Amide derivatives of dihydrocaffeic acid and their application to pharmaceuticals

Therapeutic agents for degressive diseases in the central nervous system, which contain amide derivatives of dihydrocaffeic acid of the general formula (I) ##STR1## wherein, R.sub.1 and R.sub.2 and A are defined in the specification; the compounds exert a nerve growth factor inducing action and thus are effective for the prevention of the progression of degenerative diseases in the central nervous system and the therapeutic treatment thereof.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to amide derivatives of dihydrocaffeic acid 
and their application to pharmaceutical uses. More specifically, the 
present invention relates to amide derivatives of dihydrocaffeic acid 
which are capable of inducing production and secretion of a nerve growth 
factor (hereinafter referred to as NGF) in specific tissues in the brain 
and to pharmaceutical agents containing these derivatives as effective 
constituents for the prevention of the progression of degenerative 
diseases in the central nervous system and the therapeutic treatment 
thereof. 
2. Description of the Prior Art 
With extended average life expectancy, rapid progress in research has been 
made all over the world in order to establish methods for early diagnosis, 
ethiological study and therapeutic treatment of various gerontological 
diseases; degenerative diseases in the central nervous system are a major 
object of this research. In particular, senile dementia of Alzheimer type 
(hereinafter abbreviated to as SDAT), a typical disease of such diseases, 
is now becoming a big social problem because the number of the cases is 
markedly increasing, mainly in developed countries, and the patients 
suffer through a miserable progressive course. Although many researchers 
and clinicians have been intensively studying the pathology of this 
disease, particularly in recent years, the fundamental cause of the 
disease has not been elucidated and therefore no effective methods for the 
early diagnosis and treatment of the disease have been established. 
However, a number of pathological observations demonstrates that the direct 
causes of the early characteristic symptoms of SDAT, such as memory 
failure and disorientation, are the progressive changes in large cell 
cholinergic nerve fibers which project into the memory and learning 
centers, i.e., the cerebral cortex and hippocampus, from the cerebral 
basal ganglia and dysfunctions in said controlled areas caused by this 
change. In fact, a few case reports showed that the symptoms were slightly 
improved by administering an acetylcholine biosynthesis precursor or a 
cholinesterase inhibitor as an activator to SDAT patients in order to 
activate the cholinergic system in the brain. However, in general, the 
observed effects were not so significant as expected. 
Since discovery of NGF by R. Levi-Monterlcini, S. Cohen and others, 
considerable research on NGF has been carried out. To date, it has been 
proved by physiological experiments that NGF is an essential factor for 
differentiation and growth of sensory and sympathetic nerve cells in the 
peripheral nervous system, particularly in the embryonal period, and 
further for the survival of the sympathetic nerve cells and maintenance of 
their functions in the maturation period. 
However, because NGF is a physiologically active substance which exists 
only in an extremely small quantity, accurate knowledge regarding 
distribution and movement of NGF in tissues, which directly demonstrates 
the action of NGF in the body, has not been attained in spite of intensive 
research for a long period of time. Only recently, a highly sensitive 
enzyme-linked immunosorbent assay (hereinafter referred to as ELISA) for 
an active subunit of NGF (beta-NGF, hereinafter simply designated as NGF) 
was developed and improved with sufficient sensitivity and specificity to 
study the matters described above (S. Furukawa et al.: J. Neurochem., 40, 
734-744, 1983 and S. Korshing and H. Thoenen: Proc. Natl. Acad. Sci., USA, 
80, 3513-3516, 1983). 
Furthermore, the NGF gene was cloned and its structure was analyzed, which 
makes it possible to establish a method for the quantitative measurement 
of its messenger RNA (hereinafter abbreviated as mRNA) by using the 
complementary DNA (hereinafter abbreviated as cDNA) of beta-NGF (D. L. 
Shelton and L. F. Reichardt: Proc. Natl. Acad. Sci., USA, 81, 7951-7955, 
1984 and R. Heumann et al.: EMBO J., 3, 3183-3189, 1984). 
Then, using the techniques described above, it was proved that there is a 
positive correlation between the degree of control by the sympathetic 
nerve in the peripheral nervous system and expression of the NGF gene in 
the tissues being controlled. 
More surprisingly, NGF is detected also in the central nervous system, 
particularly in the hippocampus, the neocortex, the septal area of the 
olfactory bulb and basal forebrain, the Broca's diagonal band and the 
large cell basal ganglia, and moreover mRNA concentrations are high in the 
hippocampus and the neocortex and are as low in the septal area of the 
basal forebrain as in other brain areas where NGF is not detected (S. 
Korshing et al.: EMBO J., 4, 1389-1393, 1985). Later these observations 
were re-examined one after another by other research groups (D. L. Shelton 
and L. F. Reichardt: Proc. Natl. Acad. Sci., USA 83, 2714-2718, 1986 and 
S. Whittemore et al.: Proc. Natl. Acad. Sci., USA, 83, 817-821, 1986). 
These findings demonstrate that the NGF gene is expressed not only in the 
peripheral nervous system but also in the central nervous system and 
moreover that NGF is produced and secreted in the areas controlled by 
cholinergic nerve fibers which project into the neocortex and hippocampus, 
i.e., the memory and learning center, from the nucleus of origin of the 
cerebral ganglia, captured at the nerve endings and then brought to the 
cellular body of the nucleus of origin by reverse axon transport. It was 
proved by a series of physiological experiments that NGF is an essential 
factor for the survival of these cholinergic nerve cells and maintenance 
of their functions; it was thus proved from these observations that NGF 
specifically functions also in the central nervous system as one of the 
"nerve nutrition factors". 
Later, these findings were re-examined by various research groups and also 
verified from research on NGF receptors and NGF distribution in the brain. 
During the course of the research on the function of NGF in the central 
nerve system as a nerve nutrition factor, the present inventors concluded 
that although a direct cause of the disturbance in memory and learning, 
which is an early symptom of SDAT, may be progressive changes of the 
cholinergic nerve fibers and dysfunction caused by these changes in the 
areas being controlled, the disease may be caused more fundamentally by 
disturbance in production and secretion of NGF in these areas being 
controlled by responsible nerves. 
In other words, the present inventors believe that marked improvement 
cannot be attained by conventional nosotrophic therapy for SDAT, for 
example by providing acetylcholine or by increasing availability of 
acetylcholine, but it may be far more effective as a therapy to secure the 
production and excretion of NGF in the cerebral cortex and hippocampus so 
as to stop a functionally vicious cycle established within the controlling 
nerves, if possible. 
However, great pharmaceutical and pharmacological difficulties still exist 
in substitution therapy using NGF itself which is a protein having a 
molecular weight of more than 10,000 although a way of possible mass 
production of human type beta-NGF by cloning of the gene has opened. In 
particular, as to the application to the central nerve system, the 
prospect of development is still far from certain. 
From the point of view mentioned above, for a substantial and effective NGF 
substitution therapy, it is of great importance to search for a low 
molecular weight molecule which can induce production and excretion of NGF 
in specified tissues. The present inventors have already reported on 
catechol derivatives which have this action (for example, Fukazawa: 
Japanese Patent Laid-open No. 53767/1990 and No. 152950/1990). 
Furthermore, there are reports by Furukawa et al. (Y. Furukawa et al.: J. 
Biol. Chem., 261, 6039, (1986) and FEBS Letters, 208, 258, (1986)). 
As mentioned above, it is expected that compounds and modified compounds 
thereof, being modified based on pharmacological and pharmaceutical 
considerations, have a capability to promote production and secretion of 
NGF which functions as the "nerve nutrition factor" and acts on specific 
nerves in the tissues being controlled, and thus possibly increase the 
amount of available NGF to degenerated sites of the nerves by means of 
ordinary administration of said compounds, thereby recovering the 
functions of said specific nerves. In particular, use of these compounds 
for the therapy of SDAT, a disease in the central nervous system for which 
fundamental therapy has not yet been established, is ideal. If treated in 
the early stage of the disease and administered at the peripheral system, 
these compounds enhance capability of NGF production and secretion in the 
cerebral cortex and the hippocampus area in the central nervous system, 
prevent the progress of characteristic changes in the nerves being 
controlled by NGF, i.e., the cholinergic nerve system, and promote repair 
of damaged nerve cells or re-control by remaining nerve cells, thereby 
providing a revolutionary therapy based on the new action concept 
attributed to flexibility of brain functions. 
However, later, research showed that none of the catechol derivatives so 
far reported were satisfactorily absorbable or retainable when orally 
administered. The present inventors continued their study in order to 
solve this problem and consequently found that the compounds of the 
present invention are increasingly absorbable when orally administered and 
their retention in the blood is highly improved as compared to the 
compounds described in Japanese Patent Laid-open No. 152950/1990 and No. 
99046/1991 which were applied previously by the present inventors. 
Furthermore, it was found that the amount of NGF increased in various 
parts of brain when the compounds of the present invention were orally 
administered to rats, with which the present invention was deemed to be 
completed. 
DISCLOSURE OF THE INVENTION 
Accordingly, the present invention comprises first pharmaceutical agents 
containing amide derivatives of dihydroxycaffeic acid represented by the 
general formula (I) and their salts as effective constituents for the 
prevention of the progression of degenerative diseases in the central 
nervous system and the therapeutic treatment thereof, 
##STR2## 
(in which R.sub.1 and R.sub.2 can be identical or different and are a 
hydrogen atom, an alkyl group having 1-4 C atoms, an aryl, propargyl, 
benzyl or pyridylmethyl group, or R.sub.1 and R.sub.2 are bound together 
to form a --CH2CH.sub.2 -- group or --CR.sub.3 R.sub.4 -- group wherein 
R.sub.3 and R.sub.4 are each independently a hydrogen atom, an alkyl group 
having 1-4 C atoms or a phenyl group; A is a cyclohexylamino group, 
--NR.sub.5 R.sub.6, 
##STR3## 
wherein R.sub.5 is a hydrogen atom or an alkyl group having 1-6 C atoms; 
R.sub.6 is an alkyl group having 1-6 C atoms; n is an integer from 2 to 7 
exclusive; X is an oxygen atom or a .dbd.NR.sub.7 group wherein R.sub.7 is 
a hydrogen atom or an alkyl group having 1-4 C atoms; the case where 
R.sub.1 and R.sub.2 in the formula are both hydrogen atoms is excluded.) 
In the general formula (I), R.sub.1 and R.sub.2 can be identical or 
different as defined above but are preferably identical. A is preferably 
##STR4## 
In the general formula (I), the alkyl groups having 1-4 C atoms of R.sub.1, 
R.sub.2, R.sub.3, R.sub.4, R.sub.7 and R.sub.8 include methyl, ethyl, 
propyl, isopropyl and butyl groups. The alkyl groups having 1-6 C atoms of 
R.sub.5 and R.sub.6 include methyl, ethyl, propyl, butyl, pentyl and hexyl 
group. Examples of the 
##STR5## 
group of A include aziridyl, azetidyl, pyrrolidyl and piperidyl groups. 
Examples of the 
##STR6## 
group of A include morpholino, piperazinyl and 4-methyl-1-piperazinyl 
groups. 
Furthermore, among the compounds represented by the general formula (I), 
the following compounds are novel compounds and thus the second aspect of 
the invention is the invention of these novel compounds. 
Namely, the first group of compounds are amide derivatives of 
dihydrocaffeic acid of the general formula (I) and their salts, in which A 
is as defined above and R.sub.1 and R.sub.2 are an aryl, propargyl, benzyl 
or pyridylmethyl group or otherwise R.sub.1 and R.sub.2 are bound together 
to form a --CH.sub.2 CH.sub.2 -- group or a --CR.sub.3 R.sub.4 -- group 
(in which R.sub.3 and R.sub.4 are each independently a hydrogen atom or an 
alkyl group having 1-4 C atoms or a phenyl group; the case where R.sub.3 
and R.sub.4 are both hydrogen atoms is excluded.) 
The second group of the compounds are amide derivatives of dihydrocaffeic 
acid represented by the following general formula (II) and their salts, 
##STR7## 
(in which A is a cyclohexylamino group, --NR.sub.6 R.sub.6, 
##STR8## 
wherein R.sub.6 is an alkyl group having 1-6 C atoms; n is an integer from 
2 to 7 except 5; and X is an oxygen atom or a .dbd.NR.sub.7 group wherein 
R.sub.7 is an alkyl group having 1-4 C atoms). 
Furthermore, the third group of the compounds are amide derivatives of 
dihydrocaffeic acid of the general formula ( I ) and their salts, in which 
R.sub.1 and R.sub.2 can be identical or different and are each a hydrogen 
atom or an alkyl group having 1-4 C atoms but not together hydrogen atoms; 
and A is a cyclohexylamino group, 
##STR9## 
(wherein R.sub.5 is a hydrogen atom or an alkyl group having 1-6 C atoms; 
R.sub.6 is an alkyl group having 1-6 C atoms and R.sub.8 is an alkyl group 
having 1-4 C atoms). 
The compounds of the present invention (represented by the general formula 
(I)) can be the pharmacologically acceptable salts. Examples of these 
salts include salts of alkali metals or alkaline earth metals such as 
sodium salts, potassium salts or calcium salts, salts of basic amino acids 
such as lysine or appropriate organic bases in the case where the 
compounds have acidic groups. On the other hand, if the compounds have 
basic groups, examples of these salts include salts of halogenized 
hydroacid, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid 
or hydroiodic acid, salts of inorganic acids such as nitric acid, 
perchloric acid, sulfuric acid or phosphoric acid, salts of lower 
alkylsulfonic acids, such as methanesulfonic acid, 
trifluoromethanesulfonic acid or ethanesulfonic acid, salts of 
arylsulfonic acids, such as benzensulfonic or p-toluenesulfonic acid, 
salts of organic acids, such as fumaric acid, succinic acid, citric acid, 
tartaric acid, oxalic acid, maleic acid or ascorbic acid, and salts of 
acidic amino acids such as glutamic or aspattic acid. 
Processes of manufacturing the compounds of the present invention will be 
described as follows: 
In the first method, a dihydrocaffeic acid ethyl ester which is readily 
available and a corresponding amine are thermally condensed to obtain a 
compound of amide derivative of dihydrocaffeic acid of the general formula 
(I) in which R.sub.1 and R.sub.2 are both hydrogen atoms. This method is 
disclosed in Japanese Patent Laid-open No. 53767/1990 and No. 152950/1990. 
A target compound is obtained by reacting this compound with a compound 
having the general formula R.sub.1 --X, X--C.sub.2 C.sub.2 --X or 
X--CR.sub.3 R.sub.4 --X (in which R.sub.1, R.sub.3 and R.sub.4 are as 
defined above and X is a chlorine, bromine or iodine atom) in the presence 
of a base normally in a molar ratio of the former to the latter of 1:1 to 
1:10. The base being used here is an inorganic base such as sodium 
hydroxide, potassium hydroxide, potassium carbonate or sodium 
hydrogencarbonate or an organic base such as pyridine, triethylamine, 
dimethylamine, sodium methoxide or potassium tert-butoxide. Further, metal 
copper or cupric oxide can be added to the reaction mixture. 
There is no limit as to the solvent being used. For example, water, 
methanol, acetone, benzene, toluene, tetrahydrofuram or dimethylfomamide 
is used alone or in combination. In this case, reaction temperature ranges 
preferably from 0.degree. C. to the boiling point of the solvent used. 
In the second method, a dihydrocaffeic acid ethyl ester and a compound of 
the above-mentioned general formula R.sub.1 --X, X--CH.sub.2 CH.sub.2 --X 
or X--CR.sub.3 R.sub.4 --X (in which R.sub.1, R.sub.3 and R.sub.4 are the 
same as defined above) are first reacted also in the presence of a base 
normally in a molar ratio of the former to the latter of 1:1 to 1:10. In 
this case, the kind of base and reaction conditions are the same as 
previously described. Subsequently, the resultant compound (an ester) is 
thermally condensed with a corresponding amine or a carboxylic acid 
compound obtained by hydrolysis is reacted with thionyl chloride, 
phosphorus pentachloride or the like to make an acid chloride and then 
condensed with a corresponding amine, or otherwise the carboxylic acid is 
condensed with a corresponding amine using various condensing agents. The 
term "thermally" herein used means that heating is carried out at a 
temperature ranging from room temperature to, in a certain cases, 
200.degree. C. In this case, the reaction proceeds mostly in the absence 
of solvent; in certain cases, an excessive amount of the corresponding 
amine or an inactive solvent such as toluene or xylene can be used. 
Further, the various condensing agents mean those which are normally used 
in the field of peptide chemistry, such as DCC (dicyclohexylcarbodimide) 
or CDI (carbonyldimidazole). 
The methods described above are shown with chemical formulae as follows: 
The first method is: 
##STR10## 
The second method is: 
##STR11## 
[in the formulae, R.sub.1, R.sub.3, R.sub.4 and X are the same as defined 
above. H-A represents an amine corresponding to A in the formula (I).] 
Furthermore, among the compounds of the general formula (I) according to 
the present invention, a group of compounds in which R.sub.1 and R.sub.2 
are bound together to form --CR.sub.3 R.sub.4 -- (in which R.sub.3 and 
R.sub.4 are as defined above) are obtained by reacting compounds in which 
R.sub.1 and R.sub.2 are together hydrogen atoms in the dihydroxycaffeic 
acid amide derivative of the general formula (I) and a compound 
represented by the general formula R.sub.3 R.sub.4 CO or R.sub.3 R.sub.4 
(OCH.sub.3).sub.2 (in which R.sub.3 and R.sub.4 are as defined above) 
normally in a molar ratio of the former to the latter of 1:1 to 1:5. There 
is no limit as to solvent being herein used; benzene, toluene, xylene, 
tetrahydrofuran or the like can be preferably used alone or in 
combination. In certain cases, an acid such as sulfuric acid or 
p-toluenesulfonic acid is added. The reaction temperature ranges from room 
temperature to the boiling point of the solvent being used, preferably the 
azeotropic point of water and the solvent being used in order to remove 
generated water. 
The following compounds are obtained in analogous reactions and treatments: 
N-butyl-3-(2-phenyl-1,3-benzodioxol-6-yl)propionamide, 
N-butyl-3-(3,4-dipyridylmethyloxphenyl)propionamide, 
N-methyl-N-butyl-3-(1,4-benzodioxane-6-yl)propionamide, 
N-methyl-N-butyl-3-(3,4-dimethoxyphenyl)propionamide, 
N-methyl-N-butyl-3-(3,4-dipropargyloxyphenyl)propionamide, 
N-methyl-N-butyl-3-(3,4-dipropyloxyphenyl)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-benzodioxol-6-yl)propionamide, 
N-cyclohexyl-3-(2,2-dimethyl-1,3-benzodioxol-6-yl)propionamide, 
N-[3-(1,4-benzodioxane-6-yl)propionyl]pyrrolidine, 
N-[3-(3,4-dibenzyloxyphenyl)propionyl]piperazine, 
N-[3-(3,4-dipropargyloxyphehyl)propionyl]morpholine, 
N-[3-(3,4-diaryloxyphenyl)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-methylenedioxyphenyl)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. 
Effectiveness of the compounds of the present invention as pharmaceutical 
agents for the prevention of the progressions of degenerative diseases in 
the central nervous system and the therapeutic treatment thereof was 
confirmed by the following experiments: Namely, it was previously reported 
that the compounds of the general formula (I) in which R.sub.1 is a 
hydrogen atom as represented below 
##STR12## 
(in which A is the same substituent group as defined above) exerted an 
extremely strong action to promote NGF production and secretion in a 
system in which L-M cells of a mouse fibroblast cell line and astroglia 
cells, which are known as important cells for NGF production and excretion 
in tissues in the central nervous system, were used (Japanese Patent 
Laid-open No. 53767/1990 and No. 152950/1990). The compounds of the 
present invention represented by the general formula (I) are those in 
which the hydrogen atoms of the compound described above are protected by 
various substitute groups described above and they are thus so-called 
pro-drug compounds. Namely, the compounds of the formula represented above 
were modified so as to improve their enteral absorbability, durability in 
the blood and capability to reach the brain tissues, which increases 
medicinal effectiveness. In fact, after the compounds of the present 
invention were orally administered to rats, measurements in the blood 
showed that the compounds were maintained in high concentrations for a 
long period of time, thereby the effectiveness being confirmed. 
Furthermore, when the compounds of the present invention were orally 
administered to rats at a dose of 1-5 mg/kg body weight, marked increase 
in NGF concentrations in the brain tissues was observed; the high NGF 
concentrations were detected particularly in areas of the flotal lobe 
cortex and hippocampus. Furthermore, marked anti-dementia effect was 
detected in various animal model experiments for anti-dementia study using 
rats. Thus it was confirmed that the compounds of the present invention 
can make effective agents for the prevention of the progression of 
generative diseases in the central nervous system, especially SDAT, and 
the therapeutic treatment thereof. 
Furthermore, when the compounds of the present invention are used as 
pharmaceutical agents for the prevention of the progression of 
degenerative diseases in the central nervous system and the therapeutic 
treatment thereof, the dosage and form of agents naturally vary depending 
on physical properties of the compounds, the symptoms of a patient to be 
treated or the like; however, a daily dose of 50-500 mg for adult in one 
or several dosages in a form of tablet, granule, powder, suspension, 
capsule or the like can be used for oral administration and a daily dose 
of 1-100 mg for adult in one or several dosages in a form of injectable 
preparation, suppository, transfusion or the like can be used for 
parenteral administration. 
For example, when the compounds are used in tablet form, crystalline 
cellulose, light dehydrated silica or the like is used as an absorbent and 
corn starch, lactose, calcium phosphate, magnesium stearate or the like 
can be used as an excipient. 
Furthermore, when the compounds are used in an injectable preparation, it 
can be in the form of aqueous solution, suspension in water using cotton 
seed oil, corn oil, peanut oil, olive oil or the like, and furthermore, 
emulsion, for example, with surface active agents such as HCO-60 or the 
like. 
Furthermore, there is no limit as to the amount of effective ingredients in 
the agents; in general 0.1-99% by weight, preferably 1.0-50% by weight is 
used.