JPH032155A - Carbamic acid ester derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H or lower alkyl: R<2> is H, lower alkyl or (substituted) aromatic group; R<3> and R<4> are H or lower alkyl; n is 0-7: ring A is 5 to 8-membered ring which may contain hetero atom; ring B is (substituted) benzene ring; ring C is (substituted) aromatic group] or its salt. EXAMPLE:2-[5-[N-ethyl-N-[[3-(methylaminocarbonyloxy) phenyl]methyl]amino]pentyl]-5-nitro-1H-isoindolo-1,3(2H)-dione hydrochloride. USE:The compound has choline esterase inhibiting action and is useful as a cerebral function improving agent for senile dementia, Alzheimers disease, etc. PREPARATION:The compound of formula I can be produced by reacting a compound of formula II with a compound of formula R<3>-N=C=O [R<3> is the above-mentioned group or group of formula III (Y<1> is eliminable group)] in a solvent at 0-120 deg.C optionally in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel carbamic acid ester derivative or a salt thereof useful as a medicine, particularly as a brain function improving agent in senile dementia, Alzheimer's disease, etc.

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

However, physostigmine has drawbacks such as short duration of action and high toxicity.

An object of the present invention is to provide a compound that has stronger action, longer duration of action, and less toxicity than known compounds known to have brain function improving action.

Means for Solving the Problems The present inventors have made extensive efforts to search for a compound useful as a brain function improving drug having a cholinesterase inhibitory effect. Indicates an alkyl group, R
1 represents a hydrogen atom, a lower alkyl group, or an aromatic group that may have a substituent, R3 and R4 each independently represent a hydrogen atom or a lower alkyl group, and n is O-
Indicates an integer of 7, and indicates a 5- to 8-membered cyclic group which may be substituted in the ring and may contain 1 to 2 of OlS and N as ring-constituting heteroatoms, and ring B is substituted. a benzene ring which may have a substituent, and ring C represents an aromatic ring group which may have a substituent in addition to the carbamoyloxy group shown in the formula;
In addition to successfully creating the salts thereof, the inventors discovered that these compounds exhibit excellent brain function-improving effects, leading to the completion of the present invention.

That is, the present invention provides a compound represented by formula (I) [hereinafter sometimes simply referred to as compound (1)]. The present invention relates to cholinesterase inhibitors and salts thereof, their production methods, and cholinesterase inhibitors and brain function improving agents containing them.

In the formula (I), the lower alkyl group represented by R' and R' is a c, -6 alkyl group (e.g., methyl, ethyl, n-propyl, i-
Propyl, n-butyl, i-butyl, t-butyl.

n-pentyl, n-hexyl, etc.).

In the formula CI), examples of the "aromatic group" of the "aromatic group which may have a substituent" represented by R'' include a phenyl group and a naphthyl group.

Examples of substituents for these aromatic groups include CI-4
Alkyl (e.g. methyl, ethyl, propyl.

butyl, etc.), halogen atoms (e.g., chlor, bromo, iodo), nitro, cyano, hydroxy, Cl-4 alkoxy (e.g., methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy), CI-, alkylthio (e.g., methylthio , ethylthio, propylthio, isopropylthio, butylthio), amines.

Mono- or di-CI-4 alkyl substituted amino (e.g. methylamino, ethylamino, propylamino, dimethylamino, diethylamino), C, alkylcarbonylamino (e.g. acetylamino, propionylamino,
butyrylamino, etc.), Cl-4 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), C,, alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, imbutoxycarbonyl), hydroxy Carbonyl, C7-. Alkylcarbonyl (e.g., methylcarbonyl, ethylcarbonyl,
butylcarbonyl (1-cyclohexylcarbonyl), carbamoyl, mono- or di-Cl-4 alkyl-substituted carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl).

propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), Cl-11
Alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), phenyl optionally having 1 to 4 substituents, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl C
8-4 alkyl carbamoinohenyl rubamoyl,
Phenyl C1-4 alkylcarbonylamino, benzoylamino, phenyl C3-4 alkylsulfonyl, phenylsulfonyl, phenyl C+-t alkylsulfinyl, phenyl C1-4 alkylsulfonylamino and phenylsulfonylamine [in each phenyl group or naphthyl group] Examples of substituents include CI-4 such as methyl, ethyl, propyl, butyl, isopropyl, etc.
Cl in alkyl groups, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, etc.
-4 alkoxy group, chloro, bromo.

Halogen atoms such as cords, hydroxyl groups, benzyloxy,
Examples include amine, mono- or di-C3-4 alkyl-substituted amino, nitro+Cl-4 alkoxycarbonyl, and the like. ] etc.

The number of substituents for these aromatic groups is suitably about 1 to 3.

In the formula (r), examples of the substituent on ring B include C8-4 alkyl (e.g., methyl, ethyl, propyl, butyl, etc.), halogen atom (e.g., chloro, bromo, iodo, etc.), nitro, cyano, Hydroxy TCI-4
Flukoxy (e.g. methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), Cl-
4-furkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), amino, mono- or di-C7-4 alkyl substituted amino (e.g., methylamino, ethylamino, propylamine, dimethylamino, diethylamino, etc.), cyclic Aminos (e.g. pyrrolidino).

piperidino, hexamethyleneimine 7, etc.), Cl-4furkylcarbonylamino (e.g., acetylamino, propionylamino, butyrylamine 7, etc.), C3-4 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino) ), C,,, alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, imbutoxycarbonyl, etc.), hydroxycarbonyl + Cl-8 alkylcarbonyl (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl, cyclohexylcarbonyl) etc.), carbamoyl, mono- or di-C1-4 alkyl-substituted carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl).

dibutylcarbamoyl, etc.), C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), phenyl, naphthyl which may have a 1-4 (II substituent) , phenoxy, benzoyl, phenoxycarbonyl, phenyl CI-4 alkylcarbamoyl, phenylcarbamoyl, phenyl CI
-, Al-oxycarbonylamino.

benzoylamino, phenyl C1-4 alkylsulfonyl, phenylsulfonyl, phenyl C3-4 furkylsulfinyl, phenyl C, alkylsulfonylamino and phenylsulfonylamino (substituents on each phenyl group or naphthyl group include, for example, methyl , CI-4 alkyl groups such as ethinopepropyl, butyl, and isopropyl; CI-4 alkoxy groups such as methoxy, ethoxy, n-propyloxy, i-propyloxy, and n-butyloxy; halogen atoms such as chlor, bromo, and iodo; , hydroxyl group, benzyloxy, amino, such as methylamine, dimethylamino, etc., mono- or di-C
Examples include l-4 alkyl-substituted amino, nitro+Cl-4 alkoxycarbonyl, and the like. ) etc.

As ring B, 1 to 3 substituents selected from these (
(If there are two or more, they may be the same or different)
It is preferable that the benzene ring has the following.

Ring A may be a carbocyclic ring, or may contain 0, S,
A heterocycle containing 1 to 2 N atoms may be used. Moreover, it may be saturated or unsaturated.

Examples of the substituent that ring A may have include a hydroxyl group, an oxo group, a lower alkoxycarbonyl group, and an aromatic group that may have a substituent.

Here, the lower alkoxycarbonyl is C1-4 alkoxycarbonyl (eg, methoxycarbonyl).

Ethoxycarbonyl, n-propoxycarbonyl, n-
butoxycarbonyl, t-butoxycarbonyl, etc.).

In addition, the "aromatic group" and its "substituent" in the "aromatic group which may have a substituent" as a substituent on the ring include a substituent represented by "R". Examples of the "aromatic group" and "substituent" of "Aromatic Group" include the groups listed above.

Specifically, R+ is preferably methyl, ethyl, i-propyl, etc., with ethyl being particularly preferred.

R'' is preferably a hydrogen atom.

R' and R' are each independently a hydrogen atom.

Methyl, ethyl, etc. are preferred. Preferably, n is 3 or 4.5.

For example, it is an aromatic group that has a substituent and may further have a substituent. Examples of such an aromatic group include a phenyl group,
Examples include naphthyl group. Examples of substituents that ring C may have in addition to the above carbamoyloxy group include those described above as substituents for ring B.

Preferred examples of the compound represented by formula (I) (in the formula, each symbol is as defined above) are mentioned.

Substituents for ring B include Cl-4 alkoxy, nitro,
Cyan, a halogen atom, Cl-4furkylcarbonylamino, c, -i alkylsulfonyl, etc. are preferable, and the number thereof is preferably 0 to 2.

Ring C is preferably a benzene ring, and its substituents are preferably methyl, ethyl, etc., but it is also preferable that the benzene ring has no substituent.

The compound (1) of the present invention may form acid addition salts, especially physiologically acceptable acid addition salts, such as inorganic acids (eg, hydrochloric acid).

salts with nitric acid, phosphoric acid, hydrobromic acid, sulfuric acid) or organic acids (acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methane) sulfonic acid, benzenesulfonic acid).

Further, when the target compound (1) has an acidic group such as -COOH, the target compound (1) is, for example, sodium, potassium, calcium, or magnesium.

Salts may be formed with inorganic bases such as ammonia or with organic bases such as triethylamine.

Next, a method for producing the compound (I) of the present invention will be described.

The following description of the manufacturing method covers not only the target compound (T) itself, but also
Although this also applies to the above-mentioned salts thereof, they will simply be abbreviated as compound (I) in the following explanation.

Compound (1) is, for example, represented by formula (II) [wherein each symbol has the same meaning as above]. ] and the compound represented by the formula (III) R'-N-C=O(I[I) [wherein R3 has the same meaning as above. The compound represented by 2 can be prepared by a method known per se, for example, in the Journal of Organic Chemistry (J, Org.

Chew, ), λdan, 779 (1961),
Journal of the American Chemical Society (J, Am.

Chem, j3oc,), , 8.1736 (19
26) or a method similar thereto.

Further, compound (1) is, for example, compound (If) and the formula . ] by a method known per se, for example, in the Journal of Organic Chemistry (J, Org.

Chem, ), 32. 851 (1967),
31. 1150 (1966) or a method similar thereto.

Examples of the alkyl or arylsulfonyl alkyl represented by Yl include methyl and ethyl.

As the aryl, 01-4 lower alkyl such as propyl is usually used, for example, phenyl which may be substituted such as phenyl or p-methylphenyl.

The compound represented by the above formula (II) is, for example, a compound represented by the formula (V) [wherein Y' represents a leaving group such as halogen, alkyl or arylsulfonyloxy, and each of the other
Self-name has the same meaning as above. A compound represented by
Formula (Vl) p+ to 4 [Each symbol in the formula has the same meaning as above. It can be produced by reacting a compound represented by or a salt thereof.

Y! Examples of the alkyl or arylsulfonyl represented by M include methyl and ethyl.

As the aryl, C1-4 lower alkyl such as propyl is usually used, and optionally substituted phenyl such as phenyl and p-methylphenyl is usually used.

R8-? l-The "lower alkyl group" shown is r
Examples of the "lower alkyl group" in "lower alkyl group represented by R', R', R' and R4" include the groups listed above. Examples of the salt of the compound represented by formula (Vr) include the acid addition salts h< as described above for the target compound (1).

This reaction is carried out with or without a solvent,
This reaction is carried out in the presence or absence of a base.

Examples of the base include sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide,
Examples include inorganic bases such as sodium methoxide, sodium ethoxide, and sodium hydride, and organic bases such as pyridine, 4-dimethylaminopyridine, and triethylamine. When a solvent is used, the solvent is, for example, methanol.

Lower alcohols such as ethanol, propatool, impropatool, n-butanol, t-butanol, ethers such as dioxane, ether, tetrahydrofuran, aromatic hydrocarbons such as toluene, benzene, xylene, dimethylformamide, dimethylacetamide , amides such as hexamethylphosphonotriamide, and esters such as ethyl acetate and butyl acetate, which do not inhibit the progress of the reaction, are appropriately used. This reaction was carried out under cooling (approximately 0'C to 10'C) and at room temperature (approximately 10'C to 40'C).
) or under heating (Q40°C to 120°C), and the reaction time is usually 10 minutes to 48 hours, preferably 2 to 16 hours. Also used compound (VT)
Usually, m is preferably 0.3 for compound (V).
~5.0 times the mole. When a base is used, the amount of the base used is usually from about an equimolar amount to an excess amount, preferably 1.1 to 5 times the molar amount, relative to compound (Vl). Furthermore, this reaction may be carried out in the presence of an iodide compound such as sodium iodide, potassium iodide, lithium iodide, etc., if desired. When the reaction is carried out in the presence of these iodine compounds, the amount used is usually 1 to 5 molar equivalents, preferably 1.1 to 1.5 molar equivalents, relative to compound (V).

Further, the compound (If) thus obtained can be used as a starting compound to lead to another compound similarly included in the compound (II).

A compound containing a group represented by the formula is a compound having a rubonyl group on ring A] by a known method, for example, the Journal of Organic Chemistry (J, Org.
, Chem, ) 33. 2457 (1968)
It can be produced by hydrolysis followed by decarboxylation by the method described in , or a method similar thereto.

As a specific example, a compound (I[) represented by the formula [wherein R'' represents a lower alkyl group, m is 1゜2 or 3.Other symbols have the same meanings as above, and After decarboxylation, each symbol in the formula has the same meaning as above.

The compound represented by the above formula (V) can be prepared by a known method, for example, the Journal of Organic Chemistry (J
, Org, Chem, ), 33. 2457
(1968).

Acta Chim, Acad, Sci.
Hung-)+32+121 (1962),
39, 391 (1963) or a method similar thereto.

Further, the compound represented by the above formula (VI) can be prepared by a known method, for example, as described in the Journal of the American Chemical Society (J, Am, Chem, Soc,
) + Shu, 1658 (1945),
Alternatively, it can be manufactured by a method similar thereto.

In addition, compound (I) can be obtained by reacting the compound represented by the above formula (V) with the compound represented by formula (■) "[Each symbol in the formula has the same meaning as above.]" or a salt thereof. This reaction can also be carried out by reacting a compound represented by formula (V) with a compound represented by formula (Vl) or a salt thereof, as described above as a method for producing a compound represented by formula (II). This can be done in the same way as the ``Let's do it'' method.

Compound (1) can also be produced by other known methods or methods analogous thereto.

Compound (I) of the present invention acts on the central nervous system of mammals, has strong cholinesterase inhibitory activity, and has excellent anti-amnestic effects against various amnesic-inducing effects in humans and animals (e.g. mice). show.

Compared to physostigmine, the compound (1) of the present invention has an extremely good separation of its effects on the central nervous system and its effects on peripheral nerves.
Peripheral nerve effects such as flushing effects and diarrhea are slight or very slight, have a long duration of action, have low toxicity, and are highly effective when administered orally.

Therefore, the compounds of the present invention are useful for improving brain function in mammals including humans.

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

The compounds of the present invention can be administered orally or parenterally to mammals including humans in various dosage forms such as tablets, granules, capsules, injections, and skewers. The dosage varies depending on the type of disease, symptoms, etc., but in general, for adults, when administered orally, it is approximately 0.00 ml per day.
01-1 mgs, preferably 0.001-0.3 mg,
More preferably, it is 0.003 to 0.1 mg.

Effect of the invention The compound according to the present invention acts on the central nervous system of mammals,
Has strong cholinesterase inhibitory activity. Therefore, it can be used for the prevention and treatment of senile dementia, Alzheimer's disease, Huntington's chorea, etc., and is useful as a medicine.

In the following, the present invention will be explained in more detail with reference to Examples, Reference Examples, Formulation Examples, and Experimental Examples, but the present invention is not limited thereto.

Unless otherwise specified, elution in column chromatography in Examples and Reference Examples was performed using TLC (ThinLayer
The analysis was carried out under observation using chromatography (thin layer chromatography). In the TLC observation, Merck's 60 F t=- was used as the TLC plate, the solvent used as the elution solvent in column chromatography was used as the developing solvent, and a UV detector was used as the detection method. In addition, the phenomenon in which 48% HBr is sprayed onto a spot on a TLC plate, heated to hydrolyze it, then ninhydrin reagent is sprayed, and the color changes from red to reddish purple when heated again is also used as a detection method. The eluate fractions containing the substance were identified and collected.

Unless otherwise specified, Kieselgel 60 (70 to 230 mesh) manufactured by Merck was used as the silica gel for the column.

Note that "normal temperature" or "room temperature" usually means about 5°C to 40°C, and normal pressure means around -atmospheric pressure.

Further, unless otherwise specified, % indicates ff1ffi percentage.

Reference Example 1 2-(5-bromopentyl)-5-nitroIH-isoindole-1,3(2H)-dione υ Sodium hydride is added to a solution of 4-nitrophthalimide (10.5 g) in dimethylformamide (50 d). (1,38
g) was gradually added at room temperature and stirred at 60°C for 30 minutes. A solution of 1.5-dibromopentane (25 g) in acetone (50 g) was added to the reaction mixture, and the mixture was heated under reflux for 16 hours. After cooling, the precipitate was removed, the solvent was distilled off under reduced pressure, and the remaining solid was recrystallized from dichloromethane-ether (1:10 (v/v)) to give 17.3 g of colorless crystals with a melting point of 78-79°C. I got it.

Elemental analysis value CI3H+s B r N *Calculated value as Oa: C45,77H3,84N 8.21 Experimental value: C45,5883,78N 7.99 Reference example 2 2-(4-bromobutyl)-5,6-dimethoxy-l −
Ethyl indanone-2-carboxylate 5.6-Simethoxyethyl 1-indanone-2-carboxylate (2,, Og
Sodium hydride (0.22 g) was added to a dimethylformamide (15d) solution of ) and stirred at room temperature for 30 minutes, then 1,4-dibromobutane (3.3 g) was added and further stirred for 2 hours. Add water to terminate the reaction,
The product was extracted with dichloromethane, washed with water, the dichloromethane solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The remaining oil was purified by silica gel column chromatography (developing solvent: dichloromethane-ethyl acetate =
20:1 (V/V)) and distill off the solvent of the solution containing the target product to obtain colorless crystals with a melting point of 94-96°C.
3g was obtained.

Elemental analysis value Calculated value as C+sHt, Bro s:
C54,15)i 5.1111 Experimental value: C54
,02H5,73 Reference Example 3 2-[5-[N-ethyl-N-[(3-hydroxyphenyl)methyl]aminocopentyl-5-nitro-IH
-Isoindole-1,3(2H)-dionebutyl-1-indanone 2-(5-bromopentyl)-5-nitro-
IH-isoindole-1,3(2H)-dione (0,
A mixture of a toluene (IFM) solution of N-ethyl-N-[(3dihydroxyphenyl)methylamino (0.8 g) and N-ethyl-N-[(3-dihydroxyphenyl)methylamino (0.8 g) was heated under reflux for 12 hours, and then the solvent was distilled off under reduced pressure. The remaining oil was subjected to silica gel column chromatography (developing solvent: ethyl acetate-methanol = 30:1
(V/V)) and the solvent of the solution containing the target product was removed under reduced pressure to obtain 0.6 g of a colorless oil.

Elemental analysis value Calculated value as CttHt5N so s:
C64,22H6,12N 10.21 Experimental value:
C63,99H6,01N 9.98 Reference Example 4 5.6-Simethoxy 2-[4-[, N-ethyl-M-
[(3-hydroxyphenyl)methyl]amino] Reference P
+2 ethyl 2-(4-bromobutyl)-5,6-simethoxy 1-indanone-2-carboxylate (0,6 g)
and N-ethyl-N-[(3-hydroxyphenyl)methylamino (1.0 g) in toluene (15d) for 12
After heating under reflux for an hour, the solvent was distilled off under reduced pressure. After dissolving the remaining oil in ethanol (10ml), a solution of potassium hydroxide (0.63g) in water (2d) was added, and the mixture was heated under reflux for 6 hours.

After removing the solvent under linear pressure, water (51) was added.

The product was extracted with dichloromethane.1. After washing with water, the dichloromethane solvent was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The remaining oil was purified by column chromatography (developing solvent: ethyl acetate-methanol = 20:1 (
The solvent of the solution containing the target product was distilled off under reduced pressure to obtain 0.3 g of a colorless oil.

Elemental analysis value C, H3, NO, calculated value: C
72,52H7,86N 3.52 Experimental value: C72,
43H7,61N 3.34 Example 1 2-[5-[N-ethyl-N-[[3-(methylaminocarbonyloxy)phenyl]methyl]amino]pentyl]-5-nitro-IH-isoindole-1 ,3(
2H)-dione hydrochloride Reference Example 3 2-[5-[N-ethyl-N-[(3-hydroxyphenyl)methylcoaminocobentyl]-5-nitro IH-isoindole-1,3 To a solution of (2H)-dione (0.35 g) in dichloromethane (3 bottles) were added methyl isocyanate (55 μQ), followed by triethylamine (1 drop), and the mixture was stirred at room temperature for 10 minutes. After adding water (10d) to the reaction solution, the product was extracted with dichloromethane, washed with water, and the dichloromethane solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A 3N hydrogen chloride solution in ethanol (0.28 g) was added to the remaining oil, and the solvent was distilled off to obtain 0.38 g of amorphous powder.

Elemental analysis values C,, H,, N, 0.・Calculated as HCQ (e[: C57,0985,79N 11.1 (1 experimental value: C5B, 93 H5,71N 11.02 Example 2 5.6-Simethoxy 2-[4-[N-ethyl-N- [
[3-(Methylaminocarbonyloxy)phenylcomethyl]amino]butyl]-1-indanone hydrochloride Colorless crystals having a melting point of 89-92°C were obtained in the same manner as in Example 1.

Elemental analysis value C1Hs-N *Calculated value as Os・HCρ: C63,80H7,18N 5.71 Experimental value: C
63,57H7,09N 5.66 Formulation Example 1 (1) 5.6-Simethoxy2-[4-[N-ethyl-N-[[3-(methylaminocarbonyloxy)phenyl]methyl]amino]butyl]- 1-Indanone・
Hydrochloride (compound obtained according to Example 2) 0 mg (2) Lactose 198 g (3
) Corn starch 50g (4)
Magnesium stearate 2g (1), (
2) and 20g of corn starch, 15g
16 g of corn starch and (4) were added to this, and the mixture was compressed with a compression tablet machine to form tablets 1.
Diameter 3I containing (1) 0.005+++g per tablet
2000 tablets were manufactured using I11.

Formulation Example 2 (1) 5.6-Simethoxy2-[4-[N-ethyl-N-[[3-(methylaminocarbonyloxy)phenyl]methyl]amino]butyl]-1-indanone.
Hydrochloride (compound obtained according to Example 2) 0 mg (2) Lactose 198 g (
3) Corn starch 50g (4
) Magnesium stearate 2g (1)
, (2) and 20g of corn starch, 1
Granulate with a paste made from 5 g of corn starch and 25 g of water, add 15 g of corn starch and (4), and compress the mixture with a compression tablet machine to obtain (1) 0.01 mg per tablet. 2000 tablets with a diameter of 5 mm were manufactured.

[Experimental example] The cholinesterase inhibitory effect of the compound of the present invention was
An investigation was conducted using tyl-[FH])-acetylcholine. That is, as a cholinesterase source, 11i
star S of male rat cerebral cortex homogenate.

Using both components, (acetyl-[coH]) as a substrate
- Add acetylcholine and the compound of the present invention as a test substance, stop the reaction after incubating for 30 minutes, add a toluene scintillator and shake, and [3H]-acetic acid produced by the reaction is transferred to the toluene layer. Cholinesterase activity was determined by counting with a liquid scintillation counter.

The cholinesterase inhibitory activity of the test compound was expressed as a 50% inhibitory concentration ((C,.). The cholinesterase action of physostigmine was also measured by the same method. The results are shown in Table 1.

Table 1

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents a hydrogen atom or a lower alkyl group,
R^2 represents a hydrogen atom or a lower alkyl group or an aromatic group which may have a substituent, R^3 and R^4 each independently represent a hydrogen atom or a lower alkyl group,
n represents an integer of 0 to 7, ring A represents a 5- to 8-membered cyclic group which may be substituted and may contain 1 to 2 of O, S, and N as ring-constituting heteroatoms; Ring B represents an optionally substituted benzene ring, and Ring C represents an aromatic ring group which may further have a substituent in addition to the carbamoyloxy group shown in the formula. ] A carbamic acid ester derivative or a salt thereof. 2. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, each symbol has the meaning as described in claim 1. ] and a compound represented by the formula R^3-N=C=O [wherein R^3 has the meaning as described in claim 1]. ] There are compounds or formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, Y^1 represents a leaving group, and R^3 and R^4 have the meanings as described in claim 1 . 2. A method for producing a compound according to claim 1, which comprises reacting with a compound represented by: 3. A cholinesterase inhibitor comprising the carbamic acid ester derivative according to claim 1 or a salt thereof. 4. The agent according to claim 3, which is a brain function improving agent.