, and the intermediate compound include the acid addition salts described above for the compound (I).

The compound (I) thus obtained can be converted to a salt thereof as described above according to a conventional method, and when obtained as a salt of the compound of the formula (I), it can be converted to a free compound according to a conventional method. it can.

The compound of formula (I) or a salt thereof produced as described above can be isolated and purified by known means, for example, filtration, chromatography, recrystallization and the like.

Effect of the Invention The compound (I) or a salt thereof of the present invention acts on the central nervous system of mammals, has a strong inhibitory effect on acetylcholinesterase, and has various amnesia in mice as shown in the following experimental examples. An anti-amnesic effect was observed against the provocative effect.

Furthermore, as shown in the following experimental examples, the compound (I) of the present invention has a very good separation of the effect on the central nervous system and the effect on the peripheral nerve compared with the above-mentioned known acetylcholinesterase inhibitor, At doses showing an anti-amnesic effect (0.03 mg to 10 mg / body), peripheral nerve effects such as mydriasis, salivation, and diarrhea are absent or very slight, and are extremely effective by oral administration. It is useful as an agent for improving brain function in mammals.

Examples of useful target names of the compounds of the present invention include senile dementia, Alzheimer's disease, Huntington's disease, hyperkinetic disease, mania and the like, and can be used for the prevention or treatment of these diseases.

In using the compound of the present invention as a brain function improving agent as described above, for example, according to a method known per se,
It can be orally or parenterally administered to mammals including humans in various forms such as tablets, granules, capsules, injections, and suppositories. The dosage varies depending on the type of the target disease, symptoms, etc., but in general, in the case of oral administration, in the case of oral administration, 0.1 mg to 500 mg, preferably 1 mg to 50 mg per day.
It is.

Examples Hereinafter, the present invention will be described more specifically with reference to Examples, Preparation Examples, and Experimental Examples.

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

Example 1 1,3-dimethyl-5-dimethylaminocarbonyloxypyrazole hydrochloride Ethyl acetoacetate (5.20 g) and methylhydrazine (2.14 ml) were dissolved in ethanol (50 ml), stirred at 80 ° C. for 3 hours, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate.
3.3 g of 3-dimethyl-5-hydroxypyrazole were obtained.
Dissolve 1.12 g of this 1,3-dimethyl-5-hydroxypyrazole in dimethylformamide (10 ml), add 0.44 g of 60% oily sodium hydride, stir at room temperature for 30 minutes, add 0.92 ml of dimethylcarbamyl chloride, and further add Stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in dichloromethane (50 ml), washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The remaining oil was dissolved in dioxane (50 ml), a 3N hydrogen chloride ethanol solution (4 ml) was added, and the solvent was concentrated. A solid was deposited on the way. This was collected by filtration to obtain 1.8 g of colorless crystals having a melting point of 122 to 127 ° C.

Elemental analysis value Calculated value for C ₈ H ₁₄ Cl ₁ N ₃ O ₂ C 43.74 H 6.42 N 19.12 Experimental value C 43.72 H 6.45 N 18.77 Example 2 5-dimethylaminocarbonyloxy-1,3-diphenylpyrazole 7.69 g of ethyl benzoylacetate and 3.9 of phenylhydrazine
After dissolving 4 ml in ethanol (50 ml) and stirring at 80 ° C. for 1 hour, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 4.6 g of 1,3-diphenyl-5-hydroxypyrazole.
I got 1.18 g of this 1,3-diphenyl-5-hydroxypyrazole was dissolved in dioxane (20 ml), 0.22 g of 60% oily sodium hydride was added, the mixture was stirred at 80 ° C. for 30 minutes, and 0.46 ml of dimethylcarbamyl chloride was added. Stirred at C for 30 minutes. The solvent is distilled off, the residue is dissolved in ethyl acetate (50 ml), washed with water, dried over anhydrous magnesium sulfate, the solvent is distilled off, and the residue is recrystallized from ethanol / hexane [1/1 (V / V)]. This gave 1.0 g of colorless crystals having a melting point of 81-82 ° C.

Elemental analysis value Calculated value for C ₁₈ H ₁₇ N ₃ O ₂ C 70.33 H 5.57 N 13.67 Experimental value C 70.38 H 5.54 N 13.78 Example 3 5-Dimethylaminocarbonyloxy-3-methyl-1
-Phenylpyrazole 5.20 g of ethyl acetoacetate and 3.94 m1 of phenylhydrazine
Was dissolved in xylene (50 ml) and stirred at 130 ° C. for 3 hours. After the solvent was distilled off, the residue was suspended in ethyl ether and collected.
-Hydroxy-3-methyl-1-phenylpyrazole 4.
3 g were obtained. 0.87 g of this 5-hydroxy-3-methyl-1-phenylpyrazole is dimethylformamide (10 ml)
, And 0.22 g of 60% oily sodium hydride was added thereto. After stirring at 80 ° C. for 30 minutes, dimethylcarbamyl chloride (0.46 ml) was added.
Was added and further stirred at 80 ° C. for 30 minutes. After evaporating the solvent, the oil was dissolved in ethyl acetate (50 ml), washed with water and dried over anhydrous magnesium sulfate, the solvent was removed, and the remaining oily compound was subjected to a silica gel column [developing solvent, methanol / dichloromethane (1/99 (V / V))] to give 0.5 g of the desired colorless oily compound.

Elemental analysis value Calculated value for C ₁₃ H ₁₅ N ₃ O ₂ C 63.66 H 6.16 N 17.13 Experimental value C 63.63 H 6.14 N 17.21 Example 4 5-Dimethylaminocarbonyloxy-1-methyl-3
-Phenylpyrazole / hydrochloride 7.69 g of ethyl benzoyl acetate and 2.14 m of methylhydrazine
1 and 5-hydroxy-1
5.3 g of -methyl-3-phenylpyrazole were obtained. This 5
-Hydroxy-1-methyl-3-phenylpyrazole 1.
Dissolve 74 g in dimethylformamide (10 ml), add 0.44 g of 60% sodium hydride, stir at 80 ° C for 30 minutes, add 0.92 ml of dimethylcarbamyl chloride, further stir at 80 ° C for 30 minutes, evaporate the solvent The remaining oily compound was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, 3N hydrogen chloride in methanol (3 ml) was added to the solution, and the solvent was distilled off. Recrystallization from ethyl gave 1.5 g of colorless crystals having a melting point of 88-105 ° C.

Elemental analysis value calculated as C ₁₃ H ₁₆ Cl ₁ N ₃ O ₂ C 55.42 H 5.72 N 14.91 Experimental value C 55.51 H 5.67 N 15.15 Example 5 1-benzyl-5-dimethylaminocarbonyloxy-
3-methylpyrazole 5.20 g of ethyl acetoacetate, 7.80 g of benzylhydrazine dihydrochloride, and 10 g of anhydrous sodium hydrogencarbonate in xylene (100 m
After suspending in 1) and stirring at 120 ° C. for 5 hours, insoluble materials are removed by filtration,
The solvent was distilled off under reduced pressure, the residue was dissolved in dichloromethane (50 ml), washed with water, dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was subjected to a silica gel column [eluent: methanol / dichloromethane (5/95 (V / V ))], The solvent in the fraction containing the desired product was distilled off, the residue was suspended in ethyl ether, and filtered to give 1-benzyl-5-hydroxy-3-methylpyrazole (1.8 g). Obtained. Dissolve 1.06 g of this 1-benzyl-5-hydroxy-3-methylpyrazole in dimethylformamide (10 ml), add 0.22 g of 60% sodium hydride, stir at room temperature for 30 minutes, add 0.46 ml of dimethylcarbamyl chloride, and further add At room temperature
After stirring for 30 minutes, the solvent was distilled off, the remaining oily compound was dissolved in dichloromethane (50 ml), washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the remaining oil was removed using a silica gel column [developing solvent: Methanol / dichloromethane (5/95 (V / V))], and the solvent of the fraction containing the desired product was distilled off to obtain 1.1 g of colorless crystals having a melting point of 32-35 ° C.

Elemental analysis value Calculated value for C ₁₄ H ₁₇ N ₃ O ₂ C 64.85 H 6.61 N 16.21 Experimental value C 64.75 H 6.59 N 16.12 Example 6 1-dimethylaminocarbonyloxy-3-phenylisoxazole 7.69 g of ethyl benzoylacetate, 2.8 g of hydroxylamine hydrochloride and 5.1 g of anhydrous sodium hydrogencarbonate were added to ethanol (5
After stirring at 80 ° C. for 3 hours, the insoluble material was removed by filtration, the solvent was distilled off, and the residue was recrystallized from ethanol / ethyl ether [1/4 (V / V)]. 5.2 g of -hydroxy-3-phenylisoxazole were obtained. 1.61 g of this 5-hydroxy-3-phenylisoxazole was dissolved in dimethylformamide (10 ml), and the solution was dissolved in 0.5% of 60% sodium hydride.
After adding 44 g and stirring at 80 ° C. for 30 minutes, 0.92 ml of dimethylcarbamyl chloride 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 (50 ml), washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified on a silica gel column [eluent: methanol / dichloromethane (5/95 (V / V))), the solvent in the fraction containing the target substance was removed, and the product was recrystallized from n-hexane.
0.5 g of colorless crystals at 62 ° C. were obtained.

Elemental analysis value Calculated value for C ₁₂ H ₁₂ N ₂ O ₃ C 62.06 H 5.21 N 12.06 Experimental value C 62.19 H 5.18 N 12.27 Formulation Example 1 (1) 1-benzyl-5-dimethylaminocarbonyloxy-3-methylpyrazole 10 g (2) Lactose 198 g (3) Corn starch 50 g (4) Magnesium stearate 2 g (1) (2) and 20 g of corn starch are mixed and granulated with a base made from 15 g of corn starch and 25 ml of water. Then, 15 g of corn starch and (4) were added and the mixture was compressed to produce 2,000 3 mm diameter tablets containing 5 mg of (1) per tablet.

Formulation Example 2 (1) 5-dimethylaminocarbonyloxy-3-methyl-1-phenylpyrazole 20 g (2) lactose 198 g (3) corn starch 40 g (4) magnesium stearate 2 g (1) (2) and 20 g of corn The starch was mixed and granulated with a base made from 15 g of corn starch and 25 ml of water, to which was added 15 g of corn starch and (4), and the mixture was compressed with a compression tablet machine to give (1 tablet). ) 2000 tablets of 5 mm diameter containing 1 mg were produced.

[Examples] Cholinesterase inhibitory action The cholinesterase inhibitory action of the compound of the present invention was determined by (acet esterase).
yl- ^[3 H]) - it was studied using acetylcholine. That is, as cholinesterase source, using the S ₁ fraction of Wistar male rat cerebral cortex homogenate as a substrate (acetyl- ^[3 H]) - acetylcholine, also adding the compound of the present invention as an object, after the incubation for 30 minutes The reaction was stopped, a toluene-based scintillator was added, and the mixture was shaken. [ ³ H] -acetic acid produced by the reaction was transferred to a toluene layer, and counted by a liquid scintillation counter to determine a cholinesterase inhibitory activity.

The cholinesterase inhibitory activity of the test compound was represented by a 50% inhibitory concentration (IC ₅₀ ). The cholinesterase inhibitory effect of physostigmine was also measured by the same method. The results are shown in Table 1.

It can be seen that the compound of the present invention exhibits the same acetylcholinesterase inhibitory action as physostigmine, which is a known acetylcholinesterase inhibitor.

Biological test a) Effect on amnesia induced by carbon dioxide The cognitive effect of compound (I) of the present invention was examined by a passive avoidance test. That is, a 5-week-old male mouse is first placed in a bright room of a passive avoidance learning apparatus consisting of two rooms of light and dark. The mouse quickly moves to a dark room due to its habit. When moved, mice are given a current of 0.6 mA from the darkroom floor for 3 seconds under non-evacuable conditions. Mice have remembered this electric shock for several weeks. The formation of this memory was impaired by the following kinds of operations, and the effect of the compound (I) of the present invention on this memory impairment was examined. That is, immediately after receiving the electric shock, the mouse was put into a 4 liter glass container filled with carbon dioxide gas, and when the breathing stopped, the mouse was taken out and the natural respiration was recovered by artificial respiration. This operation causes the mouse to forget that it has received an electric shock.

Therefore, the following day, a memory recovery test was performed. That is, the time required for the mouse to return to the darkness of the passive avoidance learning device and move to the dark room was measured. Mice who forgot to receive the electric shock moved to the darkroom again in 10 to 20 seconds. On the other hand, the mice to which the compound (I) of the present invention was administered recovered the memory and did not try to move to the dark room, or even if they did, it took a long time to move. Therefore, the effect of the test compound was determined by comparing the average value of the time during which the mouse remained in the light room during this test (latency) (8 mice per group) with the control group (only 5% gum arabic suspension containing no test compound). Was administered by comparison with the group administered with. The results were expressed as a percentage change when the average value in the control group was set to 100 (Table 2). The test compound is 5%
As a gum arabic suspension, intraperitoneally (i.
p.)

b) Effect on scopolamine-induced amnesia The effect on scopolamine-induced amnesia was examined by one trial passive avoidance experiment using C57BL / 6 mice. The learning procedure is basically the same as that of Burbach et al. [Scinece,
221 , 1310-1312 (1983)]. The apparatus used in the experiment consisted of a dark room with a grid floor and a light room connected to the dark room. When the mouse was placed in the light room, the mouse could be freely moved to the dark room. Using this device, a single electric shock (0.4 mA, 3 seconds) is applied when the mouse enters the dark room. Scopolamine (1 mg / kg) used to induce amnesia shocks 15
Administer intraperitoneally (ip) minutes before. Twenty-four hours later, an electric shock memory retention test was performed. Retention of passive avoidance behavior was measured by the time-to-latency of a mouse placed in a bright room before entering a dark room. Test compounds are dissolved in saline or tested as a gum arabic suspension.
Administered intraperitoneally (ip) minutes before. Mice in the control group to which only saline was administered generally showed an avoidance time of 20 seconds or less, and amnesia occurred.

The median latency in the group administered with the compound of the present invention was expressed as a percentage corresponding to that of the control group, and the significance test was performed using the Mann-Whitney U test. 9 to 12 mice were used for testing in each group
It is an animal.

 The results are shown in Table 2.

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

General Symptoms (Side Effects) Using 4 mice per group, the mice were placed in a stainless steel observation cage of 13 × 18 × 25 cm, and were acclimated to the cage for about 1 hour before administration of the test compound. The symptoms (side effects) of the mice after administration of each compound were observed and recorded over time until 2 to 4 hours after administration. Peripheral neurological symptoms observed during administration of cholinesterase inhibitors include diarrhea, salivation,
Tremor, hypothermia, and sedation were observed as effects of the mydriasis on the central nervous system, and the frequency of occurrence and severity of the symptoms were evaluated as indices.

The water-soluble compound was dissolved in physiological saline, and the insoluble compound was administered intraperitoneally (ip) or orally (po) as a 5% gum arabic suspension.

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

: Notable: Medium +: Mild-: Not recognized From the above, the compound of the present invention, compared to physostigmine,
It turns out that the side effects are extremely minor.

LD ₅₀ value using mice Using a group of 10 mice, half of the test drug required for death (mg / kg, intraperitoneal (ip) administration or oral (p.
o.) Administration) (LD ₅₀ ) was determined. The results are shown in Table 4.

From the above, it can be seen that the compound of the present invention has extremely low toxicity and is safe compared to physostigmine.

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Claims (2)

(57) [Claims] (1) Expression [In the formula, X represents -O- or -R ₄ N-, R ₁ , R ₂ , R ₃ and R
₄ represents a hydrogen or hydrocarbon residue, respectively. ] The pharmaceutical preparation for cholinesterase inhibition characterized by containing the carbamate compound represented by these, or its salt. 2. The preparation according to claim 1, which is a brain function improving agent for senile dementia and / or Alzheimer's disease.