JP3113447B2 - Aminocarboxylic acid derivatives, their production and use - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicament, more specifically, a cholinesterase inhibitor, particularly a therapeutic / prophylactic agent for senile dementia in senile dementia, Alzheimer's disease, etc., and a novel aminocarboxylic acid derivative as an active ingredient thereof. Or a salt or ester thereof, a method for producing these compounds, and uses of the compounds.

[0002]

2. Description of the Related Art With the aging of society, various compounds having a therapeutic / preventive action for senile dementia have been proposed.
Among them, physostigmine, a natural product that is a cholinesterase inhibitor, has been found to have therapeutic and preventive effects on senile dementia (International Journal of Clinical
Pharmacology, Therapy and Toxicology, Vol. 29,
No. 1, pp. 23-37 (1991)). However, physostigmine has drawbacks such as a short duration of action and high toxicity.

On the other hand, various compounds having cholinesterase inhibitory activity have been proposed as synthetic compounds (for example, EP-A-0,378,207;
-79151 and JP-A-2-169569).

More specifically, the above-mentioned EP-A-0,37
8,207 discloses a cyclic amine compound represented by the following formula and a salt thereof.

[0005]

Embedded image [Wherein, B represents an optionally substituted saturated or unsaturated 5
Represents a 7-membered aza heterocyclic group, A represents a bond or a hydrocarbon residue, an alkylene group or an alkenylene group which may be substituted with an oxo group or a hydroxy group,

[0006]

Embedded image R ₂ and R ₃ each independently represent a hydrogen atom or a hydrocarbon residue which may have a substituent (but not simultaneously a hydrogen atom), or form a cyclic amino group together with an adjacent nitrogen atom N may be 0, 1 or 2
And p represents 1 or 2] and a salt thereof are disclosed. In this document,
Specifically, the following compounds and the like are described.

[0007]

Embedded image JP-A-64-79151 and JP-A-02-169
No. 569 discloses a cyclic amine derivative represented by the following general formula and a pharmaceutically acceptable salt thereof.

[0008]

Embedded image [In the formula, J is (a) a substituted or unsubstituted group shown below; a phenyl group, a pyridyl group, a pyrazyl group, a quinolyl group, a cyclohexyl group, a quinoxalyl group or a teryl group, and (b) a phenyl group. A monovalent or divalent group selected from the group consisting of: indanyl, indanonyl, indenyl, indenonyl,
Indandionyl, tetralonyl, benzperonyl, indanolyl, formula

[0009]

Embedded image (C) a monovalent group derived from a cyclic amide compound,
(D) a lower alkyl group, or (e) a formula R ¹ —CH ＝ CH
(Wherein R ¹ represents a hydrogen atom or a lower alkoxycarbonyl group).

[0010] B is the formula ^{- (C (R 2) H} ) n - , a group represented by the formula ^{-CO- (C (R 2) H} ) n - , a group represented by the formula -NR ² - (C (R ² ) H) _n- wherein R ² represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or a benzyl group; CO-NR ⁴ - (C
A group represented by (R ² ) H) _n- (wherein R ⁴ represents a hydrogen atom, a lower alkyl group or a phenyl group);
^{H = CH- (C (R 2} ) H) n - , a group of the formula -O
A group represented by —COO— (C (R ² ) H) _n —,
^{-CO-NH- (C (R 2} ) H) n - , a group represented by the formula ^{-NH-CO- (C (R 2} ) H) n - , a group represented by the formula -CH ₂ -CO-NH- ^{(C (R 2) H)} n - , a group represented by the formula ^{-CO-NH- (C (R 2} ) H) n - , a group represented by the formula -C (OH) H- (C ( R 2) H) _n - group (in the above equations, n represents 0 or an integer from 1 to 10 .R ² in the formula ^{- (C (R 2) H} ) represented by _n - alkylene group represented by the substituent Or a hydrogen atom or a methyl group in such a manner as to have no or one or more methyl groups), a formula = (CH-CH = CH) _b- (wherein b represents an integer of 1 to 3), a group represented by the formula:
A group represented by CH- (CH ₂ ) _c- (wherein, c represents an integer of 0 or an integer of 1 to 9), and a formula = (CH-CH) _d =
(Wherein d represents 0 or an integer of 1 to 5), a group represented by the formula: ＣＨCO—CH ＝ CH—CH ₂ —,
Formula _{-CO-CH 2 -C (OH)} H-CH 2 - , a group represented by the formula _{-C (CH 3) H-CO} -NH-CH 2 - , a group of the formula -CH = CH-CO- NH- (CH _{2) 2} -
, A group represented by the formula -NH-, a group represented by the formula -O-, a group represented by the formula -S-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group.

T represents a nitrogen atom or a carbon atom.

Q represents a nitrogen atom, a carbon atom or a group represented by the formula> N → O.

K represents a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group optionally substituted with a phenyl group, a cinnamyl group optionally substituted with a phenyl group, a lower alkyl group, a pyridylmethyl group, a cycloalkyl group; It means an alkyl group, adamantanemethyl group, furylmethyl group, cycloalkyl group, lower alkoxycarbonyl group or acyl group.

Q represents an integer of 1 to 3.

[0015]

Embedded image In these documents, the following compounds are specifically described.

[0016]

Embedded image

[0017]

In today's world where senile dementia is increasing, it has a stronger action, a longer action time and a longer activity than known compounds having a therapeutic or preventive action for senile dementia. Excellent senile dementia treatment with low toxicity
The development of prophylactic agents is desired.

Accordingly, an object of the present invention is to provide a novel aminocarboxylic acid derivative or a salt or salt thereof which has a stronger action, has a longer action time and is less toxic as an active ingredient of an agent for treating or preventing senile dementia. An object of the present invention is to provide a method for producing the ester and these compounds.

Another object of the present invention is to provide an aminocarboxylic acid derivative or a salt or ester thereof having high water solubility and cholinesterase inhibitory activity, and a process for producing these compounds.

Still another object of the present invention is to provide a cholinesterase inhibitor having the above-mentioned excellent medicinal effects.

[0021]

Means for Solving the Problems In view of the above-mentioned current situation, the present inventors have conducted various studies on biological activity and pharmacological action. As a result, the present inventors have found that an amino group and a carboxyl group are bonded to a benzene ring. It has been found that a compound having a structural feature has unexpectedly excellent therapeutic and preventive effects on senile dementia based on this unique chemical structure, and that the compound has high water solubility. The present invention has been completed based on the findings.

That is, the aminocarboxylic acid derivative of the present invention or a salt or ester thereof is characterized by the following formula.

[0023]

Embedded image [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydrocarbon group which may have a substituent, or an acyl group which may have a substituent, and the ring A is further substituted. A benzene ring which may have a group, X represents a ＣＯCO group or -CH
(OH) — group, Y is an amino group which may have a substituent or a nitrogen-containing saturated heterocyclic group which may have a substituent, k and m each independently represent 0 to 4; Where either k or m is an integer of 1 to 4, and n is 1 to
An integer of 3 is shown. And a salt or ester thereof.

In the above compound, k = 3 and m = 0, and Y may be a 4-piperidinyl group which may have a substituent.

The compound of the present invention or a salt or ester thereof has the formula

[0026]

Embedded image Wherein each symbol is as defined above, or a salt or ester thereof,

[0027]

Embedded image (Wherein, Z ¹ represents a leaving group, Y and n have the same meanings as described above) or a salt thereof, and if necessary, subjected to a reduction reaction to produce a reaction product. it can.

The cholinesterase inhibitor of the present invention contains the above-mentioned aminocarboxylic acid derivative or a salt or ester thereof, and is useful as an agent for treating or preventing senile dementia.

The compound (I) of the present invention or a salt or ester thereof has the following formula (II)

[0030]

Embedded image A substituted moiety represented by the following formula (III) or an ester thereof

[0031]

Embedded image Is a novel compound having a chemical structural feature at the point where it is bonded, and exhibits an excellent therapeutic / prophylactic action for senile dementia and high water solubility based on this feature.

In the compound represented by the formula (I),
R ¹ and R ² each independently represent a hydrogen atom, a hydrocarbon group which may have a substituent, or an acyl group which may have a substituent.

The "hydrocarbon group" of the "hydrocarbon group optionally having substituent (s)" represented by R ¹ and R ² includes, for example, a C _{1- group} consisting of a chain or a ring or a combination thereof. ₁₈ hydrocarbon groups.

As the chain hydrocarbon group, for example, a linear or branched C _1-11 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl, etc.), a linear or branched C _2-6 alkenyl group (eg, vinyl, allyl, 2-butenyl, etc.) and a linear or branched C _2-6 alkenyl group. _2-6 alkynyl groups (for example, propargyl, 2-butynyl and the like) and the like.

Examples of the cyclic hydrocarbon group include C _3-7
A monocyclic cycloalkyl group (eg, cyclobutyl, cyclopentyl, cyclohexyl, etc.), a C _8-14 bridged cyclic saturated hydrocarbon group (eg, bicyclo [3.2.1] oct-
2-yl, bicyclo [3.3.1] non-2-yl, adamantan-2-yl and the like, and a C _6-14 aryl group (eg, a phenyl group and a naphthyl group).

The hydrocarbon group consisting of a combination of a chain and a ring includes, for example, C _7-18 aralkyl (for example,
Phenyl-C _1-12 alkyl such as benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl and phenylhexyl; naphthyl-C _1-8 alkyl such as α-naphthylmethyl; diphenyl-C such as diphenylmethyl and diphenylethyl _1-3 alkyl),
C _6-14 aryl -C _2-12 alkenyl (e.g., styryl, cinnamyl, 4-phenyl-2-butenyl, phenyl -C _2-12 alkenyl such as 4-phenyl-3-butenyl), C _6-14 aryl -C _2-12 alkynyl (for example, phenyl-C such as phenylethynyl, 3-phenyl-2-propynyl, 3-phenyl-1-propynyl and the like)
_2-12 alkynyl, etc.), C _3-7 cycloalkyl-C _1-6
Alkyl (eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl , Cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclopropylpentyl, cyclobutylpentyl, cyclopentylpentyl, cyclohexylpentyl, cycloheptylpentyl, cyclopropylhexyl, cyclobutyl Tylhexyl, cyclopentylhexyl,
Cyclohexylhexyl, cycloheptylhexyl, etc.).

Preferred "hydrocarbon groups" represented by R ¹ and R ² include, for example, a linear or branched C _1-11 alkyl group, more preferably a linear or branched C _1-7 alkyl group. Alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-
Pentyl, n-hexyl, etc.), or a C _7-18 aralkyl group, more preferably a C _7-10 aralkyl group (eg, phenyl-C _1-4 alkyl such as benzyl, phenylethyl, phenylpropyl, etc.). .

The "hydrocarbon group" represented by R ¹ and R ² may have a substituent. Such a substituent includes a general substituent of a hydrocarbon group and the like. Specifically, C _1-11 alkyl, C _2-6 alkenyl, C
Examples of the substituent which the _2-6 alkynyl, C _3-7 monocyclic cycloalkyl and C _8-14 bridged cyclic saturated hydrocarbon group may have include, for example, a halogen atom (for example, fluoro, chloro, bromo, Iodine), nitro group, cyano group, hydroxyl group, C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.),
A C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio, etc.), an amino group, a mono- or di-C
_1-4 alkylamino groups (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), for example, one nitrogen atom and one heteroatom selected from nitrogen, oxygen and sulfur
A 5- to 7-membered cyclic amino group optionally having up to 3 (eg, pyrrolidino, piperidino, morpholino, etc.), C
_1-4 acylamino groups (eg, acetylamino, propionylamino, butyrylamino, etc.), C _1-4 alkylsulfonylamino groups (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-4 alkoxycarbonyl groups (eg, methoxy Carbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, C _1-6 acyl group (for example, formyl, acetyl,
Propionyl, butyryl, etc.), carbamoyl group, mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) And the like. The number of these substituents substituted on the hydrocarbon group is
Usually, it is about 1 to 5 pieces.

C _6-14 aryl groups represented by R ¹ and R ² , C _7-18 aralkyl, C _6-14 aryl-C _2-12 alkenyl, C _6-14 aryl-C _2-12 alkynyl, C ₃ Examples of the substituent which the _-7 cycloalkyl-C _1-6 alkyl group may have include, for example, a C _1-4 alkyl group (for example, methyl, ethyl, propyl, butyl, etc.), a halogen atom (for example, fluoro , Chloro, bromo, iodo), nitro, cyano, hydroxyl, C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, isopropoxy, etc.), C _1-4 alkylthio (eg, methylthio, Ethylthio, propylthio, isopropylthio, butylthio, etc.), amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino) A 5- to 7-membered cyclic amino group which may have 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to one nitrogen atom (for example, Pyrrolidino, piperidino, morpholino, etc.), C _1-4 acylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, mono- or di-C _1-4 alkylaminocarbonyloxy group (eg, methylaminocarbonyl) Oxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), C _1-4 alkoxycarbonyl group (Eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.), carboxyl group, C _1-6 acyl group (eg, acetyl, propionyl, butyryl, etc.), C _3-7
Cycloalkylcarbonyl (eg, cyclohexylcarbonyl, etc.), carbamoyl group, mono- or di-C _1-4
Alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), C _{3- 7} cycloalkylsulfonyl (eg, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.) or phenyl, naphthyl, mono- or di-phenyl-C _1-3 alkyl optionally having 1 to 4 substituents (eg, benzyl, diphenylmethyl), phenoxy, benzoyl, phenoxycarbonyl, benzylcarbonyl, phenyl -C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl -C
_1-4 acylamino, benzoylamino, phenyl-C
_1-4 alkylsulfonyl, phenylsulfonyl, phenyl--C _1-4 alkylsulfinyl, phenyl -C _1-4 alkylsulfonylamino or phenylsulfonylamino group can be exemplified.

In these substituents, an aryl group such as a phenyl group or a naphthyl group may further have a substituent. As such substituents, for example methyl, ethyl, propyl, butyl, C _1-4 alkyl groups such as isopropyl, methoxy, ethoxy, n- propoxy, i- propoxy, C _1-4 alkoxy group such as n- butoxy , A halogen atom such as chloro, bromo, iodo and the like, a hydroxyl group, a benzyloxy group, an amino group, a mono- or di-C _1-4 alkylamino group as described above, a nitro group, a C _1-6 acyl group as described above, a benzoyl group And the like.

These C _6-14 aryl group, C _7-18 aralkyl, C _6-14 aryl-C _2-12 alkenyl, C _6-14 aryl-C _2-12 alkynyl, C _3-7 cycloalkyl-C _{1 -6}
The number of substituents which may be substituted on the alkyl group is 1 to 5
About one is appropriate.

The “acyl group” of the “optionally substituted acyl group” represented by R ¹ and R ² includes, for example, an acyl group of a carboxylic acid (eg, formyl, acetyl, propionyl, C _2-8 acyl such as butyryl, arylcarbonyl such as benzoyl, etc., acyl group of sulfonic acid (eg, C _1-7 alkylsulfonyl such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, etc.) Acyl group of phosphonic acid (eg, phenylphosphonyl such as C _1-7 alkylphosphonyl such as methanephosphonyl, ethanephosphonyl, propanephosphonyl, benzenephosphonyl, p-toluenephosphonyl); A substituted oxycarbonyl group (eg, methoxycarbonyl, C _2-8 alkoxycarbonyl such as t- butoxycarbonyl, C _7-8 aralkyloxy, such as benzyloxycarbonyl - carbonyl)
And the like. Among these acyl groups, for example, formyl, C _2-8 acyl (eg, acetyl, etc.)
Are preferred.

Examples of the substituent which the acyl group may have include, for example, a halogen atom (for example, fluoro, chloro, bromo, iodo), a nitro group, a hydroxyl group, an amino group, mono- or di-C _{1. -6} alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.).
The number of substitution of these substituents is 1 to 3, preferably 1 to 2.
About one.

In the compound represented by the formula (I), the benzene ring represented by the ring A may further have a substituent in addition to being substituted by a group represented by the following formula.

[0045]

Embedded image Examples of such a substituent include the aforementioned R ¹ or R ²
C _6-14 aryl group, C _7-18 aralkyl, C _6-14 aryl-C _2-12 alkenyl, C _6-14 aryl-C _2-12 alkynyl, C _3-7 cycloalkyl-C _1-6 alkyl And the like, and the number thereof is 1 to 3.

Preferred substituents which the benzene ring may further have include, for example, halogen atoms such as fluoro and chloro, halogeno-C _1-3 alkyl such as trifluoromethyl, and C ₁ such as methyl. _-3 alkyl group, C _1-3 alkoxy group such as methoxy, hydroxyl group and the like. Particularly, a halogen atom such as fluoro or a hydroxyl group is preferred.

In the compound represented by the above formula (I),
X represents = CO or -CH (OH)-.

In the compound represented by the formula (I),
Y represents an amino group which may be substituted or a nitrogen-containing saturated heterocyclic group which may have a substituent.

The “optionally substituted amino group” represented by Y includes, for example, a group represented by the following formula (IV).

[0050]

Embedded image [Wherein, R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a hydrocarbon group which may have a substituent, or an acyl group which may have a substituent. Examples of the optionally substituted hydrocarbon group represented by R ³ and R ⁴ include, for example, the optionally substituted hydrocarbon group described above for R ¹ or R ^2. No.

Preferred examples of the optionally substituted hydrocarbon group represented by R ³ and R ⁴ include, for example, a linear or branched C _1-11 alkyl group, more preferably a linear C _1-11 alkyl group. Or branched C _1-7 alkyl groups (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl, etc.) or C _{7 -18} aralkyl group (for example, phenyl-C _1-12 alkyl such as phenylmethyl, phenylethyl, phenylpropyl, phenylhexyl and naphthyl-C _1-8 alkyl such as α-naphthylmethyl), more preferably C _{7- 10} aralkyl groups (eg, phenylmethyl,
Phenylethyl, phenylpropyl, etc.). These hydrocarbon groups include a halogen atom (eg, fluoro, chloro, etc.) and a C _1-4 alkoxy group (eg,
Methoxy, ethoxy, etc.) or a hydroxy group. The number of substituents substituted is about 1 to 3.

The “acyl group” of the “optionally substituted acyl group” represented by R ³ and R ⁴ includes the acyl groups exemplified in the above-mentioned R ¹ and R ² , for example, carboxylic acid Acyl groups (eg, formyl, C _2-8 acyl, benzoyl, etc.), sulfonic acid acyl groups (eg, C _1-7 alkylsulfonyl, phenylsulfonyl, etc.), and phosphonic acid acyl groups (eg, C _1-7 Alkylphosphonyl, phenylphosphonyl, etc.), substituted oxycarbonyl group (for example, C _2-8 alkoxycarbonyl,
_7-8 aralkyloxy-carbonyl, etc.). Among these acyl groups, for example, formyl,
C _2-8 acyl (eg, acetyl and the like) and the like are preferable.

Examples of the substituent which the acyl group may have include, for example, a halogen atom (for example, fluoro, chloro, bromo, iodo), a nitro group, a hydroxyl group, an amino group, a mono- or di-C ₁ group. _-6 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.).
The number of substitution of these substituents is 1 to 3, preferably 1 to 2.
About one.

Preferred R ³ and R ⁴ include, for example, a linear or branched C _1-7 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl).
Butyl, tert-butyl, n-pentyl, n-hexyl, etc.) or a _C7-10 aralkyl group (eg, benzyl, phenylethyl, phenylpropyl, etc.), and the like.
Particularly, C _1-3 alkyl such as methyl and ethyl, and C _7-10 such as phenylmethyl are preferable.

As the "nitrogen-containing saturated heterocyclic group optionally having substituent (s)" for Y, the "nitrogen-containing saturated heterocyclic group" includes, in addition to the carbon atom and one nitrogen atom,
Heteroatoms 1 such as nitrogen atom, oxygen atom and sulfur atom
And a 5- to 9-membered nitrogen-containing saturated heterocyclic group which may contain up to 3 members. These nitrogen-containing saturated heterocyclic groups may be groups having a bond at the ring-forming nitrogen atom or groups having a bond at the ring-forming carbon atom. Examples of the group having a bond at the ring-forming nitrogen atom include a group represented by the following formula (V).

[0056]

Embedded image (The ring Q ¹ is a 5- to 9-membered nitrogen-containing saturated atom which may contain, in addition to a carbon atom and one nitrogen atom, one or two heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like. More specifically, examples of the group having a bond at a ring-constituting nitrogen atom include the following groups.

[0057]

Embedded image Examples of the group having a bond at the ring-constituting carbon atom include a group represented by the following formula (VI).

[0058]

Embedded image (The ring Q ² is a 5- to 9-membered nitrogen-containing saturated atom which may contain, in addition to a carbon atom and one nitrogen atom, one or two heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like. More specifically, examples of the group having a bond at a ring-constituting carbon atom include the following groups.

[0059]

Embedded image Particularly preferred nitrogen-containing saturated heterocyclic group Y has the following formula (Va)
A 1-piperazinyl group optionally having a substituent represented by:

[0060]

Embedded image Alternatively, a 4-piperidinyl group optionally having a substituent represented by the following formula (VI-a) is included.

[0061]

Embedded image (In the above formula, R ⁵ represents a hydrogen atom or a substituent.) Examples of the substituent which the “nitrogen-containing saturated heterocyclic group” may have include, for example, those described in the section of R ¹ and R ² above. A hydrocarbon group which may have a substituent, an acyl group which may have a substituent described in the section of R ¹ and R ² , a halogen atom (for example, fluoro, chloro, bromo, iodo), nitro Group, cyano group, oxo group, hydroxyl group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropyl) or di -C _1-4 alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino - thio, etc.), amino group, mono ), A carbon atom and one nitrogen atom, and a 5- to 7-membered cyclic amino group (for example, pyrrolidino, piperidino) which may contain 1 to 3 heteroatoms (eg, a nitrogen atom, an oxygen atom and a sulfur atom). , Morpholino, thiomorpholino, etc.),
C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl Groups (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), phenyl-C _1-4 alkyl-oxycarbonyl (eg, benzyloxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, methylcarbonyl , Ethylcarbonyl, propylcarbonyl, etc.), a benzoyl group which may have a substituent (here, examples of the substituent include C _1-4 alkyl such as methyl, ethyl, etc., for example, fluoro, chloro,
Halogen atoms such as bromo; C _1-4 alkoxy such as methoxy and ethoxy; mono- or di-C _1-4 alkylamines such as methylamine and dimethylamine; 5- to 7-membered cyclic aminos such as piperidino and morpholino; 1-3 selected from groups, nitro, hydroxy, etc.
And specific examples include 4-fluorobenzoyl and 3,4-dimethoxybenzoyl), a carbamoyl group, a mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, etc.), C _It can be selected from _1-6 alkylsulfonyl groups (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.). The number of these substituents is 1 to 5
About one.

[0062] Yes Such Among substituents, the substituents mentioned in the section above R ¹ and R ² terms in optionally substituted hydrocarbon group or even mentioned R ¹ and R ² An optionally substituted acyl group is preferred.

Preferred hydrocarbon groups include, for example, a linear or branched C _1-11 alkyl group, more preferably a linear or branched C _1-7 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-
Butyl, n-pentyl, n-hexyl, etc.), C _7-18 aralkyl groups (eg, phenyl-C _1-12 alkyl such as phenylmethyl, phenylethyl, phenylpropyl, phenylhexyl and naphthyl- such as α-naphthylmethyl). C _1-8 alkyl, etc., more preferably C _7-10 aralkyl group (for example, phenylmethyl, phenylethyl,
Phenylpropyl and the like, and a diphenyl-C _1-3 alkyl group (eg, diphenylmethyl and the like).

The hydrocarbon group includes, for example, a halogen atom (eg, fluoro, chloro, bromo, iodo), C
_It may be substituted with a _1-4 alkyl group (eg, methyl, ethyl, etc.), a nitro group, a C _1-4 alkoxy group (eg, methoxy, ethoxy, etc.), a hydroxyl group and the like. The substitution position of the substituent may be on a carbon atom and / or a nitrogen atom of the nitrogen-containing saturated heterocycle.

Preferred acyl groups include, for example, formyl and C _2-8 acyl such as acetyl, propionyl and butyryl. C _2-8 acyl is usually unsubstituted in many cases.

In the above formula (I), k and m each independently represent an integer of 0 to 4, and n represents an integer of 1 to 3. Here, one of k and m represents an integer of 1 to 4.

In the compound represented by the formula (I),
The carboxyl group of the group represented by the formula (III) is represented by the following formula
As represented by (III-a), an ester may be formed.

[0068]

Embedded image (In the formula, R ⁶ represents an optionally substituted hydrocarbon group, and k has the same meaning as described above.) An optionally substituted hydrocarbon group represented by R ⁶ Include, for example, the hydrocarbon group which may have a substituent exemplified in the above-mentioned R ¹ and R ² . Preferred hydrocarbon groups include, for example, chain or branched C
_1-11 alkyl group, more preferably linear or branched C
_{A 1-7} alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, etc.), a C _7-18 aralkyl group (eg, phenylmethyl, phenylethyl, phenylpropyl, naphthyl -C _1-8 alkyl such as phenyl -C _1-12 alkyl or α- naphthylmethyl, such as phenyl hexyl), more preferably C _{7- 10} aralkyl group (e.g., phenyl, phenyl Ethyl, phenylpropyl, etc.), and a diphenyl-C _1-3 alkyl group (eg, diphenylmethyl, etc.).

Further preferred hydrocarbon groups represented by R ⁶ include C _1-4 alkyl groups such as methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl.

The compound of the present invention represented by the above formula (I) or a salt or ester thereof is a novel compound and has a better cholinesterase inhibitory action. In addition, the compounds of the present invention exhibit high water solubility. Preferred embodiments of the compound of the present invention are as follows.

As R ¹ and R ² , for example, R ¹ is a hydrogen atom, R ² is a hydrogen atom, linear or branched C _1-4.
Alkyl group (eg, methyl, ethyl, etc.), linear or branched C _2-6 alkenyl group (eg, vinyl, allyl, 2-butenyl, etc.), linear or branched C _2-6 Alkynyl group (eg, propargyl, 2-butynyl etc.), formyl, C _2-8 acyl (eg, acetyl, propionyl, butyryl etc.), arylcarbonyl group (eg, benzoyl etc.), C _7-10 aralkyl group (eg, Phenylmethyl, phenylethyl, phenylpropyl, etc.) and diphenyl-C _1-3 alkyl groups (eg, diphenylmethyl etc.). Among them, R ¹ is a hydrogen atom, R ² is a hydrogen atom, a linear or branched C _1-4 alkyl group, formyl, C _2-8 acyl, phenylcarbonyl group, C _7-10 aralkyl group. Is preferred.

As Y, for example, (a) a group represented by the above formula (IV), in particular, one of R ³ and R ⁴ is a linear or branched C _1-7 alkyl group (for example, methyl , Ethyl, n
-Propyl, i-propyl, n-butyl, i-butyl,
tert-butyl, n-pentyl, n-hexyl, etc.) and the other is a C _7-10 aralkyl group (eg, phenylmethyl, phenylethyl, phenylpropyl, etc.), or (b) a carbon atom and one nitrogen In addition to the atoms, for example, a 5- to 9-membered nitrogen-containing saturated heterocyclic group which may contain 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom is preferred. These nitrogen-containing saturated heterocyclic groups may have a substituent, for example, an optionally substituted acyl group or an optionally substituted C _7-10 aralkyl group.

Particularly, as Y, a nitrogen-containing saturated heterocyclic group represented by the aforementioned Q ¹ ring or Q ² ring, that is, a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to a carbon atom and one nitrogen atom A 5- to 9-membered, preferably 5- to 7-membered, nitrogen-containing saturated heterocyclic group which may contain 1 to 2 heteroatoms selected from These nitrogen-containing saturated heterocyclic groups are preferably, on a nitrogen atom constituting a ring, an acyl group which may have a substituent or a C _7-10 aralkyl group which may have a substituent. It may have a substituent.

More specifically, pyrrolidine, piperidine, piperazine, morpholine, and the like, which are substituted with an optionally substituted acyl group or C _7-10 aralkyl group, etc.
1,2,3,4-tetrahydroquinoline, 1,2,3
4-tetrahydroisoquinoline, 2,3,4,5-tetrahydro-1H-1-benzazepine, 2,3,4,5
-Tetrahydro-1H-2-benzazepine, 2,3
Groups having a skeleton such as 4,5-tetrahydro-1H-3-benzazepine are preferred. In particular, pyrrolidine, piperidine, substituted with an optionally substituted acyl group or an optionally substituted C _7-10 aralkyl group,
Groups having a skeleton such as piperazine and morpholine are preferred.

Further preferred Y is a 1-piperazinyl group optionally having a substituent represented by the formula (Va),
4- which may have a substituent represented by the formula (VI-a)
A piperidinyl group is contained, and in particular, a 4-piperidinyl group which may be substituted with an acyl group or a C _7-10 aralkyl group is preferable.

The substituents of these acyl groups or C _7-10 aralkyl groups include, for example, halogen atoms (eg, fluoro, chloro, bromo, etc.) and C _1-4 alkyl groups (eg, methyl, ethyl, n- Propyl, i-propyl, n
-Butyl, i-butyl, tert-butyl, etc.), nitro groups, hydroxyl groups, C _1-4 alkoxy groups (eg, methoxy, ethoxy, propoxy, butoxy, etc.) and the like.

It is preferable that k is an integer of 0 to 3 and m is an integer of 0 to 3, particularly k = 3 and m = 0. Further, preferable n is 2.

In the group represented by the formula (III-a), the substituent R ⁶ is preferably a hydrogen atom or a C _1-4 alkyl group.

More specifically, the following compounds belonging to compound (I) of the present invention and salts thereof are preferred. In the table, Ac represents an acetyl group and Ph represents a phenyl group.

[0080]

[Table 1]

[0081]

[Table 2]

[0082]

[Table 3]

[0083]

[Table 4]

[0084]

[Table 5]

[0085]

[Table 6]

[0086]

[Table 7]

[0087]

[Table 8]

[0088]

[Table 9]

[0089]

[Table 10] Since the aminocarboxylic acid derivative of the present invention has an amino group which may be substituted and a carboxyl group or an ester thereof, it has a feature of exhibiting high water solubility by forming a salt.

The salt of compound (I) of the present invention is preferably a physiologically acceptable base addition salt or acid addition salt.
In the compound of the present invention, the carboxyl group of the group represented by the formula (V) directly or indirectly bonded to the benzene ring A is an inorganic base (for example, an alkali metal such as sodium or potassium, calcium, magnesium or the like). Alkaline earth metals, ammonia, etc.) or organic bases (eg,
Tri-C such as trimethylamine and triethylamine
_{(E.g., 1-3} alkylamines). Further, when the compound of the present invention has an acidic group such as a carboxyl group at another site, a salt may be formed in the same manner as described above.

In the compound of the present invention, the optionally substituted amino group or nitrogen atom may be, for example, an inorganic acid (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) or an organic acid (eg, Acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.).

Further, when the compound of the present invention has a free carboxyl group and an optionally substituted amino group, the compound of the present invention may form an inner salt. Such salts are also included in the target compound of the present invention.

The method for producing the compound (I) of the present invention or a salt thereof will be described below. The description of the production method applies not only to the compound (I) itself, but also to a salt thereof, but is simply referred to as the compound (I) in the following description.

Among the compounds of the present invention, the compound wherein X is ＣＯCO is a compound represented by the following formula (VII) or a salt thereof:

[0095]

Embedded image [Wherein the symbols are as defined above. The compound can be produced by reacting a compound represented by the following formula (VIII) or a salt thereof.

[0096]

Embedded image [In the formula, Z ¹ represents a leaving group, and other symbols have the same meanings as described above. Examples of the leaving group represented by Z ¹ include a halogen atom (eg, chloro, bromo, iodo), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy), C _6-10 aryl Sulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy) and the like. Particularly, as the leaving group, for example, a halogen atom (for example, chloro or the like) is preferable.

Compound (VII) or a salt thereof can be produced by a known method or a method analogous thereto. For example, JP-A-59-204131, EP-A-109,65
3 or a method analogous thereto.

Compound (VIII) or a salt thereof can also be produced by a known method or a method analogous thereto. For example, Chemical Pharmaceutical Bulletin (Chem.
Pharm. Bull.) 34 , 3747-3761 (1986), EP-A-0,
378, 207 and the like.

When the compounds (VII) and (VIII) have an acidic group such as a carboxyl group, salts of the compounds (VII) and (VIII) include, for example, inorganic bases (eg, sodium, potassium, etc.). Alkali metals, calcium,
Alkaline earth metals such as magnesium, ammonia and the like or organic bases (eg tri-C _1-3 alkylamine such as trimethylamine and triethylamine)
And salts thereof. Further, the compound (VII) and
When (VIII) has a nitrogen atom, compounds (VII) and (V
Examples of the salt of III) include, for example, an inorganic acid (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) or an organic acid (eg,
Acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.).

The reaction of compound (VII) or a salt thereof with compound (VIII) or a salt thereof is carried out, for example, by reacting compound (VII) or a salt thereof with compound (VIII) or a salt thereof in the absence of a solvent, or If necessary, the reaction can be performed in a solvent.

The solvent may be any one which can be generally used for a chemical reaction, as long as the reaction is not hindered. For example, hydrocarbon solvents (for example, aliphatic hydrocarbons such as pentane and hexane) , Benzene, aromatic hydrocarbons such as toluene, nitrobenzene, etc.), halogenated hydrocarbon solvents (eg, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.), ether solvents (eg, ethyl ether, tetrahydrofuran) , Dioxane, dimethoxyethane, etc.), nitroalkane (eg, nitromethane, propionitrile, etc.), and organic solvents such as carbon disulfide. Particularly, halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane, nitrobenzene, carbon disulfide and the like are preferable.

The amount of the solvent to be used is generally 0.5-100 ml, preferably 5-20 ml, per 1 mmol of compound (VIII) or a salt thereof. The reaction temperature is usually −30 ° C.
To about 150 ° C, preferably about 20 ° C to 100 ° C. The reaction time is generally 0.5 to 72 hours, preferably 1 to 72 hours.
~ 16 hours.

The reaction is usually carried out in the presence of a Lewis acid. Examples of the Lewis acid include aluminum chloride, aluminum bromide, zinc chloride, titanium chloride, tin (IV) chloride, boron trifluoride, iron (II) chloride, and iron (II) chloride.
I), antimony pentachloride (V), bismuth (III) chloride, mercury (II) chloride, hydrogen fluoride, sulfuric acid, polyphosphoric acid and the like are used. Among them, a Friedel-Crafts catalyst such as aluminum chloride is preferred.

The amount of the Lewis acid to be used is generally 1 to 10 mol, preferably 2 mol, per 1 mol of compound (VIII) or a salt thereof.
10 to 10 moles.

The amount of compound (VII) or a salt thereof to be used is generally about 1-20 mol, preferably about 1-5 mol, per 1 mol of compound (VIII) or a salt thereof.

In the above reaction, the following groups in compound (VIII) or a salt thereof

[0107]

Embedded image Is introduced into the compound (VII) or a salt thereof at any substitutable position of the ring A. For example, when the skeleton of compound (VII) or a salt thereof is 4-
In the case of methyl [2- (acetylamino) phenyl] butyrate, it is mainly introduced at the 4-position. However, compounds introduced at other positions (positions 3, 5, 6) can also be generated and separated.

In the compounds of the present invention, X is が C =
The compound represented by O is, for example, a compound represented by the following formula (IX) or a salt or an ester thereof:

[0109]

Embedded image A compound represented by the following formula (X) or a salt thereof is reacted with Z ³ -Y (X) wherein Z ² and Z ³ represent groups capable of reacting and leaving together, and other symbols are as defined above. Is shown. ] It can also be produced by reacting.

Examples of the leaving group represented by Z ² include a halogen atom (eg, chloro, bromo, iodo, etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.)
C _6-10 arylsulfonyloxy (for example, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.)
And the like. Among them, as Z ² , for example,
Halogen atoms such as chloro and bromo are preferred.

Examples of the leaving group represented by Z ³ include a hydrogen atom and a trialkylsilyl group (for example, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and the like). Among them, for example, a hydrogen atom is preferable.

The starting compound (X) or a salt thereof can be produced by a method known per se or a method analogous thereto.

As the salt or ester of compound (IX),
The same salts as those of the compound (I) are used.

The salts of compounds (IX) and (X) include, for example, inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid)
And organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartar, citric wine, cider wine, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) Are used. Further, when the compounds (IX) and (X) have an acidic group such as -COOH, the compounds (IX) and (X) may be an inorganic base (for example, an alkali metal such as sodium, potassium, calcium, magnesium or the like) Salts may be formed with ammonia, such as alkaline earth metals, or organic bases, such as tri-C _1-3 alkylamines such as triethylamine.

The amount of compound (X) or a salt thereof used in this reaction is usually 1.0 to 50.0 moles, preferably 1. mole, per 1 mole of compound (IX) or a salt or ester thereof. It is 0 to 10.0 times mol. This reaction can be carried out under cooling or under heating (0 ° C to 120 ° C). The reaction time is generally 10 minutes to 48 hours, preferably 2 to 16 hours.

This reaction can be carried out in the absence of a solvent or, if necessary, in a solvent. As such a solvent, any solvent may be used as long as it does not inhibit the progress of the reaction. For example, lower alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol, dioxane, ether, tetrahydrofuran Ethers such as benzene,
Aromatic hydrocarbons such as toluene and xylene, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphonotriamide, and esters such as ethyl acetate and butyl acetate are used.

The amount of the solvent to be used is generally 0.5 mol, per 1 mmol of compound (IX) or a salt or ester thereof.
１００100 ml, preferably 5-20 ml.

The reaction can be carried out in the presence of a base, if necessary. As the base used,
For example, carbonates of alkali metals such as sodium carbonate, potassium carbonate and lithium carbonate, hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, alkoxides of alkali metals such as sodium methoxide and sodium ethoxide, hydrogenation Inorganic bases such as sodium: organic bases such as pyridine, 4-dimethylaminopyridine and triethylamine.

The amount of the base to be used is generally equimolar to excess, preferably 1.0 mol, relative to compound (X) or a salt thereof.
It is a 5.0-fold molar amount.

In this reaction, if desired, an iodide compound (eg, sodium iodide, potassium iodide,
The reaction may be promoted in the presence of lithium iodide). The amount of the iodide compound to be used is generally 1 to 5 molar equivalents, preferably 1.0 to 1.5 molar equivalents, relative to compound (IX) or a salt or ester thereof.

The starting compound (IX) or a salt or ester thereof is, for example, represented by the following formula:

[0122]

Embedded image Wherein each symbol is as defined above. A compound represented by the following formula:

[0123]

Embedded image [In the formula, Z ⁴ represents a leaving group, and the other symbols have the same meanings as described above. And a compound represented by the following formula:

The leaving group represented by Z ⁴ includes, for example, a halogen atom (eg, chloro, bromo, iodo, etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.)
C _6-10 arylsulfonyloxy (for example, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.)
Are used. Particularly, for example, a halogen atom (for example, chloro or the like) is preferable.

Compound (XI) can be produced by a method known per se or a method analogous thereto.

The reaction of compound (VII) or a salt thereof with compound (XI) can be carried out under the same conditions as in the reaction of compound (VII) or a salt thereof with compound (VIII) or a salt thereof.

In the above reaction, the group in compound (XI)

[0128]

Embedded image Is introduced into the compound (VII) or a salt thereof at any of the substitutable positions on the ring A, for example,
Compound (VII) or a salt thereof has a skeleton in which Ring A is unsubstituted
In the case of methyl [-[2- (acetylamino) phenylbutyrate], it is mainly introduced at position 4. However, compounds introduced at other positions (positions 3, 5, and 6) are also formed. ,
Can be separated.

The compound thus obtained, wherein X is ＣＯCO, a salt thereof or an ester thereof, may be obtained by a known means, for example, concentration, liquid conversion, phase transfer, solvent extraction, fractional distillation,
It can be isolated and purified by distillation, crystallization, recrystallization, chromatography, etc., but may be used as a raw material in the next step as it is without isolation.

Further, among the compounds (I) of the present invention, a compound wherein X is -CH (OH)-can be produced by subjecting a compound wherein X is ＣＯCO to a reduction reaction. As the reduction reaction, a known method, for example, New Experimental Chemistry Course, Chapter 15
Volume, Oxidation and Reduction (II), Maruzen Co., Ltd. (1977)
(For example, reduction with sodium borohydride, etc.) described above, or a method analogous thereto.

Further, among the compounds (I) of the present invention, a compound having a free carboxyl group represented by the formula (III) or a salt thereof and an ester represented by the formula (III-a) Compounds having a bond are mutually convertible.

[0132] The esterification reaction of a carboxyl group, conventional esterification reaction, for example, a compound having a free carboxyl group or a salt thereof represented by the formula (III), R ⁶
By reacting an alcohol represented by OH (wherein R ⁶ is the same as described above) or a corresponding alkyl halide in the presence or absence of a solvent, if necessary, in the presence of an acid catalyst. Can do it.

Examples of the solvent include solvents that do not adversely affect the reaction, for example, hydrocarbon solvents (for example, aliphatic hydrocarbons such as pentane, hexane and octane, alicyclic hydrocarbons such as cyclohexane, benzene, toluene, and xylene Aromatic hydrocarbons, etc.), halogenated hydrocarbons (for example, dichloromethane and carbon tetrachloride), ethers (for example, diethyl ether and the like), ketones (for example, methyl ethyl ketone and the like) and the like. Further, the alcohol can be used as a reaction solvent.

Examples of the acid catalyst include inorganic acids (for example, hydrochloric acid,
Phosphoric acid, sulfuric acid, etc.), and organic acids (eg, methanesulfonic acid, benzenesulfonic acid, etc.). The amount of the acid catalyst used is, for example, based on the compound having a free carboxyl group represented by the above formula (III) or a salt thereof.
0.01 to 10% by weight, preferably 0.05 to 5% by weight
It is about.

The amount of the alcohol represented by R ⁶ OH (where R ⁶ is the same as above) is usually 1 mol of the compound having a free carboxyl group represented by the formula (III) or a salt thereof. The amount is usually 1.0 to 50.0 times, preferably 1.0 to 10.0 times the mol.

The esterification reaction is usually carried out at 70 to 150.
C., preferably at about 80 to 120 ° C., under normal pressure or reduced pressure. The reaction is completed usually in 1 to 48 hours, preferably in about 1 to 24 hours.

The esterification reaction may be carried out by other conventional methods, for example, by converting a compound having a carboxyl group represented by the formula (III) into an acid halide with a halogenating agent such as thionyl chloride, A reaction method may be employed.

The hydrolysis reaction for generating a free carboxyl group from an ester can be carried out in a conventional manner, for example, in the presence of an acid catalyst or a base as described above. Examples of the base include an inorganic base (for example, an alkali metal such as sodium, potassium, and calcium) and an organic base (for example, a tri-C _1-3 alkylamine such as triethylamine). The hydrolysis reaction may be performed in the presence of a solvent or water that does not adversely affect the reaction, similarly to the esterification reaction.

Further, if necessary, R ⁶ can be substituted with a different kind of hydrocarbon group by a conventional transesterification reaction. In this transesterification reaction, the formula (III-a)
A conventional alcoholysis reaction in which a compound having an ester bond represented by the following formula and an alcohol corresponding to a hydrocarbon group to be substituted are reacted in the presence of a catalyst such as sodium alkoxide can be employed.

In each of the above reactions, when the starting compound has an amino group, a carboxyl group, a hydroxyl group or the like as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups. Good. After the reaction, the desired compound can be obtained by removing the protecting group as necessary.

Examples of the amino-protecting group include, for example, C
_1-6 acyl (eg, formyl, acetyl, ethylcarbonyl, etc.), benzoyl, C _1-6 alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl (eg, phenoxycarbonyl, etc.), C _{7 -15} aralkyloxy-
Examples include carbonyl (eg, benzyloxycarbonyl, fluorenyloxycarbonyl, etc.), trityl, phthaloyl and the like. These protecting groups may have a substituent. As the substituent, a halogen atom (for example,
Fluoro, chloro, bromo, iodo), C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like. The number of substituents is about 1 to 3.

Examples of the carboxyl-protecting group include C _1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like. No.
These protecting groups may have a substituent. The substituent includes a halogen atom (eg, fluoro, chloro, bromo, iodo), C _1-6 acyl (eg, formyl, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group and the like. The number is about 1 to 3.

The protecting group for the hydroxyl group includes, for example, C
_1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.),
Phenyl, C _7-10 aralkyl (eg, benzyl etc.), C _1-6 acyl (eg, formyl, acetyl, ethylcarbonyl etc.), phenyloxycarbonyl (eg, phenoxycarbonyl etc.), C _7-10 aralkyl-carbonyl (eg, phenyloxycarbonyl) For example, benzyloxycarbonyl), pyranyl, furanyl, silyl and the like. These protecting groups may have a substituent. Examples of the substituent include a halogen atom (e.g., fluoro, chloro, bromo, iodo), C _1-6 alkyl, phenyl, C _7-10 aralkyl and nitro group and the like, the number of the substituents is 1 to 4
About one.

As the method for removing the protecting group, a method known per se or a method analogous thereto is used.
Acid, base, reduction, hydrazine, phenylhydrazine, N
-A method of treating with sodium methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or the like, or an irradiation treatment with ultraviolet light.

When the thus obtained compound (I) or a salt thereof or an ester thereof has an acylamino group which may have a substituent, the compound is subjected to a deacylation reaction to obtain an amino group or a monosubstituted amino group. It can be a compound having a group, a salt thereof, or an ester thereof.

Compound (I) having an acylamino group which may have a substituent or a salt or ester thereof can be prepared by a known method, for example, concentration, liquid conversion, phase transfer, solvent extraction, fractionation, distillation. The product may be isolated and purified by crystallization, recrystallization, chromatography, etc., but may be used as a raw material for deacylation as it is without isolation.

The deacylation of the compound (I) having an acylamino group which may have a substituent or a salt thereof or an ester thereof is carried out, for example, by using a mineral acid (for example, nitric acid,
In an aqueous solution of an acid such as hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, or a base such as an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), usually 10% ~ 150 ° C, preferably 50 ~
It can be performed by maintaining the temperature at 100 ° C.

The amount of the acid or base to be used is generally 1 to 10 based on compound (I) or a salt or ester thereof.
It is 0 equivalent, preferably 1 to 40 equivalent. The strength of the acid and base is usually about 0.1 to 10 normal, preferably 2 to 10 normal.
10 rules. The reaction time depends on the reaction temperature, but is usually about 1 to 24 hours, preferably about 2 to 10 hours.

The thus-obtained compound (I) having an amino group or a monosubstituted amino group, a salt thereof, or an ester thereof is obtained by introducing an optionally substituted hydrocarbon group into the amino group or the monosubstituted amino group. By doing so, compound (I) in which the amino group is substituted with a hydrocarbon group which may have a substituent, a salt thereof, or an ester thereof can be produced.

The compound (I) having an amino group or a monosubstituted amino group or a salt or an ester thereof used as a starting compound can be obtained by a known method, for example, concentration, liquid conversion, phase transfer, solvent extraction, fractionation, It can be used after isolation and purification by distillation, crystallization, recrystallization, chromatography and the like, but it may be used as a raw material as it is without isolation.

The compound (I) or a salt or ester thereof in which an amino group is substituted by a hydrocarbon group which may have a substituent is a compound (I) or a salt thereof having an amino group or a monosubstituted amino group. Or its ester,
It can also be produced by a reaction with a compound represented by the following formula.

[0152] ⁷ -Z ⁵ (XII) wherein, R ⁷ is a hydrocarbon group which may have a substituent, Z ⁵ represents a leaving group] R have a substituent represented by R ⁷ Examples of the optionally substituted hydrocarbon group include R ¹ and R ²
The hydrocarbon group which may have a substituent described in (1) is used as it is.

Examples of the leaving group represented by Z ⁵ include a halogen atom (eg, chloro, bromo, iodo), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy),
_6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy) and the like. Particularly, for example, a halogen atom (for example, chloro or the like) is preferable.

The above reaction is carried out in the presence or absence of a solvent.
The reaction can be performed in the presence of a base, if necessary.

When a solvent is used, a solvent which does not inhibit the progress of the reaction, for example, lower alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol, dioxane, ether,
Ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, benzene and xylene, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphonotriamide, and esters such as ethyl acetate and butyl acetate are used.

As the base, for example, sodium carbonate,
Inorganic bases such as alkali metal carbonates such as potassium carbonate and lithium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and sodium hydride Organic bases such as pyridine, 4-dimethylaminopyridine and triethylamine are used.

When a base is used, it is generally used in an amount of about an equimolar amount to an excess amount, preferably an equimolar amount, based on the compound (I) having an amino group or a monosubstituted amino group or a salt or ester thereof. , About 1.1 to 5 times the molar amount.

The amount of compound (XII) to be used is generally 0.3 to 5.0 moles per mole of compound (I) having an amino group or a monosubstituted amino group, or a salt or ester thereof. It is.

The above reaction can be carried out at an appropriate temperature, for example, under cooling (about 0 ° C. to 10 ° C.), at room temperature (about 10 ° C. to 40 ° C.), or under heating (about 40 ° C. to 120 ° C.). ,
The reaction time is generally 10 minutes to 48 hours, preferably 2 to 48 hours.
16 hours.

Further, the above reaction may be promoted in the presence of an iodide compound, for example, sodium iodide, potassium iodide, lithium iodide or the like, if desired.
The amount of the iodide compound to be used is generally, based on compound (XII),
The molar equivalent is 1 to 5 times, preferably 1.1 to 1.5 times.

The compound (XII) can be produced by a known method or a method analogous thereto.

The compound (I) thus obtained can be converted into a salt according to a conventional method when it is in a free form, and can be converted into a free form or another salt according to a conventional method when a salt is formed. it can. The resulting compound (I) or a salt thereof or an ester thereof can be isolated and purified by a known means as described above.

The compound (I) or a salt or ester thereof includes stereoisomers based on the presence of an asymmetric carbon atom. Such a stereoisomer can also be isolated and purified by a known means as described above, or a means such as fractional recrystallization or chromatography using an optically active column.

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

The compound (I) of the present invention or a salt thereof or an ester thereof has a very good effect on the central nervous system and that on the peripheral nerve as compared with physostigmine, and at a dose showing an anti-amnestic effect, It has no or very slight peripheral nerve effects such as convulsions, salivation and diarrhea, has a long duration of action and low toxicity. Further, the compound of the present invention has high water solubility,
Not only oral administration, but also parenteral administration such as transdermal administration,
These administrations produce significant effects.

The acute toxicity (LD ₅₀ ) of the compound (I) of the present invention or a salt or ester thereof is 100 mg / kg.
That is all. Therefore, the compounds of the present invention are useful as safe brain function improving agents for mammals including humans.

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. Or it can be used for treatment.

The compound of the present invention can be generally formulated with a pharmaceutically acceptable carrier or excipient and orally or parenterally administered to mammals including humans.

The dosage form of the preparation includes oral preparations (for example, solid preparations such as powders, tablets, granules and capsules, liquids such as liquids, suspensions and emulsions) and parenteral preparations (for example, Suppositories, injections such as solutions and suspensions). These formulations can be prepared using known methods.

Examples of carriers for solid preparations include lactose,
Excipients such as powdered sugar, mannitol, corn starch, talc, crystalline cellulose (such as Avicel), magnesium stearate, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine; starch, pregelatinized starch, sucrose, gelatin , Gum arabic powder, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin; carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carme Disintegrators such as loin calcium; anionic surfactants such as sodium alkyl sulfate; polyoxyethylene sorby Surfactants such as nonionic surfactants such as fatty acid esters, polyoxyethylene fatty acid esters and polyoxyethylene castor oil derivatives; coloring agents; flavoring agents; adsorbents; preservatives; wetting agents; antistatic agents; Extenders and the like. Among these carriers, at least an excipient and a binder are frequently used, and a disintegrant is often used in combination.

Further, the solid preparation may be a coated preparation obtained by coating fine granules, granules, pills, tablets and the like with a coating agent.

The injection is preferably sterilized and isotonic with blood. The injection may contain water, a diluent such as ethyl alcohol, salt for making it isotonic with blood, glucose, glycerin, and the like, as well as a buffer, a preservative, and the like.

The dose of the compound of the present invention is generally about 0. 0 per day for oral administration to an adult (body weight 70 kg), although there are differences depending on the type and symptoms of the target disease.
The amount is from 01 mg to 50 mg, preferably from 0.1 to 30 mg, more preferably from 0.5 to 10 mg.

The cholinesterase inhibitor of the present invention usually contains about 0.01 to 70% by weight, preferably about 1 to 50% by weight of the compound (I) in the preparation. Further, the content of the compound (I) of the present invention in the dosage unit form varies depending on the kind and symptom of the target disease, but is usually about 10 to 1000 mg in many cases.

[0175]

The compound of the present invention has excellent cholinesterase inhibitory activity and is useful as a drug for treating and preventing senile dementia.

[0176]

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

Elution by column chromatography in Experimental Examples and Reference Examples was performed by TLC (Thin Lay) unless otherwise specified.
er Chromatography). In the TLC observation, the 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate, a solvent used as an elution solvent in column chromatography as a developing solvent, employing a UV detector as a detection method. In addition, 48% HB was added to the spot on the TLC plate.
r, sprayed, heated and hydrolyzed, sprayed with a ninhydrin reagent and heated again to confirm the eluted fraction containing the target compound by using the phenomenon that turns red to purple-red as a detection method. ,collected. Unless otherwise specified, silica gel for the column was Kieselgel 60 (70-230) manufactured by Merck.
Mesh).

It should be noted that “normal temperature” or “room temperature” usually means a temperature of about 5 to 40 ° C., and “normal pressure” means around one atmosphere.

Unless otherwise specified, “%” indicates percentage by weight.

Reference Example Methyl 4- [2- (acetylamino) phenyl] butyrate

[0181]

Embedded image A mixture of 30 g of 2,3,4,5-tetrahydro-1H-1,4-benzazepin-2-one and 180 ml of concentrated hydrochloric acid was heated to reflux for 16 hours. The concentrated hydrochloric acid was distilled off under reduced pressure, and the resulting residue was dissolved in 300 ml of methanol. 0.3 ml of concentrated hydrochloric acid was added to the solution, and the mixture was heated under reflux for 1 hour, and then methanol was distilled off under reduced pressure.

The obtained residue was diluted with 300 ml of dichloromethane.
And washed sequentially with a 5% aqueous sodium hydroxide solution and water. After the dichloromethane solution was dried over anhydrous sodium sulfate, 18 ml of acetic anhydride was added, and the mixture was heated under reflux for 30 minutes.

After cooling the reaction mixture to room temperature, it was washed successively with 5% sodium hydroxide and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 31 g of the title compound as colorless crystals having a melting point of 84 to 85 ° C.

Elemental analysis: C ₁₃ H ₁₇ NO ₃ Calculated: C, 66.36; H, 7.28; N,
5.95 experimental: C, 6.318; H, 7.29; N,
5.93 Example 1 Methyl 4- [5-[[3- (1-acetylpiperidin-4-yl) -1-oxo] propyl] -2- (acetylamino) phenyl] butyrate (A) and 4- [ Methyl 4-[[3- (1-acetylpiperidin-4-yl) -1-oxo] propyl] -2- (acetylamino) phenyl] butyrate (B)

[0185]

Embedded image Methyl 4- [2- (acetylamino) phenyl] butyrate 3
10 g of carbon disulfide solution of 1 g and 32 g of 3- (1-acetylpiperidin-4-yl) propionyl chloride
Then, 77 gk of aluminum chloride powder was added little by little, and the mixture was heated under reflux for 16 hours. After pouring the reaction mixture into ice water, the product was extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The obtained residue was subjected to silica gel column chromatography [developing solvent: ethyl acetate-methanol = 2.
0: 1 (V / V)] to give the starting compound 4- [2
While collecting 14 g of methyl [-(acetylamino) phenyl] butyrate, 5 g of the title compound (A) was obtained as a colorless amorphous powder, and 11.5 g of the title compound (B) was obtained as a viscous oil.

Elemental analysis of the title compound (A) C ₂₃ H ₃₂
Calculated for N ₂ O ₅ : C, 66.32; H, 7.74; N,
6.73 experimental values: C, 66.24; H, 7.80; N,
6.63 Elemental analysis of title compound (B) Calculated for C ₂₃ H ₃₂ N ₂ O ₅ Calculated: C, 66.32; H, 7.74; N,
6.73 experimental: C, 66.29; H, 7.75; N,
6.70 Example 2 Methyl 4- [2-amino-4-[[1-oxo-3- (piperidin-4-yl)] propyl] phenyl] butyrate

[0188]

Embedded image Methyl 4- [4-[[3- (1-acetylpiperidin-4-yl) -1-oxo] propyl] -2- (acetylamino) phenyl] butyrate (Compound (B) of Example 1)
A mixture of 11.2 g and 300 ml of concentrated hydrochloric acid was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature, washed with ethyl acetate, and concentrated hydrochloric acid was distilled off under reduced pressure. The obtained residue was dissolved in methanol (200 ml), concentrated hydrochloric acid (0.5 ml) was added, and the mixture was heated under reflux for 1 hour. Methanol was distilled off under reduced pressure, the resulting residue was dissolved in water, and 10% sodium hydroxide was added to adjust the pH to about 10.

The product was extracted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was recrystallized from dichloromethane-ether to give 7.4 g of the title compound, melting point 132-13.
Obtained as colorless crystals at 4 ° C.

Elemental analysis: C ₁₉ H ₂₈ N ₂ O ₃ Calculated: C, 68.65; H, 8.49; N,
8.43 experimental: C, 68.44; H, 8.30; N,
8.20 Example 3 4- [2-Amino-4-[[1-oxo-3- [1-
Methyl (phenylmethyl) piperidin-4-yl]] propyl] phenyl] butyrate

[0191]

Embedded image 7.3 g of the compound obtained in Example 2 and 3.95 of potassium carbonate
g, methanol 100 ml and dichloromethane 100
5 ml of a dichloromethane solution of 3.6 g of benzyl bromide was added dropwise to the mixed suspension at 0 to 5 ° C., and the mixture was stirred at room temperature for 2 hours.

Under reduced pressure, the solvent was distilled off from the reaction mixture, and the obtained residue was dissolved in water and extracted with dichloromethane.
After the extract was washed with water, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 7.2 g of the title compound as colorless needles having a melting point of 76 to 77 ° C.

Elemental analysis: calculated as C ₂₆ H ₃₄ N ₂ O ₃ Calculated: C, 73.90; H, 8.11; N,
6.63 experimental values: C, 73.85; H, 8.18; N,
6.64 Example 4 4- [2-amino-4-[[1-oxo-3- [1-
(Phenylmethyl) piperidin-4-yl]] propyl] phenyl] butyric acid dihydrochloride 3/2 hydrate

[0194]

Embedded image A mixture of 2.2 g of the compound obtained in Example 3 and 20 ml of concentrated hydrochloric acid was heated and stirred at 70 ° C. for 16 hours. After completion of the reaction, concentrated hydrochloric acid was distilled off under reduced pressure.
and 2 g of activated carbon was added and heated at 50 ° C. for 2 hours. The activated carbon was removed by filtration, and the obtained pale yellow solution was concentrated under reduced pressure to obtain 1.35 g of the title compound as a pale yellow amorphous powder.

Elemental analysis value C ₂₅ H ₃₂ N ₂ O ₃ .2HCl
· 3 / 2H ₂ O Calculated: C, 59.05; H, 7.33 ; N,
5.51 experimental: C, 58.82; H, 7.26; N,
5.29 Example 5 4- [2-amino-4-[[1-hydroxy-3- [1
-(Phenylmethyl) piperidin-4-yl]] propyl] phenyl] butyric acid sodium salt monohydrate

[0196]

Embedded image 20 m of a methanol solution of 1.2 g of the compound obtained in Example 4
To 1 was added 0.3 g of sodium borohydride in small portions at room temperature. After stirring the mixture for 20 minutes, ice water was added. After the methanol was distilled off under reduced pressure, the product was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solvent: ethyl acetate-methanol = 20: 2 (V / V)].
4- [2-amino-4-[[1-hydroxy-3- [1
1.2 g of methyl-(phenylmethyl) piperidin-4-yl]] propyl] phenyl] butyrate was obtained as a colorless oil.

This oil was dissolved in 2 ml of methanol,
An aqueous solution of 0.12 g of sodium hydroxide and 100 ml of water was added, and the mixture was heated under reflux for 4 hours. Water was distilled off from the reaction mixture under reduced pressure to obtain 1.1 g of the title compound as a colorless amorphous powder.

Elemental analysis value C ₂₅ H ₃₃ N ₂ NaO ₃ .H ₂
Calculated as O: C, 66.65; H, 7.83; N,
6.22 Experimental: C, 66.56; H, 7.71; N,
6.23 Formulation Example 1 (1) 4- [2-amino-4-[[1-oxo-3- [1
-(Phenylmethyl) piperidin-4-yl]] propyl] phenyl] butyric acid dihydrochloride 3/2 hydrate (Compound of Example 4) 1 g (2) Lactose 197 g (3) Corn starch 50 g (4) Stearic acid Magnesium 2g Component (1) 1g, Component (2) 197g and 20g
Of corn starch and granulated with a paste prepared from 15 g of corn starch and 25 ml of water. To the obtained granules, 15 g of corn starch and 2 g of the above-mentioned component (4) were added, and the mixture was compressed with a compression tablet machine to give a tablet of 3 mm in diameter containing 0.5 mg of the above-mentioned component (1) per tablet. Pieces were manufactured.

Formulation Example 2 (1) 4- [2-amino-4-[[1-oxo-3- [1
-(Phenylmethyl) piperidin-4-yl]] propyl] phenyl] butyric acid dihydrochloride 3/2 hydrate (Compound of Example 4) 1 g (2) Lactose 197 g (3) Corn starch 50 g (4) Stearic acid Magnesium 2g Component (1) 2g, Component (2) 197g and 20g
Of corn starch and granulated with a paste made from 15 g of corn starch and 25 ml of water. To the obtained granules, 15 g of corn starch and 2 g of component (4) were added, and the mixture was compressed with a compression tablet machine to give 2,000 3 mm-diameter tablets containing 1.0 mg of component (1) per tablet. Was manufactured.

Formulation Example 3 (1) 4- [2-amino-4-[[1-oxo-3- [1
-(Phenylmethyl) piperidin-4-yl]] propyl] phenyl] butyric acid dihydrochloride 3/2 hydrate (compound of Example 4) 2.0 mg (2) glucose 2.5 mg (3) distilled water for injection The above component (1) 2.0 mg and the component (2) 2.5 mg were dissolved in distilled water for injection (5 ml in total), and distilled water for injection was added to make a total volume of 5 ml. And then sterilized by pressure to obtain an injection having the above composition.

Formulation Example 4 (1) 4- [2-amino-4-[[1-oxo-3- [1
-(Phenylmethyl) piperidin-4-yl]] propyl] phenyl] butyric acid dihydrochloride 3/2 hydrate (the compound of Example 4) 2.0 mg (2) common salt 20.0 mg (3) distilled water for injection The above component (1) 2.0 mg and the component (2) 20.0 mg were dissolved in a total amount of 2 ml of distilled water for injection, and distilled water for injection was further added to make the total amount 2 ml.
After replacing with nitrogen, the solution was sterilized under pressure to obtain an injection having the above composition.

EXPERIMENTAL EXAMPLE The cholinesterase inhibitory effect of the compound of the present invention was examined using (acetase).
yl- [ ³ H])-acetylcholine.
That is, as a substrate (acetyl ^[3 H]) - acetylcholine, and to a system comprising a compound of the invention as a subject, the addition of S ₁ fraction of male Wistar rat cerebral cortex homogenate as a cholinesterase source, 30 minutes after incubation, the reaction was stopped, and shaken with toluene-based scintillator was produced by the reaction ^[3
H] -acetic acid was transferred to a toluene layer and counted by a liquid scintillation counter to determine the cholinesterase inhibitory activity.

The cholinesterase inhibitory activity of the test compound was represented by a 50% inhibitory concentration (IC ₅₀ ). As a control, the cholinesterase inhibitory activity of physostigmine was also measured by the same method. The results are shown in the table below.

Compound Acetylcholinesterase (Example No.) Inhibitory activity IC ₅₀ (μM) 3 0.0562 4 0.161 Physostigmine 0.220 From the above table, the compounds of the present invention show superior acetylcholinesterase inhibitory activity over Physostigmine. Have.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 211/18 A61K 31/445 A61P 25/28 A61P 43/00 111 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] (1) Formula (1) [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydrocarbon group which may have a substituent, or an acyl group which may have a substituent, and the ring A is further substituted. A benzene ring which may have a group, X represents a ＣＯCO group or -CH
(OH) — group, Y is an amino group which may have a substituent or a nitrogen-containing saturated heterocyclic group which may have a substituent, k and m each independently represent 0 to 4; Where either k or m is an integer of 1 to 4, and n is 1 to
An integer of 3 is shown. And a salt or ester thereof. 2. The compound according to claim 1, wherein k = 3 and m = 0. 3. The compound according to claim 1, wherein Y is a 4-piperidinyl group which may have a substituent. 4. A compound of the formula (Wherein each symbol has the same meaning as in claim 1) or a salt or ester thereof, and a compound represented by the formula: (Wherein, Z ¹ represents a leaving group, Y and n have the same meanings as in claim 1) or a salt thereof, and if necessary, the reaction product is subjected to a reduction reaction. A method for producing an aminocarboxylic acid derivative or a salt or ester thereof to be attached. 5. A cholinesterase inhibitor comprising the aminocarboxylic acid derivative according to claim 1 or a salt or ester thereof. 6. The cholinesterase inhibitor according to claim 5, which is used as a therapeutic / prophylactic agent for senile dementia.