JPH0678286B2 - Dihydrocaffeic acid derivative and therapeutic agent containing it as an active ingredient - Google Patents

Description

TECHNICAL FIELD The present invention relates to a dihydrocaffeic acid derivative and its use in medicine. More specifically, nerve growth factor (Nerve growth factor, NGF) in specific tissues in the brain
The present invention relates to a dihydrocaffeic acid derivative having a production / secretion-inducing action, and an agent for preventing and treating the progression of central nerve degenerative disease containing the derivative as an active ingredient.

[Conventional technology]

Along with the extension of life expectancy worldwide, research for early diagnosis of various geriatric diseases and establishment of causal treatment is rapidly progressing. Central neurodegenerative diseases are also the main subjects of study. In particular, the typical disease is the Senile Dementia of Alzheimer Type (SDAT)
Abbreviated) indicates that there is a marked increase trend, mainly in developed countries,
It is becoming a big social problem due to the progressive and tragic course. In particular, in recent years, although many researchers and clinicians have challenged this pathological condition, effective early diagnosis methods and therapeutic methods have not yet been established as well as the fundamental elucidation of the etiology.

However, the direct cause of memory loss and disorientation, which are the characteristic early pathologies of SDAT, is due to the large-scale cholinergic nerve bundle projections from the basal cerebrum to the cerebral cortex and hippocampus, which are memory / learning centers. A large number of pathological findings have been accumulated, which indicate progressive degeneration and dysfunction of the control region. In fact, acetylcholine biosynthesis precursors or cholinesterase inhibitors were administered to SDAT patients as activating therapy of the brain cholinergic system, and some cases of symptom improvement have been reported, but generally, as expected The effect of is not recognized.

NGF has been the subject of numerous studies since it was discovered by R. Levi-Monterlcini, S. Cohen, and others, and has already been differentiated into the peripheral nervous system, especially in embryonic sensory and sympathetic nerve cell differentiation and growth, and in the sympathetic nerves during maturity. It has been proved by physiological experiments that it is an essential factor for cell survival and function maintenance.

However, NGF is an ultratrace physiologically active substance, and despite many years of research, accurate results regarding its tissue distribution and kinetics that directly support its in vivo action were not obtained. Most recently, a highly sensitive enzyme-linked immunosorbent assay (Enzym) for the active subunit of NGF (β-NGF, hereinafter simply referred to as NGF)
Development and improvement of e-Linked Immunosorbent Assay (ELISA) have progressed, and detection sensitivity and specificity that can withstand the above studies have been secured (S. Furukawa et al .: J. Neurochem. 40 ,
734-744, 1983 and S. Korshing and H. Thoenen: Proc. Nat.
I. Acad. Sci. USA 80 , 3513-3516, 1983).

In addition, a method for quantifying the messenger RNA (abbreviated as mRNA) using the β-NGF complementary DNA (abbreviated as cDNA) as a probe was also established by cloning the NGF gene and structurally analyzing it (DLShelton and LF Reichardt). : Proc.
Natl. Acad. Sci. USA 81 , 7951-7955,1984 and R. Heumann
Et al: EMBO J. 3,3183-3189, 1984).

Using these techniques, it was first demonstrated that a positive correlation was established between the degree of sympathetic innervation in the peripheral nervous system and the gene expression of NGF in the innervating tissues.

Even more surprisingly, NGF was also detected in the central nervous system of the rat, especially in the hippocampus, neocortex, olfactory bulb and septal area of the basal forebrain, Broca's diagonal zone, and basal ganglia, and its mRNA content was high in the hippocampus. , High in the neocortex and in the basal septal area
NGF was found to be as low as other areas of the brain where it was not detected (S. Korshing et al .: EMBO J. 4, 1389-1393, 1985). The results were subsequently repeated by other research groups (DL Shelton and LF Reichardt: Proc. Natl. Acad.
Sci. USA 83 , 2714-2718, 1986 and S. Whittemore et al: Pro.
c. Natl. Acad. Sci. USA 83 , 817-821, 1986).

This fact indicates that NGF is expressed not only in the peripheral nervous system but also in the central nervous system, and that choline is projected from the origin nucleus of the basal cerebrum to the neocortex, which is the center of memory and learning, and the hippocampus. It is shown that it is produced and secreted in the dominated region of the agonistic nerve bundle, taken up by the nerve endings, and reaches the cell body of the nucleus of origin by reverse axon transport. A series of physiological experiments have already demonstrated that NGF is an essential factor for survival and maintenance of function of this cholinergic nerve, and therefore these results indicate that NGF is also in the central nervous system.
Has been proved to specifically function as one of the "neurotrophic factors".

This result was subsequently replicated by several research groups and supported by studies on NGF receptors and distribution in the brain. While studying the function of NGF as a neurotrophic factor in the central nervous system, the present inventors have found that the immediate cause of memory / learning disorder, which is an early symptom of SDAT, is the progressive degeneration of cholinergic nerve bundles. Therefore, even if it is due to the functional dysfunction of the innervation region caused by it, it has been borne in mind that the deficiency of NGF production / secretion in the innervation region may be a more fundamental cause.

In other words, conventional symptomatic therapy for SDAT, such as acetylcholine replacement therapy and availability improvement therapy, does not produce a significant improvement, and secures NGF production / secretion in the cerebral cortex and hippocampus, and the It is considered to be far more effective if it is possible to break the functional vicious circle established in.

The human β-NG has already been cloned by cloning the gene.
Although the path to the large-scale preparation of F has been opened up, the molecular weight is 1
There are significant pharmacological and pharmacological constraints associated with replacement therapy of NGF itself, which is a protein of over 0,000. At present, there is no prospect of development regarding application to the central nervous system.

From the above viewpoints, as a substantial and effective replacement therapy for NGF, it is important to search for a low molecular weight compound having an ability to induce the production / secretion ability of NGF in a specific tissue. We have already reported a catechol derivative having this action (Ikeda: Japanese Patent Application Laid-Open No. 63-83020, Japanese Patent Application No. 63-63516).
etc). There are also reports by Furukawa and others (Y. Furukawa and others: J. Bio.
l. Chem. , 261 , 6039 (1986) and FEBS Letters 208 258.
(1986)).

[Problems to be Solved by the Invention]

An object of the present invention is to provide a pharmaceutical product capable of inducing the production / secretion ability of NGF in a specific tissue as a substantial and effective replacement therapy for NGF. In other words, the NG that functions as a "neurotrophic factor" for specific nerves
The compound itself having the activity of promoting production / secretion of the innervating tissue of F or its modified compound based on pharmacological and pharmaceutical considerations increases the amount of NGF supplied to the neurodegenerative local area by a usual administration method, It is expected to be able to restore the nerve function. In particular, the use of these compounds is ideal for SDAT, which is a central disease for which a fundamental cure has not yet been established. In the early stage of onset, these enhance peripheral production of NGF in the cerebral cortex and hippocampus of the central nervous system by peripheral administration to prevent the progression of characteristic degeneration of the cholinergic nervous system, which is the innervating nerve,
It is possible to provide an epoch-making therapeutic method based on a new concept of action that depends on the plasticity of brain function by promoting repair of damaged nerve cells or re-innervation by residual nerve cells.

[Means for Solving the Problems]

The present inventors have searched for a low molecular weight compound having the ability to induce the production / secretion ability of NGF in a specific tissue.

As a result, they have found that a specific dihydrocaffeic acid derivative has an action of inducing NGF production / secretion ability, and is effective in preventing and treating the progression of central nervous degenerative disease, and completed the present invention.

That is, the present invention has the general formula (I) (In the formula, R ₁ represents a hydrogen atom or an acetyl group, R ₂ and R ₃
Each independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an allyl group or a substituted allyl group. However, the case where the combination of R ₂ and R ₃ is selected from hydrogen and an alkyl group having 3 or less carbon atoms is excluded. ) Related to the dihydrocaffeic acid derivative.

In the dihydrocaffeic acid derivative represented by the general formula (I), the alkyl group is a methyl group, an ethyl group, a propyl group, a butyl group, a hexyl group, an octyl group, a decyl group, a lauryl group, a hexadecyl group, a stearyl group or the like. A chain alkyl group or an isopropyl group, a branched alkyl group such as an isobutyl group, a cycloalkyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or the like, an allyl group, a phenyl group, Examples of the substituted allyl group include a benzyl group, a phenethyl group, a p-methylphenyl group, and an o-methylphenyl group.

Further, the present invention provides the compound represented by the general formula (II) (In the formula, R ₁ is a hydrogen atom or an acetyl group, R ₄ is a lower alkoxy group or Indicates.

Here, R ₂ and R ₃ each independently represent a hydrogen atom, an alkyl group, a cycloalkyl group, an allyl group or a substituted allyl group. n represents an integer of 1, 2 or 3. The present invention relates to an agent for preventing and treating the progression of central nervous degenerative disease, which comprises a dihydrocaffeic acid derivative represented by the formula (1) as an active ingredient.

In the dihydrocaffeic acid derivative represented by the general formula (II), the lower alkoxy group represents a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like, an alkyl group,
The cycloalkyl group, the allyl group and the substituted allyl group have the same meanings as in the case of the general formula (I).

Specifically, 3,4-dihydroxyphenylpropionic acid methyl ester, 3,4-dihydroxyphenylpropionic acid propyl ester, 3,4-dihydroxyphenylpropionic acid butyl ester, 3,4-dihydroxyphenylacetic acid methyl ester, 3, 4-dihydroxyphenylacetic acid ethyl ester, 3,4-dihydroxyphenylacetic acid propyl ester, 3,4-dihydroxyphenylacetic acid butyl ester, 3,4-dihydroxyphenylbutyric acid methyl ester, 3,4-dihydroxyphenylbutyric acid ethyl ester, 3, 4-dihydroxyphenyl butyric acid propyl ester, 3,4-dihydroxyphenyl butyric acid butyl ester,
3,4-diacetoxyphenylpropionic acid methyl ester, 3,4-diacetoxyphenylpropionic acid propyl ester, 3,4-diacetoxyphenylpropionic acid butyl ester, 3,4-diacetoxyphenylacetic acid methyl ester, 3,4 -Diacetoxyphenylacetic acid ethyl ester, 3,4-diacetoxyphenylacetic acid propyl ester, 3,4-diacetoxyphenylacetic acid butyl ester,
3,4-Diacedoxyphenylbutyric acid methyl ester, 3,4-
Diacetoxyphenyl butyric acid ester ester, 3,4-diacetoxyphenyl butyric acid propyl ester, 3,4-diacetoxyphenyl butyric acid butyl ester, 3,4-dihydroxyphenylpropionamide, N-methyl-3,4-dihydroxyphenylpropionamide , N-ethyl-3,
4-dihydroxyphenylpropionamide, N-propyl-3,4-dihydroxyphenylpropionamide,
3,4-Dihydroxyphenylacetic acid amide, N-ethyl-
3,4-Dihydroxyphenylacetic acid amide, N-ethyl-
3,4-dihydroxyphenylacetic acid amide, N-propyl-3,4-dihydroxyphenylacetic acid amide, N-butyl-3,4-dihydroxyphenylacetic acid amide, 3,4-dihydroxyphenylbutyric acid amide, N-methyl-3, 4-dihydroxyphenylbutyric acid amide, N-ethyl-3,4-dihydroxyphenylbutyric acid amide, N-propyl-3,4-dihydroxyphenylbutyric acid amide, N-butyl-3,4-dihydroxyphenylbutyric acid amide, N, N- Dimethyl-3,4-dihydroxyphenylpropionamide, 3,4-diacetoxyphenylpropionamide, N-methyl-3,4-diacetoxyphenylpropionamide, N-ethyl-3,
4-diacetoxyphenylpropionamide, N-propyl-3,4-diacetoxyphenylpropionamide,
3,4-diacetoxyphenylacetic acid amide, N-methyl-
3,4-diacetoxyphenylacetic acid amide, N-methyl-
3,4-diacetoxyphenylacetic acid amide, N-propyl-3,4-diacetoxyphenylacetic acid amide, N-butyl-3,4-diacetoxyphenylacetic acid amide, 3,4-diacetoxyphenyl butyric acid amide, N- Methyl-3,4-diacetoxyphenylbutyric acid amide, N-ethyl-3,4-diacetoxyphenylbutyric acid amide, N-propyl-3,4-diacetoxyphenylbutyric acid amide, N-butyl-3,4-diacetoxy Phenylbutyric acid amide, N, N-dimethyl-3,4-diacetoxyphenylpropionamide, N-hexyl-
3,4-dihydroxyphenylpropionamide, N-octyl-3,4-dihydroxyphenylpropionamide, N-decyl-3,4-dihydroxyphenylpropionamide, N-stearyl-3,4-dihydroxyphenylpropionamide, N- Cyclohexyl-3,4-dihydroxyphenylpropionamide, N-cycloheptyl-3,4-dihydroxyphenylpropionamide, N
-Phenyl-3,4-dihydroxyphenylpropionamide, N-α-naphthyl-3,4-dihydroxyphenylpropionamide, N-benzyl-3,4-dihydroxyphenylpropionamide, N-phenethyl-3,4-dihydroxyphenylpropionamide Onamide, N-p-methylphenyl-3,4-dihydroxyphenylpropionamide, N-1-adamantyl-3,4-dihydroxyphenylpropionamide, N-hexyl-3,4-dihydroxyphenylacetic acid amide, N-octyl -3,4-dihydroxyphenylacetic acid amide, N-decyl-3,4-dihydroxyphenylacetic acid amide, N-stearyl-3,4-dihydroxyphenylacetic acid amide, N-cyclohexyl-3,
4-dihydroxyphenylacetic acid amide, N-cycloheptyl-3,4-dihydroxyphenylacetic acid amide, N-phenyl-3,4-dihydroxyphenylacetic acid amide, N-
α-naphthyl-3,4-dihydroxyphenylacetic acid amide, N-benzyl-3,4-dihydroxyphenylacetic acid amide, N-phenethyl-3,4-dihydroxyphenylacetic acid amide, N-p-methylphenyl-3,4- Dihydroxyphenylacetic acid amide, N-1-adamantyl-3,4-
Dihydroxyphenylacetic acid amide, N-hexyl-3,4
-Dihydroxyphenylbutyric acid amide, N-octyl-3,
4-dihydroxyphenylbutyric acid amide, N-decyl-3,4
-Dihydroxyphenylbutyric acid amide, N-stearyl-
3,4-Dihydroxyphenylbutyric acid amide, N-cyclohexyl-3,4-dihydroxyphenylbutyric acid amide, N-
Cycloheptyl-3,4-dihydroxyphenylbutyric acid amide, N-phenyl-3,4-dihydroxyphenylbutyric acid amide, N-α-naphthyl-3,4-dihydroxyphenylbutyric acid amide, N-benzyl-3,4-dihydroxyphenyl Butyric acid amide, N-phenethyl-3,4-dihydroxyphenylbutyric acid amide, Np-methylphenyl-3,4-dihydroxyphenylbutyric acid amide, N-1-adamantyl-3,4-dihydroxyphenylbutyric acid amide, N-hexyl -3,4-diacetoxyphenylpropionamide, N
-Octyl-3,4-diacetoxyphenylpropionamide, N-decyl-3,4-diacetoxyphenylpropionamide, N-stearyl-3,4-diacetoxyphenylpropionamide, N-cyclohexyl-3,4-di Acetoxyphenylpropionamide, N-cycloheptyl-3,4-diacetoxyphenylpropionamide,
N-phenyl-3,4-diacetoxyphenylpropionamide, N-α-naphthyl-3,4-diacetoxyphenylpropionamide, N-benzyl-3,4-diacetoxyphenylpropionamide, N-phenethyl-3, 4-
Examples thereof include diacetoxyphenylpropionamide, Np-methylphenyl-3,4-diacetoxyphenylpropionamide, N-1-adamantyl-3,4-diacetoxyphenylpropionamide, and the like.

Next, a method for producing the compound of the present invention will be described. The first method for producing the compound of the general formula (I) is a method of thermally condensing the readily available dihydrocaffeic acid ethyl ester and the corresponding amines.

Here, “thermally” means heating in the range from room temperature to 200 ° C. in some cases. In this case, most of the reaction proceeds without solvent, but in some cases, excess corresponding amines or an inert solvent such as toluene or xylene may be used.

In the second method, dihydrocaffeic acid, which is easily available, is converted into acetic anhydride or acetyl chloride into a diacetyl compound by a conventional method, and then the corresponding acid chloride is converted to tiniol chloride, and the corresponding amines are used in the presence of a base. It is a method of reacting below. In this case, the base is an organic base such as pyridine or triethylamine, an inorganic base such as sodium hydroxide or potassium hydroxide, or an excess amount of the corresponding amine.
The reaction temperature is preferably in the range of 0 ° C to 50 ° C, and as the solvent, the above organic bases, water, chloroform, THF, benzene and the like organic solvents are preferable.

In the general formula (II), a group of ester compounds in which R ₄ is a lower alkoxy group is condensed in the presence of an acid of an alcohol corresponding to an easily available compound (eg, dihydrocaffeic acid) in which R ₄ is a hydroxyl group. Can be easily obtained by. Here, the acid is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or the like. Furthermore, the amide compound group of the general formula (II) is
One is easily obtained by condensing the ester compounds described above with the corresponding amines. Here, thermal is a heating reaction in the range from room temperature to 200 ° C. in some cases. As another method, it can be produced by a method in which an easily available compound in which R ₄ is a hydroxyl group is reacted with, for example, thionyl chloride to form a corresponding acid chloride, and then a corresponding amine is reacted.

Next, the efficacy of the compound of the present invention as a preventive and therapeutic agent for central nervous system degenerative disease was confirmed by the following tests.

That is, Furukawa (Y.Furukawa et al: J.Biol.Chem. , 261 ,
Produced and secreted by using the mouse fibroblast established strain, LM cells (ATCC, CCLI, 2) reported in 6039 (1986)) and allowing the compound of the present invention to coexist in the medium.
A method of measuring the NGF concentration by a highly sensitive ELISA method was used.

Furthermore, in a system using astroglial cells, which are considered to be the major NGF-producing / secreting cells in central tissues,
NGF concentration was measured. From these tests, it was found that the compound of the present invention has a very strong ability to promote NGF production / secretion. Therefore, the compound of the present invention is a central nerve degenerative disease,
Especially, it was confirmed that it could be an effective anti-progressive and therapeutic agent for SDAT.

When the compound of the present invention is used as an agent for preventing and treating the progression of central nervous degenerative disease, its dose and dosage form naturally vary depending on the physical properties of the compound, symptoms of the administration subject, etc., but it is orally administered. In the case of an adult, 50 to 500 mg per day
Is divided into one or several doses, and as tablets, granules, powders, suspensions, capsules and the like, or parenterally, 1 to 100 mg is divided into one or several doses, for example, injection It can be administered as an agent, a suppository, an isotonic solution for ring fluid.

For example, in the case of tablets, crystalline cellulose, light anhydrous silicic acid or the like is used as the absorbent, and corn starch, lactose, calcium phosphate, magnesium stearate or the like is used as the excipient. When used as an injection, an aqueous solution of the compound or a suspension aqueous solution of cottonseed oil, corn oil, peanut oil, olive oil, etc.
It is used as an emulsion using a surfactant such as O-60.

〔Example〕

Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to these examples.

Production Example 1 3,4-Diacetoxyphenylpropionic acid ethyl ester (Compound No 27) a) Dissolve 18.2 g of dihydrocaffeic acid in 200 ml of ethanol and add 1 ml of concentrated sulfuric acid. After heating under reflux for 3 hours, ethanol was distilled off under reduced pressure, and the residue was washed with ethyl acetate.
It is dissolved in 0 ml, washed with aqueous sodium hydrogen carbonate and water, and dried over anhydrous Glauber's salt. When ethyl acetate was distilled off under reduced pressure, mp.46-4
19.8 g of 3,4-dihydroxyphenylpropionic acid ethyl ester at 7 ° C was obtained.

b) 2.1 g of 3,4-dihydroxyphenylpropionic acid ethyl ester is dissolved in 10 ml of pyridine, and 4.2 g of acetic anhydride is appropriately added. After stirring with heating at 65-70 ℃ for 1 hour, 100ml of ice water
And neutralize with 6N hydrochloric acid, then add 50 ml of chloroform.
Extract with. The extract was washed with water and dried over anhydrous Glauber's salt, and 2.3 g of 3,4-diacetoxyphenylpropionic acid ethyl ester was obtained as an oily substance that was distilled off under reduced pressure.

NMR δ ppm (CDCl ₃ ): 1.24 (t, 3H), 2.28 (s, 6H), 2,60 (t, 2H), 3.9 (t, 2H), 4.10 (q, 2H), 6.98 to 7.08 (m, 3H) Production Example 2 N-Methyl-3,4-dihydroxyphenylpropionamide (Compound No39) 3,4-Dihydroxyphenylpropionic acid ethyl ester (2 g) was mixed with 40% methylamine aqueous solution (2.1 g), and the mixture was heated in an autoclave at 150 ° C. Heat and stir for 2 hours. After cooling, the reaction solution was acidified, extracted with 25 ml of ethyl acetate three times, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography. Elution with chloroform: methanol = 20: 1 yielded pure N-methyl-3,4-dihydroxyphenylpropionamide.
0.35 g was obtained.

Melting point 117 to 118 ° C IR ν cm ^-1 (KBr): 1620, 1600, 1520, 1300, 1270 NMR δppm (DMSO-d ₆ ): 2.1 to 2.4 (m, 2H), 2.4 to 2.8 (m, 5H), 6.1 ~ 6.6 (m, 3
H), 7.56 (br, 1H), 8.44 (br, 2H) Example 1 N-n-butyl-3,4-dihydroxyphenylpropionamide (Compound NO.1) 3,4-dihydroxyphenylpropionic acid ethyl ester 5 g And n-butylamine (3.5 g) are mixed and heated and stirred in an autoclave at 150 ° C. for 2 hours. After cooling, it is concentrated and the residue is purified by silica gel chromatography.

Chloroform: methanol = 20: 1 to flow out pure N
5.45 g of -n-butyl 3,4-dihydroxyphenylpropionamide was obtained as a colorless viscous oil.

_{NMR δppm (DMSO-d 6)} : 0.88 (t, 3H), 1.00~1.60 (m, 4H), 2.20~2.40 (m, 2H), 2.40~2.80 (m, 2H), 2.80~3.20 (m, 2H ), 6.30 to 6.70 (m, 3H), 7.58 (t, 1H), 8.38 (s, 1H), 8.50 (s, 1H) Example 2 N-n-butyl-3,4-diacetoxyphenylpropionamide ( Compound NO.2) N-n-butyl-3,4-dihydroxyphenylpropionamide (2.0 g) is dissolved in pyridine (10 ml), and acetic anhydride (3.4 g) is added dropwise. After stirring with heating at 65-70 ℃ for 1 hour, ice water 100m
Pour into 1 l, neutralize with 6N hydrochloric acid 25ml, chloroform 50ml
Extract 3 times with. The extract is washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. Hexane was added to the residue for crystallization, and the crystals were collected by filtration and Nn-butyl-3,4-
2.3 g of diacetoxyphenylpropionamide was obtained.

_{mp.71~73 ℃ NMR δppm (CDCl 3)} : 0.88 (t, 3H), 1.00~1.60 (m, 4H), 2.24 (s, 6H), 2.20~2.48 (m, 2H), 2.70~3.28 (m , 4H), 5.60 (br, 1H), 7.00 (m, 3H) Example 3 N-n-pentyl-3,4-dihydroxyphenylpropionamide (Compound NO.3) 3,4-dihydroxyphenylpropionic acid ethyl ester N-pentyl-3,4-dihydroxyphenylpropionamide was obtained by performing the same treatment as in Example 1 by using the above and n-pentylamine.

Oily matter NMR δppm (CDCl ₃ ): 0.70 to 1.00 (m, 3H), 1.00 to 1.60 (m, 6H), 2.30 to 2.60 (m, 2H), 2.60 to 3.00 (m, 2H), 3.00 to 3.30 (m , 2H), 5.70 (br, 1H), 6.40 to 6.90 (m, 3H), 6.00 to 8.00 (br, 2H) Example 4 Nn-hexyl-3,4-dihydroxyphenylpropionamide (Compound NO.4 ) N-n-hexyl-3,4-dihydroxyphenylpropionamide was obtained by performing the same treatment as in Example 1 using 3,4-dihydroxyphenylpropionic acid ethyl ester and n-hexylamine.

mp.69~70 ℃ NMR δppm (DMSO-d 6): 0.80~1.00 (m, 3H), 1.26 (s, 10H), 2.16~2.48 (m, 2H), 2.80~3.20 (m, 2H), 6.36 -6.70 (m, 3H), 7.64-7.84 (m, 1H), 8.60 (br, 2H) Example 5 Nn-hexyl-3,4-diacetoxyphenylpropionamide (Compound NO.5) Nn N-hexyl-3,4-diacetoxyphenylpropionamide was obtained by the same procedure as in Example 2 using -hexyl-3,4-dihydroxyphenylpropionamide.

_{mp.70~72 ℃ NMR δppm (CDCl 3)} : 0.80~1.00 (m, 3H), 1.00~1.60 (m, 10H), 2.26 (s, 6H), 2.80~3.30 (m, 4H), 5.70 (br , 1H), 7.00 to 7.20 (m, 3H), Example 6 N-lauryl-3,4-dihydroxyphenylpropionamide (Compound NO.6) 3,4-dihydroxyphenylpropionic acid ethyl ester and laurylamine were used. By the same procedure as in Example 1, N-lauryl-3,4-dihydroxyphenylpropionamide was obtained.

mp.100~102 ℃ NMR δppm (DMSO-d 6): 0.80~1.00 (m, 3H), 1.24 (s, 22H), 2.20~2.48 (m, 2H), 2.90~3.20 (m, 2H), 6.40 ~ 6.76 (m, 3H), 7.72 (br, 1H), 8.40-8.80 (m, 2H) Example 7 N-n-butyl, N-methy-3,4-dihydroxyphenylpropionamide (Compound NO.7) Example 1 using 3,4-dihydroxyphenylpropionic acid ethyl ester and N-methyl-n-butylamine
Nn-butyl-N-methyl-3,4-dihydroxyphenylpropionamide was obtained by carrying out the same treatment as described above.

_{mp.96~98 ℃ NMR δppm (CDCl 3)} : 0.38~0.80 (m, 3H), 0.80~1.40 (m, 4H), 2.03~2.53 (m, 4H), 2.53~2.80 (m, 3H), 2.80 ~ 3.33 (m, 2H), 6.06 to 6.70 (m, 3H), 6.70 to 7.53 (br, 2H) Example 8 N-stearyl-3,4-dihydroxyphenylpropionamide (Compound NO.8) 3,4- N-lauryl-3,4-dihydroxyphenylpropionamide was obtained by the same treatment as in Example 1 using ethyl dihydroxyphenylpropionate and stearylamine.

mp.100~102 ℃ NMR δppm (DMSO-d 6): 0.80~1.00 (m, 3H), 1.24 (s, 30H), 2.10~2.40 (m, 4H), 2.40~2.60 (m, 2H), 2.80 ~ 3.10 (m, 2H), 6.30 ~ 6.68 (m, 3H), 7.70 (br, 1H), 8.50 (s, 1H), 8.70 (s, 1H) Example 9 N, N-di-n-hexyl- 3,4-dihydroxyphenylpropionamide (Compound No. 9) 3,4-dihydroxyphenylpropionic acid ethyl ester and di-n-hexylamine were used to perform the same treatment as in Example 1 to obtain N, N. -Di-n-hexyl-3,4
-Dihydroxyphenylpropionamide was obtained.

Oil _{NMR δppm (CDCl 3): 0.60~1.00} (m, 6H), 1.00~1.60 (m, 16H), 2.40~3.00 (m, 4H), 3.00~3.40 (m, 4H), 6.10~7.00 (m , 5H) Example 10 N-Cyclohexyl-3,4-dihydroxyphenylpropionamide (Compound NO.10) 3,4-Dihydroxyphenylpropionic acid ethyl ester and cyclohexylamine were used to carry out the same treatment as in Example 1. N-cyclohexyl-3,4-
Dihydroxyphenylpropionamide was obtained.

Oily solidified matter NMR δppm (CDCl ₃ ): 0.10 to 2.00 (m, 11H), 2.20 to 2.60 (m, 2H), 2.60 to 2.90 (m, 2H), 5.40 to 5.60 (m, 1H), 6.00 to 7.00 ( m, 3H), 8.10 (br, 1H) Example 11 N-methyl, N-benzyl-3,4-dihydroxyphenylpropionamide (Compound NO.11) 3,4-dihydroxyphenylpropionic acid ethyl ester and N- N-methyl, N-benzyl-3,4-dihydroxyphenylpropionamide was obtained by the same treatment as in Example 1 with methylbenzylamine.

_{mp.107~109 ℃ NMR δppm (CDCl 3)} : 2.40~3.00 (m, 7H), 4.50 (s, 2H), 6.40~7.80 (m, 10H) Example 12 N-phenyl-3,4-dihydroxy-phenylpropyl On-amide (Compound NO.12) N-phenyl-3,4-dihydroxyphenylpropionamide was obtained by the same treatment as in Example 1 using 3,4-dihydroxyphenylpropionic acid ethyl ester and aniline. It was

Oil _{NMR δppm (DMSO-d 6)} : 2.40~2.90 (m, 4H), 6.30~6.80 (m, 3H), 6.80~7.70 (m, 5H), 8.50 (br, 2H), 9.76 (s, 1H Example 13 N-adamantyl-3,4-dihydroxyphenylpropionamide (Compound No. 13) 3,4-dihydroxyphenylpropionic acid ethyl ester and 1-aminoadamantane were used, and the same treatment as in Example 1 was performed. Gave N-Atamantyl-3,4-dihydroxyphenylpropionamide.

mp 213~5 ℃ NMR δppm (DMSO- d 6): 1.60 (m, 6H), 1.80~2.10 (m, 8H), 2.10~2.30 (m, 2H), 2.40~2.70 (m, 3H) 6.30~6.60 (M, 3H), 8.40 to 8.80 (br, 2H) Example 14 <Acute toxicity> One group of 5-week-old ddY male mice was used, and the test compound (compounds NO.1 to 13) was 0.5%. It suspended in Tween80 and used for the experiment. The test compound was intraperitoneally administered, and the number of deaths was measured 1 day and 4 days later, and the LD ₅₀ value was calculated.

All compounds had LD ₅₀ values of 1000 mg / kg or more, and acute toxicity was very weak.

Example 15 <NGF production / secretion promoting action on mouse L / M cells> Furukawa et al.'S method (Y. Furukawa et al .: J. Biol. Chem .261 , 6039-6).
047, 1986).

That is, LM cells were pre-cultured in 199 medium (Gibco) supplemented with 0.5% peptone, and about 3 × 10 ⁴ cells were cultured in a 24-well culture plate (Falcon, culture area per culture well 2.1 cm ² ). /
The cells in the culture well are seeded and cultured at 37 ° C. for 3 days to be completely confluent (about 10 ⁶ cells / culture well). 0.5% medium
The medium is replaced with 199 medium (0.5 ml / culture hole) supplemented with bovine serum albumin (Fifth fraction, Armor). The test compound is contained in the main medium at a predetermined concentration, and NGF in the culture medium after 24 hours is added.
The concentration sensitive ELISA method (S.Furukawa et:. J.Neurochem 40, 7
34-744, 1983).

The result was obtained as a magnification with respect to the concentration in the culture medium of the subject which was cultured in a medium containing no test compound. The detection limit of this ELISA method is 0.25 pg / ml, and the control NGF concentration is usually
50-200 pg / 0.5 ml / culture hole. Values are shown as the average of 4 trials using the same cell preparation.

The results are shown in Tables 1 and 2.

Example 16 <NGF production / secretion promoting action on mouse brain astroglial cells> Astroglial cells were induced from the mouse forebrain and transferred to a culture system (S. Furukawa et al .: Biochem. Biophys. Res. Commun. 13
6 , 57-63.1986).

That is, the mouse brain on the 8th day of life was cut into small pieces, and calcium- and magnesium-free phosphate buffered saline (hereinafter referred to as PB
After washing with S), it is treated in PBS containing 0.25% trypsin at 37 ° C for 30 minutes, and the tissue is loosened with a Pasteur pipette to give a suspension. Collect cells and cell aggregates by centrifugation at 200 xg for 5 minutes. Dulbecco's modified Eagle medium containing 10% fetal bovine serum, 5 × 10 ⁻⁵ unit ml penicillin, 5 μg / ml streptomycin (hereinafter DMEM medium,
Gibco) and change the medium every 3 days,
Primary culture for 0-14 days. When you reach confluence,
Treat with trypsin, distribute to another incubator, and subculture. Further subculture twice or more to obtain a morphologically uniform cell population. The PAP staining method (peroxidase anti-peroxidase staining method) using anti-human glial fibril protein (GFAP) rabbit antiserum was used in this experiment, and was a cell population stained at 97% or more. Called glial cells.

Astroglial cells in 24-well culture plate (Falcon,
Approximately 3 × 10 ⁴ cells / culture hole are seeded in a culture area per culture hole of 2.1 cm ² ) and cultured in DMEM medium containing 10% fetal bovine serum for 3 days to complete confluence (about 10 ⁷ cells / culture hole). The medium is replaced with DMEM medium containing 0.5% bovine serum albumin (fifth fraction) (0.5 ml / culture hole), and the cells are cultured for 3 days. 3 more
The medium is replaced every day to culture the cells at a stationary phase (quiscent stag
e). The test compound is replaced with 0.5 ml of the same medium containing a predetermined concentration, and after 24 hours, the NGF concentration in the culture medium is measured by the above-mentioned high-sensitivity ELISA method. The results were obtained as the magnification against the concentration in the control culture medium, which was cultured in the medium containing no test compound. The detection limit of this ELISA is 0.25 pg /
The control NGF concentration was usually 1-10 pg / 0.5 ml culture wells. Values are shown as the average of 4 trials using the same cell preparation. The results are shown in Tables 1 and 3.

Claims (2)

[Claims] 1. A general formula (I) (In the formula, R ₁ represents a hydrogen atom or an acetyl group, R ₂ and R ₃
Each independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an allyl group or a substituted allyl group. However, the case where the combination of R ₂ and R ₃ is selected from hydrogen and an alkyl group having 3 or less carbon atoms is excluded. ) A dihydrocaffeic acid derivative represented by: 2. General formula (II) (In the formula, R ₁ is a hydrogen atom or an acetyl group, R ₄ is a lower alkoxy group or Indicates. Here, R ₂ and R ₃ each independently represent a hydrogen atom, an alkyl group, a cycloalkyl group, an allyl group or a substituted allyl group. n represents an integer of 1, 2 or 3. ) A prophylactic and therapeutic agent for central nervous system degenerative disease, which comprises a dihydrocaffeic acid derivative represented by the formula (1) as an active ingredient.