JPH04187665A - Nerve growth factor production and secretion promoter - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H or OH-protecting group; R<2> is NR<3>R<4> (R<3> is substitutable alkyl, cycloalkyl, substitutable aryl, substitutable aralkyl or substitutable heterocyclic group; R<4> is H or R<3>) or substitutable heterocyclic group bonded at N on the ring; m is 0 or 1; n is 0-5; X is halogen, provided that m and n are not simultaneously H] and its salt. EXAMPLE:N-3-Acetoxy-4-chlorocinnamoylamino-1-adamantane. USE:Having excellent nerve growth factor producing and secretion promoting actions with hardly any toxicity and useful as a therapeutic agent for dementia, cerebral ischemic disorder and various nerve injuries. PREPARATION:A reactive derivative of a carboxylic acid expressed by formula II (Y is leaving group) is reacted with a compound expressed by formula III in the presence of a base in an inert solvent at -10 to +50 deg.C, preferably 0-30 deg.C temperature to afford the objective compound expressed by formula I.

Description

[Detailed Description of the Invention] [Objective] (Industrial Application Field) The present invention provides an excellent nerve growth factor INerve grow.
The present invention relates to a novel compound that has an effect of promoting the production or secretion of thfactor (hereinafter abbreviated as NGF) and has few side effects.

(Prior art) NGF, discovered by Levi-Montaleini et al. in 1954, is one of the nutrients and growth factors necessary for the growth and maintenance of nerve tissue function. It has become known that it is effective in treating central dysfunction, especially Alzheimer's dementia and cerebral ischemia pathological models.

However, since it is a high-molecular protein (molecular weight is 13,000 as a monomer and 26,000 as a dimer),
When considered as a drug, there are problems with administration methods and safety.

On the other hand, catechol neurotransmitters such as adrenaline and noradrenaline and similar catechol compounds
Although it is known to promote production, there are side effects, especially nerve [llI! It has stimulatory and other effects.

(Problems to be Solved by the Invention) The present inventors have conducted intensive research over many years on the synthesis of derivatives that have nerve growth factor production or secretion-promoting effects and their pharmacological activities, and as a result, they have found that they are similar to known compounds. discovered that a novel compound with a different structure has an excellent nerve growth factor production or secretion promoting effect and has few side effects, and the present invention [Structure] The novel compound of the present invention has the general formula [ In the formula, R1 represents a hydrogen atom or a hydroxyl group protecting group, and R2 is
- In the group C formula represented by NfR31fR41 in stock, R3 is a lower alkyl group, a lower alkyl group substituted with a substituent selected from the following substituent group A, a cycloalkyl group, an aryl group, the following substituent group Aryl group or aralkyl group substituted with a substituent selected from A, an aralkyl group substituted with a substituent selected from Substituent Group A below, a heterocyclic group, or a substituent selected from Substituent Group B below represents a heterocyclic group substituted with R4 represents a hydrogen atom and a group selected from the groups defined for R3. ), represents a heterocyclic group bonded via a nitrogen atom on a ring, or a heterocyclic group bonded via a nitrogen atom on a ring, substituted with a substituent selected from substituent group B below, m is 0 or 1 Show.

n indicates an integer from O to 5; X represents a halogen atom.

However, neither m nor n represents O. Furthermore, the novel nerve growth factor production or secretion promoting agent of the present invention contains the above-mentioned -Kanzo fIl compound or a salt thereof as an active ingredient.

Halogen atoms, lower alkoxy groups and heterocyclic groups.

Table 1 Lower alkyl group, aryl group, aralkyl group, halogen atom, lower alkoxy group, lower alkoxycarbonyl group, and halogeno lower alkyl group on the i-base.

In the above-mentioned formula iI), the "hydroxyl protecting group" in the definition of R indicates a protecting group in the reaction and a protecting group for prodrug formation when administered to a living body, such as methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, S-butyl, t
- lower alkyl groups such as butyl, pentyl, hexyl; methanesulfonyloxy, ethanesulfonyloxy,
Lower alkanesulfonyloxy groups such as l-propanesulfonyloxy, fluorinated lower alkanesulfonyloxy groups such as nitrifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy, or arylsulfonyloxy such as benzenesulfonyloxy and p-toluenesulfonyloxy. Groups: formyl, acetyl, propionyl, butyryl, imbutyryl, pentanoyl,
pivaloyl, valeryl, invaleryl, octanoyl,
Alkylcarbonyl groups such as lauroyl, myristoyl, tridecanoyl, balmitoyl, stearoyl, halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl, ( E)-2-methyl-2
- Aliphatic acyl groups such as unsaturated alkylcarbonyl groups such as butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl, and B-naphthoyl; halogenoarylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl; Lower alkylated arylcarbonyl groups such as 2,4.6-trimethylbenzoyl and 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, and nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl. arylcarbonyl group,
Aromatic acyl groups such as lower alkoxycarbonylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl, arylated arylcarbonyl groups such as 4-phenylbenzoyl: tetrahydrobilan-2-yl, 3-bromotetrahydrobilane- Tetrahydropyranyl or tetrahydrothiopyranyl groups such as 2-yl, 4-methoxytetrahydrobilan-4-yl, tetrahydrothiobilan-2-yl, 4-methoxytetrahydrothiopyran-4-yl: tetrahydrofuran-2 -yl, tetrahydrothiofuranyl or tetrahydrothiofuranyl groups such as tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl silyl groups such as tri-lower alkylsilyl groups substituted with 1 to 2 aryl groups such as diphenylbutylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl; methoxy; Methyl, 1
．． Lower alkoxymethyl groups such as 1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoyamimethyl, t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2 .2. Alkoxymethyl groups such as halogen lower alkoxymethyl such as 2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl; lower alkoxylated ethyl groups such as l-ethoxyethyl and lf bilanlopoxy)ethyl; 2. Substituted ethyl groups such as halogenated ethyl groups such as 2゜2-trichloroethyl: pencil, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Lower alkyl groups substituted with 1 to 3 aryl groups such as 4-methylbenzyl, 2.4.6-trimethylbenzyl, 3.4.5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyl The aryl table is substituted with lower alkyl, lower alkoxy, halogen, cyano groups such as diphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, methyl, biveronyl. an aralkyl group such as a lower alkyl group substituted with 1 to 3 aryl groups, a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutycarbonyl, 2,2.
Alkoxycarbonyl groups such as lower alkoxycarbonyl groups substituted with halogen or tri-lower alkylsilyl groups such as 24-lichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; alkenyloxycarbonyl groups such as vinyloxycarbonyl and allyloxycarbonyl; , benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3.4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, with 1 to 2 lower alkoxy or nitro groups; Protecting groups in reactions such as aralkyloxycarbonyl groups, which may be substituted on the aryl ring, and prodrugs when administered to living organisms, such as amino acid residues such as pivaloyloxymethyloxycarbonyl, glycyl, and alanyl. Preferable examples include aliphatic acyl group and a protecting group for prodrug formation when administered to a living body.

"Lower alkyl group" in the definition of R3 and "lower alkyl group substituted with a substituent selected from substituent group A below" and "lower alkyl group" in the definition of substituent group B is, for example, methyl, ethyl, rhopropyl, isopropyl, n-butyl, isobutyl, S-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, ]-ethylpropyl, rhohexyl, 4-methylpentyl. , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3.3-dimethylbutyl, 2.2-dimethylbutyl,
1.1-dimethylbutyl, 1.2-dimethylbutyl, 1
．． 3-dimethylbutyl, 2.3-dimethylbutyl, 2-
It represents a straight chain or branched alkyl group having 1 to 6 carbon atoms such as ethylbutyl, preferably a straight chain or branched alkyl group having 1 to 4 carbon atoms.

The "cycloalkyl group" in the definition of R3 refers to an optionally condensed 3- to 10-membered saturated cyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohebutyl, norbornyl, agemantyl, Preferably it is a 5- to lo-membered saturated cyclic hydrocarbon group, and more preferably adamantyl.

In the definition of R3, "aryl group" and "aryl group substituted with a substituent selected from substituent group A below"
"aryl group" and "aryl group" in the definition of substituent group B mean a group having 5 carbon atoms, such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl.
1 to 14 aromatic hydrocarbon groups, preferably phenyl.

"Aralkyl group" and "aralkyl group substituted with a substituent selected from the following substituent group A" in the definition of R3
In the definition of "aralkyl group" and substituent group B, "
The term "aralkyl group" refers to a group in which the above-mentioned "aryl group" is bonded to the above-mentioned [lower alkyl group j, such as benzyl,
Naphthylmethyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl,
1-naphthyl ethyl, 2-naphthyl ethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl,
3-naphthylpropyl, l-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, l-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4
-Phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-
Phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl,
Examples include 4-naphthylhexyl, 5-naphthylhexyl, and 6-naphthylhexyl, and preferably an "aralkyl group J" in which the "lower alkyl group" has 1 to 4 carbon atoms.
and more preferably a benzyl group.

"Heterocyclic group" and "the following substituent group B" in the definition of R3
``Heterocyclic group'' in ``Heterocyclic group substituted with a substituent selected from ``Heterocyclic group'' and ``Heterocyclic group J'' in the definition of substituent group A means 1 to 3 sulfur atoms, oxygen atoms, and/or nitrogen atoms.
5- to 7-membered heterocyclic groups containing, for example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxasilyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl , pyrazolinyl, pyrimidinyl, pyrazinyl, indole, quinoline, inquinoline, purine, benzothiophene and aromatic heterocyclic groups such as morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazyl, tetrahydrobenzothiophene Partially or completely reduced groups corresponding to these groups such as 5- to 7-membered groups that preferably contain at least one nitrogen atom or sulfur atom and may also contain an oxygen atom can be mentioned. Indicates a multicyclic group, such as pyrrolyl, thienyl, azepinyl, pyrazolyl, imidazolyl,
Aromatic heterocyclic groups such as oxacylyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indole, quinoline, isoquinoline, purine, benzothiophene and morpholinyl , thiomorpholinyl,
Partially or fully reduced groups corresponding to these groups can be mentioned, such as pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazo°nodinyl, pyrazolinyl, piperidyl, piperazyl, and tetrahydrobenzothiophene. These are thiophene and groups corresponding to these groups, partially or completely in the radical type, piperidyl group and piperazyl group.

"Heterocyclic group bonded at the nitrogen atom on the U ring in the definition of R2" and "Heterocyclic group bonded at the nitrogen atom on the ring substituted with a substituent selected from the following substituent group B" The term "heterocyclic group bonded through the above nitrogen atom" refers to a 5- to 7-ring heterocyclic group containing at least one nitrogen atom and 1 to 3 sulfur atoms and/or oxygen atoms, and the 5th nitrogen atom For example, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxasilyl, inxazolyl, thiazolyl, inthiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indole, quinoline, Aromatic heterocyclic groups such as inquinoline, purine and morpholinyl, thiomorpholinonyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
Partially or completely reduced groups corresponding to these groups can be mentioned, such as imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, and piperazyl, and more preferred are piperidyl and piperazyl groups.

"Halogen atom" in the definition of represents a fluorine atom or a chlorine atom, more preferably a chlorine atom.

"Lower alkoxy group J in the definition of substituent group A and "lower alkoxy group" in the definition of substituent group B refers to a group in which the first two "lower alkyl groups" are bonded to an oxygen atom,
For example, methoxy, ethoxy, rhopropoxy, isopropoxy, n-butoxy, imbutoxy, S-butoxy, t-butoxy, rhopentoxy, isopentoxy, 2
-Methylbutoxy, neopentoxy, n-hexyloxy, 4-methylbentoxy, 3-methylpentoxy, 2
~Methylpentoxy, 3,3-dimethylbutoxy, 2.
2-dimethylbutoxy, 1.1-dimethylbutoxy, 1
．． 2-dimethylbutoxy, 1,3-dimethylbutoxy,
2.3 represents a straight or branched alkoxy group having 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms, such as dimethylbutoxy.
to 4 straight-chain or branched-chain alkoxy groups.

[Lower alkoxycarbonyl group] in the definition of substituent group B refers to a group in which the above-mentioned @-class alkoxy group J is bonded to a carbonyl group, and includes methoxycarbonyl, ethoxycarbonyl, lowpropoxycarbonyl, impropoxycarbonyl, n-butoxy Carbonyl, isobutoxycarbonyl, S-butoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, n-hexyloxycarbonyl, 4-methylpentoxy Carbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, l
, 2-dimethylbutoxycarbonyl, 1.3-dimethylbutoxycarbonyl, 2.3-dimethylbutoxycarbonyl, and a straight or branched alkoxycarbonyl group having 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms. to 4 straight-chain or branched-chain alkoxycarbonyl groups.

[Halogen lower alkyl group] in the definition of substituent group B
means that the above-mentioned "halogen atom J is the above-mentioned "lower alkyl group"
A group bonded to, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl,
Dibromomethyl, fluoromethyl, 2.2.2-trichloroethyl, 2,2.2-trifluoroethyl, 2-bromoethyl, 2-tritetraethyl, 2-fluoroethyl,
2. Mention may be made of groups such as 2-dibromoethyl, preferably trifluoromethyl, 2-bromoethyl,
2-tritetraloethyl and 2-fluoroethyl.

The compounds fl) according to the invention can be salts, preferably alkali metal or alkaline earth metal salts such as sodium, potassium or calcium salts, hydrogen fluoride. Acid acid, salt l! i-salts, hydrohalides such as 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-toluenesulfonate, fumarate, succinate, citrate, tartrate, oxalic acid Salts, organic acid salts such as maleate, and amino acid salts such as glutamate and aspartate can be mentioned.

The uninvented compound II) exists as a stereoisomer when R1 or R2 contains an asymmetric carbon, and when m represents 1 as a geometric isomer, each or a mixture thereof exists. Included in the present invention.

In the compound fil, preferred compounds include +1
) A compound in which R1 is a hydrogen atom, an aliphatic acyl group, or a protecting group for prodrug formation when administered to a living body +2) A compound in which R1 is a hydrogen atom or an aliphatic acyl group (]R2 is - The group represented by bottom NCR31fR41 (
In the formula, R3 is a lower alkyl group dichloroalkyl group: an aryl group substituted with a halogen atom, a heterocyclic group; or a heterocyclic group substituted with an aralkyl group, a halogen atom, a lower alkoxycarbonyl group, or a halogen lower alkyl group and R4 represents a hydrogen atom. ) or a compound which is a heterocyclic group bonded to the nitrogen atom on the ring substituted with aralkyl, halogen, lower alkoxycarbonyl or halogeno-lower alkyl+4) R2 is a group represented by the general formula NfR]+R41 (in the formula , R3 is a lower alkyl group dichloroalkyl group:
It represents an aryl group substituted with a halogen atom, or a heterocyclic group substituted with an aralkyl group or a lower alkoxycarbonyl group, and R4 represents a hydrogen atom. ) or compound (5) n is a heterocyclic group containing at least one nitrogen atom substituted with an aralkyl group, and compound (6) n is an integer of 0 to 3,
A compound (7) where x is an integer from 1 to 3 is a fluorine atom or a chlorine atom (8) A compound where X is a chlorine atom The compound fi+ of the present invention can be produced by the method described below. can.

In the formula, R1, R2, m, n and X have the same meanings as above.

Rlo represents a group similar to the "hydroxyl group protecting group" in the definition of R1.

Y represents a leaving group, and such a group is not particularly limited as long as it leaves as a nucleophilic residue, but is preferably a halogen atom such as chlorine, bromine, or iodine: methane. Lower alkanesulfonyloxy groups such as sulfonyloxy and ethanesulfonyloxy: Halogeno lower alkanesulfonyloxy groups such as trifluoromechunesulfonyloxy and pentafluoroethanesulfonyloxy: Arylsulfonyl such as benzenesulfonyloxy and p-toluenesulfonyloxy Oxy groups can be mentioned;
More preferably, it is a halogen atom.

Compounds of the invention can be combined with reactive derivatives of carboxylic acids and formula R2
A compound represented by -H (wherein R2 has the same meaning as defined above. This compound is a known compound or can be easily produced using known means.) and a base (
1,-10
The reaction can be carried out and synthesized at a temperature of 0°C to 50°C (preferably 0°C to 30°C).

The reaction time varies 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 compound of the present invention is collected from the reaction mixture according to a conventional method.

For example, adding a water-immiscible solvent to the reaction mixture,
After washing with water, it is obtained by distilling off the purifying agent.

The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

Incidentally, if desired, the "hydroxyl protecting group" of R1' can be removed to produce a compound in which R1 represents a hydrogen atom.

Removal of the protecting group varies depending on the type, but is generally carried out by methods well known in the art as follows.

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 adversely affect the reaction, but solvents 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 does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, Fatty acids like acetic acid or mixtures of these organic solvents with water? Three people 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 treating metal 1-notium or sodium in liquid ammonia or in an alcohol such as methanol or ethanol at -78°C to -20°C.

Additionally, alkylsilyl halides such as aluminum chloride-sodium iodide or trimethylsilyl iodide can be used for removal. The reaction is carried out in the presence of a solvent, and the reaction solvent to be used is not particularly specific as long as it does not participate in this reaction, but preferably,
Nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, chloroform, or a mixed solvent thereof are used. The reaction temperature varies depending on the starting materials, etc., but is usually 0°C to 50°C.

In addition, when the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

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 an alkali metal carbonate such as carbonate, hydroxide, potassium hydroxide or concentrated ammonia-methanol. The solvent to be used is not particularly limited as long as it is used in ordinary hydrolysis reactions, and includes 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, etc., and are not particularly limited.
In order to suppress side reactions, the temperature is usually 0.degree. C. to 150.degree. 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
Preferred are hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or acetic acid. The solvent 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.
50°C 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 removed by treatment with a base under the same conditions as the removal reaction for aromatic acyl groups or alkoxycarbonyl groups. In the case of allyloxycarbonyl, removal using palladium, triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with fewer side reactions.

[Effects] (-11 standard method) Furukawa et al. used a mouse connective tissue-derived fibroblast cell line 1. -11 cells produce and secrete relatively large amounts of NGF, and the order of catecholamines is
It has been reported that F production and secretion are promoted (J, Bi
ol, [:hem,, 261.6039-6047,
198B).

Therefore, in accordance with this report, we investigated whether the test compound had an effect of promoting NGF production and secretion.

199 medium containing 0.5% peptone was used for culturing LM cells. L-1+ cells were seeded in a 24-well culture plate with approximately 5xl (J' cells) per hole and cultured in a -carbon oxide incubator (37°C, 5% carbon dioxide) until reaching confluence.

After removing the culture medium, add 0.5% bovine serum albumin fFrac.
The cells were washed once with 199 medium containing tion V (manufactured by Sigma). The test compound was contained at a specified concentration in 199 medium containing 0.5% bovine serum albumin, and 0.5% L-
M cells were treated. After culturing the LM cells in a carbon dioxide incubator for 24 hours, the culture solution was collected and NGF in the culture solution was quantified.

NGF was obtained by enzyme immunoassay method (Korsching and Th
Oenen et al.'s method, Proc, Natl, Aca
d, Sci, USA, 80°3513-3516
．． 1983+. Anti-mouse β-NGF antibody (Boehringer Mannheim) in a 96-well polystyrene plate? A liquid (0.3ug/ml. pH96
) was dispensed into 75 μm holes and left at room temperature for 1 hour.

After removing the antibody, the holes were washed three times with a washing solution. Standard β−
50 μ of NGF (manufactured by Wako Pure Chemical Industries, Ltd.) solution or sample solution was dispensed into the hole and left at room temperature for 6 to 8 hours. Standard β-N
After removing GF or sample solution and washing each hole three times, β-galactosigase-labeled anti-B-NGF monoclonal antibody (manufactured by Boehringer Mannheim) dissolved M (1
00 mu/ml, pH 7,0) 50LL1 was dispensed into a hole and left at 4°C for 15 to 18 hours.

After removing the enzyme-labeled antibody and washing three times, chlorophenol red-β-D-galactopyranoside (Boehringer Mannheim) warm solution (1 mg/ml, p
H7,3) was dispensed into 100 ul of each hole.

After obtaining appropriate color development (after 2 to 3 hours at room temperature), 57
The absorbance at 0 nm was determined at 111. From the t1 curve, NG
The amount of F was calculated, and the results were expressed as relative values (%) to NGF produced and secreted by cells not treated with the test compound.

(Results) Values are percentages of double beating (no compound added), 3 times actual IA.
It is shown as the average value of (3 wells).

The novel compounds of the present invention have excellent nerve growth factor production or secretion-promoting effects and are less toxic, so they are useful as therapeutic agents for dementia, cerebral ischemic disorders, 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 preparations are manufactured by well-known methods using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents.

The dosage varies depending on the symptoms, age, etc., but the dosage is 1-1 per day.
000 mg/kg body weight can be administered once a day or in several divided doses, usually on the order of adults.

Hereinafter, the present invention will be specifically explained in detail with reference to Examples and Formulation Examples, but the present invention is limited thereto.
1 and pyridine (1 ml) were dissolved in 20 ml of methylene chloride, and while stirring under water cooling, 4-acetoxy-3-chlorocinnamoyl chloride (2.36 g) was added, followed by further 15 minutes under water cooling and 30 minutes at room temperature. Stir and add 50 ml of water.

Separate the methylene chloride layer and add the aqueous layer to methylene chloride
The combined organic layers were washed with an aqueous sodium bicarbonate solution and diluted hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain 3.1 g of the target compound.

Temperature: 134-135℃ Similarly, the following compounds were synthesized.

Example 2 N-3-acetoxy-4-chlorocinnamoylamino-adamantane Temperature: 85-86°C Temperature: 120-121"C Example 5 Melting temperature: 116-117°C Example 6 N-3-acetoxy-4-chlorophenylpropionyl-2,5-dichloroaniline Melting point: 115-116°C Melting temperature: 149-150°C Oily substance Rf (direct) 035 [Developed with ethyl acetate] Example 9 Melting point 116 -117℃ Rf value of L second oily substance: 0.21 (Developed with ethyl acetate) Melt:
147-148°C Melting point -136-137°C Torhydride penzothiophene melting: 115-116°C The amide obtained in Example 3 (1.0 g was suspended in 20 ml of methanol and stirred at room temperature) 10 mg of sodium metal was added and stirred for 2 hours until a clear solution was obtained. 200 ml of water was added to the reaction mixture and acidified with dilute hydrochloric acid. A pale yellow precipitate was collected by filtration and recrystallized from ethanol. 065 g of the target compound was obtained.

Melting point: 122-123℃ The following compounds were synthesized in the same manner.

Melting point: 116-117°C Example 16 Oily substance Rf value: 0.30 (developed with ethyl acetate) Oily substance Rf value: O, 16 (developed with ethyl acetate) Formulation example (capsule) Compound of Example 1 25 mg Lactose 153.6 mg Corn starch 100 mg L 211 long yonini 1.4 μm total 2817
After mixing the powder of the above formulation and passing it through a 60 mesh sieve, 280 mg of this powder was put into a No. 3 gelatin capsule to form a capsule.

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R1 represents a hydrogen atom or a protecting group for a hydroxyl group, and R2 is
A group represented by the general formula N (R3) (R4) (wherein R3 is a lower alkyl group, a lower alkyl group substituted with a substituent selected from the following substituent group A, a cycloalkyl group, an aryl group) , an aryl group or aralkyl group substituted with a substituent selected from substituent group A below, an aralkyl group substituted with a substituent selected from substituent group A below, a heterocyclic group, or from substituent group B below represents a heterocyclic group substituted with a selected substituent, R4 represents a hydrogen atom and a group selected from the group defined in R3), a heterocyclic group bonded via a nitrogen atom on the ring, or the following: represents a heterocyclic group substituted with a substituent selected from substituent group B and bonded to a nitrogen atom on the ring, m represents 0 or 1, n represents an integer from 0 to 5, indicates a halogen atom. However, both m and n do not represent 0. ] A compound represented by these and its salt. ¥ Substituent Group A ¥ Halogen atom, lower alkoxy group, and heterocyclic group. ¥ Substituent Group B ¥ Lower alkyl group, aryl group, aralkyl group, halogen atom, lower alkoxy group, lower alkoxycarbonyl group, and halogeno lower alkyl group. (2) A nerve growth factor production or secretion promoter comprising the compound according to claim 1 or a salt thereof as an active ingredient.