JP2730135B2 - Acid amide derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel acid amide derivative or a salt thereof which is useful as a medicament, in particular, a brain function improving agent for senile dementia, Alzheimer's disease and the like.

2. Description of the Related Art With the aging of society, various compounds having various cerebral function improving effects have been proposed. 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 an aromatic group which may have a substituent, and R ³ represents a hydrogen atom or a lower alkyl group or a substituent. A is a good aromatic group, n is an integer of 3 to 7, R ⁴ is a hydrogen atom, a lower alkyl group or an acyl group, and A is a group represented by the formula — (CH ₂ ) ₁ —
Represents 0, 1 or 2) or the formula -CR ⁵ = CR ^6- (wherein, R ⁵ and R ⁶
Represents a hydrogen atom, a lower alkyl group or a phenyl group which may have a substituent, respectively. B) may have a substituent. Shows a cyclic group. However,
BA- is a formula (Wherein, X represents a substituent and 1 is as defined above). The present inventors have succeeded in creating an acid amide derivative represented by the formula [1] or a salt thereof, and have found that these compounds exhibit an excellent cerebral function improving action, and have completed 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 ³ and R ⁴ includes 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 and R ³ include a phenyl group and a naphthyl group.

Examples of the substituent of these aromatic groups include a halogen atom (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 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxy) Carbonyl), hydroxycarbonyl, C _1-6 alkylcarbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, cyclohexylcarbonyl), carbamoyl, mono- or di-C _1-4 alkyl-substituted carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, propyl) Carbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl), phenyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenoxy optionally having 1-4 substituents C _1-4 alkylcarbamoyl and phenylcarbamoyl [Examples of the substituent on each phenyl group or naphthyl group include C _1-4 alkyl groups such as methyl, ethyl, propyl, butyl, and isopropyl, methoxy, ethoxy, n-propyl Oxy, i
A C _1-4 alkoxy group such as -propyloxy and n-butyloxy, a halogen atom such as chloro, bromo and iodo;
Hydroxyl, amino, mono- or di-C _1-4 alkyl-substituted amino, nitro, C _1-4 alkoxycarbonyl and the like. ].

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

The acyl group represented by R ⁴ includes, for example, acyl carboxylate, acyl carbamate, acyl sulfonate, and substituted acyloxycarboxylate.

Examples of the acyl carboxylate include C _1-6 alkylcarbonyl such as acetyl, propionyl, butyryl, valeryl, hexanoyl, isobutyryl and isovaleryl;
And C _7-11 arylcarbonyl such as benzoyl and naphthoyl.

Examples of the acyl carbamic acid include carbamoyl, mono- or di-substituted carbamoyl, and examples of the mono- or di-substituted carbamoyl include monocarbamoyl such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and dipropylcarbamoyl. Or di
And aromatic group carbamoyl such as C _1-4 alkylcarbamoyl, phenylcarbamoyl, and naphthylcarbamoyl.

The sulfonic acid acyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, C _1-6 alkylsulfonyl such as butylsulfonyl, phenylsulfonyl,
And aromatic sulfonyl such as naphthalene sulfonyl.

Examples of the substituted acyloxycarboxylic acid include, for example, aromatic or araliphatic such as C _1-6 alkyloxycarbonyl such as methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, and hexyloxycarbonyl, phenyloxycarbonyl, and benzyloxycarbonyl. Oxycarbonyl and the like.

R ⁵ and R ⁶ may be the same or different.

Examples of the lower alkyl group represented by R ⁵ and R ⁶ include the groups described above as “lower alkyl group represented by R ¹ , R ³ and R ⁴ ”.

As the substituent of the optionally substituted phenyl group represented by R ⁵ and R ⁶ and the optionally substituted cyclic group represented by B, C _1-4 alkyl (for example, methyl , Ethyl, propyl, butyl, etc.), halogen atoms (eg, chloro, bromo, iodo, 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, propylamino, dimethylamino, diethylamino, etc.), 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, etc.), hydroxycarbonyl, C _1-6
Alkylcarbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, cyclohexylcarbonyl, etc.), carbamoyl, mono- or di-C _1-4 alkyl-substituted carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutyi) Rucarbamoyl, etc.), C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.),
Phenyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl C optionally having 1 to 4 substituents
_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, (the substituents on each phenyl group include, for example, C _1-4 alkyl groups such as methyl, ethyl, propyl, butyl, and isopropyl; and halogen atoms such as chloro, bromo, and iodo. And mono- or di-C _1-4 alkyl-substituted amino, nitro, C _1-4 alkoxycarbonyl such as methyl, dimethylamino, etc.) and the like.

As the cyclic group represented by B, not only carbocycles,
Heterocycles containing heteroatoms such as O, S, N and the like are also included, and may be a single ring, a carbocycle, a heterocycle, or a condensed ring of both. The ring of these cyclic groups may be a saturated or unsaturated cyclic group. Generally adjacent A group in which the carbon atom bonded to is conjugated is preferred.
Thus, A represents —CR ⁵ CRCR ⁶ — and is bonded to a saturated or unsaturated cyclic group represented by B, or
Represents-(CH ₂ ) _l-, and when 1 is 0, that is, when A represents a bond, the cyclic group represented by B And a group in which a double bond is present at the position of bonding with.

Representative examples of the group represented by BA- include, for example, naphthyl, pyridyl, quinolinyl, isoquinolinyl, indolinyl, indolemethyl, 2,2-diphenylvinyl, 1,2-diphenylvinyl, 1-methyl-2
-Phenylvinyl, 2-pyridylvinyl, 2-furylvinyl, 2-thienylvinyl, indenyl, 1,2-dihydronaphthyl, 6,7-dihydro-5H-benzocycloheptenyl, 5, And a 6-dihydroquinolinyl group or a 5,6-dihydroisoquinolinyl group.

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

R ² is preferably a phenyl group or a naphthyl group which is unsubstituted or substituted with one or two alkoxy groups such as methoxy and ethoxy.
-Methoxyphenyl group, 3-methoxyphenyl group, 2,3
-A dimethoxyphenyl group or a naphthyl group is preferred.

R ³ is preferably a hydrogen atom.

 n is preferably 3,4,5.

As B—A—, a 2-pyridylvinyl group, an indenyl group, and a 1,2-dihydronaphthyl group are preferable. As a substituent of B, C _1-4 such as methyl, ethyl, propyl and the like are preferable.
C such as alkyl group, methoxy, ethoxy, propoxy, etc.
_1-4 halogen atoms such as alkoxy, nitro, cyano, hydroxy, chloro, and bromo; C _1-4 alkylcarbonylamino such as acetylamino and propionylamino;
C _1-4 alkylsulfonylamino such as methylsulfonylamino, ethylsulfonylamino, benzoylamino which may have a substituent, phenylsulfonylamino which may have a substituent, C such as methylsulfinyl and ethylsulfinyl C _1-4 alkylsulfonyl such as _1-4 alkylsulfinyl, methylsulfonyl, ethylsulfonyl and the like are preferable, and particularly, C _1-4 alkoxy, nitro,
Cyano, halogen atom, C _1-4 alkylcarbonylamino,
C _1-4 alkylsulfonyl and the like are preferred.

 The number of substituents is preferably one to three.

R ⁴ is preferably a hydrogen atom or an acetyl group.

As R ⁵ and R ⁶ , a hydrogen atom, a phenyl group, or C _1-4
A phenyl group having 1-3 substituents such as alkoxy, nitro, cyano, halogen atom, C _1-4 alkylcarbonylamino and C _1-4 alkylsulfonyl is preferred.

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,
Hydrobromic acid, sulfuric acid) or organic acids (acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) Salts.

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, the compound (I) is simply abbreviated.

Formula (II) [Wherein, Z represents a hydroxyl group or a reactive group of a carboxylic acid, and other symbols are as defined above. And a compound represented by the formula (III) Wherein each symbol is as defined above. Or a salt thereof.

The above compound (III) can be produced by a known method, for example, Crocznik Chemie (Rocz. Chem.) 43 , 1083 (1969), Pharmaco (Pavia) Edidione Scientifica (Farmaco (Pavia) Ed. Sci.) ₁₂ , 551 (1957), or a method analogous thereto.

As the reactive group of the carboxylic acid represented by Z,
N-hydroxydiacylimide esters (eg, N-hydroxysuccinyl) together with halogen atoms (eg, chloro, bromo, iodo), lower (C _1-4 ) alkoxy (eg, methoxy, ethoxy, propoxy, butoxy) and adjacent carbonyl groups Acid imide ester, N-hydroxyphthalic acid imide ester, N-hydroxy-5-norbonene-2,3
-Dicarboximide ester) group that can form a residue.

These reactions are usually carried out in hydrocarbon solvents (eg, pentane, hexane, benzene, toluene), halogenated hydrocarbon solvents (eg, dichloromethane, chloroform, dichloroethane, carbon tetrachloride), ether solvents (eg, ethyl ether). , Tetrahydrofuran, dioxane, dimethoxyethane), ester solvents (eg, ethyl acetate, butyl acetate, methyl propionate), amide solvents (eg, dimethylformamide, dimethylacetamide, hexamethylphosphonotriamide), and organic solvents such as dimethylsulfoxide In a solvent, under cooling (-10 ° C to 10 ° C), at room temperature (11 ° C
-40 ° C) or under heating (41 ° C to 120 ° C), and the reaction time is usually 10 minutes to 12 hours. The compound (III) is preferably used in an amount of 1.0 to 3.0 equivalents based on the compound (II). The reaction is optionally carried out, for example, when Z is hydroxy, in the presence of an acid activator such as carbonyldiimidazole, dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphoryl azide, and when Z is halogen or lower alkoxy, , Pyridine, 4-dimethylaminopyridine,
Organic bases such as triethylamine, diisopropylamine, triethylenediamine, tetramethylethylenediamine, and, for example, sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate, potassium carbonate, sodium carbonate, lithium carbonate, lithium hydroxide, potassium hydroxide,
The reaction can be performed in the presence of an inorganic base such as sodium hydroxide and sodium hydride.

Further, when Z is a group that forms an N-hydroxydiacylimide ester residue together with an adjacent carbonyl group,
Preferably, the reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, dioxane, chloroform, dimethylformamide, acetonitrile, water and the like. This reaction is carried out, if necessary, in the presence of the above-mentioned organic or inorganic base. The reaction temperature is usually -10C to -110C,
It is preferably 0 ° C to 30 ° C, and the reaction time is usually 5 minutes to 12 hours, preferably 30 minutes to 2 hours.

Among the compounds represented by the formula (II) as the raw material compounds, compounds wherein Z is a hydroxy group [hereinafter referred to as compound (I
I: Z = hydroxy). ], That is, the carboxylic acid is a compound (II: Z = lower alkoxy), that is, an ester form [a known compound or a known method (for example, Compt. Lendas hebmadmadile des cyanes de academy des sciences: Cell) C. Supplement (CRHebd. Seances Acad. Sci., Ser. C) 286 ,
87 (1978) [Chemical Abstracts (Chem. Abst
r.) 88: 136342]) can be prepared according to a method known per se, for example, an alkali metal hydroxide (eg, potassium hydroxide, lithium hydroxide, sodium hydroxide) , Alkali metal carbonates (eg, potassium carbonate, sodium carbonate, lithium carbonate), mineral acids (eg,
Hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydroiodic acid), organic acids (eg, acetic acid, propionic acid, trifluoroacetic acid, monochloroacetic acid, trichloroacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene) It can be easily produced by hydrolysis with sulfonic acid). The solvent used for the hydrolysis may be any commonly used solvent, for example, water, lower (C _1-4 ) alkanols (eg, methanol, ethanol, propanol, butanol), dioxane, tetrahydrofuran, dimethylformamide Are preferred. The reaction temperature is usually -10
C. to about 120.degree. C., preferably 0.degree. The reaction temperature is generally from 10 minutes to 24 hours, preferably from 30 minutes to 6 hours.

The compound (II: Z = halogen) can be prepared by subjecting the compound (II: Z = hydroxy), that is, carboxylic acid, to a method known per se, for example, a halogenating agent (eg, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, Phosphorus pentabromide, thionyl chloride, thionyl bromide, sulfuryl chloride, oxalyl chloride, cyanuric chloride, boron tribromide, hydrogen iodide)
By halogenating the compound. Examples of the acid halide obtained by halogenation include, for example,
Examples thereof include acid chloride, acid bromide, acid fluoride, and acid iodide. Among them, acid chloride and acid bromide are preferable.

The halogenation is performed without a solvent or in a commonly used solvent, and for example, an inert solvent such as chloroform, dichloromethane, dichloroethane, benzene, and toluene is preferable.

Is a compound (II: Z = hydroxy) converted to an N-hydroxydicarboxylic imide (eg, N-hydroxysuccinimide, N-
Hydroxyphthalic imide, N-hydroxy-5-norbonene-2,3-dicarboximide) in the presence of dicyclohexylcarbodiimide by a method known per se. This reaction is performed in a commonly used solvent (eg, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile, water), Can be subjected to the next reaction without isolation. Other compounds (II) can be produced by any known method or a method analogous thereto.

Further, among the compounds (I), a compound (I: R ⁴ = R ^{4 ′} ) [wherein, R ^{4 ′} is the same as R ⁴ except for hydrogen, ie, R ^{4
4 '} represents a lower alkyl group or an acyl group. ] Can be produced, for example, by introducing a lower alkyl group into a compound (I: R ⁴ ＨH) or acylating it.

For example Compound (I: R ⁴ = H) Formula ^{(IV) R 4 '-Y (} IV) [ wherein, ^{R 4'} of the same meaning as the R ⁴ except hydrogen, i.e. ^{R 5 'is} a lower alkyl A group or an acyl group;
It is R ^{4 'where} Y is halogen lower alkyl group, R ^4'
Is an acyl group, Y represents a reactive group of hydroxy, OR ^{4 '} or carboxylic acid. Can be also produced by reacting the compound represented by the formula [1] with a method known per se.

In the reaction of the compound (I: R ⁴ ＨH) with the compound (IV), a solvent is not necessarily required, but when used, it is usually a hydrocarbon solvent (eg, pentane, hexane, benzene, toluene), a halogenated solvent. Hydrocarbon solvents (eg, dichloromethane, chloroform, dichloroethane, carbon tetrachloride), ether solvents (eg, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane), amide solvents (eg, dimethylformamide, hexamethylphosphonotriamide) And an organic solvent such as dimethyl sulfoxide. The reaction can be carried out at -10 ° C to 200 ° C, preferably at 0-120 ° C. The reaction time is generally 5 minutes to 12 hours, preferably 10 minutes to 6 hours. Usually, the compound (IV) is a compound (I: R ⁵ =
H) equimolar to excess amount, preferably 1.1 to 10.
It is used in a molar amount of 0 times. R ^{4 '} is a lower alkyl group and Y
Is a halogen, this reaction can be carried out, if desired, with an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylamine, triethylenediamine, tetramethylethylenediamine, or the like, for example, sodium hydride, sodium metal, potassium amide, hydrogencarbonate Sodium, potassium bicarbonate, sodium carbonate,
The reaction can be performed in the presence of an inorganic base such as potassium carbonate, lithium hydroxide, potassium hydroxide, and sodium hydroxide. These bases are generally used in an equimolar amount to an excess amount, preferably 1.1 to 5 times the molar amount of the compound (I: R ⁴ ＨH). When R ^{4 ′} is an acyl group, the reactive group of the carboxylic acid represented by Y is halogen (eg, chlorine,
Bromine, iodine), lower (C _1-4 ) alkoxy (eg, methoxy, ethoxy, propoxy, butoxy) and N-hydroxydiacylimide ester (eg, N-hydroxysuccinimide ester, N-
Hydroxyphthalimide ester, N-hydroxy-5
-Norbonene-2,3-dicarboximide ester).

Compounds wherein R ^{4 ′} is an acyl group (I: R ⁴ H)
And also the reaction of the compound (IV), carbonyldiimidazole if desired by Y is hydroxy, di-cyclo f dicyclohexylcarbodiimide, diethyl cyanophosphate, the presence of an acid activating agent such as diphenylphosphoryl azide, Y is OR ^{4 '}
In the case of the above, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc . ^; And when Y is halogen or lower alkoxy, an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylamine, triethylenediamine, and tetramethylethylenediamine; For example, the reaction can be performed in the presence of an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate, potassium carbonate, sodium carbonate, lithium carbonate, lithium hydroxide, potassium hydroxide, and sodium hydroxide.

Further, when R ^{4 ′} -Y (IV) is an N-hydroxydiacylimide ester, the reaction is preferably carried out in a solvent such as, for example, dichloromethane, tetrahydrofuran, dioxane, chloroform, dimethylformamide, acetonitrile, water and the like. This reaction is optionally carried out using the organic compound described above for the case where Y is halogen or lower alkoxy,
Performed in the presence of an inorganic base.

When the reaction is carried out in the presence of the above-mentioned acid activator, acid, halide or base, any of them is generally equimolar amount to excess amount, preferably 1.1 to compound (I: R ⁴ ＨH).
It is used in a molar amount of up to 5 times.

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 (I) of the present invention is useful as an agent for improving brain function in mammals including humans.

Examples of useful target disease names of compound (I) of the present invention include:
For example, senile dementia, Alzheimer's disease, Huntington's chorea, hyperkinetic disease, mania and the like can be used, and can be used for prevention or treatment of these diseases.

The compound (I) 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 of target disease, symptoms, etc., but in general, in the case of oral administration, about
0.001 mg-100 mg, preferably 0.01-30 mg, more preferably
0.3 to 10 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 the 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).

"Room temperature" or "room temperature" usually means about 5 ° C.
From 40 to 40 ° C and normal pressure means around 1 atm.

 Further, unless otherwise specified,% indicates weight percentage.

Reference Example 1 N-benzyl-N-methyl-1,4-butanediamine
Dihydrochloride A solution of 11 g of 2- [4-N-benzyl-N-methyl) aminobutyl] -1H-isoindole-1,3 (2H) -dione hydrochloride and 5 ml of hydrazine monohydrate in 150 ml of ethanol is heated for 30 minutes. Refluxed. After allowing to cool, the precipitate was removed, and the solvent was distilled off under reduced pressure, and the oil obtained was allowed to stand at room temperature for 24 hours. 20.5 ml of 3N hydrochloric acid in ethanol was added to the oily substance obtained by removing the generated precipitate, and the solvent was removed under reduced pressure. The remaining solid was recrystallized from ethanol-ether (1:10 (V / V)) to obtain 7.9 g of colorless crystals having a melting point of 100 to 103 ° C.

Elemental analysis C ₁₂ H ₂₀ N ₂ · 2HCl Calculated: C 54.34 H 8.36 N 10.56 Found: C 54.11 H 8.21 N 10.38 compounds shown in Table 1 in the same manner as in Reference Example 2 Reference Example 1 was obtained .

Reference Example 3 N-[(2-methoxyphenyl) methyl] -N-ethyl-1,5-pentanediamine A colorless oil was obtained in the same manner as in Reference Example 1.

Elemental analysis value: C ₁₅ H ₂₆ N ₂ O Calculated value: C 71.96 H 10.47 N 11.19 Experimental value: C 71.79 H 10.31 N 11.00 Example 1 3,4-dihydro-6,7-dimethoxy-N- [5- [ N-
Ethyl-N- (phenylmethyl) amino] pentyl] naphthalene-2-carboxylic acid amide hydrochloride 0.85 g of 3,4-dihydro-6,7-dimethoxynaphthalene-2-carboxylic acid, Reference Example 2 N-benzyl compound No. 3
0.74 g of diethyl dianophosphate was added to a 4 ml solution of dimethylformamide containing 0.8 g of N-ethyl-1,5-pentanediamine and 0.7 ml of triethylamine under ice-cooling.
After stirring for 1 hour under ice cooling, 50 ml of water was added. The product was extracted with dichloromethane, the dichloromethane solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The remaining oil was subjected to silica gel column chromatography (developing solvent; ethyl acetate-methanol = 20: 1 (V / V)).
The solvent in the solution containing the target substance was distilled off, and 1.2 ml of 3N hydrogen chloride in ethanol was added. The solvent was distilled off to obtain 1.5 g of a non-crystalline powder made of moisture.

Elemental analysis value: C ₂₇ H ₃₆ N ₂ O ₃ .HCl Calculated value: C 68.55 H 7.88 N 5.92 Experimental value: C 68.51 H 7.73 N 5.81 Example 2 In the same manner as in Example 1, the compound shown in Table 2 was obtained. Obtained.

Example 3 N-acetyl-3,4-dihydro-6,7-dimethoxy-N
-[5- [N-ethyl-N- (phenylmethyl) amino] pentyl] naphthalene-2-carboxylic acid amide hydrochloride 3,4-dihydro-6,7-dimethoxy-N- of Example 1
[5- [N-ethyl-N- (phenylmethyl) amino]
Pentyl] naphthalene-2-carboxylic acid amide hydrochloride
0.24 g was dissolved in acetic anhydride (3 ml), p-toluenesulfonic acid monohydrate was added in a catalytic amount, and the mixture was heated and stirred at 80 ° C. for 8 hours. After release, 50 ml of water was added. The product was extracted with dichloromethane, the dichloromethane solution 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)), the solvent of the solution containing the target substance was distilled off, and 0.2 ml of a 3N hydrogen chloride ethanol solution was added. Was added and the solvent was distilled off to obtain 0.2 g of amorphous powder.

Elemental analysis: C ₂₉ H ₃₈ N ₂ O ₄ .HCl Calculated: C 67.62 H 7.63 N 5.44 Experimental: C 67.44 H 7.58 N 5.40 Example 4 (E) -N-acetyl-N- [5- [N -Ethyl-N
-(Phenylmethyl) amino] pentyl] -3- (3-
Pyridyl) -2-propenamide hydrochloride In the same manner as in Example 3, a hygroscopic amorphous powder was obtained.

Elemental analysis value: C ₂₄ H ₃₁ N ₃ O ₂ · HCl Calculated value: C 67.04 H 7.50 N 9.77 Experimental value: C 66.93 H 7.41 N 9.52 Formulation Example 1 (1) 3,4-dihydro-6,7-dimethoxy- N- [5-
[N-ethyl-N-[(2-methoxyphenyl) methyl] amino] pentyl] naphthalene-2-carboxylic acid amide hydrochloride (compound obtained according to Example 2-2) 1 g (2) Lactose 197 g (3) 50 g of corn starch (4) 2 g of magnesium stearate (1), (2) and 20 g of corn starch are mixed and granulated together with a paste made from 15 g of corn starch and 25 ml of water, and then 15 g of corn starch and (4) is added and the mixture is compressed on a compression tablet machine to give tablets (3) 3 mm in diameter containing 0.5 mg per tablet (1).
Pieces were manufactured.

Formulation Example 2 (1) 3,4-dihydro-6,7-dimethoxy-N- [5-
[N-ethyl-N-[(2-methoxyphenyl) methyl] amino] pentyl] naphthalene-2-carboxylic acid amide hydrochloride (compound obtained according to Example 2-2) 2 g (2) Lactose 196 g (3) 50 g of corn starch (4) 2 g of magnesium stearate (1), (2) and 20 g of corn starch are mixed and granulated together with a paste made from 15 g of corn starch and 25 ml of water, to which 15 g of corn starch and ( 4) was added and the mixture was compressed with a compression tablet machine to produce 2,000 tablets having a diameter of 5 mm and containing 1 mg per tablet (1) (Example) The cholinesterase inhibitory effect of the compound of the present invention was determined by (acet).
The study was performed using yl-([ ³ H])-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, the incubation for 30 minutes after stopping the reaction, shaken with toluene-based scintillator was produced by the reaction ^([3 H]) - by counting in a liquid scintillation counter is shifted to the toluene layer acetic acid, was determined cholinesterase activity.

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. Third result
It is shown in the table.

For example, Compound 2-1 represents Compound No. 1 of Example 2.

The above results show that the compounds of the present invention exhibit excellent acetylcholinesterase inhibitory activity.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07C 233/78 9547-4H C07C 233/78 233/91 9547-4H 233/91 233/92 9547- 4H 233/92 235/26 9547-4H 235/26 235/30 9547-4H 235/30 235/34 9547-4H 235/34 235/40 9547-4H 235/40

Claims (9)

(57) [Claims] (1) Expression Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² is an aromatic group which may have a substituent, R ³ is a hydrogen atom, a lower alkyl group or a group Good aromatic groups,
n is an integer of 3 to 7, R ⁴ is a hydrogen atom, a lower alkyl group or an acyl group, and BA is a C _1-4 alkyl, halogen atom, nitro, cyano, hydroxy, C _{1- 4} alkoxy, C _1-4 alkylthio, amino, mono- or di-C _1-4 alkyl-substituted amino, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylamino, C _1-4 alkoxycarbonyl, hydroxycarbonyl, C _{1 -6} alkylcarbonyl, carbamoyl,
Mono or di C _1-4 alkyl substituted carbamoyl, C _1-6
Alkylsulfonyl and C _1-4 alkyl groups, halogen atoms, hydroxyl groups, benzyloxy, amino, mono or di
Phenyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl-C _1- which may have 1 to 4 substituents selected from C _1-4 o-alkyl-substituted amino, nitro and C _1-4 alkoxycarbonyl in the phenyl moiety. 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 Or a naphthyl group optionally having 1 to 3 substituents selected from phenylsulfonylamino, a pyridyl group, a quinolinyl group, an isoquinolinyl group,
Indolinyl group, indolemethyl group, 2,2-diphenylvinyl group, 1,2-diphenylvinyl group, 1-methyl-
2-phenylvinyl group, 2-pyridylvinyl group, 2-furylvinyl group, 2-thienylvinyl group, indenyl group,
A 1,2-dihydronaphthyl group, a 6,7-dihydro-5H-benzocycloheptenyl group, a 5,6-dihydroquinolinyl group, or a 5,6-dihydroisoquinolinyl group. ] The acid amide derivative represented by these, or its salt. (2) R ¹ is a hydrogen atom or a C _1-6 alkyl group;
² is a halogen atom, nitro, cyano, hydroxy, C _1-4 alkoxy, C _1-4 alkylthio, amino, mono- or di-C _1-4 alkyl-substituted amino, C _1-4 alkoxycarbonyl, hydroxycarbonyl, C _1-6
Alkylcarbonyl, cyclohexylcarbonyl,
Carbamoyl, mono or di C _1-4 alkyl substituted carbamoyl and C _1-4 alkyl group, C _1-4 alkoxy group, halogen atom, hydroxyl group, amino, mono or di C _1-4 alkyl substituted amino, nitro and C _1- Phenyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl-C which may have 1 to 4 substituents selected from ₄ alkoxycarbonyl in the phenyl or naphthyl moiety
_1-4 is a phenyl or naphthyl group optionally having 1 to 3 substituents selected from alkylcarbamoyl or phenylcarbamoyl; R ³ is (1) a hydrogen atom,
(2) a C _1-6 alkyl group or (3) a halogen atom, nitro, cyano, hydroxy, C _1-4 alkoxy,
C _1-4 alkylthio, amino, mono or di C _1-4 alkyl substituted amino, C _1-4 alkoxycarbonyl, hydroxycarbonyl, C _1-6 alkylcarbonyl, cyclohexylcarbonyl, carbamoyl, mono or di C _1-4 alkyl substituted Carbamoyl and C _1-4 alkyl groups, C _1-4 alkoxy groups, halogen atoms, hydroxyl groups, amino, mono- or di-C _1-4 alkyl-substituted amino, nitro and
Phenyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl-C _1-4 alkylcarbamoyl or phenylcarbamoyl which may have 1 to 4 substituents selected from C _1-4 alkoxycarbonyl in the phenyl or naphthyl moiety A phenyl or naphthyl group optionally having 1 to 3 substituents selected; n is an integer of 3 to 7; R ⁴ is (1) hydrogen atom, (2) C _1-6
Alkyl group or (3) C _1-6 alkylcarbonyl, C _7-11
Arylcarbonyl, carbamoyl, mono or di C _1-4
Alkylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl, C _1-6 alkylsulfonyl, phenylsulfonyl, naphthalenesulfonyl, C _1-6 alkyloxycarbonyl, compound of claim 1, wherein an acyl group selected from aryloxycarbonyl and benzyloxycarbonyl . Wherein R ¹ is methyl, ethyl or isopropyl; R ² is located in unsubstituted or one or two substituted with C _1-4 alkoxy group a phenyl or naphthyl group; R ³
Is a hydrogen atom; n is 3, 4 or 5; R ⁴ is a hydrogen atom or an acetyl group; B-A- is a C _1-4 alkyl, C _1-4 alkoxy, nitro, Cyano, hydroxy, halogen, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylamino, benzoylamino, phenylsulfonylamino, C _1-4
1-3 substituents selected from alkylsulphinyl and C _1-4 alkylsulphonyl may have a 2-Pirijirubiniru, indenyl or 1,2-dihydronaphthyl compound of claims 1 is a group wherein. 4. The compound according to claim 3, wherein R ¹ is ethyl. 5. The compound according to claim 3, wherein R ² is a phenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 2,3-dimethoxyphenyl group or a naphthyl group. 6. The compound according to claim 3, wherein the substituent of the moiety B is C _1-4 alkoxy, nitro, cyano, halogen, C _1-4 alkylcarbonylamino or C _1-4 alkylsulfonyl. (7) [In the formula, Z represents a hydroxyl group or a reactive group of a carboxylic acid, and B and A have the same meaning as in claim 1. A compound represented by the formula: [Wherein each symbol of R ¹ , R ² , R ³ , R ⁴ and n has the same meaning as in claim 1]. And reacting with a compound represented by the formula [Each symbol in the formula is as defined above. Or a salt thereof, or a compound represented by the formula (B) [Each symbol in the formula is as defined above. A lower alkyl group is introduced into the compound represented by the formula [In the formula, R ^{4 ′} represents a lower alkyl group or an acyl group, and other symbols are as defined above. The method for producing a compound according to claim 1, wherein the acid amide derivative represented by the formula (I) or a salt thereof is produced. 8. A cholinesterase inhibitor comprising the acid amide derivative according to claim 1 or a salt thereof. 9. The agent according to claim 8, which is a brain function improving agent.