JPH0386853A - Substituted phenol derivative and its use - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is H or OH-protecting group; R2 is alkyl, cycloalkyl which may form a condensed ring together with aryl, aryl, aralkyl or heterocyclic group; R3 is H or same as R2; R2 and R3 may together with N form a cyclic amino; (n) is 1-3; (m) is 1-6; when (n) is 2 or 3, R1 are above groups different from each other) and its salt. EXAMPLE:N-(2,5-dichlorophenyl)-3,4-diacetoxyphenylpropionamide. USE:An agent for producing and secreting nerve growth factor. Useful for the treating agent of dementia, cerebral ischemic disorder and various nervous damage. PREPARATION:The compound of formula I can be produced by reacting an acid halide of formula II (R1' is OH-protecting group; Y is halogen) with an amine of formula III in an inert solvent (e.g. methylene chloride) at -10 to +50 deg.C.

Description

[Detailed Description of the Invention] [Purpose] (Industrial Application Field) The present invention is directed to the use of excellent nerve growth factors.
The present invention relates to a novel compound that has the effect of promoting the production and secretion of thfactor (hereinafter abbreviated as NGF).

(Industrial Utilization Techniques and Conventional Techniques) NGF, discovered by Levi-Montaleini et al. in 1954, is one of the nutrients and growth factors necessary for the growth and function maintenance of nerve tissues. In recent years, it has become known that it is effective in accelerating recovery from peripheral nerve damage and in treating central dysfunction, especially Alzheimer's dementia and cerebral ischemia pathological models.
(mer: 13,000, dimer: 26,000), there are problems with administration methods and safety.

-L neurotransmitter button and similar catechol compounds are N
Although it is known to promote GF production, it is desirable that it not have any effects other than the intended physiological effects, especially nerve excitatory effects.

(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 found that a novel compound with a completely different structure from known secretion promoters of nerve growth factor production has been discovered. The present invention has been completed based on the discovery that the present invention has a secretion-promoting effect on nerve growth factor production.

[Structure of the invention]

The present invention is directed to a general formula having a novel action of increasing nerve growth factor production [wherein R4 represents a hydrogen atom or a hydroxyl group protecting group,
R2 represents an alkyl group, a cycloalkyl group which may be condensed with an aryl group, an aryl group, an aralkyl group, or a heterocyclic group, and R3 represents a hydrogen atom and a group having the same meaning as R2, but R2 and R6 may be taken together with the adjacent nitrogen atom to form a cyclic amino group. n represents an integer of 1 to 3, and m represents an integer of 1 to 6. When n is 2 or 3, R1 can represent a different group as mentioned above. ] The present invention relates to a substituted phenol derivative represented by the following and a pharmacologically acceptable salt thereof.

Suitable compounds for the present invention include the above-mentioned type (1).
), R1 represents a protecting group for a hydrogen atom: hydroxyl group, that is, a protecting group for reaction and a protective group for prodrug formation when administered to a living body, such as methyl, ethyl, propyl, inpropyl, Butyl, isobutyl, S-butyl,
Lower alkyl groups such as t-butyl, K-methyl, hexyl; alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, imbutyryl, pentanoyl, piparoyl, valeryl, invaleryl, hexanoyl, octanoyl, lauroyl, noglumitoyl, stearoyl , halodanated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, and unsaturated alkyl groups such as (E)-2-methyl-2-butenoyl. Aliphatic acyl groups such as carbonyl groups; benzoyl, α-naphthoyl,
β-naphthoyl younaarylcarM-nyl group, 2-f
lomobenzoyl, 4-chlorobenzoyl iomino 10
lower alkylated arylcarbonyl group such as 2,4,6-)limethylpenzoyl, 4-toluoyl, lower alkoxylated arylcarbonyl group such as 4-anisoyl, 4-nitrobenzoyl , nitrated arylcarmenyl groups such as 2-nitrobenzoyl, lower alkoxycarbonylated arylcarmenyl groups such as 2-(methoxycarbonyl)benzoyl, 4-tunylben-! Aromatic acyl group such as aryl or nyl group; tetrahydrobilan-2-yl, 3-bromotetrahydrobilan-2
-yl, 4-methoxytetrahydrobilan-4-yl,
Tetrahydropyranyl or tetrahydrothiopyranyl groups, such as tetrahydrothiobilan-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuranyl, such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl; Tetrahydrothiofuranyl group; trimethylsilyl, triethylsilyl, inpropyldimethylsilyl, t-butyldimethylsilyl,
Tri-lower alkylsilyl groups such as methyldiisopropylsilyl, methyldi-t-butylsilyl, triimpropylsilyl; 1 to 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiimpropylsilyl; silyl groups such as tri-lower alkylsilyl groups substituted with alkoxymethyl group, lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl,
2,2,2-)lichloroethoxymethyl, bis(2
-Alkoxymethyl groups such as halogenated lower alkoxymethyl such as chloroethoxy)methyl: lower alkoxylated ethyl groups such as 1-ethoxyethyl, 1-methyl-1-methoxyethyl, and 1-(impropoxy)ethyl;
2.2. Substituted ethyl groups such as 2-trichloroethyl, etc.; benzyl, phenethyl, 3
-Phenylnorobil, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α
-Naphthyldiphenylmethyl, lower alkyl group substituted with 1 to 3 aryl groups such as 9-anthrylmethyl, 4-methylbenzyl, 2,4.6-)limethylbenzyl, 3,4.5- 1J#-lupenzyl, 4-methoxybenzol, 4-methoxyphenyldiphenylmethyl, 2-nitropenzyl, 4-nitrobenzyl, 4-rio.

benzyl, 4-bromobenzyl, 4-cyanobenzyl,
4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl, piperonyl, and other aryl rings substituted with lower alkyl, lower alkoxy, nitro, halogen, or cyano groups; substituted with 1 to 3 aryl groups; Aralkyl groups such as lower alkyl groups; lower alkoxy groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, and isobutoxycarbonyl are nyl groups, 2,2.2-)! Jchloroethoxycarbonyl, 2-) Lower alkoxycarboxylic substituted with halogen or tri-lower alkylsilyl group such as IJ methylsilylethoxycarbonyl is an alkoxycarbonyl group such as nyl group; such as vinyloxycarbonyl, allyloxycarbonyl alkenyloxycarbonyl is a nyl group; Aralkyloxycarbonyl group whose aryl ring may be substituted with lower alkoxy or nitro groups; When n is 2, R1 at the ortho position together represents methylene, methylmethylene, ethylene, globylene, trimethylene , tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, intamethylene,
For reactions such as alkylene groups having 1 to 6 carbon atoms such as hexamethylene; lower alkylidene groups such as methylidene, ethylidene, and ingropylidene; aralkylidene groups such as benzylidene, or alkoxyethylidene groups such as methoxyethylidene and ethoxyethylidene. Protecting groups in 3 and the aforementioned aliphatic buttons and aromatic acyl groups: Aliphatic acyloxyalkyl carbonyl groups such as pivaloyloxymethyloxycarbonyl; carboxy-substituted aliphatic acyl group which may be esterified such as xybutanoyl; carbamoyl group which may be alkylated such as carbamoyl, dimethylcarbamoyl, diethylcarbamoyl; or glycyl, N-acetylglycyl, alanyl , N-acetylalanyl, arginyl, lysyl, and other amino acid acyl groups which may be acylated.

R2 is a linear or branched chain having 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, 1-butyl, pentyl, hexyl, octyl, dodecyl, and octadecyl. Alkyl group; cycloalkyl group having 3 to 10 carbon atoms which may be fused with an aryl group such as cyclopropyl, cyclobutyl, cyclohexyl, nor is lunyl, adamantyl, and 2-indanyl; carbon such as phenyl and naphthyl Aryl group having 6 to 10 carbon atoms; aralkyl group having 7 to 9 carbon atoms such as benzyl, phenethyl, 3-phenylpropyl; or furyl, thienyl, benz[b
] Thienyl, tetrahydropenz [b] Thienyl, pyrrolyl, pyrazolyl, oxasilyl, inoxasilyl,
imidazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimizonyl, pyridazinyl, pyrazinyl, indolyl,
Quinolyl, Inquinolyl, Benzimidazolyl, PuIJ
1 oxygen atom, sulfur atom or nitrogen atom such as
Indicates an optionally fused 5- to 7-membered heterocyclic group containing 3 to 3 members.

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 glovil, inglovir, butyl, isobutyl, hexyl, lower alkoxy groups such as methoxy, ethoxy, propoxy, impropoxy, hydroxyl groups, halogen atoms such as fluorine, chlorine, bromine, iodine, trifluoromethyl, 2,2.2-) halogenated lower alkyl group such as lifluoroethyl, ortho lower alkylenedioxy group such as methylenedioxy, ethylenedioxy, propylenedioxy, nitro group, ano group, Di-lower alkylamino groups such as dimethylamino and diethylamino, lower alkoxycarbonyl groups such as carbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, impropoxycarbonyl, carbamoyl groups, acetyl, propionyl, butyryl, etc. Examples include lower aliphatic acyl groups, and aromatic acyl groups such as benzoyl, p-chlorobenzoyl, m-chloropensoyl, and p-anisoyl.

R3 represents a hydrogen atom or a group having the same meaning as R2 above, but for example, when R2 and R3 are the same as in 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, 4-methyl-1-piperazinyl, may form a 5- or 6-membered cyclic amino group together with adjacent nitrogen atoms.

Compound (I) of the present invention can be used as a pharmacologically acceptable non-toxic salt, but such salts preferably include sodium salt, potassium salt or calcium salt when it has an acidic group. salts of alkali metals or alkaline earth metals such as; hydrofluorides when having basic groups;
Hydrohalides such as hydrochloride, hydrobromide, hydroiodide, inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; methanesulfonates, trifluoromethanesulfonic acid salts, lower alkyl sulfonates such as ethanesulfonate, benzenesulfonate, arylsulfonates such as p-)luenesulfonate, fumarates, succinates, citrates, tartrates, Organic acid salts such as oxalate and maleate, and glutamate, AsA'
Amino acid salts such as laginate can be mentioned.

When the compound of the present invention contains an asymmetric carbon in R1 or R2, stereoisomers exist, and each stereoisomer or a mixture thereof is included in the present invention.

Particularly preferred compounds represented by the above-mentioned formula (1) include R4 representing a hydrogen atom; a protecting group for a hydroxyl group forming a prodrug such as acetyl, benzoyl, bivaloxypro/zonoyl, and glycyl, and R2 representing an adamantyl atom; a cycloalkyl group such as; an aryl group such as phenyl substituted with 2 to 3 chlorine atoms or bromine atoms; a heterocyclic group such as thienyl or tetrahydrobenzo[b]thienyl substituted with methoxycarbonyl; Compounds in which R3 represents a hydrogen atom, n represents 2 or 3, and m represents 2, 3 or 4 can be mentioned.

The nerve growth factor production secretagogue of the present invention can be produced by the method described below.

In the above formula, R4' represents the above-mentioned hydroxyl group-protecting group, Y represents a halogen atom, and R2 and R3 have the same meanings as described above.

This compound generally consists of a hydroxyl-protected acid halide of the formula (2Ql) and an amine of the formula (I[[), which is a known compound or can be easily prepared using known means. The reaction with a base such as pyridine, triethylamine, 4-dimethylaminopyridine in an inert solvent such as a chlorinated hydrocarbon, ether or hydrocarbon, such as methylene chloride, tetrahydrofuran or toluene. In the presence of
The temperature is preferably 0°C to 30°C. The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 1 to 3 hours.

After completion of the reaction, the target compound (I) 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. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, Halodanized hydrocarbons such as chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane, and dimethoxyethane; methanol, ethanol, n-
7'Alcohols such as lonognol, impropatol, n-butanol, inbutanol, inamyl alcohol, dimethylformamide, dimethylacedo□
Amides such as hexamethyl phosphorotriamide; and sulfoxides such as dimethyl sulfoxide can be mentioned.

Removal of the protecting group varies depending on the type of protecting group, but is generally carried out as follows by methods 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 does not inhibit the reaction. There is no particular limitation as long as it is suitable, but ethers such as tetrahydrofuran and dioxane are suitable. 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 protecting group for the hydroxyl group is an aralkyloxycarbonyl group or an aralkyl group, it can usually be removed by contacting with a reducing agent, such as a catalyst such as radium on carbon, platinum, or Raney nickel. using
This is achieved by performing catalytic reduction at room temperature. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in this reaction.
Alcohols such as methanol and ethanol, and ethers such as tetrahydrofuran and dioxane.
A mixed solvent with IIR fusui is suitable. The reaction temperature and reaction time vary depending on the starting materials and the reducing agent used, but are usually 5 minutes to 12 hours at 0° C. to room temperature.

It can also be removed by placing it in liquid ammonia or alcohol such as methanol or ethanol at -78°C to -20°C and allowing metallic lithium or sodium to act on it.

When the hydroxyl protecting group is an aliphatic acyl group, aromatic acyl group or alkoxycarbonyl 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 alcoholades such as sodium methoxide, alkali metals such as aqueous ammonia, sodium carbonate, and potassium carbonate. It is carried out using carbonates, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or concentrated ammonia-methanol. The solvent used is not particularly limited, and may include water, methanol, ethanol, n-pronognol, etc. Alcohols or Hachitrahydrofuran,
Organic solvents such as ethers such as dioxane or mixed solvents of water and organic solvents are suitable. The reaction temperature and reaction time are not particularly limited as they vary depending on the starting materials and the base used, but in order to suppress side reactions, they are usually at 0°C to 150°C for 1 to 10 hours.

When the hydroxyl-protecting 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 solvent. The acid used is
Suitable examples include hydrochloric acid, acetic acid-sulfuric acid, pi-mylene sulfone, and acetic acid. The solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these organic solvents and water may be used. suitable. The reaction temperature and reaction time vary depending on the starting materials and the type of acid used, but are usually 0°C to 50°C and 10 minutes to 18 hours.

When the protecting group for the hydroxyl group is an alkenyloxycarbonyl group, the same removal reaction conditions as when the protecting group for the hydroxyl group is an aliphatic acyl group, an aromatic acyl group, or an alkoxycarbonyl group are used. It can be desorbed by processing. In the case of allyloxycarbonyl, the method of removing radium and trinoenylphosphine or nickel tetracal using nyl is particularly convenient and can be carried out with fewer side reactions.

The following examples illustrate methods for preparing the inventive compounds from known starting compounds. The invention described above is not limited to these examples.

Example 1 2.5-dichloranily (1,621, 10mM)
and pyridine (1-) were dissolved in 20 ml of methylene chloride, and while stirring under water cooling, 3,4-diacetoxyphenylpropionyl chloride (2,62II) was added, and the mixture was further stirred for 15 minutes under water cooling and 30 minutes at room temperature. − of water was added.

The methylene chloride layer was separated, and the aqueous layer was diluted with methylene chloride (20 m
JX2), the combined organic layers were washed with deuterated water and diluted hydrochloric acid, dried over anhydrous nitrogen, and the solvent was concentrated to obtain 3.2 g of the target compound.

Melting point 96-97°C.

The following compounds were synthesized in the same manner.

In addition, the Rf value is Art, 5715 (0,25
Using mml TLC, n-hexane:ethyl acetate =
The measurement was carried out by developing with a 1=1 solvent.

Table-1 Table 1-2 Table 1-3 Table-4 Table-5 Example 2< -6 Melting point table 1-7 Example melting point 2 -(CH2)16CH3 79-80°5-2 116-117°6- 2 1l (Rf = 0.26) (Rf = 0.66) Example 67 The amide (1.0 g) obtained in Example 1 was mixed with methanol 2
The mixture was stirred at room temperature, and 10 m9 of metallic sodium was added thereto while stirring at room temperature, and the mixture was stirred for 2 hours until a clear solution was obtained.

200 mL of water was added to the reaction mixture, and the mixture was made acidic with dilute hydrochloric acid. The slightly yellow precipitate was collected by filtration and recrystallized from ethanol to obtain 0.5z9 of the target compound. Melting point 130-
131℃.

Table 3-1 Example Table 2 Melting Point Example Table 3 Melting Point [Effect] (Method for Measuring Effect) It has been reported that catecholamines promote the production and secretion of NGF (J.

Biol, Chem, 261.6039-6047.
1986).

Therefore, in accordance with this report, we investigated the presence or absence of the NGF production and secretion promoting effect of the test compound.

199 medium containing 0.5 polypeptone was used for culturing LM cells. LM cells were placed in a 24-well culture plate with a size of approximately 5 x 10 cells per hole in a CO incubator (37°C,
The cells were cultured at 1 s% CO2 to reach confluence. After removing the culture medium, add 0.5% bovine serum albumin (F
Cells were washed once with 199 medium containing lactation V, Sigma). The test compound was added to 199 medium containing 0.5% bovine serum albumin at a specified concentration.
0.5- to LM cells. 24 L-M cells
After culturing in a CO2 incubator for an hour, the culture solution was collected and NGF in the culture solution was quantified.

NGF was determined by enzyme-linked immunosorbent assay (Korsching and Tho
Enen.

Proc, Natl, Acad, Sci, US
A, 80.3513-3516.1983). Anti-mouse βN in a 96-well polystyrene plate.
CF antibody (Boehringer Mannheim
) solution (0.3 μi/ml y pH 9.6) was dispensed into 6 wells of 75 μt each and left at room temperature for 1 hour. After removing the antibody, the 6 holes were washed three times with a washing solution. 50 μt of standard βNCF (Wako Tsumugi Pharmaceutical) solution or sample solution was dispensed into 6 wells and left at room temperature for 6-8 hours. After removing the standard βNGF or sample solution and washing each hole three times, β-Ga
Lactosi-dase-labeled anti-βNGF monoclonal antibody (Boehr-inger Mannheim
) solution (100 mU/ml, pH 7.0) was dispensed into 6 wells and left at 4°C for 15-18 hours. After removing the enzyme-labeled antibody and washing three times, the Chlorop
henolred-β-D-galactopyra
-noside (Boehrjnger Mann
heim) solution (1mp/1nt.

PH7.3) was dispensed into 6 wells of 100 μt each. After adequate color development was obtained (after 2-3 hours at room temperature), the absorbance at 570 nm was measured. Standard curve, calculate the amount of INGF,
The results show the production and secretion of NGFi in cells untreated with the test compound.
It is expressed as a relative value (multiple).

Known compounds Multi-control (Compound concentration: 20γ/, /) Epinephrin 140±24 Isoproterenol 168±22 L-POPA 117±7 Shishimanii compound concentration: 10γ/ml Values (%control) are controls (compound pure/added)
It is shown as the average value of three experiments (3 wells).

The novel compound of the present invention has an excellent secretion-promoting effect on nerve growth factor production and is not toxic, so it is useful as a therapeutic agent for dementia, cerebral ischemic injury, and various nerve injuries.

Examples of the administration form of the compound of the present invention include 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 dosage varies depending on the symptoms, age, etc., but it is usually administered to adults at 1 to 1,000 doses per day, once or in divided doses.Example of formulation (capsules) 153 .6■ Corn starch 00 The powders of the above formulation were mixed and passed through a sieve, and then 280 m9 of this powder was placed in a No. 3 gelatin capsule to form a capsule.

Claims (1)

[Claims] 1. General formula ▲ Numerical formulas, chemical formulas, tables, etc. It represents a good cycloalkyl group, aryl group, aralkyl group or heterocyclic group, and R_3 represents a hydrogen atom or a group having the same meaning as R_2, but R_2 and R_3 together form a cyclic amino group together with the adjacent nitrogen atom. may be formed. n represents an integer of 1 to 3, and m represents an integer of 1 to 6. When n is 2 or 3, R_1 can represent different groups as mentioned above. ] A substituted phenol derivative represented by and a pharmacologically acceptable salt thereof. 2. A nerve growth factor production and secretion promoter comprising the substituted phenol derivative and its salt according to claim 1 as an active ingredient.