JPH03163053A - Condensed-ring phenol derivative and use thereof - Google Patents

Abstract

NEW MATERIAL:The condensed-ring phenol derivative of formula I (R1 is H or hydroxyl-protecting group; R2 is alkyl, or cycloalkyl, aryl, aralkyl or heterocyclic group which may be condensed with aryl; R3 is H or a group defined in R2; R2 and R3 may together with adjacent N form a cyclic amino group; n is 1-3; l and m are 0-3; when n is 2 or 3, R1 groups may be different from each other; dotted line is single bond or double bond) and its salt. EXAMPLE:N-(2,4-dichlorophenyl)-6,7-diacetoxy-1,2,3,4-tetrahydro-2-naph thonic acid amide. USE:It has excellent action to promote the secretion of neurocyte growth factor and is useful as a drug. PREPARATION:The compound of formula I can be produced according to the reaction formula by reacting a compound of formula II with an amine of formula III at 0-30 deg.C.

Description

[Detailed Description of the Invention] [Objective] [Industrial Field of Application] The present invention provides an excellent nerve growth factor (Nervegrow).
The present invention relates to a novel compound having an effect of promoting secretion of th facLor (hereinafter abbreviated as NGF) production.

Utilization technology and conventional technology above 11>! NGF, discovered by Levl-Montalel et al. in 1995, is one of the nutrients and lengthening factors necessary for the elongation and function maintenance of nervous tissue. In recent years, it has become known that high molecular weight proteins (molecular weight, ＋＊ o
No. 13,000 ar, 26,000 dimmer), so there are problems with the administration method and safety.

Catechol neurotransmitters such as adrenaline and noradrenaline and catechol compounds similar to a are known to promote NGF production, but they must not have any effects other than the intended physiological effects, especially neuroexcitatory effects. is desirable.

(Problem to be solved by the invention) The inventors,
As a result of many years of intensive research into the synthesis of derivatives that have the effect of promoting secretion of nerve growth factor production and their pharmacological activities, we have discovered that a novel compound with a completely different structure from known secretion promoters of nerve growth factor production has been developed. The present invention was completed based on the discovery that it has the effect of promoting secretion of nerve growth factor production.

[Configuration of the Invention] The present invention has a novel action of increasing nerve growth factor production [wherein R1 represents a hydrogen atom or a hydroxyl group protecting group, and R
2 represents an alkyl group, a dichloroalkyl group which may be fused with an aryl group, an aryl group, an aralkyl group, or a heterocyclic group, and R3 represents a hydrogen atom or a group having a synonym with R2, but R2 and R3 may be combined with the adjacent nitrogen atom to form a cyclic ami7 group. n represents an integer of 1 to 3, and k and m represent integers of 0 to 3.

When n is 2 or 3, Rl can represent different groups as mentioned above. Dotted line portions indicate single or double bonds. ] The present invention relates to a fused ring phenol derivative represented by the following and a pharmacologically acceptable salt thereof.

Suitable compounds in the present invention include the general formula (1
), Rl represents a hydrogen atom: a protecting group for a hydroxyl group, that is, a protecting group in the reaction and a protecting group for prodrug formation when administered to a living body, such as methyl, ethyl, proyl, isobrobyl, butyl, isobutyl. , S-butyl,
Lower alkyl groups such as t-butyl, butyl, hexyl; alkylcarbonyls such as formyl, acetyl, probionyl, butyryl, imbutyryl, bentanoyl, pivaloyl, valeryl, inbasilyl, hexanoyl, octanoyl, lauroyl, palmitoyl, stearoyl halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkylcarbonyl groups such as methoxyacetyl, (E)-2-methyl-2-butenoyl Aliphatic acyl groups such as unsaturated alkylcarbonyl groups; benzoyl, α-naphthoyl, β
-Arylcarbonyl groups such as naphthoyl, halogenated arylcarbonyl groups such as 2-promobenzoyl, 4-chlorobenzoyl, lower alkylated arylcarbonyl groups such as 2,4.6-}limethylbenzoyl, 4-toluoyl; groups, lower alkoxylated arylcarbonyl groups such as 4-aninyyl, 4-nitrobenzoyl,
nitrated arylcarbonyl groups such as 2-nitrobenzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl,
Aromatic acyl groups such as arylated arylcarbonyl groups such as 4-phenylbenzoyl: tetrahydropyran-
Tetrahydropyranyl such as 2-inole, 3-promotetrahydropyran-2-yl, 4-methoxytetrahydrobilan-4-yl, tetrahydrocthiobilan-2-yl, 4-methquinetetrahydrocthiopyran-4-yl or a tetrahydro-thiopyranyl group: a tetrahydrofuranyl or tetrahydrothiofuranyl group such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, improvildimethylsilyl, t-butyldimethylsilyl, methyldiisopropyranyl; Bilsilyl, methyldi[-butylsilyl,
Tri-lower alkylsilyl group such as triisopropylsilyl, tri-lower alkylsilyl group substituted with 1 to 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisoprobylsilyl, phenyldiisopropylonril; Silyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, impropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxymethyl groups, a lower alkoxylated lower alkoxymethyl group such as methoxyethoxymethyl, 2,2.
Alkoxymethyl group such as halogenated lower alkoxymethyl such as 2-trichloroethoxymethyl, pis(2-chloroethoxymethyl); 1-ethoxyethyl, l-methyl-l-methoxyethyl, l-(isopropoxyethyl) Lower alkoxylated ethyl groups such as ethyl; 2 1 2
1 Halogenated ethyl groups such as 2-trichloroethyl; benzyl, phenethyl, 3-phenylprobyl,
Lower alkyl group substituted with 1 to 3 aryl groups such as α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl , 2,4,6-trimethylbenzyl, 3,4.5-
trimethynolebenzinole, 4-methoxybenzinole, 4
-methoxiphenyldiphenylmethyl, 2-nito-a-benzyl, 4-nito-a-benzyl, 4-chloro-a-benzyl, 4-
Aryl ring substituted with promobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl, piperonyl, lower alkyl, lower alkoxy, nitro, hagen, cyano group Aralkyl groups such as lower alkyl groups substituted with 1 to 3 aryl groups; lower alkoxycarbonyl groups such as methoxycarbonyl, ethquin carbonyl, t-butoxycarbonyl, imbutoxycarbonyl, 2,
2.Alkoxycarbonyl groups such as lower alkoxycarponyl groups substituted with halogen or tri-lower alkylsilyl groups such as 2-trichloroethoxycarbonyl and 2-trimethylnrylethoxycarbonyl; such as vinyloxycarbonyl and allyloxycarbonyl alkenyloxycarponyl group;
-methoxybenzyloxycarbonyl, 3. 4-
an aralkyloxycarbonyl group whose aryl ring may be substituted with a lower alkoxy or nitro group of 1 to 2@, such as dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl; n is 2, Rl at the ortho position
having 1 or more carbon atoms such as methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene, hexamethylene, which together represent 6 alkylene groups; methylidene,
Lower alkylidene groups such as ethylidene and impropylidene; protecting groups in reactions such as aralkylidene groups such as benzylidene or alkoxyethylidene groups such as methoxyethylidene and ethoxyethylidene, and the aforementioned fatty acids and aromatic acyl groups; pivaloyl Aliphatic acyloxyalkyloxycarbonyl groups such as oxymethyloxycarbonyl; 3-carboxypropanoyl, 3-
Carboxy-substituted aliphatic acyl groups that may be esterified such as ethoxycarbonylpropanoyl, 4-carpo-hand-sibutanoyl; carbamoyl groups that may be alkylated such as carbamoyl, dimethylcarbamoyl, diethylcarpasoyl; or glycyl , N-7 cetylglycyl, alanyl, N-acetylalanyl, arginyl, lysyl, and other amino acid acyl groups that may be acylated. .

R2 is, for example, a linear or branched chain having 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, t-butyl, pentyl, hexyl, octyl, dodecyl, and octadecyl. Chain alkyl group; cycloalkyl group having 3 to 10 carbon atoms which may be condensed with an aryl group such as cycloprobyl, cyclobutyl, cyclohexyl, norbornyl, adamantyl, 2-indanyl; phenyl, naphthyl An aryl group having 6 to 1 carbon atoms such as; an aralkyl group having 7 to 9 carbon atoms such as benzyl, phenethyl, 3-7 phenylpropyl; or furyl, chenyl, benzo [bl chenyl, tetrahydrobenzo [b] Chenil,
Pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,
inxa/lyl, thiazolyl, inthiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, birazinyl,
5 to 7 which may be fused and contain 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms, such as indolyl, quinolyl, inquinolyl, penzimidazolyl, brynyl
Indicates a member complex radical.

The above aryl group, aralkyl group, and heterocyclic group may have 1 to 4 substituents selected from the following on the ring, and examples of the substituent include methyl, ethyl,
Lower alkyl groups such as polyvinyl, isopropyl, butyl, isobutyl, S-butyl, t-butyl, hentyl, hexyl; lower alkoxy groups such as metoxy, etoxy, propoxy, impropoxy, hydroxyl, fluorine, Halogen atoms such as chlorine, bromine, iodine, fluoromethyl, trifluoro-a-methyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, 2, 2, 2
- halogenated lower alkyl groups such as trichloroethyl, 2,2,2-trifluoroethyl, 2-promoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl, methylenedioxy, ethylene dioxyl ,
Ortho-substituted lower alkylene dioxy groups such as propylene dioxyl, nitro groups, amino groups, di-lower alkylene dioxy groups such as dimethylamihadiethylamino, diano groups, carboxy groups, methoxycarponyl , lower alkoxycarbonyl groups such as ethoxycarbonyl, propoxycarbonyl, and imbropoxycarbonyl, carbomoyl groups, lower aliphatic acyl groups such as acetyl, propionyl, and butyryl, and aromatic groups such as benzoyl, p-chlorobenzoyl, and p-aninyl. Mention may be made of group acyl groups.

R3 represents a hydrogen atom or a group having the same meaning as R2 above, such as 1-pyrrolidinyl, piperidihamorholyhaciomorpholyha1-piperazinyl, 4-methyl-1-
R2 and R3 may be taken together to form a 5- to 6-membered flexible amino group with the adjacent nitrogen atom, such as in piverazinyl.

Compound (1) of the present invention can be made into a pharmacologically acceptable non-toxic salt, but such salts preferably include alkali metal or alkali salts such as sodium salts, potassium salts or calcium salts. Salts of earth metals; inorganic salts such as hydrohalides such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, nitrates, perchlorates, sulfates, phosphates, etc. Acid salts: methanesulfonates, trifluoromethanesulfonates, lower alkylsulfonates such as ethanesulfonates, benzenesulfonates, arylsulfonates such as p-toluenesulfonates, fumarates, Examples include organic acid salts such as succinate, citrate, tartrate, oxalate, and maleate, and amino acid salts such as glutamate and aspartate.

When the compound of the present invention contains an asymmetric carbon in Rl or R2, stereoisomers exist, and each stereoisomer or a mixture thereof is included in the present invention.

Particularly preferred compounds represented by the above general formula (1) include those in which R1 is a hydrogen atom; represents a protecting group for a hydroxyl group forming R2, and R2 is a cycloalkyl group such as adamantyl; an aryl group such as phenyl substituted with 2 to 3 halogen atoms or bromine atoms; A compound that represents a heterocyclic group such as chenyl, tetrahydrobenzo [bl chenyl, R3 represents a hydrogen atom, n represents 2 or 3, and 1 represents 0 or 1% m represents 1.2 or 3 can be mentioned.

Compound (1) of the present invention can be produced by the method described below.

In the above formula, Rl' represents the above-mentioned hydroxyl group-protecting group, X represents a halogen atom, and Rl, R2 and R3 have the same meanings as described above.

An acid halide with a protected hydroxyl group represented by the general formula (
For example, a compound obtained as shown in the reference example),
The reaction with an amine of formula (II+), which is a known compound or can be readily prepared using known means, can be carried out using an inert solvent, a chlorinated hydrocarbon, an ether or The reaction is carried out in a hydrocarbon, such as methylene chloride, tetrahydrofuran or toluene, in the presence of a base such as pyridine, triethylamine, 4-dimethylaminopyridine, etc., at a temperature of -10°C to 50°C, but preferably O ℃ to 30℃. The reaction time is
Although it varies mainly depending on the reaction temperature, raw material compound, or type of solvent used, it is usually 1 to 3 hours.

After the completion of the reaction, the target compound (1) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is immiscible with water to the reaction mixture, washing with water, and then distilling off the solvent. If necessary, the obtained target compound can be further purified by conventional methods such as recrystallization, reprecipitation, chromatography, etc. The solvent to be used is particularly limited as long as it dissolves the target compound to some extent. However, preferred are aromatic hydrocarbons such as pezine, toluene, and xylene; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and probyl acetate; ethers. , tetrahydrofuran, dioxane, dimethquinethane; alcohols such as methanol, ethanol, n-propanol, impropanol, n-butanol, imbutanol, isoamyl alcohol; dimethylformamide, dimethylacetamide, hexamethylphosphor Amides such as lotriamide: Sulfoxides such as dimethyl sulfoxide may be mentioned.

Next, the removal of the hydroxyl protecting group R1°, which is carried out as necessary, varies depending on the type, but is generally carried out as follows by a method well known in the art.

When a tri-lower alkylsilyl group is used as a protecting group for a hydroxyl group, it is usually removed by treatment with a compound that generates a fluorine anion, such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but polymers such as tetrahydrofuran and dioxane are preferred. Although the reaction temperature and reaction time are not particularly limited, the reaction is usually carried out at room temperature for 10 to 18 hours.

When the hydroxyl protecting group is an aralkyloxycarbonyl group or an aralkyl group, it can usually be removed by contacting with a reducing agent. For example, this can be achieved by carrying out catalytic reduction at room temperature using a catalyst such as palladium on carbon, platinum, or Raney nickel. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it is not involved in this reaction, but alcohols such as methanol and ethanol, and ethers such as tetrahydrofuran and dioteisan are used. A mixed solvent of these organic solvents and water is suitable. The reaction temperature and reaction time vary depending on the starting materials and the reducing agent used, but are usually at 0°C to room temperature.
The duration ranges from 5 minutes to 12 hours.

It can also be removed by applying metallic lithium or sodium in liquid ammonia or in an alcohol such as methanol or ethanol at -78°C to -20°C.

When the protecting group for the hydroxyl group is an aliphatic acyl group, an aromatic acyl group, or an alkoxylic acid group, it can be removed by treatment with a base in the presence of a solvent. The base is not particularly limited as long as it does not affect other parts of the compound, but preferably metal alcoholates such as sodium methoxide, aqueous ammonia,
It is carried out using alkali metal carbonates such as sodium carbonate, potassium carbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or concentrated ammonia methanol. The solvent used is not particularly limited as long as it is used in ordinary hydrolysis reactions, and examples include water, alcohols such as methanol, ethanol, and n-propanol, and ethers such as tetrahydrofuran and dioxane. An organic solvent or a mixed solvent of water and an organic solvent is suitable. The reaction temperature and reaction time vary depending on the starting materials and the base used, and are not particularly limited, but in order to suppress side reactions, they are usually O'C to! 50℃
The duration is 1 to 10 hours.

When the protecting group for the hydroxyl group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, or a substituted ethyl group, it can be removed by treatment with an acid in a normal solvent. The acid used is
Suitable examples include hydrochloric acid, acetic acid-Wta, p-toluenesulfonic acid, and acetic acid. The solvent used is not particularly limited as long as it does not participate in this reaction, but methanol,
Alcohols such as ethanol; ethers such as tetrahydrofuran, dioxane, or a mixed solvent of these organic solvents and water are suitable. The reaction temperature and reaction time vary depending on the starting materials and the type of acid used, but are usually at 0°C to 50°C and for 10 minutes to 18 hours.

When the protecting group for the hydroxyl group is an alkenyloxycarbonyl group, the protecting group for the hydroxyl group is usually an aliphatic acyl group,
It can be eliminated by treatment with a base under the same conditions as the removal reaction for aromatic anru groups or alkoxycarbonyl groups. In the case of allylic carbonyl, removal using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with fewer side reactions.

The following Reference Examples and Examples illustrate methods for producing the compounds of the present invention from known starting compounds. The invention described above is not limited to these examples.

Reference Example 1 6.7-dimethoxy-1-tetralone 2. under nitrogen stream.
78 g (0.0135 mol) to 100 g
The mixture was dissolved in +1 dimethyl carbonate, 0.26 g of sodium methoxide was added, and the mixture was heated under reflux for 5 hours. After cooling, the reaction solution was neutralized with a 2N acetic acid aqueous solution, ethyl acetate was added thereto, and then this was washed successively with an aqueous sodium bicarbonate solution and a 0.5N hydrochloric acid solution. After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain the title compound as white crystals (2.8 g (O 0106 mol 74.5%)).

Reference Example 2 1 g (0.038 mol) of the compound of Reference Example 1
was dissolved in a mixed solvent of So ml acetic acid and 30 ml methanol, and hydrogenated using a 10% palladium on carbon catalyst.

After absorbing about 170 ml of hydrogen, the palladium on carbon catalyst was filtered off and the solvent was distilled off to give the title compound 0.
．． 91 g (3.64 mmol. 98.3%
) white crystals were obtained.

Reference Example 3 0.9 g of the compound of Reference Example 2 was added to 47% hydrogen bromide water 30
ml and heated under reflux for 4 hours. After concentration, water-cooled sewage water was added and the resulting crystals were collected by filtration, yielding 0.7 g (3.361 cm o1) of pale yellow crystals of the title compound.
．． 98.8%) was obtained.

Reference Example 4 0.7 g of the compound of Reference Example 3 was dissolved in 3o-1 of acetic anhydride, 1 drop of sulfuric acid was added, and the mixture was stirred for 2 hours. 30 water here
One more time was added and the mixture was further stirred for 2 hours. Ether was added, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off.

When toluene is added to the residue and the remaining acetic acid is removed azeotropically,
0.96 @ (3.H s+mol. 9?,8
%) (The target compound indicated by D was obtained.

Reference example 5 Reference example l of 1.9 g (7.19 mmol)
The compound was dissolved in 30 parts of methanol and 4 g of sodium borohydride was added thereto at 45°C over 20 minutes. After further stirring for 40 minutes, the solvent was concentrated by about half, ethyl acetate was added, and the mixture was washed successively with aqueous sodium hydrogen carbonate, 0.5N hydrochloric acid, and saturated brine. After drying this with anhydrous sodium sulfate and distilling off the solvent, 1.9 g (7.14
．． 99.3%) of the title compound was obtained.

Reference Example 6 6.7-dimethoxy3.4-dihydro-2-naphthoic acid 1.9 g of the compound of Reference Example 5 was dissolved in 70 μl of dichloromethane, and at 0° C. triethylamine 2.98 μl and thionyl chloride 0 .78 ml were added one after another, and the mixture was brought to room temperature and stirred for 1 hour. Water and ethyl acetate were added thereto at 0°C, and the mixture was washed successively with aqueous sodium bicarbonate, 0.5 N hydrochloric acid, and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After drying and evaporating the solvent, the title compound was obtained.

Reference Example 7 6.7- and droxy-3,4-dihydro-2-naphthotechnic acid The compound obtained in Reference Example 6 was dissolved in 51 liters of dichloromethane, and boron tribromide was dissolved in IM dichloromethane at -78°C under a nitrogen stream. 301 liters of the solution was added dropwise.

The mixture was warmed to room temperature and stirred for 3 hours. After cooling, pour the reaction mixture into ice water! The mixture was stirred for hours and extracted with ethyl acetate.

This was washed with saturated brine, treated with anhydrous sodium sulfate and activated carbon, and then [1] was distilled off. The residual liquid was separated and purified using silica gel column chromatography 7E to yield 0.63 g.
(3.1H mmol, 42.9 oz) of the title compound was obtained as white crystals.

Reference Example 8 Naphthoic acid 0.7 g of the compound of Reference Example 7 was dissolved in 30 ml of acetic anhydride, 1 drop of sulfuric acid was added, and the mixture was stirred for 2 hours. Thirty pengs of water here! The mixture was added and further stirred for 2 hours. Add ether, water,
After sequentially washing with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off. Adding toluene to the residue and removing the remaining acetic acid by azeotropic distillation yields 0.96 i (3.211
The title compound with a concentration of 97.8% was obtained.

Example 1 Reference example 4 of amide 0.17 g (0.58 g-o1)
One drop of dimethylformamide was added to the compound (6.1 dichloromethane solution) and cooled to 0°C. To this, 0.4 g of oxalyl chloride was added, the temperature was raised to room temperature, and the mixture was stirred for 2 hours, after which the solvent was completely distilled off. This was dissolved in Sml of dichloromethane and 2,4-dichloroaniline 0.
113 g (0.71 mol) and 0.71 mol of triethynoleamine. O? IB (0.7 mmol
) and stirred for 3 hours. Add ethyl acetate to this, add water,
The organic layer was washed successively with diluted sodium bicarbonate water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to obtain 0.201 g (0.4611 theoretical o1. 79.2%) of the title compound.

Melting point 166-168°C Example 2 N-(3-quinolyl)-6.1-diacetoxy1. +
+0 0.17 g (0.58 mmol) of the Ihi compound of Reference Example 4 (6 days 1 volume fi of dichloromethane)
One drop of dimethylolefonolemamide was added and the mixture was cooled to 0°C. To this, 0.4 g of ihioxalyl ε-chloride was added, and the mixture was heated to room temperature and stirred for 2 hours, and then the solvent was completely distilled off to dryness. Dissolve this in 6 ml of dichloromethane and add 3-
Aminoquinoline 0.084 g (0.58 e+
mol ) and} IJ ethylamine 0.088 m
g (0.82 mm square 01) was added and stirred for 3 hours. Add ethyl acetate to this, add water, and dilute sodium bicarbonate}
The organic layer was washed successively with IJum water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was separated and purified by column chromatography to obtain 0.207 g (0.495 mmol. 84.1%) of the title compound.

Melting point: 194-196°C Example 3 One drop of dimethylhonolemamide was added to 0.13 g (0.45 wool) of the compound of Reference Example 4 (6 ml dichloromethane solution), and the mixture was cooled to 0°C. 0.4 g of oxalyl chloride was added thereto, the mixture was heated to room temperature and stirred for 2 hours, and then the solvent was completely distilled off to dryness. This is 6
Dissolved in dichloromethane of 1% l-adamantylamine 0.06? g (0.58■■ol) and triethylamine 0. Of+Il mg (0.
67 mmol) was added and stirred for 3 hours. Ethyl acetate was added thereto, and the mixture was washed successively with water, diluted sodium bicarbonate water, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to give 0.114 g (
0.26g smol. 60.3%)
Ta.

Melting point: 234-235°C The title compound of Example 4 was obtained by adding 1 drop of dimethylolefonolemamide to 0.075 g (0.26 mol) of the compound of Reference Example 8 (5 liters of dichloromethane solution). The mixture was added and cooled to 0°C. 0.3 g of oxalyl hydroxide was added thereto, the temperature was raised to room temperature, the mixture was stirred for 2 hours, and then the solvent was completely distilled off to dryness. This is 5
0.050 g (0.31 mmol) of 2,4-dichloroaniline and 0.039 mg (OJ9) of triethynoleamine were dissolved in 1 liter of dichloromethane.
(1) was added and stirred for 3 hours. Ethyl acetate was added thereto, and the mixture was washed successively with water, diluted sodium bicarbonate water, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was separated and purified using glue column chromatography to obtain a concentration of 0.1% of the target compound.
00 g (0.23 mmol, 89.4%
)Obtained.

Melting point 180-182°C Example 5 1 mouth O O. One drop of dimethylformamide was added to 082 g' (0.28 mmol) of the compound of Reference Example 8 (dichloromethane solution of S1), and the mixture was cooled to 0°C. 0.3 g of oxalil chloride was added thereto, the temperature was raised to room temperature, and the mixture was stirred for 2 hours, and then the solvent was completely distilled off to dryness. This is S ml
3-aminoquinoline dissolved in dichloromethane of 0.0
49 K (0.34 mmol) and triethylamine 0.043 mg (0.42 mea
1) was added and stirred for 3 hours. Ethyl acetate was added thereto, and the mixture was washed successively with water, diluted sodium bicarbonate water, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to obtain 0.096 g of the title compound.
(0.231 mmol, 81.S%) was obtained.

Melting point: 214-216°C Example 6 One drop of dimethylformamide was added to 0.072 g (0.25 smol) of the compound of Reference Example 8 (5 ml of dichloromethane solution), and the mixture was cooled to 0°C. 0.3 g of oxalyl chloride was added thereto, the temperature was raised to room temperature, and the mixture was stirred for 2 hours, and then the solvent was completely distilled off to dryness. This was dissolved in 5 to 1 dichloromethane, and 0.045 g (0.30 mmol) of 1-adamane f-+reamine and 0.038 mg (0.7 mmol) of triethylamine were added.
1) was added and stirred for 3 hours. Ethyl acetate was added thereto, and the mixture was washed successively with water, diluted sodium bicarbonate solution, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to obtain the title compound at a concentration of 0.011
2 g (0.194 mmol. 78.4%
)Obtained.

Melting point: 224-226°C [Method of measuring effect] Furukawa et al. found that LM cells, a fibroblast cell line derived from mouse connective tissue, produced a relatively large amount of NGF.
secretion, catecholamines are responsible for this NGF production,
It has been reported that it promotes secretion (J.BIol.C
hes. , 251. 8039-6047. 198
6) +1 Therefore, according to this report, NGP of the test compound
The presence or absence of production and secretion-promoting effects was investigated.

For culturing LM cells, 199 containing 0.5% beptone
A medium was used. Approximately SxlO' cells were sown in each well of a 24-well culture plate in a CO2 incubator (
37℃. S%CoR) until reaching confluence. After removing the culture solution, 0. S% bovine serum albumin (
Fraction V. Cells were washed once with 199 medium containing Sigma. The test compound was added to 199 medium containing 0.5% bovine serum albumin at a specified concentration, and 0.
5 ml LM cells were treated. After culturing LM cells in a C02 incubator for 24 hours, the culture medium was collected, and NGF in the culture medium was quantified.

NGF was determined by enzyme-linked immunosorbent assay (Iorsehlng and T.
hoenenProc. Natl. Acad. S
ci. USA, 110. 3513-3516.1
9113). Anti-mouse βNOF antibody (BoehrInga) was added to a 96-well polystyrene plate.
rMannheig+) solution (0.3 u g/ml.
75 μl of pH 9.6) was dispensed into each hole and left at room temperature for 1 hour. After removing the antibody, each hole was washed three times with a washing solution. 50 μl of standard βNOF (Wako Pure Chemical Industries) solution or wipe solution was dispensed into each hole and left at room temperature for 6-8 hours. After removing the standard βNGF or sample solution and washing each hole three times,
41 anti-βNGF monoclonal antibody (Boeh
rlngetMannhelm) solution (100 g+
U/ml, pll 7.0) Soμl was dispensed into each hole and left at 4°C for 15-18 hours. After removing the 0 enzyme-labeled antibody and washing three times, Ch1oropheno
lred-β-D-galactopyranosid
e (Boehrlnger Mannheim) solution (
lmg/if, pH 7.3) was dispensed into each hole in an amount of 100 μl. After a suitable color development was obtained (after 2-3 hours at room temperature), the absorbance of 57O n- was measured. The amount of NGF was calculated from the standard curve, and the results were expressed as relative values (%) to the NGF fit produced and secreted by cells not treated with the test compound.

(Results) Known compound %control (Compound concentration: 20γ/ml) Eplnephr1n 140±24Isopr
oterenol 188±22L-DOPA
11? ±7 Cajole Ae1d 123±14 Example compound %control (Compound concentration = lOγ/ml) l 5 7 5
2 1 6 73
9 4 l4
4 5 95
3 4 l6
5 5 8 Numerical value (%
Control) is shown as the average value of three experiments (3 wells) of the control (no compound added).

The novel compound of the present invention has an excellent secretion-promoting effect on nerve growth factor production and is low in toxicity, so it is useful as a therapeutic agent for dementia, cerebral ischemic injury, and various nerve injuries.

The administration form of the compound of the present invention includes, for example, oral administration in the form of tablets, capsules, granules, powders, or syrups, or parenteral administration in the form of injections or suppositories. These formulations include excipients, binders,
It is manufactured by a well-known method using additives such as a disintegrant, a lubricant, a stabilizer, and a flavoring agent. The amount to be used varies depending on the symptoms, age, etc., but 1-1000 mg per day can usually be administered to the patient once a day or in several divided doses.

Formulation example (capsule) N-(1-7 damantyl)-6.7-diacetoxy-1.2,3.4-tetrahydro-2-naphthoic acid amide (compound of Example 3) 25 mg milk @ 153.6 mg corn Powder: 1 GG mg Stearin Shun Magnesium: 1.4 mg Total: 280 mg The powders of the above formulation were mixed and passed through a 60 mesh sieve, and then 280 mg of this powder was placed in a No. 3 gelatin capsule to form a capsule.

Claims (1)

[Claims] 1. General formula I ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (I) [In the formula, R1 represents a hydrogen atom or a protecting group for a hydroxyl group, and R
2 represents an alkyl group, a cycloalkyl group which may be fused with an aryl group, an aryl group, an aralkyl group, or a heterocyclic group, and R3 represents a hydrogen atom or a group having the same meaning as R2, but R2 and R3 may be taken together with adjacent nitrogen atoms to form a cyclic amino group. n represents an integer of 1 to 3, and l and m represent integers of 0 to 3. When n is 2 or 3, R1 can represent different groups as mentioned above. Dotted line portions indicate single or double bonds. ] A fused ring phenol derivative and a pharmacologically acceptable salt thereof. 2. A nerve growth factor production and secretion promoter comprising the fused ring phenol derivative and its pharmacologically acceptable salt according to claim 1 as an active ingredient.