JP2725378B2 - Carbamate derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel carbamic acid ester derivative or a salt thereof which is useful as a medicament, particularly a cerebral 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. Among them, physostigmine, a cholinesterase inhibitor, has been found to have a brain function improving effect.

Problems to be Solved by the Invention Physostigmine, however, has disadvantages such as short duration of action and high toxicity.

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

Means for Solving the Problems The present inventors have made intensive efforts to search for a compound useful as a brain function improving agent having a cholinesterase inhibitory action. [Wherein, 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, and R ³ and R ⁴ are each independently hand,
Represents a hydrogen atom or a lower alkyl group, n represents an integer of 0 to 7, ring A may be substituted, and may contain 1 to 2 of O, S, N as a ring-constituting heteroatom It represents a 5- to 8-membered cyclic group, ring B represents an optionally substituted benzene ring, and ring C represents an aromatic group which may have a substituent in addition to the carbamoyloxy group of the formula. And succeeded in creating the carbamic acid ester derivative represented by the formula [1] or a salt thereof, and found that these compounds exhibit an excellent cerebral function improving action, thereby completing the present invention.

That is, the present invention provides a compound represented by the formula (I) [hereinafter sometimes simply referred to as compound (I). Or a salt thereof, a method for producing them, and a cholinesterase inhibitor and a brain function improving agent containing them.

In the above formula (I), the lower alkyl group represented by R ¹ , R ² , R ³ and R ⁴ is a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n -Butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, etc.).

In the formula (I), examples of the “aromatic group” of the “aromatic group optionally having substituent (s)” represented by R ² include a phenyl group and a naphthyl group.

Examples of the substituent for these aromatic groups include C _1-4 alkyl (eg, methyl, ethyl, propyl, butyl, etc.), halogen atoms (eg, chloro, bromo, iodo),
Nitro, cyano, hydroxy, C _1-4 alkoxy (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy), C _1-4 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio), amino, mono Or di C _1-4 alkyl-substituted amino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino), C _1-4 alkylcarbonylamino (eg, acetylamino, propionylamino, butyrylamino, etc.), C _{1- 4} alkylsulfonylamino (for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), C
_1-4 alkoxycarbonyl (eg, methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl), hydroxycarbonyl, C _1-6 alkylcarbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, cyclohexylcarbonyl),
Carbamoyl, mono- or di-C _1-4 alkyl-substituted carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl,
Propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), having 1-4 substituents Phenyl, naphthyl, phenoxy,
Benzoyl, phenoxycarbonyl, phenyl C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl C
_1-4 alkylcarbonylamino, benzoylamino, phenyl C _1-4 alkylsulfonyl, phenylsulfonyl,
Phenyl C _1-4 alkylsulfinyl, phenyl C _1-4 alkylsulfonylamino and phenylsulfonylamino [Substituents of each phenyl group or naphthyl group include, for example, C ₁ -such as methyl, ethyl, propyl, butyl and isopropyl] ₄ alkyl group, methoxy, ethoxy, n-propyloxy, i-propyloxy, n
A C _1-4 alkoxy group such as -butyloxy, a halogen atom such as chloro, bromo and iodo, a hydroxyl group, benzyloxy, amino, mono- or di-C _1-4 alkyl-substituted amino, nitro, C _1-4 alkoxycarbonyl and the like. Can be ]
And so on.

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

In the formula (I), examples of the substituent of ring B include C _1-4 alkyl (eg, methyl, ethyl, propyl,
Butyl, etc.), halogen atoms (eg, chloro, bromo,
Iodine, etc.), nitro, cyano, hydroxy, C _1-4 alkoxy (eg, methoxy, ethoxy, propyloxy,
Butyloxy, isopropyloxy, etc.), C _1-4 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), amino, mono- or di-C _1-4 alkyl-substituted amino (eg, methylamino, ethylamino, propyl) Amino, dimethylamino,
Diethylamino, etc.), cyclic amino (eg, pyrrolidino, piperidino, hexamethyleneimino, etc.), C _1-4 alkylcarbonylamino (eg, acetylamino, propionylamino, butyrylamino, etc.), C _1-4 alkylsulfonylamino (eg, methyl Sulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc., C _1-4 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.), hydroxycarbonyl, C _1-6 alkylcarbonyl (eg, methyl Carbonyl, ethylcarbonyl, butylcarbonyl, cyclohexylcarbonyl, etc.), carbamoyl, mono or di C _1-4
Alkyl-substituted carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.) ) Optionally substituted phenyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl C _1-4 alkylcarbonylamino, benzoylamino, phenyl C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl-C _1-4 alkylsulfinyl, phenyl-C _1-4 alkylsulfonylamino and phenylsulfonylamino (Examples of the substituent of each of the phenyl or naphthyl group, for example methyl,
C _1-4 alkyl groups such as ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, n-propyloxy,
C _1-4 alkoxy groups such as i-propyloxy and n-butyloxy, halogen atoms such as chloro, bromo and iodo, hydroxyl groups, benzyloxy, amino, for example, mono- or di-C _1-4 alkyl such as methylamino and dimethylamino Substituted amino, nitro, C _1-4 alkoxycarbonyl and the like can be mentioned. ).

As ring B, it is preferable that the benzene ring has 1 to 3 substituents selected from these (in the case of two or more, they may be the same or different).

Ring A is a carbocyclic ring, and O, S, N
May be a heterocyclic ring containing 1 or 2 It may be saturated or unsaturated.

Examples of the substituent which ring A may have include a hydrogen group, an oxo group, a lower alkoxycarbonyl group and an aromatic group which may have a substituent. Here, examples of the lower alkoxycarbonyl include C _1-4 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, etc.).

Further, as the "aromatic group" of the "aromatic group optionally having substituent (s)" as the substituent of ring A and the "substituent", "having a substituent represented by R ² Examples of the “aromatic group” and “substituent” of the “aromatic group” include the groups described above.

Ring C is Is an aromatic group which may have a substituent further having a substituent, and such an aromatic group includes
Examples include a phenyl group and a naphthyl group. In addition to the above-mentioned carbamoyloxy group, the substituent that ring C may further have includes those described above as the substituent of ring B.

In a preferred embodiment of the compound represented by the formula (I), R ¹ is preferably methyl, ethyl, i-propyl or the like, and particularly preferably ethyl.

R ² is preferably a hydrogen atom.

R ³ and R ⁴ are each independently a hydrogen atom, methyl,
Ethyl and the like are preferred. n is preferably 3,4,5.

As a preferable group of the group, specifically, for example, (Each symbol in the formula is as defined above).

As the substituent of ring B, R ¹ alkoxy, nitro, cyano, halogen atom, R ¹ alkylcarbonylamino, R ¹ alkylsulfonyl and the like are preferable, and the number is preferably 0 to 2.

Ring C is preferably a benzene ring, and the substituent thereof is preferably methyl, ethyl, or the like. However, the case where the benzene ring has no substituent is also preferable.

The compound (I) of the present invention may form an acid addition salt, particularly a physiologically acceptable acid addition salt. Examples of such salts include inorganic acids (eg, hydrochloric acid, nitric acid, phosphoric acid,
Salts with hydrobromic acid, sulfuric acid, or organic acids (acetic, formic, propionic, fumaric, maleic, succinic,
Tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid).

When the target compound (I) has an acidic group such as —COOH, the target compound (I) is, for example, an inorganic base such as sodium, potassium, calcium, magnesium, ammonia or the like, for example, triethylamine or the like. It may form a salt with an organic base.

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

The following description of the production method applies not only to the target compound (I) itself, but also to the above-mentioned salts thereof, but in the following description, it is simply abbreviated as the compound (I).

Compound (I) is, for example, of the formula (II) Wherein each symbol is as defined above. ] With a compound represented by the formula ^{(III) R 3 -N = C} = O (III) [ wherein, R ³ is as defined above. The compound represented by the formula (I) can be produced by a method known per se, for example, in Journal of Organic Chemistry (J. Org. Chem.), 26 , 779 (196).
1), Journal of American Chemical Society (J. Am. Chem. Soc.), 48 , 1736 (1926), or a method analogous thereto.

Compound (I) is, for example, compound (II) and compound of formula (I
V) [In the formula, Y ¹ represents a leaving group such as halogen or alkyl or arylsulfonyloxy, and R ³ and R ⁴ have the same meaning as described above. The compound represented by the formula (I) can be prepared by a method known per se, for example, the method of Janal of Organic Chemistry (J. Org. Chem.), 32 , 851 (1967, 31 , 1150 (196)
It can be produced by the method described in 6) or a method analogous thereto.

The alkyl or arylsulfonyloxy represented by Y ¹ includes, for example, C _1-4 lower alkyl such as methyl, ethyl and propyl, and the aryl includes, for example, substituted phenyl and p-methylphenyl. Good phenyl is usually applied.

The compound represented by the formula (II) is, for example, a compound represented by the formula (V) [In the formula, Y ² represents a leaving group such as halogen, alkyl or arylsulfonyloxy, and other symbols have the same meanings as described above. And a compound represented by the formula (VI) [Each symbol in the formula is as defined above. Or a salt thereof.

Examples of the alkyl or arylsulfonyloxy represented by Y ² include, for example, C _1-4 lower alkyl such as methyl, ethyl, and propyl, and examples of the aryl include a substituted alkyl such as phenyl and p-methylphenyl. Good phenyl is usually applied.

As the "lower alkyl group" for R ⁵ , "R ¹ , R ² ,
The “lower alkyl group” of the “lower alkyl group represented by R ³ and R ⁴ ” includes the groups mentioned above. Examples of the salt of the compound represented by the formula (VI) include the acid addition salts described above with respect to the target compound (I).

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

Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and sodium hydroxide, and organic bases such as pyridine, 4-dimethylaminopyridine, and triethylamine. Bases. When a solvent is used, examples of the solvent include lower alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and t-butanol; ethers such as dioxane, ether and tetrahydrofuran; and aromatics such as toluene, benzene and xylene. Solvents that do not hinder the progress of the reaction, such as aromatic hydrocarbons, amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphonotriamide, and esters such as ethyl acetate and butyl acetate are used for application. This reaction is performed under cooling (about 0 ° C to 10 ° C) and at room temperature (about 10 ° C to 40 ° C)
C.) or under heating (about 40 ° C. to 120 ° C.), and the reaction time is usually 10 minutes to 48 hours, preferably 2 minutes.
~ 16 hours. The amount of compound (VI) to be used is usually preferably 0.3 to 5.0 moles per mole of compound (V). When a base is used, the amount of the base to be used is generally about an equimolar amount to an excess amount, preferably 1.1 to 5 molar times, relative to compound (VI). Further, this reaction may be carried out in the presence of an iodide compound such as sodium iodide, potassium iodide, lithium iodide and the like, if desired. When the reaction is carried out in the presence of these iodine compounds, the amount used is generally 1 to 5 molar equivalents, preferably 1.1 to 1.5 molar equivalents, relative to compound (V).

The compound (II) thus obtained can be used as a starting compound to lead to another compound contained in the compound (II).

For example, in compound (II), on ring A The compound containing the group represented by In Compound known methods have a lower alkoxycarbonyl group in position α in the groups represented, for example, Journal of Organic Chemistry (J.Org.Chem.) 33, 24
57 (1968) or a method analogous thereto, followed by hydrolysis followed by decarboxylation.

As a specific example, the expression [In the formula, R ⁶ ′ represents a lower alkyl group, and m is 1, 2 or
3, each other symbol is as defined above. By subjecting compound (II) represented by the formula [Each symbol in the formula is as defined above. And a method for producing the compound (II) represented by the formula:

The compound represented by the above formula (V) can be prepared by a known method, for example, Journal of Organic Chemistry (J. Org. Chem.), 33 , 2457 (1968), 39 , 2637 (1974).
By the method described in or a method similar thereto,
Alternatively, for example, Acta Chim.Acad.Sci.Hun
g.), 32 , 121 (1962), 39 , 391 (1963), or a method analogous thereto.

Further, the compound represented by the above formula (VI) can be synthesized by a known method, for example, Journal of American Chemical Society (J. Am. Chem. Soc.), 67 , 1658 (1945).
Or a method analogous thereto.

Compound (I) is a compound represented by the formula (V) and a compound represented by the formula (VII): [Each symbol in the formula is as defined above. Or a salt thereof. This reaction is carried out in the same manner as in the method for producing the compound represented by the formula (II) described above, wherein the compound represented by the formula (V) is reacted with the compound represented by the formula (VI) or a salt thereof. be able to.

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

The compound (I) of the present invention acts on the central nervous system of mammals, has a strong cholinesterase inhibitory activity, and exhibits an excellent anti-amnestic effect against various amnesic-inducing effects in humans or animals (eg, mice).

Compared with physostigmine, the compound (I) of the present invention has a very good separation between the effect on the central nervous system and the effect on the peripheral nerves. It has no or very little effect, has a long duration of action, has low toxicity, and is extremely effective by oral administration.

Therefore, the compound of the present invention is useful as an agent for improving brain function in mammals including humans.

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

The compound of the present invention can be orally or parenterally administered to mammals including humans in various forms such as tablets, granules, capsules, injections, suppositories and the like. The dosage varies depending on the type and symptoms of the target disease, but in general, for adults, oral administration of the drug should be 0.0001 per day.
~ 1 mg, preferably 0.001-0.3 mg, more preferably 0.003
~ 0.1 mg.

Effects of the Invention The compounds according to the present invention act on the central nervous system of mammals and have strong cholinesterase inhibitory activity. Therefore, it can be used for prevention and treatment of, for example, senile dementia, Alzheimer's disease, Huntington's disease, etc., and is useful as a medicine.

Examples Hereinafter, the present invention will be described more specifically with reference to Examples, Reference Examples, Formulation Examples, and Experimental Examples, but the present invention is not limited thereto.

Elution in column chromatography in Examples and Reference Examples is TLC (Thin Layer Chromatograp) unless otherwise specified.
hy, thin layer chromatography). In the TLC observation, Merck (Me
The 60F ₂₅₄ of rck) Co., the solvent used as an elution solvent in column chromatography as a developing solvent, employing a UV detector as a detection method. Also, spraying 48% HBr onto the spot on the TLC plate, heating and hydrolyzing, spraying a ninhydrin reagent, and heating again to change the color from red to reddish purple is also used as a detection method. The eluted fractions containing the product were identified and collected. Unless otherwise specified, silica gel for columns is Kieselgel 60 (70-23) manufactured by Merck.
0 mesh).

The term “normal temperature” or “room temperature” usually means about 5 ° C. to 40 ° C., and means normal pressure or near one atmosphere.

 Further, unless otherwise specified,% indicates weight percentage.

Reference Example 1 2- (5-bromopentyl) -5-nitro-1H-isoindole-1,3 (2H) -dione Sodium hydride (1.38 g) was gradually added to a solution of 4-nitrophthalimide (10.5 g) in dimethylformamide (50 ml) at room temperature, followed by stirring at 60 ° C. for 30 minutes. 1,5 in the reaction solution
A solution of dibromopentane (25 g) in acetone (50 ml) was added, 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 obtain 17.3 g of colorless crystals having a melting point of 78 to 79 ° C. Was.

Elemental analysis value: C ₁₃ H ₁₃ BrN ₂ O ₄ Calculated value: C 45.77 H 3.84 N 8.21 Experimental value: C 45.58 H 3.78 N 7.99 Reference Example 2 2- (4-bromobutyl) -5,6-dimethoxy-1-
Ethyl indanone-2-carboxylate Sodium hydride (0.22 g) was added to a solution of ethyl 5,6-dimethoxy-1-indanone-2-carboxylate (2.0 g) in dimethylformamide (15 ml), and the mixture was stirred at room temperature for 30 minutes. Butane (3.3 g) was added and stirred for an additional 2 hours. Water was added to terminate the reaction, the product was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The remaining oil is subjected to silica gel column chromatography (developing solvent; dichloromethane-ethyl acetate = 2).
0: 1 (V / V)), and the solvent in the solution containing the desired product was distilled off to obtain 2.3 g of colorless crystals having a melting point of 94 to 96 ° C.

Elemental analysis value: C ₁₈ H ₂₃ BrO ₅ Calculated value: C 54.15 H 5.81 Experimental value: C 54.02 H 5.73 Reference Example 3 2- [5- [N-ethyl-N-[(3-hydroxyphenyl) methyl] amino] Pentyl] -5-nitro-1H
-Isoindole-1,3 (2H) -dione 2- (5-bromopentyl) -5-nitro-1H-isoindole-1,3 (2H) -dione (0.9 g) of Reference Example 1 and N-ethyl-N-[(3-hydroxyphenyl) methyl] A mixture of the amine (0.8 g) and a toluene (15 ml) solution 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)) to remove the solvent of the solution containing the target substance under reduced pressure, and to obtain 0.6 g of a colorless oil.
I got

Elemental analysis: calculated as C ₂₂ H ₂₅ N ₃ O ₅ Calculated: C 64.22 H 6.12 N 10.21 Experimental: C 63.99 H 6.01 N 9.98 Reference Example 4 5,6-dimethoxy-2- [4- [N-ethyl-N −
[(3-hydroxyphenyl) methyl] amino] butyl] -1-indanone Ethyl 2- (4-bromobutyl) -5,6-dimethoxy-1-indanone-2-carboxylate of Reference Example 2 (0.6 g)
And a solution of N-ethyl-N-[(3-hydroxyphenyl) methyl] amine (1.0 g) in toluene (15 ml) was heated under reflux for 12 hours, and then the solvent was distilled off under reduced pressure. The remaining oil was dissolved in ethanol (10 ml) and potassium hydroxide (0.
A solution of 63 g) in water (2 ml) was added and the mixture was refluxed for 6 hours. After the solvent was distilled off under reduced pressure, water (50 ml) was added. After the product was extracted with dichloromethane and washed with water, the dichloromethane solvent was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The remaining oil was subjected to column chromatography (developing solvent; ethyl acetate-methanol = 20: 1 (V / V)), and the solvent of the solution containing the desired product was distilled off under reduced pressure to obtain 0.3 g of a colorless oil. Was.

Elemental analysis: calculated as C ₂₄ H ₃₁ NO ₄ Calculated: C 72.52 H 7.86 N 3.52 Experimental: C 72.43 H 7.61 N 3.34 Example 1 2- [5- [N-ethyl-N-[[3- (methylamino Carbonyloxy) phenyl] methyl] amino] pentyl] -5-nitro-1H-isoindole-1,3 (2H)
-Dione hydrochloride 2- [5- [N-ethyl-N-[(3-hydroxyphenyl) methyl] amino] pentyl] -5 of Reference Example 3
Nitro-1H-isoindole-1,3 (2H) -dione (0.3
To a solution of 5 g) in dichloromethane (3 ml) was added methyl isocyanate (55 μl), followed by one drop of triethylamine, and the mixture was stirred at room temperature for 10 minutes. After adding water (10 ml) to the reaction solution, 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. A methanol solution (0.28 ml) of 3N hydrogen chloride was added to the remaining oil, and the solvent was distilled off to obtain 0.38 g of an amorphous powder.

Elemental analysis: calculated as C ₂₄ H ₂₈ N ₄ O ₆ .HCl Calculated: C 57.09 H 5.79 N 11.10 Experimental: C 56.93 H 5.71 N 11.02 Example 2 5,6-Dimethoxy-2- [4- [N-ethyl -N-
[[3- (methylaminocarbonyloxy) phenyl]]
Methyl] amino] butyl] -1-indanone hydrochloride In the same manner as in Example 1, colorless crystals having a melting point of 89-92 ° C. were obtained.

Elemental decomposition value Calculated as C ₂₆ H ₃₄ N ₂ O ₅ .HCl Calculated value: C 63.60 H 7.18 N 5.71 Experimental value: C 63.57 H 7.09 N 5.66 Formulation Example 1 (1) 5,6-Dimethoxy-2- [4- [ N-ethyl-N
-[[3- (methylaminocarbonyloxy) phenyl] methyl] amino] butyl] -1-indanone hydrochloride (compound obtained according to Example 2) 10 mg (2) lactose 198 g (3) corn starch 50 g (4) 2 g of magnesium stearate (1), (2) and 20 g of corn starch were mixed, granulated with a paste made from 15 g of corn starch and 25 ml of water, and 15 g of corn starch and (4) were added thereto. The mixture is compressed on a compression tablet machine to give tablets of 3 mm diameter containing 0.005 mg of (1) per tablet.
00 pieces were produced.

Formulation Example 2 (1) 5,6-Dimethoxy-2- [4- [N-ethyl-N
-[[3- (methylaminocarbonyloxy) phenyl] methyl] amino] butyl] -1-indanone hydrochloride (compound obtained according to Example 2) 20 mg (2) Lactose 198 g (3) Corn starch 50 g (4) 2 g of magnesium stearate (1), (2) and 20 g of corn starch are mixed, granulated with a paste made from 15 g of corn starch and 25 ml of water, and 15 g of corn starch and (4) are added thereto. The mixture is compressed on a compression tablet machine to give tablets 1
2000 tablets of 5 mm diameter containing 0.01 mg per tablet (1) were produced.

[Experimental Example] The cholinesterase inhibitory effect of the compound of the present invention was confirmed by (acet
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 the cholinesterase activity was determined by counting with a liquid scintillation counter.

The cholinesterase inhibitory activity of the test compound was represented by a 50% inhibitory concentration (IC ₅₀ ). The cholinesterase activity of physostigmine was also measured by the same method. First result
It is shown in the table.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/40 AAB A61K 31/40 AAB C07D 209/48 C07C 69/757 // C07C 69/757 7457 −4H 225/18 225/18 C07D 209/48 Z

Claims (18)

(57) [Claims] (1) Expression (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, a lower alkyl group or an aromatic group which may have a substituent, and R ³ and R ⁴ are each independently Represents a hydrogen atom or a lower alkyl group, n represents an integer of 0 to 7, ring A may be substituted, and contains 1 to 2 of O, S, N as a ring-constituting heteroatom. Represents a 5- to 8-membered cyclic group, ring B represents an optionally substituted benzene ring, and ring C represents an aromatic group which may further have a substituent other than the carbamoyloxy group of the formula. Show. ] Or a salt thereof. 2. The derivative according to claim ¹ , wherein R ¹ is a hydrogen atom or a C _1-6 alkyl group. 3. R ² is (i) hydrogen atom, (ii) C _1-6 alkyl group or (iii) (1) C _1-4 alkyl, (2) halogen atom, (3) nitro, (4) Cyano, (5) hydroxy,
(6) C _1-4 alkoxy, (7) C _1-4 alkylthio,
(8) amino, (9) mono- or di-C _1-4 alkyl-substituted amino, (10) C _1-4 alkylcarbonylamino, (11) C
_1-4 alkylsulfonylamino, (12) C _1-4 alkoxycarbonyl, (13) hydroxycarbonyl, (14) C _1-6
Alkylcarbonyl, (15) carbamoyl, (16) mono- or di-C _1-4 alkyl-substituted carbamoyl, (17) C _1-6 alkylsulfonyl and (18) C _1-4 alkyl group, C _1-4 alkoxy group, halogen Atom, hydroxyl, benzyloxy, amino, mono- or di-C _1-4 alkyl-substituted amino, substituent 1 to 1 selected from nitro and C _1-4 alkoxycarbonyl
Phenyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl C _1-4 alkylcarbonylamino, benzoyl which may have 4 on each phenyl group or naphthyl group Amino, phenyl C _1-4
Alkylsulfonyl, phenylsulfonyl, phenyl C
The derivative according to claim 1, which is a phenyl group or a naphthyl group which may have 1 to 3 substituents selected from _1-4 alkylsulfinyl, phenyl _C1-4 alkylsulfonylamino and phenylsulfonylamino. 4. The derivative according to claim 1, wherein R ³ and R ⁴ are each a hydrogen atom or a C _1-6 alkyl group. 5. The method according to claim 1, wherein the substituent on ring A is (i) a hydroxyl group, (ii) an oxo group, (iii) a C _1-4 alkoxycarbonyl group or (iv)
(1) C _1-4 alkyl, (2) halogen atom, (3) nitro, (4) cyano, (5) hydroxy, (6) C _1-4 alkoxy, (7) C _1-4 alkylthio, (8 )amino,
(9) mono or di C _1-4 alkyl substituted amino, (10) C
_1-4 alkylcarbonylamino, (11) _C1-4 alkylsulfonylamino, (12) _C1-4 alkoxycarbonyl,
(13) hydroxycarbonyl, (14) C _1-6 alkylcarbonyl, (15) carbamoyl, (16) mono or di C _1-4
Alkyl substituted carbamoyl, (17) C _1-6 alkylsulfonyl and (18) C _1-4 alkyl group, C _1-4 alkoxy group, halogen atom, hydroxyl group, benzyloxy, amino, mono- or di-C _1-4 alkyl substituted Phenyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl C _1- which may have 1 to 4 substituents selected from amino, nitro and C _1-4 alkoxycarbonyl on each phenyl group or naphthyl group; ₄ alkylcarbonyl carbamoyl, phenyl carbonium moil, phenyl C _1-4 alkylcarbonylamino, benzoylamino, phenyl-C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl-C _1-4 alkylsulfinyl, phenyl-C _1-4 alkylsulfonylamino and phenyl Substituents selected from sulfonylamino are 1-3
The derivative according to claim 1, which is a phenyl group or a naphthyl group which may have one or more. 6. The ring B has 1 to 3 substituents (i) C _1-4 alkyl, (ii) halogen atom, (iii) nitro, (iv) cyano, (v) hydroxy, (vi) C _1-4 alkoxy, (vi
i) C _1-4 alkylthio, (viii) amino, (ix) mono- or di-C _1-4 alkyl-substituted amino, (x) pyrrolidino, piperidino or hexamethylene imino, (xi) C _1-4 alkylcarbonylamino, xii) C _1-4 alkylsulfonylamino, (xiii) C _1-4 alkoxycarbonyl, (xiv)
Hydroxycarbonyl, (xv) C _1-6 alkylcarbonyl, (xvi) carbamoyl, (xvii) mono or diC _1-4
Alkyl-substituted carbamoyl, (xviii) C _1-6 alkylsulfonyl and (xix) C _1-4 alkyl group, C _1-4 alkoxy group, halogen atom, hydroxyl group, benzyloxy, amino,
Mono or di C _1-4 alkyl substituted amino, nitro and C _1-4
Phenyl optionally having 1 to 4 substituents selected from alkoxycarbonyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl C _1-4 alkylcarbonylamino, benzoyl Amino, phenyl
C _1-4 alkylsulfonyl, phenylsulfonyl, derivative according to claim 1, wherein is phenyl C _1-4 alkylsulfinyl, phenyl-C _1-4 alkylsulfonylamino or phenylsulfonylamino. 7. The ring C is substituted as (i) C _1-4 alkyl, (ii) halogen atom, (iii) nitro, (iv) cyano, (v) hydroxy, (vi) C _1-4 alkoxy. , (Vi
i) C _1-4 alkylthio, (viii) amino, (ix) mono- or di-C _1-4 alkyl-substituted amino, (x) pyrrolidino, piperidino or hexamethylene imino, (xi) C _1-4 alkylcarbonylamino, xii) C _1-4 alkylsulfonylamino, (xiii) C _1-4 alkoxycarbonyl, (xiv)
Hydroxycarbonyl, (xv) C _1-6 alkylcarbonyl, (xvi) carbamoyl, (xvii) mono or diC _1-4
Alkyl-substituted carbamoyl, (xviii) C _1-6 alkylsulfonyl or (xix) C _1-4 alkyl group, C _1-4 alkoxy group, halogen atom, hydroxyl group, benzyloxy, amino,
Mono or di C _1-4 alkyl substituted amino, nitro and C _1-4
Phenyl optionally having 1 to 4 substituents selected from alkoxycarbonyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl C _1-4 alkylcarbonylamino, benzoyl Amino, phenyl
C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl C _1-4 alkylsulfinyl, phenyl C _1-4 alkylsulfonylamino or phenylsulfonylamino which may further have (1) a phenyl group or (2) a naphthyl group A derivative according to claim 1. 8. The derivative according to claim 1, wherein R ¹ is methyl, ethyl or i-propyl. 9. The derivative according to claim 1, wherein R ² is a hydrogen atom. 10. The derivative according to claim 1, wherein R ³ and R ⁴ are each a hydrogen atom, methyl or ethyl. 11. The derivative according to claim 1, wherein n is 3, 4 or 5. 12. (Wherein each symbol has the same meaning as described in claim 1). 13. The derivative according to claim 1, wherein the substituent on ring B is C _1-4 alkoxy, nitro, cyano, a halogen atom, C _1-4 alkylcarbonylamino or C _1-4 alkylsulfonyl. 14. The derivative according to claim 1, wherein ring C is a benzene ring optionally substituted with methyl or ethyl. 15. The derivative according to claim 1, wherein ring C is a benzene ring. 16. The expression Wherein each symbol is as defined in claim 1, or a salt thereof, and a compound represented by the formula: R ³ —N ＝ C ＝ O, wherein R ³ is defined in claim 1. It has the meaning as given. Or a compound represented by the formula: [Wherein, Y ¹ represents a leaving group, and R ³ and R ⁴ have the same meaning as described in claim 1. The method for producing a compound or a salt thereof according to claim 1, wherein the compound is reacted with a compound represented by the formula: 17. A cholinesterase inhibitor comprising the carbamate derivative according to claim 1 or a salt thereof. 18. The agent according to claim 17, which is a brain function improving agent.