JPH0532646A - Dihydrocaffeic acid amide derivative and use thereof for medicine - Google Patents

Abstract

PURPOSE:To obtain a new dihydrocaffeic amide derivative useful as advance preventing agent and therapeutic agent for central nerve regressive diseases, having improved oral absorption, durability of concentration in blood and cerebral tissue transition and production and secretion inducing action on nerve growth factor. CONSTITUTION:A compound shown by formula I (R1 and R2 are H, 1-4C alkyl, aryl, propargyl, benzyl, pyridylmethyl or R1 and R2 are bonded to form CH2CH2 or CR3R4; R3 and R4 are H, 1-4C alkyl or phenyl; A is cyclohexylamino, NR5R6, formula II or formula III; R5 and R5 are 1-5C alkyl and R5 is further H; n is 2-7 integer; X is 0 or NR7; R7 is H, 1-4C alkyl with a compound wherein the proviso that R1:R2:H is omitted) or a salt thereof such as N-butyl-3-(3,4- dimethoxyphenyl)-propionamide. The compound is obtained by reacting a compound shown by formula IV with a compound shown by the formula H-A to give a compound shown by formula V and reacting the compound with compounds shown by formula VI to formula VIII (X is Cl, Br or I) in the presence of a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a dihydrocaffeic acid amide derivative and its use in medicine. More specifically, nerve growth factor (Nerve gr
The present invention relates to a dihydrocaffeic acid amide derivative having an action of inducing production / secretion of owth factor (hereinafter abbreviated as NGF), and a preventive and therapeutic agent for the progression of central nerve degenerative disease containing the derivative.

[0002]

2. Description of the Related Art With the extension of life expectancy, research for early diagnosis of various senile diseases and establishment of causal treatment is rapidly progressing worldwide, and central nerve degenerative diseases are the major researches. It is the target.

In particular, the typical disease, Alzheimer's type dementia (Senile Dementia of Alzheimer Type,
Since SDAT (abbreviated as SDAT) has a remarkable tendency to increase mainly in developed countries, and patients follow a progressive and dire course, it is becoming a big social problem. 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 characteristic early symptoms of SDAT, is projected from the basal cerebrum to the cerebral cortex and hippocampus, which are memory / learning centers, and large cell cholinergic properties. A large number of pathological findings have been accumulated which indicate progressive degeneration of nerve bundles and resulting dysfunction of the innervated area.

[0005] In fact, although acetylcholine biosynthesis precursors or cholinesterase inhibitors have been administered to SDAT patients as a treatment for activating the cholinergic system in the brain, some cases of symptom improvement have been reported, but in general, Not as effective as expected.

NGF is produced by R. Levi-Monterlcini and S. Cohen.
Since its discovery by Dr. et al., It has been the subject of numerous studies and is already an essential factor for the differentiation and growth of the peripheral nervous system, especially in the fetal stage of sensory and sympathetic nerve cells, and in the survival and function maintenance of sympathetic nerve cells in the mature period. It has been proved by physiological experiments.

However, since NGF is an ultratrace amount physiologically active substance, accurate results regarding tissue distribution and kinetics that directly support the action in vivo have not been obtained despite many years of research.

[0008] Most recently, a highly sensitive enzyme-linked immunosorbent assay (Enzyme-Linked Immunosorbent As) for the active subunit of NGF (β-NGF, hereinafter simply referred to as NGF).
say, the following ELISA) has been developed and improved, and the detection sensitivity and specificity that can withstand the above examination have been secured (S. Furukawa et al .: J. Neurochem. 40 , 734-744, 1938 and S. .Korshing and H. Thoenen: Pro. Natl. Acad. Sc
i. USA 80 , 3513-3516, 1983).

Further, the NGF gene was cloned and subjected to structural analysis to find a complementary DNA (cD
NA (abbreviated as NA) as a probe and its messenger R
A method for quantifying NA (abbreviated as mRNA) has also been established (DL Shelton and LF Reichardt: Proc. Natl. Aca.
d. Sci. USA 81 , 7951-7955, 1984 and R. Heumann
EMBO J. 3,3183-3189, 1984).

[0010] 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.

Further, surprisingly, NGF was also detected in the central nervous system of the rat, especially in the hippocampus, neocortex, olfactory bulb and basal forebrain, the diagonal zone of Broca, and the basal ganglia of large cells. The content is high in the hippocampus and neocortex,
In the septal area of the basal region, NGF was found to be as low as other regions of the brain (S. Korshing et al .: EMBO J.
4,1389-1393, 1985).

This fact was subsequently tested by other research groups one after another (DL Shelton and LF Reichardt.
: Proc. Natl. Acad. Sci. USA 83 , 2714-2718, 1986
And S. Whittemore et al .: Proc. 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,
Moreover, it is produced and secreted in the innervation region of the cholinergic nerve bundle projecting from the origin of the cerebral basal nucleus to the neocortex, which is the center of memory and learning, and the hippocampus, and is taken in from the nerve endings and reverse axon transport. Indicates that the cell body of the nucleus of progenitor is reached.

It has already been proved by a series of physiological experiments that NGF is an essential factor for survival and function maintenance of the cholinergic nerve. Therefore, this result indicates that NGF is also a "neurotrophic factor" in the central nervous system. It has been proved that it specifically functions as one of the above.

This result was subsequently supplemented by several research groups and also supported by studies on NGF receptors and distribution in the brain.

The present inventors have studied the function of NGF as a neurotrophic factor in the central nervous system.
Even if the immediate cause of the memory / learning disorder, which is an early symptom of the disease, is the progressive degeneration of cholinergic nerve bundles and the resulting functional dysfunction of the innervated area, the deficiency of NGF production / secretion in the innervated area is the only cause. It came to the point that it could be a more fundamental etiology.

That is, conventional symptomatic therapy for SDAT, such as acetylcholine replacement therapy and availability.
It is not possible to obtain a marked improvement with the improvement therapy of urine, but rather, it is possible to secure the production and secretion of NGF in the cerebral cortex and hippocampus, and to break the functional vicious cycle established with the innervating nerve. Would be much more effective.

Although it has been said that the cloning of the gene has already opened the way to the large-scale preparation of human β-NGF, NG, which is a protein having a molecular weight of more than 10,000
Due to F's own replacement therapy, there are significant pharmacological and pharmacological constraints. 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 the ability to induce the production / secretion ability of NGF in a specific tissue. We have already reported a catechol derivative having this action (Fukasawa: JP-A-2-53).
767, JP-A-2-125950, etc.). There are also reports by Furukawa et al. (Y. Furukawa et al .: j. Biol. Chem., 261 , 6039).
(1986) and FEBS Letters 208 258 (1986).

As described above, a compound having NGF functioning as a "neurotrophic factor" for a specific nerve and having an activity of promoting production / secretion of the innervating tissue, or a compound based on pharmacological and pharmaceutical considerations. The modified compound is expected to increase the amount of NGF supplied to the local area of neurodegeneration and restore the nerve function by a usual administration method.

In particular, the use of these compounds is ideal for SDAT, which is a central disease for which a radical therapy has not yet been established. In the early stage of onset, these enhance the production and secretion of NGF in the cerebral cortex and hippocampus of the central nervous system by administration to the shoots, and prevent the progression of characteristic degeneration of the cholinergic nervous system, which is the innervating nerve. However, it is possible to provide the epoch-making therapeutic method based on a new concept of action based on the plasticity of brain function by promoting the repair of damaged nerve cells or the reinnervation by residual nerve cells.

[0022]

However, any of the catechol derivatives that have been reported so far have been found by subsequent studies to have insufficient absorption and durability when orally administered.

The inventors of the present invention continued to investigate in order to solve this problem, and as a result, disclosed in Japanese Patent Application Laid-Open No. 2-1
52950, it was found that the compounds of the present invention have markedly increased oral absorbability and improved blood persistence as compared with the compounds described in JP-A-3-99046.

Furthermore, when the compound of the present invention was orally administered to rats, it was confirmed that the NGF was increased in each part of the brain, and the present invention was completed.

[0025]

The present invention firstly relates to the general formula (I):

[0026]

[Chemical 6] (In the formula, R₁ And R₂ May be the same or different,
Hydrogen atom, C₁-_Four Alkyl group, allyl group, propargy
Group, benzyl group, pyridylmethyl group or R₁And R₂ 
Are bound to -CH₂ CH₂ -Group, -CR₃ R_Four Show the group
You Where R₃ , R _Four Are each independently a hydrogen atom, C
₁-_Four Represents an alkyl group and a phenyl group. A is cyclohex
Sylamino group, -NR_Five R₆ Base,

[0027]

[Chemical 7] Indicates. Wherein R ₅ is a hydrogen atom, C ₁ - ₆ alkyl group,
R ₆ is C ₁ - ₆ alkyl group, n 2-7 integer, X is an oxygen atom or = NR ₇ group. Wherein R ₇ is a hydrogen atom or a C ₁ - shows a ₄ alkyl group. Where R ₁ and R
Except when both ₂ are hydrogen atoms. ) Is a dihydrocaffeic acid amide derivative or a salt thereof as an active ingredient, which is an agent for preventing and treating the progression of central nervous degenerative disease.

In the general formula (I), R ₁ and R ₂ may be the same or different as described above, but the same one is preferable. As A

[0029]

[Chemical 8] Is preferred.

In the general formula (I), R ₁ , R ₂ , R ₃ ,
C ₁ of the R _4, R ₇ or R ₈ - The ₄ alkyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group. C ₁ of R _5, R ₆ - and ₆ alkyl group, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group.

Of A

[0032]

[Chemical 9] Specific examples of the group include aziridyl group, azetidyl group,
Examples thereof include a pyrrolidyl group and a piperidyl group. Of A

[0033]

[Chemical 10] Specific examples of the group include a morpholino group, a piperazinyl group, and a 4-methyl-1-piperazinyl group.

Among the compounds represented by the general formula (I), the following compounds are novel compounds, and the present invention is the second invention of these novel compounds.

That is, in the general formula (I), A is as described above, R ₁ and R ₂ are allyl group, propargyl group, benzyl group, pyridylmethyl group, or R
₁ and R ₂ are bonded to each other to form a —CH ₂ CH ₂ — group, —CR
₃ R ₄ - group (wherein R _3, R ₄ are each independently hydrogen atom, C ₁ - ₄ alkyl group, a case where a phenyl group provided that Shikichu R _3, R ₄ are both hydrogen atoms. except.)
A first group which is a dihydrocaffeic acid amide derivative and a salt thereof which form

Next, the general formula (II)

[0037]

[Chemical 11] (In the formula, A is a cyclohexylamino group, —N (R ₆ ) ₂
Base,

[0038]

[Chemical 12] Indicates. Wherein R ₆ is C ₁ - ₆ alkyl group, n 2-7 except 5 integer, X is an oxygen atom or = NR ₇ group. Wherein R ₇ is C ₁ - represents an alkyl group having _4. ) A dihydrocaffeic acid amide derivative represented by the formula (1) and a salt thereof in a second group.

Further, in the general formula (I), R ₁ and R ₂
May hydrogen atom be identical or different are, C ₁ - shows a ₄ alkyl groups, rather than hydrogen atoms at the same time, A is cyclohexylamino group, -NR ₅ N ₆ group or

[0040]

[Chemical 13] Is. (Wherein R ₅ is a hydrogen atom, C ₁ - ₆ alkyl group, R ₆ is C ₁ - ₆ alkyl group, R ₈ is C ₁ -. Shows ₄ alkyl) dihydro caffeic acid amide derivatives and their Group 3 which is salt.

The compound of the present invention (general formula (I)) may be a pharmacologically acceptable salt. As such a salt, when the main compound has an acidic group, a sodium salt is used. , An alkali metal or alkaline earth salt such as potassium salt or calcium salt, a basic amino acid salt such as lysine, or a suitable organic base.

On the other hand, when the main compound has a basic group, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrates, perchloric acid. salt,
Inorganic acid salts such as sulfates and phosphates, methanesulfonate,
Lower alkyl sulfonates such as trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, aryl sulfonates such as p-toluene sulfonate, fumarate, succinate, citrate, Examples thereof include organic acid salts such as tartrate, oxalate, maleate and ascorbate, and acidic amino acid salts such as glutamate and aspartate.

Next, a method for producing the compound of the present invention will be described.

In the first method, the readily available dihydrocaffeic acid ethyl ester is thermally condensed with the corresponding amines to obtain R _{1 in} the structural formula of the dihydrocaffeic acid amide derivative of the general formula (I). , R ₂ are both hydrogen atoms. The manufacturing method is JP-A-2-53.
767 and Japanese Patent Application Laid-Open No. 2-152950. This compound was prepared in the presence of a base and represented by the general formula R ₁ —X, X—CH ₂
CH ₂ -X or X-CR ₃ R ₄ -X (wherein, R _1, R
₃ , R ₄ are the same as above, and X is a chlorine atom, a bromine atom or an iodine atom. It is obtained by reacting the compound represented by (4) with the former and the latter in a ratio of usually 1: 1 to 1:10 (molar ratio).

Here, the base is an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate or sodium hydrogen carbonate or an organic base such as pyridine, triethylamine, dimethylamine, sodium methoxide, potassium tert or butoxide. Further, metallic copper, cupric oxide and the like may be allowed to coexist during the reaction.

The solvent to be used is not particularly limited, but water, methanol, acetone, benzene, toluene,
Tetrahydrofuran, dimethylformamide or the like may be used alone or in a mixture. At this time, the reaction temperature is preferably in the range of 0 ° C. to the boiling point of the solvent used.

As a second method, dihydrocaffeic acid ethyl ester and the general formula R
_{1 -X, X-CH 2 CH} 2 -X or X-CR ₃ R ₄ -
The compound represented by X (wherein R ₁ , R ₃ , R ₄ and X are the same as above) is usually the former: the latter 1: 1 to 1:10.
First, the reaction is performed at a ratio of (molar ratio). At this time, the type of base, the reaction conditions and the like are the same as those described above. Subsequently, the reaction product (ester) is thermally condensed with the corresponding amine or the carboxylic acid obtained by hydrolysis is reacted with thionyl chloride, phosphorus pentachloride or the like to form an acid chloride, and then the corresponding amine is obtained. Or the carboxylic acid and the corresponding amines are condensed by using various condensing agents.

The term "thermally" as used herein refers to 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. Also, various condensing agents are D
It is usually used in the field of peptide chemistry such as CC (dicyclohexylcarbodiimide) and CDI (carbonyldiimidazole).

When the above is represented by a chemical formula, the first method is

[0050]

[Chemical 14] The second method

[0051]

[Chemical 15] [In the formula, R ₁ , R ₃ , R ₄ , and X are the same as described above, and H-A represents an amine corresponding to A in the general formula (I). Further, in the compound of the present invention, in the general formula (I), R ₁ and R
A compound group represented by —CR ₃ R ₄ — (R ₃ and R ₄ are the same as above) in which ₂ is bonded is a dihydrocaffeic acid amide derivative of the general formula (I), in which both R ₁ and R ₂ are hydrogen. A compound that is an atom and the general formula R ₃ R ₄ CO or R ₃
R ₄ C (OCH ₃ ) ₂ (wherein R ₃ and R ₄ are the same as above)
It is usually obtained by reacting the compound represented by the formula (1) with the latter in a ratio of 1: 1 to 1: 5 (molar ratio) with respect to the former.

The solvent used here is not particularly limited, but benzene, toluene, xylene, tetrahydrofuran and the like are preferable, and they may be used alone or in combination. Acids such as concentrated sulfuric acid and p-toluenesulfonic acid may be added in some cases. The reaction temperature is from room temperature to the boiling point of the solvent used, and preferably, the azeotropic temperature of water and the solvent used is good in order to remove water produced.

The following compounds are obtained by the same reaction and treatment.

N-butyl-3- (2-phenyl-1,3)
-Benzodioxol-6-yl) propionamide,
N-butyl-3- (3.4-dipyridylmethyloxyphenyl) propionamide, N-methyl-N-butyl-
3- (1,4-benzodioxan-6-yl) propionamide, N-methyl-N-butyl-3- (3,4-dimethoxyphenyl) propionamide, N-methyl-N
-Butyl-3- (3,4-dibenzyloxyphenyl)
Propionamide, N-methyl-N-butyl-3-
(3,4-Dipropargyloxyphenyl) propionamide, N-methyl-N-butyl-3- (3,4-diallyloxyphenyl) propionamide, N-methyl-N
-Butyl-3- (2-methyl-1,3-benzodioxol-6-yl) propionamide, N-methyl-N-
Butyl-3- (2,2-dimethyl-1,3-benzodioxol-6-yl) propionamide, N-methyl-
N-butyl-3- (2-phenyl-1,3-benzodioxol-6-yl) propionamide, N-methyl-
N-butyl-3- (3,4-dipyridylmethyloxyphenyl) propionamide, N-cyclohexyl-3-
(3,4-dimethoxyphenyl) propionamide, N
-Cyclohexyl-3- (3,4-dipropargyloxyphenyl) propionamide, N-cyclohexyl-3
-(2-phenyl-1,3-benzodioxole-6-
Il) propionamide, N-cyclohexyl-3-
(2,2-dimethyl-1,3-benzodioxole-6
-Yl) propionamide, N- [3- (1,4-benzodioxan-6-yl) propionyl] pyrrolidine,
N- [3- (3,4-dibenzyloxyphenyl) propionyl] piperazine, N- [3- (3,4-dipropargyloxyphenyl) propionyl] morpholine, N
-[3- (3,4-Diallyloxyphenyl) propionyl] pyrrolidine, N- [3- (2-methyl-1,3-
Benzodioxol-6-yl) propionyl] morpholine, N- [3- (2,2-dimethyl-1,3-benzodioxol-6-yl) propionyl] morpholine,
N- [3- (3,4-dipyridylmethyloxyphenyl) propionyl] morpholine, N, N-dimethyl-3
-(3,4-methylenedioxyphenyl) propionamide, N-methyl-N-ethyl-3- (3,4-methylenedioxyphenyl) propionamide, N, N-diethyl-3- (3,4-) Methylenedioxyphenyl) propionamide, N, N-dipropyl-3- (3,4-methylenedioxyphenyl) propionamide, N, N-
Dibutyl-3- (3,4-methylenedioxyphenyl)
Propionamide, N, N-dipentyl-3- (3,4
-Methylenedioxyphenyl) propionamide, N-
[3- (3,4-methylenedioxyphenyl) propionyl] piperidine, N-butyl-3- (3,4-methylenedioxyphenyl) propionamide, N-pentyl-3- (3,4-methylenedioxy) Phenyl) propionamide, N-hexyl-3- (3,4-methylenedioxyphenyl) propionamide, N- [3- (3-methoxy-4-hydroxyphenyl) propionyl] piperidine, N-butyl-3- ( 3-methoxy-4-hydroxyphenyl) propionamide, N-cyclohexyl-3- (3-methoxy-4-hydroxyphenyl) propionamide, N-methyl-N-butyl-3- (3-methoxy-4-hydroxyphenyl) ) Propionamide.

The effectiveness 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, the following compound in which R ₁ in the general formula (I) is a hydrogen atom

[0056]

[Chemical 16] (Wherein A represents the same substituent as described above) in a system using LM cells which are a mouse fibroblast established strain and astroglial cells which are considered to be major NGF producing / secreting cells of central tissues. It has already been reported that it exhibits a very strong NGF production / secretion promoting action (Japanese Patent Application Laid-Open No. 2-53767,
2-152950).

The compound represented by the general formula (I) in the present invention is a so-called prodrug compound in which the hydroxyl group of the above compound is protected by the various substituents described above.

That is, in order to further improve the effectiveness of the above-mentioned compound, which is the main body of activity, as a medicine, oral absorption, sustained blood concentration, and transfer to brain tissue were improved.

In fact, when the blood concentration of the drug after oral administration of the compound of the present invention to rats was measured, the drug was observed at a high concentration for a long time, and its usefulness was confirmed. Furthermore, when the compound of the present invention was orally administered to rats at 1 to 5 mg / kg, the NGF concentration in the brain tissue was measured, and a remarkable increase in the concentration was observed. Particularly, in the frontal cortex and hippocampus region, the remarkable NGF amount was significantly increased. was detected. Furthermore, in various anti-dementia models using rats, the compound of the present invention
It showed a marked anti-dementia effect.

The following facts confirmed the possibility that the compound of the present invention could be an effective antiprogressive and therapeutic agent for central nervous system degenerative diseases, especially SDAT.

When the compound of the present invention is used as an agent for preventing and treating the progression of central nervous degenerative disease, the dose and dosage form may naturally vary depending on the physical properties of the compound, symptoms of the administration subject, etc. , 50 to 500 mg per day for adults is divided into 1 or several times, and as tablets, granules, powders, suspensions, capsules, etc., and 1 to 100 mg for parenteral administration. It can be administered once or divided into several times, for example, injections, suppositories, isotonic solutions for ring fluid.

For example, in the case of tablets, crystalline cellulose, light anhydrous silicic acid or the like is used as the adsorbent, and corn starch, lactose, calcium phosphate, magnesium stearate or the like is used as the excipient.

In the case of an injection, an aqueous solution of a compound or a suspension aqueous solution of cottonseed oil, corn oil, peanut oil, olive oil, etc., and an emulsion using a surfactant such as HCO-60, etc. used.

The amount of the active ingredient contained in the agent is not particularly limited, but is usually 0.1% to 99% by weight, preferably 1.0 to 50% by weight.

[0065]

EXAMPLES The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to these examples.

Formulation Example 1 (capsule) N- [3- (1,3-benzodioxol-5-yl)
-Propionyl] -pyrrolidine, Example 12 Compound 50 mg Lactose 150 mg Corn starch 85 mg Calcium phosphate 5 mg After mixing the above compositions, a capsule filling machine was used to form a capsule.

Example 1 1.5 g of N-butyl-3- (3,4-dimethoxyphenyl) -propionamide and N-butyl-3- (3,4-dihydroxyphenyl) propionamide were added to 10 ml of N, N-. Once dissolved in dimethylformamide, 2.3 g of anhydrous potassium carbonate was added. Next, 1.5 ml of methyl iodide was added and the mixture was stirred at room temperature for 4 hours. After standing overnight, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was collected, washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of chloroform: methanol = 100: 1 to obtain 0.87 g of N-butyl-3- (3,4-dimethoxyphenyl) -propionamide as a crystalline powder. It was

Examples 2, 3, 4, 5, 6, 7 By the same reaction and treatment as in Example 1, the compounds of Examples 2, 3, 4, 5, 6, 7 shown in Table 1 were obtained. Obtained.

Example 8 N-Butyl-3- (1,4-benzodioxan-6-yl) -propionamide, N-butyl-3- (3.4-
1. Dissolve 1.5 g of dihydroxyphenyl) -propionamide in 10 ml of N, N-dimethylformamide, 2.
3 g of anhydrous potassium carbonate was added. Then, 2.3 g of 1,2-dibromoethane and 100 mg of cupric oxide were added, and the mixture was stirred at 130 to 140 ° C. for 4 hours. After cooling, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was collected, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of chloroform: methanol = 100: 1 to give 0.62 g of oily N-butyl-3- (1,4-benzodioxan-6-yl) -propionamide. Got

Example 9 The compound of Example 9 shown in Table 1 was obtained by the same reaction and treatment as shown in Example 8.

Example 10 N-Butyl-3- (2,2-dimethyl-1,3-benzodioxol-5-yl) -propionamide, N-butyl-3- (3.4-dihydroxyphenyl) 1.5 g of propionamide was dissolved in a mixed solvent of 30 ml of benzene and 10 ml of tetrahydrofuran, and 4 ml of acetone dimethyl acetal was added. Then, a small amount of p-toluenesulfonic acid was added and stirring was continued under reflux for 11 hours. Further, 2 ml of acetone dimethyl acetal was added, and stirring was continued under reflux for 6 hours. After cooling, the mixture was poured into ice water containing sodium hydrogen carbonate and stirred well. The mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using a mixed solvent of chloroform: methanol = 100: 1 to give oily N-butyl-3- (2,2-dimethyl-1, 0.84 g of 3-benzodioxol-5-yl) -propionamide was obtained.

Example 11 By the same reaction and treatment as in Example 10, the compound of Example 11 shown in Table 1 was obtained.

Example 12 N- [3- (1,3-benzodioxol-5-yl)
0.92 g of -propionyl] pyrrolidine, N- [3- (3,4-dihydroxyphenyl) -propionyl] -pyrrolidine was dissolved in 10 ml of N, N-dimethylformamide, 1.2 g of dibromomethane, 1.2 g of anhydrous 130 with potassium carbonate and 100 mg cupric oxide
Stir at ~ 140 ° C for 4 hours. After cooling, the mixture was poured into ice water, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using a mixed solvent of chloroform: methanol = 100: 1 to give oily N- [3
0.59 g of-(1,3-benzodioxol-5-yl) propionyl] -pyrrolidine was obtained.

Embodiments 13, 14, 15, 16, 17, 1
8 and 19 The compounds of Examples 13, 14, 15, 16, 17, 18 and 19 shown in Table 1 were obtained by the same reaction and treatment as shown in Example 12.

Example 20 N- [3- (3,4-dipyridylmethyloxyphenyl) propionyl] piperidine, N- [3- (3,4-
1. Dihydroxyphenyl) propionyl] piperidine 2.
0 g was dissolved in 50 ml of N, N-dimethylformamide, and 1.8 g of potassium tert-butoxide was added under ice cooling. After returning to room temperature and stirring for 30 minutes, 2.5 g of 3-chloromethylpyridine was added. The mixture was stirred for 1 hour, concentrated, dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using a mixed solvent of chloroform: methanol = 50: 1 to give oily N- [3-
1.07 g of (3,4-dipyridylmethyloxyphenyl) propionyl] piperidine was obtained.

[0076]

[Table 1]

[0077]

[Table 2]

[0078]

[Table 3]

[0079]

[Table 4] Test Example 1 <NGF-producing action in rat brain> A test compound was orally administered to 6-week-old rats three times in the morning, in the evening, and next morning, and 4 hours after the final administration, the rats were decapitated under ether anesthesia. After exsanguination
The whole brain was immediately removed.

The isolated whole brain was divided into tissues of the frontal cortex, septum, hippocampus, striatum, and cerebral cortex on an ice-cold petri dish, and then rapidly frozen with liquid nitrogen in an Eppendorf tube for use. It was stored frozen at −80 ° C. until the time. When used, appropriate amount of these tissues (10-50
(about mg), and then ice-cooled homogenizing at a rate of 2-3% (w / v) for septum and 5% (w / v) for other tissues.
buffer (20mM Tris-HCl pH7.6, 0.5M NaCl, 10mM EDT
A, 2% BSA, 0.5% tween20, 20U / ml aprotinin, 0.1mM PM
(SF) was added and homogenized 40 times with a glass homogenizer. Then homogenate 100 by ultracentrifuge,
Centrifuge at 000 xg, 4 ° C for 10 minutes, and eluate the supernatant.
The sample for SA measurement was frozen and stored at −20 ° C. until use. After thawing the extract, low speed centrifugation (1000
The sample was processed at 0 rpm for 10 minutes and then subjected to measurement.

The NGF concentration was measured by the method of Furukawa et al. (S. Furu
kawa et al .: J. Neurochem, 40 , 734-744, 1983).
The calibration curve was used with the β-NGF standard solution. The results are shown in Table-2, and other compounds also showed a remarkable NGF producing action.

[0082]

[Table 5]

[0083]

[Table 6] Test Example 2 Drug blood concentration measurement SPF Wister male, 7 months old, body weight 400-50
0 g of rats were fasted overnight, and three animals were used for each group for the experiment.

Administration was carried out by orally using an oral probe at a rate of 20 mg / ml / kg, and plasma was collected from the jugular vein at 20 minutes, 1 and 2 hours after administration. Whole blood was collected and centrifuged in a test tube previously treated with heparin. The measurement was performed using HPLC, and the peak area was determined from the calibration curve of the standard product.

The values for the comparative compounds of compounds 1 and 2 are shown in Table 3 below.

[0086]

[Table 7]

[0087]

The compound according to the present invention is used as an agent for preventing and treating the progression of central degenerative diseases.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/445 7252-4C 31/495 7252-4C 31/535 ADS 7252-4C C07C 235/34 7106 -4H C07D 213/30 6701-4C 295/18 Z 6701-4C 317/46 7729-4C 317/60 7729-4C 319/18 7729-4C (72) Inventor Yukio Fukayama 1900, Togo, Mobara-shi, Chiba Prefecture 1 Mitsui Toatsu Chemicals, Inc.

Claims (9)

[Claims] 1. The general formula (I) [Chemical 1] (In the formula, R₁ And R₂ May be the same or different,
Hydrogen atom, C₁-_Four Alkyl group, allyl group, propargy
Group, benzyl group, pyridylmethyl group or R₁And R₂ 
Are bound to -CH₂ CH₂ -Group, -CR₃ R_Four Show the group
You Where R₃ , R _Four Are each independently a hydrogen atom, C
₁-_Four Represents an alkyl group and a phenyl group. A is cyclohex
Sylamino group, -NR_Five R₆ Base, [Chemical 2] Indicates. Where R_Five Is a hydrogen atom, C₁-₆ An alkyl group of
R₆ Is C₁-₆ Alkyl group, n is an integer of 2 to 7, X is an acid
Elementary atom or = NR₇ Indicates a group. Where R₇ Is a hydrogen atom
Or C₁-_Four Is an alkyl group. However, in the formula R₁ And R
₂ Except when both are hydrogen atoms. )
Effective with dihydrocaffeic acid amide derivative or its salt
Prevents the progression of central nervous system degenerative disease contained as an ingredient
And therapeutic agents. 2. A dihydrocaffeic acid amide derivative represented by the general formula (I) and a salt thereof. (In the formula, A is the same as that described in claim 1 and R ₁ and R ₂ may be the same or different; an allyl group, a propargyl group, a benzyl group, a pyridylmethyl group, or R ₁ and R _2; They are bonded to each other to represent a —CH ₂ CH ₂ — group or a —CR ₃ R ₄ group.
Wherein R _3, R ₄ are each independently hydrogen atom, C ₁ - ₄
Represents an alkyl group and a phenyl group. However, R ₃ and R ₄
Except when both are hydrogen atoms. ) 3. A compound represented by the general formula (II): (In the formula, A is a cyclohexylamino group, —N (R ₆ ) ₂
Group, Indicates. Wherein R ₆ is C ₁ - ₆ alkyl group, n 2-7 except 5 integer, X is an oxygen atom or = NR ₇ group. Wherein R ₇ is C ₁ - represents an alkyl group having _4. ) A dihydrocaffeic acid amide derivative represented by the formula (I) and a salt thereof. 4. A dihydrocaffeic acid amide derivative represented by the general formula (I) and a salt thereof. (In the formula, R ₁ and R
₂ may be identical or different, a hydrogen atom, C ₁ - ₄
, But is not a hydrogen atom at the same time. A is a cyclohexylamino group, -NR ₅ R ₆ group, or Indicates. Wherein R ₅ is a hydrogen atom, C ₁ - ₆ alkyl group,
R ₆ is C ₁ - ₆ alkyl group, R ₈ is C ₁ - represents an alkyl group having _4. ) 5. A preventive and / or therapeutic agent for the progression of central nerve degenerative disease, which comprises the dihydrocaffeic acid amide derivative according to claim 2, 3 or 4 and a salt thereof as an active ingredient. 6. An agent for preventing and treating the progression of central nervous system degenerative disease according to claim 1, wherein A in the general formula (I) is a piperidino group. 7. A preventive and / or therapeutic agent for the progression of central nervous system degenerative disease, wherein R ₁ and R ₂ in the general formula (I) are combined to form —CH ₂ —. 8. A method for treating central degenerative diseases, which comprises using the agent according to claim 1, 5, 6 or 7. 9. Use of the compound of claim 1 as an agent for preventing and treating the progression of central nervous degenerative disease.