Pyridinecarboxamide derivatives of the formula ##STR1## (wherein n represents an integer of 14-18, and R represents a hydrogen atom or a straight or branched C.sub.1 -C.sub.4 alkyl group) or physiologically acceptable salts thereof. The compounds have excellent inhibiting activity of cerebral edema, especially ischemic cerebral edema, and inhibiting activity of delayed death of neuronal cells (an inhibiting activity of Ca-influx in neuronal cells). Cerebral edema is a pathologic condition accompanying cerebrovascular disorders, especially the acute stage of cerebrovascular disorders and then the compounds are useful as an agent for inhibiting cerebral edema or a therapeutic agent for cerebrovascular disorders. Moreover, the compounds have no hypotensive action which is considered to be side-effect in treating the acute stage cerebrovascular disorders and hardly show a behavior suppressing action so that they are an excellent therapeutic agent for, in particular, the acute stage cerebrovascular disorders. Moreover, the compounds show a cerebral protective activity (an anti-anoxic activity), an increasing activity of cerebral blood flow, and an inhibiting activity of lipid peroxidation and these activities may lead to the increased utility as a therapeutic agent for cerebrovascular disorders.

TECHNICAL FIELD 
This invention relates to a novel pyridinecarboxamide derivative. More 
particularly, this invention relates to an 
N-(.omega.-nitroxyalkyl)-6-piperazinylpyridine-3-carboxamide derivative, a 
process for the preparation thereof and a pharmaceutical preparation which 
comprises as an active ingredient said derivative. Moreover, this 
invention relates to a therapeutic agent for cerebrovascular disorders or 
cerebral edema which comprises as an active ingredient said 
pyridinecarboxamide derivative. Moreover, this invention relates to a 
method for the treatment of cerebrovascular disorders or cerebral edema 
which comprises administering said pyridinecarboxamide derivative. 
Moreover, this invention relates to an intermediate for the synthesis of 
said pyridinecarboxamide derivative. 
BACKGROUND ART 
Neuronal cells are weak to ischemia and may easily be damaged, but there is 
a recoverable area around the ischemic neuronal cells, which is referred 
to as the "Penumbra" (Astrup, J., Siesjo, B., Symon, L.; Stroke, 
12:723-725 1981). In the therapy of cerebrovascular disorders at the acute 
stage, it is important to protect the neuronal cells in the penumbra area 
from cell damage and maintain cerebral functions. 
It has been known that cerebrovascular disorders caused by ischemia may 
accompany cerebral edema with an unusually increased moisture content in 
the brain in the ischemic center and penumbra area (Kenji Inamura and 
Akiro Terashi: Brain Nerv. 44(9):779-785, 1992). Cerebral edema may be 
also caused by cerebral tumor, encephalitis, heat stroke, cerebral trauma 
by a traffic accident. The edema may increase the cerebral capacity, which 
results in the increase in cerebral pressure, because the brain is closed 
within the hard skull. A precipitous increase in cerebral pressure may 
cause cerebral hernia, which makes patients fall in the dangerous state of 
their life. 
Cerebral edema may accompany sodium and calcium influx into neuronal cells, 
which are found at a higher concentration extracellularly as compared with 
the intracellular one (Takao Asano, Hiroo Johshita, Osamu Gotoh and 
others: Cerebral Surgery 13:1147-1159, 1985), and it is believed that 
calcium influx may activate calcium-dependent enzymes (proteases, 
phospholipases or the like), which results in the damage of cytoskeleton 
or cell membrane. 
Activation of phospholipase A2, a phospholipase, may release arachidonic 
acid from the phospholipid in cell membrane. Accumulation of the 
arachidonic acid may inhibit respiration of mitochondria to decrease ATP. 
Moreover, it is believed that peroxidation of lipids by the free radicals 
produced during the metabolism of arachidonic acid may cause disorders of 
cell membrane or increased permeability of the membrane to provoke the 
progress of the edema. 
In addition to such acute disorders of neuronal cells, the phenomenon 
referred to as the delayed neuronal death has been found out (Kirino T., 
Brain Res., 239:57-69, 1982). This means the phenomenon that the neuronal 
cells after a short period of ischemia fall off after several days to 
several weeks. It has now been elucidated that delayed cellular death such 
as delayed neuronal death is related with a calcium concentration in 
neuronal cells (Ogura, A., Miyamoto, M., Kudo, Y., Exptl. Brain Res., 
73:447-458, 1988). Such being the case, it is the important object in the 
treatment of cerebrovascular disorders at the acute stage to inhibit 
cerebral edema which would greatly influence upon the prognosis for life 
of patients and also could be the cause of acute and delayed neuronal 
death. 
Presently there has been mainly applied an osmotherapy for the treatment of 
cerebral edema. In this method, a liquid of hyperosmorality is injected 
into blood, whereby an osmotic pressure in blood is raised and moisture is 
withdrawn from edema tissues. However, satisfactory effects have not been 
attained as yet and there has been desired a novel anti-cerebral edema 
agent other than the osmotherapy. 
On the other hand, our copending JP-A-5-32630 discloses that 
pyridinecarboxamide derivatives having a methylene chain of 9-13 carbon 
atoms and bonded to the amido nitrogen have an activity of increasing 
cerebral blood flow. Moreover, it was reported by Sakurai et al. that the 
compound of Example 10 of said JP-A-5-32630, namely, 
N-(11-nitroxy-1-undecanyl)-6-(4-methyl-1-piperazinyl)nicotinamide could 
show a cerebral protective effect on the hypoxia and anoxia models 
(Sakurai Einosuke, Jpn. J. Pharmacol., Vol. 61, No. suppl. 1 , PAGE 289p 
1993). 
However, it has also been elucidated that the compound disclosed in 
JP-A-5-32630 has a hypotensive activity though it has an activity of 
increasing cerebral blood flow. It has been elucidated that use of a 
potent hypotensive drug at the acute stage of cerebrovascular disorders 
causes ischemia in the penumbra area with a risk of extending lesions 
(Lisk, DR. et al.: Hypertension 50:855-862, 1993). 
Accordingly, the agent for increasing cerebral blood flow as disclosed in 
JP-A-5-32630 is useful for treating cerebrovascular disorders at the 
chronic stage, but not suitable at the acute stage. 
As the compounds having a cerebral protective action (an anti-anoxia 
action) would be expected to show an inhibiting action on cerebral edema, 
it has been attempted to review and pick up those compounds having an 
anti-anoxia action. However, the compounds disclosed in Example 10 of 
JP-A-5-32630 have been regarded as undesirable for the therapy of 
cerebrovascular disorders at the acute stage, because they were observed 
to possess a behavior suppressing activity that Nizofenone and others 
possess as a side-effect. 
DISCLOSURE OF INVENTION 
This invention relates to a pyridinecarboxamide derivative represented by 
the formula (1) 
##STR2## 
(wherein n represents an integer of 14-18 and R represents a hydrogen atom 
or a C.sub.1 -C.sub.4 straight or branched alkyl group) or a 
physiologically acceptable salt thereof. 
Moreover, this invention relates to a compound represented by the formula 
(2) 
##STR3## 
(wherein n and R are as defined above and X represents a hydroxy group, a 
mesyloxy group, a tosyloxy group, a bromine atom or an iodine atom). 
Moreover, this invention relates to a 6-piperazinylpyridine-3-carboxylic 
acid represented by the formula (3) 
##STR4## 
(wherein R is as defined above) or a metal salt or acid addition salt 
thereof. 
Moreover, this invention relates to a process for the production of the 
pyridinecarboxamide derivative represented by the formula (1) which 
comprises reacting the compound represented by the formula (2) with a 
nitrating agent. 
Moreover, this invention relates to a process for the production of the 
pyridinecarboxamide derivative represented by the formula (1) which 
comprises reacting an alkali metal salt, a halide or an anhydride of the 
6-piperazinylpyridine-3-carboxylic acid represented by the formula (3) 
with an .omega.-aminoalkyl nitrate represented by the formula (4) 
--H.sub.2 N(CH.sub.2).sub.n ONO.sub.2 
(wherein n is as defined above) or an acid addition salt thereof. 
Moreover, this invention relates to a pharmaceutical composition which 
comprises the pyridinecarboxamide derivative represented by the formula 
(1) or a physiologically acceptable salt thereof and a pharmaceutically 
acceptable excipient. 
Moreover, this invention relates to a therapeutic agent for cerebrovascular 
disorders, especially cerebrovascular disorders at the acute stage, which 
comprises the pyridinecarboxamide derivative represented by the formula 
(1) or a physiologically acceptable salt thereof and a pharmaceutically 
acceptable excipient. 
Moreover, this invention relates to a therapeutic agent for cerebrovascular 
disorders at the acute stage which is used for treating cerebrovascular 
disorders caused by cerebral infarction or subarachnoid hemorrhage. 
Moreover, this invention relates to a therapeutic agent for cerebral edema 
which comprises the pyridinecarboxamide derivative represented by the 
formula (1) or a physiologically acceptable salt thereof and a 
pharmaceutically acceptable excipient. 
Moreover, this invention relates to a method for the treatment of 
cerebrovascular disorders, especially cerebrovascular disorders at the 
acute stage, which comprises administering the pyridinecarboxamide 
derivative represented by the formula (1) or a physiologically acceptable 
salt thereof to patients suffering from cerebrovascular disorders, 
especially cerebrovascular disorders at the acute stage. 
Moreover, this invention relates to a method for the treatment of cerebral 
edema which comprises administering the pyridinecarboxamide derivative 
represented by the formula (1) or a physiologically acceptable salt 
thereof to patients suffering from cerebral edema. 
The pyridinecarboxamide derivatives (1) of this invention have excellent 
inhibiting activity of cerebral edema, especially ischemic cerebral edema, 
and inhibiting activity of delayed neuronal death (inhibiting activity of 
Ca-influx in neuronal cells). Cerebral edema is the pathogenic condition 
accompanying cerebrovascular disorders, in particular, cerebrovascular 
disorders at the acute stage and then the pyridinecarboxamide derivatives 
(1) of this invention are useful as an inhibiting agent for cerebral edema 
or a therapeutic agent for cerebrovascular disorders. Moreover, the 
pyridinecarboxamide derivatives (1) of this invention have no hypotensive 
activity which has been considered as a side effect in the therapy of 
cerebrovascular disorders at the acute stage and hardly exert a behavior 
suppressing action and then they are excellent as a therapeutic agent for, 
in particular, cerebrovascular disorders at the acute stage. Moreover, the 
pyridinecarboxamide derivatives (1) of this invention have a cerebral 
protective action (an anti-anoxic action), an activity of increasing 
cerebral blood flow and an activity of inhibiting action on peroxidation 
of lipids and these actions may contribute to a far more increased utility 
of the pyridinecarboxamide derivatives (1) of this invention as a 
therapeutic agent for cerebrovascular disorders. 
Almost all cerebrovascular disorders at the acute stage may accompany 
cerebral ischemia, which may accelerate microcirculation disorders around 
lesions to make cerebral disorders far worse. 
Delayed neuronal death is meant to indicate the cell death wherein neuronal 
cells such as hippocampus CA fall off several days after a severe 
transient global cerebral ischemia due to temporal cardiac arrest and 
others. The mechanism of this action is believed to be an increase in 
glutamic acid and subsequent increase in intracellular calcium, and thus 
the pyridinecarboxamide derivatives of this invention, which can inhibit 
the delayed neuronal death, are useful as a therapeutic agent for 
cerebrovascular disorders. 
Moreover, energy deficiency caused by ischemia or release of 
neurotransmitters such as glutamine and the like may cause influx of 
calcium ions into cells and generation of free radicals. Excessive 
production of free radicals may accelerate the formation of lipoperoxide 
and may cause irreversible disorders of cell membrane and rise in 
permeability of membrane, which leads to cerebral edema and neuronal 
death. Accordingly, the pyridinecarboxamide derivatives of the invention 
which inhibit the influx of calcium ions and the formation of lipoperoxide 
are useful as a therapeutic agent for cerebrovascular disorders at the 
acute stage. 
The pathologic type of cerebrovascular disorders to which the therapeutic 
agent for cerebrovascular disorders of this invention may be applied 
includes cerebral hemorrhage, brain infarction (cerebral thrombosis, 
cerebral infarction), transient ischemic attack, subarachnoid hemorrhage 
and others. The cerebrovascular disorders at the acute stage as stated 
herein is meant to indicate the cerebrovascular disorders at the period of 
time of less than one month after the onset of cerebrovascular disorders. 
The compounds (2) and compounds (3) of this invention are useful as 
intermediates for the synthesis of the pyridinecarboxamide derivatives 
(1). 
In the pyridinecarboxamide derivatives represented by the formula (1), 
specific examples of the C.sub.1 -C.sub.4 straight or branched alkyl group 
represented by R may be a methyl group, an ethyl group, a n-propyl group, 
a n-butyl group, an isopropyl group, an isobutyl group and a sec-butyl 
group, and specific examples of the group represented by the formula 
(CH.sub.2).sub.n may be a tetradecamethylene group, a pentadecamethylene 
group, a hexadecamethylene group, a heptadecamethylene group and an 
octadecamethylene group. In particular, a tetradecamethylene group, a 
hexadecamethylene group and an octadecamethylene group are preferable. 
The pyridinecarboxamide derivatives represented by the formula (1) can be 
prepared by reacting the compounds of the formula (2) with a nitrating 
agent such as nitric acid, fuming nitric acid, tetrabutylammonium nitrate, 
strongly basic ion exchange resins (e.g., Amberlyst) of a nitrate form, 
silver nitrate or potassium nitrate in the presence or absence of a 
solvent at -40.degree. C. to 120.degree. C., preferably -40.degree. C. to 
room temperature. As the solvent, there may be mentioned dichloromethane, 
chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, toluene, 
acetonitrile, acetic anhydride, sulfuric acid and the like and a mixed 
solvent thereof. The pyridinecarboxamides represented by the formula (1) 
can be also prepared by reacting an alkali metal salt, halide or acid 
anhydride of the 6-piperazinyl-pyridine-3-carboxylic acid represented by 
the formula (3) with the .omega.-aminoalkyl nitrate represented by the 
formula (4). 
The .omega.-aminoalkyl nitrates can be synthesized from an 
.omega.-aminoalkanol or a reactive derivative thereof, an 
.omega.-bromoalkylamine, an .omega.-iodoalkylamine, a methanesulfonic acid 
.omega.-aminoalkyl ester, a toluenesulfonic acid .omega.-aminoalkyl ester 
under the same condition as in the compounds of the formula (1). 
The compounds (1) can be preferably produced by reacting a 
6-(4-R-piperazinyl)pyridine-3-carboxylic acid sodium salt or a 
6-(4-R-piperazinyl)-pyridine-3-carboxylic acid potassium salt with 0.5 to 
4 equivalents of the compound of the .omega.-aminoalkyl nitrate (4) in a 
solvent in the presence of 0.5 to 4 equivalents of a condensing agent at 
-40.degree. C. to 40.degree. C., preferably -40.degree. C. to room 
temperature. There may be incorporated in situ 0.5 to 4 equivalents of an 
additive and a base. As the solvent, there may be mentioned 
dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 
diethyl ether, dioxane, benzene, toluene, xylene, acetonitrile, 
dimethylformamide, dimethyl sulfoxide and the like and a mixed solvent 
thereof. As the condensing agent, there may be mentioned carbodiimides 
such as dicyclohexylcarbodiimide, 
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like, 
azides such as diphenylphosphoryl azide and the like, carbonyldiimidazole, 
diethyl pyrocarbonate and the like. As the additive, there may be 
mentioned N-hydroxysucccinimide, 1-hydroxybenzotriazole and the like and, 
as the base, there may be mentioned organic bases such as triethylamine, 
diisopropylethylamine, pyridine and the like. 
The compounds of the formula (2), wherein X is a bromine atom or an iodine 
atom may be synthesized by reacting the compounds wherein X is a hydroxyl 
group with hydrobromic acid or hydriodic acid. 
The compounds of the formula (2) wherein X is a mesyloxy group or a 
tosyloxy group may be synthesized by reacting the compounds wherein X is a 
hydroxyl group with mesyl chloride or tosyl chloride in the presence of a 
base. 
The compounds of the formula (2) can be synthesized by reacting a 
6-piperazinylpyridine-3-carboxylic acid of the formula (3) or a reactive 
compound thereof such as an alkali metal salt thereof, for example, a 
sodium salt or potassium salt or halide thereof with a compound of the 
formula 
EQU H.sub.2 N(CH.sub.2).sub.n X 
(wherein n and X are as defined above) in a solvent in the presence of 0.5 
to 4 equivalents of a condensing agent at a temperature from -40.degree. 
C. to 40.degree. C. There may be incorporated in situ 0.5 to 4 equivalents 
of an additive and a base. As the solvent, there may be mentioned 
dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 
diethyl ether, dioxane, benzene, toluene, xylene, acetonitrile, 
dimethylformamide, dimethyl sulfoxide and the like and a mixed solvent 
thereof. As the condensing agent, there may be mentioned carbodiimides 
such as dicyclohexylcarbodiimide, 
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like, 
azides such as diphenylphosphoryl azide and the like, carbonyldiimidazole, 
diethyl pyrocarbonate and the like As the additive, there may be mentioned 
N-hydroxysucccinimide, 1-hydroxybenzotriazole and the like and, as the 
base, there may be mentioned organic bases such as triethylamine, 
diisopropylethylamine, pyridine and the like. 
The compounds of the formula (2) wherein X is a hydroxyl group can be 
prepared by reacting a compound of the formula (5) 
##STR5## 
(wherein n is as defined above and Y is a halogen atom such as chlorine, 
bromine, iodine or the like) with 1 to 100 equivalents of a compound of 
the formula (6) 
##STR6## 
(wherein R is as defined above) in the presence or absence of a solvent at 
a temperature from room temperature to a reflux temperature or in a sealed 
tube. There may be also incorporated 0.05 to 10 equivalents of sodium 
iodide or potassium iodide in situ, or 0.5 to 10 equivalents of a base may 
be incorporated. As the solvent, there may be mentioned dichloromethane, 
chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, dioxane, 
benzene, toluene, xylene, acetonitrile, dimethylformamide, dimethyl 
sulfoxide, methanol, ethanol and the like and a mixed solvent thereof. As 
the base, there may be mentioned inorganic bases such as sodium hydrogen 
carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the 
like or organic bases such as triethylamine, diethylamine, 
diisopropylamine, diisopropylethylamine, pyridine and the like. 
The compounds of the formula (2) can be also prepared by reacting the 
compound of the formula (5) with 1 to 100 equivalents of piperazine in the 
presence or absence of a solvent at a temperature from room temperature to 
a reflux temperature or in a sealed tube to form a compound of the formula 
(7) 
##STR7## 
(wherein n is as defined above) and then reacting the compound of the 
formula (7) thus obtained with 1 to 10 equivalents of a compound of the 
formula RZ [wherein R is as defined above and Z represents a halogen atom 
such as chlorine, bromine, iodine and the like or a leaving group such as 
a sulfonate (e.g., a methanesulfonyloxy group, a toluenesulfonyloxy 
group)] in the presence or absence of a solvent at a temperature from room 
temperature to a reflux temperature or in a sealed tube. There may be also 
incorporated 0.05 to 4 equivalents of sodium iodide or potassium iodide in 
situ, or 0.5 to 10 equivalents of a base may be incorporated. As the 
solvent, there may be mentioned dichloromethane, chloroform, carbon 
tetrachloride, tetrahydrofuran, diethyl ether, dioxane, benzene, toluene, 
xylene, acetonitrile, dimethylformamide, dimethyl sulfoxide, methanol, 
ethanol and the like and a mixed solvent thereof. As the base, there may 
be mentioned inorganic bases such as sodium hydrogen carbonate, sodium 
carbonate, potassium carbonate, cesium carbonate and the like or organic 
bases such as triethylamine, diethylamine, diisopropylamine, 
diisopropylethylamine, pyridine and the like. 
The compounds of the formula (5) can be prepared by reacting a compound of 
the formula (8) 
##STR8## 
(wherein Y is as defined above) with 0.5 to 4 equivalents of a compound of 
the formula (9) 
EQU H.sub.2 N(CH.sub.2).sub.n OH 
(wherein n is as defined above) in a solvent in the presence of 0.5 to 4 
equivalents of a condensing agent at a temperature from -40.degree. C. to 
40.degree. C. There may be incorporated in situ 0.5 to 4 equivalents of an 
additive and a base. As the solvent, there may be mentioned 
dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 
diethyl ether, dioxane, benzene, toluene, xylene, acetonitrile, 
dimethylformamide, dimethyl sulfoxide and the like and a mixed solvent 
thereof. As the condensing agent, there may be mentioned carbodiimides 
such as dicyclohexylcarbodiimide, 
1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride and the like, 
azides such as diphenylphosphoryl azide and the like, carbonyldiimidazole, 
diethyl pyrocarbonate and the like. As the additive, there may be 
mentioned N-hydroxysucccinimide, 1-hydroxybenzotriazole and the like and, 
as the base, there may be mentioned organic bases such as triethylamine, 
diisopropylethylamine, pyridine and the like. 
The compounds of the formula (5) can be also prepared by reacting a 
compound of the formula (10) 
##STR9## 
(wherein Y is as defined above and W represents a halogen atom such as 
chlorine, bromine, iodine and the like) with 0.5 to 4 equivalents of the 
compound of the formula (9) in a solvent at a temperature from -40.degree. 
C. to 40.degree. C. There may be incorporated in situ 0.5 to 4 equivalents 
of a base. As the solvent, there may be mentioned dichloromethane, 
chloroform, carbon tetrachloride, tetrahydrofuran, ether, dioxane, 
benzene, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like 
and a mixed solvent thereof. As the base, there may be mentioned inorganic 
bases such as sodium hydrogen carbonate, sodium carbonate, potassium 
carbonate, cesium carbonate and the like or organic bases such as 
triethylamine, diethylamine, diisopropylamine, diisopropylethylamine, 
pyridine and the like. 
The compound of the formula (12) 
##STR10## 
(wherein n is as defined above) is obtained by reacting a compound of the 
formula (11) 
EQU HO(CH.sub.2).sub.n OH 
(wherein n is as defined above) with 0.2 to 2 equivalents of an 
azodicarboxylic acid ester, phosphine and phthalimide in a solvent at a 
temperature from -10.degree. C. to 40.degree. C. As the solvent, there may 
be mentioned dichloromethane, chloroform, carbon tetrachloride, 
tetrahydrofuran, ether, dioxane, benzene, acetonitrile, dimethylformamide, 
dimethyl sulfoxide and the like and a mixed solvent thereof. As the 
azodicarboxylic acid esters, there may be mentioned azodicarboxylic acid 
diethyl ester, azodicarboxylic acid diisopropyl ester and the like. As the 
phosphine, there may be mentioned triphenylphosphine, tributylphosphine 
and the like. 
The compounds of the formula (12) can be also prepared by reacting the 
compound of the formula (11) with hydrobromic acid to form the 
monobrominated product (an .omega.-bromoalkanol) followed by reacting with 
potassium phthalimide. 
The compounds of the formula (12) thus obtained may be allowed to react 
with an acid, a base or hydrazine in a solvent at a temperature of 
0.degree. C. to a reflux temperature to produce the compounds of the 
formula (9). As the solvent, there may be mentioned dichloromethane, 
chloroform, carbon tetrachloride, tetrahydrofuran, ether, dioxane, 
benzene, acetonitrile, dimethylformamide, dimethyl sulfoxide, methanol, 
ethanol, acetic acid, water and the like and a mixed solvent thereof. As 
the acid, there may be mentioned hydrochloric acid, sulfuric acid, acetic 
acid and the like and, as the base, sodium hydroxide, potassium hydroxide 
and the like. 
The compounds of the formula (14) 
##STR11## 
(wherein n and Q are as defined below) is obtained by reacting a compound 
of the formula (13) 
EQU QO(CH.sub.2).sub.n OH 
[wherein Q represents a protecting group such as a benzyl group, a 
substituted benzyl group (e.g., a p-methoxybenzyl group), an alkyl group 
(e.g., a methyl group or a tert-butyl group), a substituted methyl group 
(e.g., a methoxymethyl group), a substituted ethyl group (e.g., a 
1-ethoxyethyl group), a silyl group (e.g., a triethylsilyl group or a 
tert-butyldimethylsilyl group) and an acyl group (e.g., an acetyl group or 
a benzoyl group), and n is as defined above for the general formula 7] 
with 0.2 to 2 equivalents of an azodicarboxylic acid ester, phosphine or 
phthalimide in a solvent at a temperature from -10.degree. C. to 
40.degree. C. As the solvent, there may be mentioned dichloromethane, 
chloroform, carbon tetrachloride, tetrahydrofuran, ether, dioxane, 
benzene, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like 
and a mixed solvent thereof. As the azodicarboxylic acid esters, there may 
be mentioned azodicarboxylic acid diethyl ester, azodicarboxylic acid 
diisopropyl ester and the like. As the phosphine, there may be mentioned 
triphenylphosphine, tributylphosphine and the like. 
The compound of the formula (14) thus obtained may be converted to the 
formula (15) 
EQU H.sub.2 N(CH.sub.2).sub.N OQ 
(wherein n and Q are as defined above) by decomposing the N-phthalimide 
with an acid, base or hydrazine in a solvent at a temperature from 
0.degree. C. to a reflux temperature. As the solvent, there may be 
mentioned dichloromethane, chloroform, carbon tetrachloride, 
tetrahydrofuran, ether, dioxane, benzene, acetonitrile, dimethylformamide, 
dimethyl sulfoxide, methanol, ethanol, acetic acid, water and the like and 
a mixed solvent thereof. As the acid, there may be mentioned hydrochloric 
acid, sulfuric acid, acetic acid and the like and, as the base, sodium 
hydroxide, potassium hydroxide and the like. 
By the deprotection of the protecting group in the compound of the formula 
(15) thus obtained, there can be prepared the compounds of the formula 
(9), but the deprotection may be carried out prior to the decomposition of 
the N-phthalimide. Deprotection reaction may be carried out under the 
conditions as conventionally applied in compliance with the type of the 
protecting group. 
In the case where Q is a substituted benzyl group, the reaction may be 
carried out by the hydrogenation in the presence of a catalyst at a 
temperature from room temperature to a refluxing temperature. There may be 
incorporated in situ 1 to 10 equivalents of ammonium formate. As the 
solvent, there may be mentioned dichloromethane, chloroform, carbon 
tetrachloride, tetrahydrofuran, ether, dioxane, benzene, acetonitrile, 
dimethylformamide, dimethyl sulfoxide, methanol, ethanol, ethyl acetate, 
water and the like and a mixed solvent thereof, and, as the catalyst, 
palladium-carbon, platinum oxide, Raney nickel and the like. 
In the case where Q is a substituted methyl group, the reaction may be 
carried out by reacting with an acid in the presence or absence of a 
solvent at a temperature from room temperature to a refluxing temperature. 
As the solvent, there may be mentioned dichloromethane, chloroform, carbon 
tetrachloride, tetrahydrofuran, ether, dioxane, benzene, acetonitrile, 
dimethylformamide, dimethyl sulfoxide, methanol, ethanol, ethyl acetate, 
water and the like and a mixed solvent thereof. As the acid, there may be 
mentioned hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic 
acid, p-toluenesulfonic acid and the like. 
In the case where Q is a silyl group, the reaction may be carried out by 
reacting with an acid or a fluoride reagent at a temperature from 
0.degree. C. to 40.degree. C. As the solvent, there may be mentioned 
dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, ether, 
dioxane, benzene, acetonitrile, dimethylformamide, dimethyl sulfoxide, 
methanol, ethanol, ethyl acetate, water and the like and a mixed solvent 
thereof. As the acid, there may be mentioned hydrochloric acid, sulfuric 
acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and the 
like As the fluoride reagent, there may be mentioned hydrogen fluoride, 
potassium fluoride, tetrabutylammonium fluoride and the like. 
In the case where Q is an acyl group, the reaction may be carried out by 
reacting with an acid or a base in a solvent at a temperature from 
0.degree. C. to a reflux temperature. As the solvent, there may be 
mentioned dichloromethane, chloroform, carbon tetrachloride, 
tetrahydrofuran, ether, dioxane, benzene, acetonitrile, dimethylformamide, 
dimethyl sulfoxide, methanol, ethanol, ethyl acetate, water and the like 
and a mixed solvent thereof. As the acid, there may be mentioned 
hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, 
p-toluenesulfonic acid and the like As the base, there may be mentioned 
sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium 
carbonate, potassium carbonate, cesium carbonate and the like. 
The compound of the formula (17) 
##STR12## 
(wherein R' is a C.sub.1 -C.sub.6 straight or branched alkyl group or a 
phenyl group and n is as defined above) is obtained by reacting a compound 
of the formula (16) 
EQU HO(CH.sub.2).sub.n-1 COOR' 
(wherein n and R' are as defined above) with 0.5 to 4 equivalents of an 
azodicarboxylic acid ester, phosphine and phthalimide in a solvent at a 
temperature from -10.degree. C. to 40.degree. C. As the solvent, there may 
be mentioned dichloromethane, chloroform, carbon tetrachloride, 
tetrahydrofuran, ether, dioxane, benzene, acetonitrile, dimethylformamide, 
dimethyl sulfoxide and the like and a mixed solvent thereof. As the 
azodicarboxylic acid esters, there may be mentioned azocarboxylic acid 
diethyl ester, azocarboxylic acid diisopropyl ester and the like. As the 
phosphine, there may be mentioned triphenylphosphine, tributylphosphine 
and the like. 
The compound of the formula (17) is converted to the formula (18) 
EQU H.sub.2 N(CH.sub.2).sub.n-1 COOR' 
(wherein n and R' are as defined above) by decomposing the N-phthalimide in 
a solvent with an acid, a base or a hydrazine at a temperature of 
0.degree. C. to a reflux temperature. As the solvent, there may be 
mentioned dichloromethane, chloroform, carbon tetrachloride, 
tetrahydrofuran, ether, dioxane, benzene, acetonitrile, dimethylformamide, 
dimethyl sulfoxide, methanol, ethanol, acetic acid, water and the like and 
a mixed solvent thereof. As the acid, there may be mentioned hydrochloric 
acid, sulfuric acid, acetic acid and the like As the base, there may be 
mentioned sodium hydroxide, potassium hydroxide and the like. 
The compound (9) can be prepared by treating the compound (18) in a solvent 
in the presence of a reducing agent at a temperature from -78.degree. C. 
to a reflux temperature. This step may be carried out prior to the 
decomposition of the N-phthalimide. As the solvent, there may be mentioned 
dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, ether, 
dioxane, benzene, toluene, xylene and the like and a mixed solvent 
thereof. As the reducing agent, there may be mentioned aluminum reagents 
such as lithium aluminum hydride, diisobutylaluminum and the like or 
diborane and the like. 
The compound (13) can be prepared by reacting the compound (11) with 0.2 to 
2 equivalents of QX' (wherein X' is halogen such as chlorine, bromine, 
iodine and the like or a leaving group such as sulfonate and the like and 
Q is as defined above) in a solvent in the presence of 0.2 to 2 
equivalents of a base at a temperature from 0.degree. C. to a reflux 
temperature. As the solvent, there may be mentioned dichloromethane, 
chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, dioxane, 
benzene, toluene, xylene, acetonitrile, dimethylformamide, dimethyl 
sulfoxide and the like and a mixed solvent thereof. As the base, there may 
be mentioned inorganic bases such as sodium hydrogen carbonate, sodium 
carbonate, potassium carbonate, cesium carbonate and the like or organic 
bases such as triethylamine, diethylamine, diisopropylamine, 
diisopropylethylamine, pyridine, imidazole and the like. 
The compound of the formula (19) 
EQU Q'O(CH.sub.2).sub.n-1 COOR' 
[wherein n and R' are as defined above and Q' represents a benzyl group, a 
substituted benzyl group (e.g., a p-methoxybenzyl group), an alkyl group 
(e.g., a methyl group or a tert-butyl group), a substituted methyl group 
(e.g., a methoxymethyl group), a substituted ethyl group (e.g., a 
1-ethoxyethyl group) and a silyl group (e.g., a triethylsilyl group or a 
tert-butyldimethylsilyl group)] is obtained by reacting the compound (16) 
with 0.2 to 2 equivalents of Q'X' [wherein X' is halogen such as chlorine, 
bromine, iodine and the like or a leaving group such as sulfonate and the 
like and Q is as defined above and Q' represents a benzyl group, a 
substituted benzyl group (e.g., a p-methoxybenzyl group), an alkyl group 
(e.g., a methyl group or a tert-butyl group), a substituted methyl group 
(e.g., a methoxymethyl group), a substituted ethyl group (e.g., a 
1-ethoxyethyl group) and a silyl group (e.g., a triethylsilyl group or a 
tert-butyldimethylsilyl group)] in a solvent in the presence of 0.2 to 2 
equivalents of a base at a temperature from 0.degree. C. to a reflux 
temperature. As the solvent, there may be mentioned dichloromethane, 
chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, dioxane, 
benzene, toluene, xylene, acetonitrile, dimethylformamide, dimethyl 
sulfoxide and the like and a mixed solvent thereof. As the base, there may 
be mentioned inorganic bases such as sodium hydrogen carbonate, sodium 
carbonate, potassium carbonate, cesium carbonate and the like or organic 
bases such as triethylamine, diethylamine, diisopropylamine, 
diisopropylethylamine, pyridine, imidazole and the like. 
The compound (13) can be prepared by treating the compound (19) in a 
solvent in the presence of a reducing agent at a temperature from 
-78.degree. C. to a reflux temperature. As the solvent, there may be 
mentioned dichloromethane, chloroform, carbon tetrachloride, 
tetrahydrofuran, ether, dioxane, benzene, toluene, xylene and the like and 
a mixed solvent thereof. As the reducing agent, there may be mentioned 
aluminum reagents such as lithium aluminum hydride, diisobutylaluminum and 
the like or diborane and the like. 
Specific examples of the compounds of the formula (1) are given below: 
N-(14-nitroxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(14-nitroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-nitroxytetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-nitroxytetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-nitroxytetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(14-nitroxytetradecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-nitroxytetradecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(14-nitroxytetradecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(15-nitroxypentadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(15-nitroxypentadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-nitroxypentadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-nitroxypentadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-nitroxypentadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(15-nitroxypentadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-nitroxypentadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(15-nitroxypentadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(16-nitroxyhexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(16-nitroxyhexadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-nitroxyhexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-nitroxyhexadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-nitroxyhexadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide 
N-(16-nitroxyhexadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-nitroxyhexadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-nitroxyhexadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide 
N-(17-nitroxyheptadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(17-nitroxyheptadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-nitroxyheptadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-nitroxyheptadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-nitroxyheptadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(17-nitroxyheptadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-nitroxyheptadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(17-nitroxyheptadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(18-nitroxyoctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(18-nitroxyoctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-nitroxyoctadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-nitroxyoctadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-nitroxyoctadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide 
N-(18-nitroxyoctadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-nitroxyoctadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-nitroxyoctadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide 
. 
Specific examples of the compounds of the formula (2) are given below: 
N-(14-hydroxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(14-hydroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-hydroxytetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-hydroxytetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-hydroxytetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(14-hydroxytetradecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-hydroxytetradecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(14-hydroxytetradecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(15-hydroxypentadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(15-hydroxypentadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-hydroxypentadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-hydroxypentadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-hydroxypentadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(15-hydroxypentadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-hydroxypentadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(15-hydroxypentadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(16-hydroxyhexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(16-hydroxyhexadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-hydroxyhexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-hydroxyhexadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-hydroxyhexadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide 
N-(16-hydroxyhexadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-hydroxyhexadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-hydroxyhexadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide 
N-(17-hydroxyheptadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(17-hydroxyheptadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-hydroxyheptadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-hydroxyheptadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-hydroxyheptadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(17-hydroxyheptadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-hydroxyheptadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(17-hydroxyheptadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(18-hydroxyoctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(18-hydroxyoctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-hydroxyoctadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-hydroxyoctadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-hydroxyoctadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide 
N-(18-hydroxyoctadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-hydroxyoctadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-hydroxyoctadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide 
N-(14-iodotetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(14-iodotetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-iodotetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-iodotetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-iodotetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-iodotetradecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-iodotetradecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-iodotetradecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-iodopentadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(15-iodopentadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-iodopentadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-iodopentadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-iodopentadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-iodopentadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-iodopentadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-iodopentadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-iodohexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(16-iodohexadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-iodohexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-iodohexadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-iodohexadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-iodohexadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-iodohexadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-iodohexadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-iodoheptadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(17-iodoheptadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-iodoheptadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-iodoheptadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-iodoheptadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-iodoheptadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-iodoheptadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-iodoheptadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-iodooctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(18-iodooctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-iodooctadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-iodooctadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-iodooctadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-iodooctadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-iodooctadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-iodooctadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-bromotetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(14-bromotetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-bromotetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-bromotetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-bromotetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-bromotetradecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-bromotetradecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-bromotetradecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-bromopentadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(15-bromopentadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-bromopentadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-bromopentadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-bromopentadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-bromopentadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-bromopentadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-bromopentadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-bromohexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(16-bromohexadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-bromohexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-bromohexadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-bromohexadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-bromohexadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-bromohexadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-bromohexadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-bromoheptadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(17-bromoheptadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-bromoheptadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-bromoheptadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-bromoheptadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-bromoheptadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-bromoheptadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-bromoheptadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-bromooctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(18-bromooctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-bromooctadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-bromooctadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-bromooctadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-bromooctadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-bromooctadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-bromooctadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-mesyloxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(14-mesyloxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-mesyloxytetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-mesyloxytetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-mesyoxytetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(14-mesyloxytetradecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-mesyloxytetradecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(14-mesyloxytetradecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(15-mesyloxypentadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(15-mesyloxypentadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-mesyloxypentadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-mesylpentadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-mesyloxypentadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(15-mesyloxypentadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-mesyloxypentadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(15-mesyloxypentadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(16-mesyloxyhexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(16-mesyloxyhexadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-mesyloxyhexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-mesyloxyhexadecyl )-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-mesyloxyhexadecyl )-6- 
(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-mesyloxyhexadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-mesyloxyhexadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(16-mesyloxyhexadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(17-mesyloxyheptadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(17-mesyloxyheptadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-mesyloxyheptadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-mesyloxyheptadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-mesyloxyheptadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(17-mesyloxyheptadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-mesyloxyheptadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(17-mesyloxyheptadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(18-mesyloxyoctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(18-mesyloxyoctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-mesyloxyoctadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-mesyloxyoctadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-mesyloxyoctadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(18-mesyloxyoctadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-mesyloxyoctadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(18-mesyloxyoctadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(14-tosyloxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(14-tosyloxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-tosyloxytetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-tosyloxytetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-tosyltetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-tosyloxytetradecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(14-tosyloxytetradecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(14-tosyloxytetradecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(15-tosyloxypentadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(15-tosyloxypentadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-tosyloxypentadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-tosylpentadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-tosyloxypentadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(15-tosyloxypentadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(15-tosyloxypentadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(15-tosyloxypentadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(16-tosyloxyhexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(16-tosyloxyhexadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-tosyloxyhexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-tosyloxyhexadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(16-tosyloxyhexadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(16-tosyloxyhexadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3- carboxamide, 
N-(16-tosyloxyhexadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(16-tosyloxyhexadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(17-tosyloxyheptadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(17-tosyloxyheptadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-tosyloxyheptadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-tosyloxyheptadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-tosyloxyheptadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(17-tosyloxyheptadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(17-tosyloxyheptadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(17-tosyloxyheptadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxami 
de, 
N-(18-tosyloxyoctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(18-tosyloxyoctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-tosyloxyoctadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-tosyloxyoctadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-tosyloxyoctadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e, 
N-(18-tosyloxyoctadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide, 
N-(18-tosyloxyoctadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-(18-tosyloxyoctadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e. 
Specific examples of the .omega.-aminoalkyl nitrate of the formula (4) are 
given below. 
14-Aminotetradecyl nitrate, 
15-aminopentadecyl nitrate, 
16-aminohexadecyl nitrate, 
18-aminooctadecyl nitrate. 
Specific examples of the compounds of the formula (5) are given below. 
N-(14-hydroxytetradecyl)-6-chloropyridine-3-carboxamide, 
N-(15-hydroxypentadecyl)-6-chloropyridine-3-carboxamide, 
N-(16-hydroxyhexadecyl)-6-chloropyridine-3-carboxamide, 
N-(17-hydroxyheptadecyl)-6-chloropyridine-3-carboxamide, 
N-(18-hydroxyoctadecyl)-6-chloropyridine-3-carboxamide, 
N-(13-hydroxytridecyl)-6-bromopyridine-3-carboxamide, 
N-(14-hydroxytetradecyl)-6-bromopyridine-3-carboxamide, 
N-(15-hydroxypentadecyl)-6-bromopyridine-3-carboxamide, 
N-(16-hydroxyhexadecyl)-6-bromopyridine-3-carboxamide, 
N-(17-hydroxyheptadecyl)-6-bromopyridine-3-carboxamide, 
N-(18-hydroxyoctadecyl)-6-bromopyridine-3-carboxamide. 
Specific examples of the compounds of the formula (6) are given below. 
1-Methylpiperazine, 
1-ethylpiperazine, 
1-propylpiperazine, 
1-isopropylpiperazine, 
1-butylpiperazine, 
1-isobutylpiperazine, 
1-sec-butylpiperazine. 
Specific examples of the compounds of the formula (7) are given below. 
N-(14-hydroxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(15-hydroxypentadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(16-hydroxyhexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(17-hydroxyheptadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
N-(18-hydroxyoctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide. 
Specific examples of the compounds of the formula (8) are given below. 
6-Chloronicotinic acid, 
6-bromonicotinic acid. 
Specific examples of the compounds of the formula (9) are given below. 
14-Aminotetradecanol, 
15-aminopentadecanol, 
16-aminohexadecanol, 
17-aminoheptadecanol, 
18-aminooctadecanol. 
Specific examples of the compounds of the formula (10) are given below. 
6-Chloronicotinoyl chloride, 
6-bromonicotinoyl chloride. 
Specific examples of the compounds of the formula (11) are given below. 
1,14-Tetradecanediol, 
1,15-pentadecanediol, 
1,16-hexadecanediol, 
1,17-heptadecanediol, 
1,18-octadecanediol. 
Specific examples of the compounds of the formula (12) are given below. 
N-(14-Hydroxytetradecyl)phthalimide, 
N-(15-hydroxypentadecyl)phthalimide, 
N-(16-hydroxyhexadecyl)phthalimide, 
N-(17-hydroxyheptadecyl)phthalimide, 
N-(18-hydroxyoctadecyl)phthalimide. 
Specific examples of the compounds of the formula (13) are given below. 
14-Methoxymethoxytetradecanol, 
15-methoxymethoxypentadecanol, 
16-methoxymethoxyhexadecanol, 
17-methoxymethoxyheptadecanol, 
18-methoxymethoxyoctadecanol. 
Specific examples of the compounds of the formula (14) are given below. 
N-(14-Methoxymethoxytetradecyl)phthalimide, 
N-(15-methoxymethoxypentadecyl)phthalimide, 
N-(16-methoxymethoxyhexadecyl)phthalimide, 
N-(17-methoxymethoxyheptadecyl)phthalimide, 
N-(18-methoxymethoxyoctadecyl)phthalimide. 
Specific examples of the compounds of the formula (15) are given below. 
14-Methoxymethoxytetradecylamine, 
15-methoxymethoxypentadecylamine, 
16-methoxymethoxyhexadecylamine, 
17-methoxymethoxyheptadecylamine, 
18-methoxymethoxyoctadecylamine. 
Specific examples of the compounds of the formula (16) are given below. 
Methyl 14-hydroxytetradecanoate, 
methyl 15-hydroxypentadecanoate, 
methyl 16-hydroxyhexadecanoate, 
methyl 17-hydroxyheptadecanoate, 
methyl 18-hydroxyoctadecanoate, 
ethyl 14-hydroxytetradecanoate, 
ethyl 15-hydroxypentadecanoate, 
ethyl 16-hydroxyhexadecanoate, 
ethyl 17-hydroxyheptadecanoate, 
ethyl 18-hydroxyoctadecanoate. 
Specific examples of the compounds of the formula (17) are given below. 
Methyl 14-phthalimidotetradecanoate, 
methyl 15-phthalimidopentadecanoate, 
methyl 16-phthalimidohexadecanoate, 
methyl 17-phthalimidoheptadecanoate, 
methyl 18-phthalimodooctadecanoate, 
ethyl 14-phthalimidotetradecanoate, 
ethyl 15-phthalimidopentadecanoate, 
ethyl 16-phthalimidohexadecanoate, 
ethyl 17-phthalimidoheptadecanoate, 
ethyl 18-phthalimodooctadecanoate. 
Specific examples of the compounds of the formula (18) are given below. 
Methyl 14-aminotetradecanoate, 
methyl 15-aminopentadecanoate, 
methyl 16-aminohexadecanoate, 
methyl 17-aminoheptadecanoate, 
methyl 18-aminooctadecanoate, 
ethyl 14-aminotetradecanoate, 
ethyl 15-aminopentadecanoate, 
ethyl 16-aminohexadecanoate, 
ethyl 17-aminoheptadecanoate, 
ethyl 18-aminooctadecanoate. 
Specific examples of the compounds of the formula (19) are given below. 
Methyl 14-methoxymethoxytetradecanoate, 
methyl 15-methoxymethoxypentadecanoate, 
methyl 16-methoxymethoxyhexadecanoate, 
methyl 17-methoxymethoxyheptadecanoate, 
methyl 18-methoxymethoxyoctadecanoate, 
ethyl 14-methoxymethoxytetradecanoate, 
ethyl 15-methoxymethoxypentadecanoate, 
ethyl 16-methoxymethoxyhexadecanoate, 
ethyl 17-methoxymethoxyheptadecanoate, 
ethyl 18-methoxymethoxyoctadecanoate. 
As the pharmaceutically acceptable salts of the compounds according to this 
invention, there may be mentioned, for example, hydrochloride, sulfate, 
nitrate, hydrobromide, phosphate, maleate, fumarate, tartarate, malate, 
succinate, malonate, propionate, methanesulfonate, benzenesulfonate, 
p-toluenesulfonate, formate, acetate, trifluoroacetate and the like, and 
those compounds containing plural acidic functional groups such as 
carboxyl or the like may be isolated in the form of an inorganic salt with 
a paired ion such as sodium, potassium, lithium, calcium, magnesium or the 
like. 
A part of the compound represented by the formula (1) according to this 
invention may be metabolized and converted in vivo to a novel pyridine 
derivative which is effective in the treatment of cerebrovascular 
disorders. Main metabolic sites are listed below. 
1) N-Oxidation at the 4-position of the piperazine ring and at the 
1-position of the pyridine ring. 
2) Hydroxylation of the piperazine ring, the pyridine ring and 
(CH.sub.2).sub.n and ring cleavage of the piperazine ring incidental to 
the hydroxylation. 
3) Hydroxylation and dealkylation of the alkyl group at the 4-position of 
the piperazine ring. 
4) Hydrolysis of the nitrate and the pyridine carboxamide. 
Main metabolites of the pyridinecarboxamides (1) of this invention are 
recited below. 
N-(14-nitroxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide N-oxide, 
N-(14-nitroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(14-nitroxytetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(14-nitroxytetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(14-nitroxytetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e N-oxide, 
N-(14-nitroxytetradecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(14-nitroxytetradecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(14-nitroxytetradecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e N-oxide, 
N-(15-nitroxypentadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide N-oxide, 
N-(15-nitroxypentadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(15-nitroxypentadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(15-nitroxypentadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(15-nitroxypentadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e N-oxide, 
N-(15-nitroxypentadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(15-nitroxypentadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(15-nitroxypentadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e N-oxide, 
N-(16-nitroxyhexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide N-oxide, 
N-(16-nitroxyhexadecyl)-6-(4-methyl-1-piperazinyl )pyridine-3-carboxamide 
N-oxide, 
N-(16-nitroxyhexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(16-nitroxyhexadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(16-nitroxyhexadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(16-nitroxyhexadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide N- 
oxide, 
N-(16-nitroxyhexadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(16-nitroxyhexadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(17-nitroxyheptadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide N-oxide, 
N-(17-nitroxyheptadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(17-nitroxyheptadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(17-nitroxyheptadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(17-nitroxyheptadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e N-oxide, 
N-(17-nitroxyheptadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(17-nitroxyheptadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(17-nitroxyheptadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamid 
e N-oxide, 
N-(18-nitroxyoctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide N-oxide, 
N-(18-nitroxyoctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(18-nitroxyoctadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(18-nitroxyoctadecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(18-nitroxyoctadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(18-nitroxyoctadecyl)-6-(4-butyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(18-nitroxyoctadecyl)-6-(4-isobutyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide, 
N-(18-nitroxyoctadecyl)-6-(4-sec-butyl-1-piperazinyl)pyridine-3-carboxamide 
N-oxide. 
The compounds (1) or pharmaceutically acceptable salts thereof according to 
this invention may be formulated to dosage forms such as tablets, 
granules, fine granules, powders, capsules, syrups, elixirs, suspensions, 
emulsions, injections and the like by incorporating suitable excipients, 
auxiliary agents, lubricants, antiseptics, disintegrating agents, buffer 
agents, binding agents, wetting agents, emulsifiers, coloring agents, 
corringents or flavors, and they may be administered orally or 
parenterally, preferably via intravenous injection or intravenous 
instillation. 
In preparing a pharmaceutical preparation as drugs for internal use, the 
conventionally applicable auxiliaries such as lactose, sucrose, sorbitol, 
mannitol, potato starch, corn starch, cellulose derivatives, gelatin and 
the like are suitable as a carrier and lubricants such as magnesium 
stearate, Carbowax, polyethylene glycol and the like may be further added. 
The active compound in admixture with the above may be formed into 
granules, tablets, capsules and the like according to a conventional 
method. 
In preparing a pharmaceutical preparation in the form of an aqueous 
preparation, the active ingredient may be dissolved in distilled water for 
injection and, if necessary, antioxidants, stabilizers, solubilizing 
agents, water-soluble surfactants, non-aqueous solvents, buffer agents, pH 
adjusters, preservatives, isotonic agents or soothing agents may be added 
and the resultant aqueous solution may be filtered, filled and sealed in a 
conventional manner and then sterilized by means of autoclaved 
sterilization or hot air sterilization to prepare injections. 
In preparing a pharmaceutical preparation in the form of an emulsifiable 
injection, the sterilized active ingredient may be dissolved in a 
non-aqueous solvent and, if necessary, distilled water for injection, 
antioxidants, stabilizers, solubilizing agents, water-soluble surfactants, 
buffer agents, pH adjusters, preservatives, isotonic agents or soothing 
agents may be added and then the resultant emulsion may be filtered, 
filled and sealed in a conventional manner to prepare injections. 
A dose of the compound or pharmaceutically acceptable salt thereof 
according to this invention may be selected depending upon the body 
weight, age, sex, lapsed time after onset, classification of diseases and 
others, and it is 1-1000 mg per day. 
BEST MODE FOR CARRYING OUT THE INVENTION 
This invention will be more specifically illustrated by way of the 
following Preparation Examples, Pharmacological Effect and Formulation 
Examples, but this invention is not intended to be limited thereto.

EXAMPLE 1 
N-(14-Nitroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
##STR13## 
To 5 ml of fuming nitric acid cooled to -10.degree. C. was gradually added 
0.5 g of 
N-(14-hydroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
and the mixture was stirred for 30 minutes. The reaction solution was 
poured into water, neutralized with sodium hydrogen carbonate and 
extracted with chloroform. The extract was dried over anhydrous sodium 
sulfate and distilled under reduced pressure. The residue thus obtained 
was chromatographed over silica gel column to afford the title compound as 
a colorless crystal. 
mp 82-83.degree. C. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.25-1.40 (m, 20H), 1.59 (quint, 2H), 
1.71 (quint, J=6.8 Hz, 2H), 2.34 (s, 3H), 2.50 (t, J=4.8 Hz, 4H), 3.42 (t, 
J=6.8 Hz, 2H), 3.66 (t, J=4.8 Hz, 4H), 4.44 (t, J=6.8 Hz, 2H), 5.92 (brs, 
1H), 6.62 (d, J=9.2 Hz, 1H), 7.90 (dd, J=2.4, 9.2 Hz, 1H), 8.53 (d, J=2.4 
Hz, 1H) 
EXAMPLE 2 
N-(14-Nitroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
EXAMPLE 2-1 
N-(14-Aminotetradecyl nitrate 
EQU H.sub.2 N(CH.sub.2).sub.14 ONO.sub.2 
To fumic nitric acid (25 ml) cooled to -30.degree. C. was added crystals of 
14-aminotetradecanol (8.48 g) while stirring for 30 minutes. The mixture 
was stirred below -20.degree. C. for a further 30 minutes, poured into 
ice-water, neutralized with sodium hydrogen carbonate and extracted with 
chloroform. The separated organic layer was distilled off under reduced 
pressure to afford the title compound as an oily substance. This product 
was provided for the subsequent reaction without purification. 
EXAMPLE 2-2 
N-(14-Nitroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
To sodium 6-(4-methylpiperazinyl)pyridine-3-carboxylate and 
14-aminotetradecyl nitrate was added 150 ml of methylene chloride and then 
6.80 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 
(WSCI) and 5.00 g of 1-hydroxybenzotriazole (HOBt) were added at room 
temperature while stirring and then the mixture was stirred at room 
temperature for 15 hours. The reaction solution was chromatographed over a 
silica gel column and the residue was purified by recrystallization to 
afford the title compound as a colorless crystal. 
EXAMPLE 3 
N-(14-Nitroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
EXAMPLE 3-1 
N-(14-Iodotetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
##STR14## 
A solution of 
N-(14-hydroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
in 57% hydriodic acid was stirred at 120.degree. C. for 30 minutes. The 
reaction solution was diluted with water and extracted with chloroform. 
The chloroform layer was washed successively with a saturated aqueous 
solution of sodium hydrogen carbonate and a saturated aqueous solution of 
sodium chloride and then dried over anhydrous magnesium sulfate. The 
solvent was distilled off under reduced pressure to afford the title 
compound. 
EXAMPLE 3-2 
N-(14-Nitroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
To a solution of 
N-(14-iodotetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide in 
toluene-acetonitrile was added silver nitrate and the mixture was stirred 
at 35.degree. C. for 3.5 hours. The reaction solution was filtered and 
then water and chloroform were added and the mixture was washed with a 
saturated aqueous solution of sodium chloride. The organic layer was dried 
over anhydrous magnesium sulfate and distilled off. The residue thus 
obtained was chromatographed over a silica gel column to afford the title 
compound. 
EXAMPLE 4 
N-(14-Nitroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
EXAMPLE 4-1 
N-(14-Mesyloxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
##STR15## 
To a solution of 
N-(14-hydroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
in chloroform were added triethylamine, pyridine and methanesulfonyl 
chloride and the mixture was stirred at room temperature for 30 minutes. 
The reaction solution was washed successively with water, 3N-hydrochloric 
acid and a saturated aqueous solution of sodium chloride and dried over 
anhydrous magnesium sulfate. The solvent was distilled off under reduced 
pressure and the residue thus obtained was chromatographed over a silica 
gel column to afford the title compound. 
EXAMPLE 4-2 
Preparation of Amberlyst A-26(manufactured by Rohm & Haas Co.) of a nitrate 
form 
50 g of Amberlyst A-26 (Cl form) was washed successively with 300 ml each 
of methanol, water and a 2.5N aqueous solution of sodium hydroxide and 350 
ml of ion exchanged water and then converted to the nitrate form with 300 
ml of 1N-nitric acid. After conversion, it was washed with ion exchanged 
water until it became neutral and then replaced with 200 ml of ethanol and 
100 ml of acetone. The Amberlyst A-26 (a nitrate form) thus obtained was 
dried at 50.degree. C. under reduced pressure for 2 hours. 
EXAMPLE 4-3 
N-(14-Nitroxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
To a solution of 
N-(14-mesyloxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
in toluene was added Amberlyst A-26 (a nitrate form) and the mixture was 
heated under reflux for 3 hours. The ion-exchange resin was filtered off 
and the filtrate was distilled off. The residue thus obtained was 
chromatographed over a silica gel column to afford 0.85 g of the title 
compound. 
EXAMPLE 5 
N-(14-Nitroxytetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
##STR16## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(14-hydroxytetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
to afford the title compound. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.13 (t, J=7 Hz, 3H), 1.21-1.44 (m, 20H), 
1.59 (quint, J=7 Hz, 2H), 1.72 (quint, J=7 Hz, 2H), 2.47 (q, J=7 Hz, 2H), 
2.54 (t, J=5 Hz, 4H), 3.42 (q, J=7 Hz, 2H), 3.67 (t, J=5 Hz, 4H), 4.44 (t, 
J=7 Hz, 2H), 5.86-5.94 (brm, 1H), 6.63 (d, J=9 Hz, 1H), 7.90 (dd, J=2, 9 
Hz, 1H), 8.53 (d, J=2 Hz, 1H) 
EXAMPLE 6 
N-(14-Nitroxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide 
##STR17## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(14-hydroxytetradecyl)-6-(1-piperazinyl)-pyridine-3-carboxamide to 
afford the title compound. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.18-1.44 (m, 20H), 1.60 (quint, J=7 Hz, 
2H), 1.72 (quint, J=7 Hz, 2H), 1.76-2.04 (b, 1H), 3.02 (t, J=5 Hz, 4H), 
3.43 (q, J=7 Hz, 2H), 3.66 (t, J=5 Hz, 4H), 4.44 (t, J=7 Hz, 2H), 
5.87-5.96 (brs, 1H), 6.63 (d, J=9 Hz, 1H), 7.91 (dd, J=2, 9 Hz, 1H), 8.54 
(d, J=2 Hz, 1H) 
EXAMPLE 7 
N-(14-Nitroxytetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide 
##STR18## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(14-hydroxytetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide 
to afford the title compound. 
.sup.1 H NMR (CDCl.sub.3) .delta. 0.93 (t, J=7 Hz, 3H), 1.18-1.44 (m, 20H), 
1.49-1.67 (m, 4H), 1.72 (quint, J=7 Hz, 2H), 2.35 (t, J=7 Hz, 2H), 2.54 
(t, J=5 Hz, 4H), 3.42 (q, J=7 Hz, 2H), 3.66 (t, J=5 Hz, 4H), 4.44 (t, J=7 
Hz, 2H), 5.86-5.95 (bm, 1H), 6.62 (d, J=9 Hz, 1H), 7.90 (dd, J=2,9 Hz, 
1H), 8.53 (d, J=2 Hz, 1H) 
EXAMPLE 8 
N-(14-Nitroxytetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e 
##STR19## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(14-hydroxytetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxami 
de to afford the title compound. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.09 (d, J=7 Hz, 6H), 1.20-1.42 (m, 20H), 
1.55-1.62 (m, 2H), 1.72 (quint, J=7 Hz, 2H), 2.56-2.68 (m, 4H), 2.68-2.81 
(m, 1H), 3.42 (q, J=7 Hz, 2H), 3.61-3.70 (m, 4H), 4.44 (t, J=7 Hz, 2H), 
5.84-5.96 (bm, 1H), 6.62 (d, J=9 Hz, 1H), 7.89 (dd, J=2, 9 Hz, 1H), 8.53 
(d, J=2 Hz, 1H) 
EXAMPLE 9 
N-(16-Nitroxyhexadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
##STR20## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(16-hydroxyhexadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
to afford the title compound as a colorless crystal. 
mp 85-87.5.degree. C. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.41 (m, 24H), 1.55-1.62 (m, 2H), 
1.67-1.75 (m, 2H), 2.34 (s, 3H), 2.50 (t, J=4.8 Hz, 4H), 3.42 (q, J=6.8 
Hz), 3.66 (t, J=4.8 Hz, 4H), 4.44 (t, J=6.8 Hz, 2H), 5.91 (brs, 1H), 6.62 
(d, J=9.2 Hz, 1H), 7.90 (dd, J=2.9, 9.2 Hz, 1H), 8.53 (d, J=2.9 Hz, 1H) 
EXAMPLE 10 
N-(16-Nitroxyhexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
##STR21## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(16-hydroxyhexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide to 
afford the title compound as a colorless crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.13 (t, J=7 Hz, 3H), 1.21-1.44 (m, 24H), 
1.49-1.65 (m, 2H), 1.71 (quint, J=7 Hz, 2H), 2.47 (q, J=7 Hz, 2H), 2.55 
(t,J=5 Hz, 4H), 3.42 (q, J=7 Hz, 2H), 3.68 (t, J=5 Hz, 4H), 4.44 (t, J=7 
Hz, 2H), 5.85-5.93 (bm, 1H), 6.63 (d, J=9 Hz, 1H), 7.90 (dd, J=2 Hz, 9 Hz, 
1H), 8.53 (d, J=2 Hz, 1H) 
EXAMPLE 11 
N-(16-Nitroxyhexadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide 
##STR22## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(16-hydroxyhexadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e to afford the title compound as a colorless crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.08 (d, J=6 Hz, 6H), 1.18-1.44 (m, 24H), 
1.49-1.65 (m, 2H), 1.72 (quint, J=7 Hz, 2H), 2.56-2.67 (m, 4H), 2.67-2.81 
(m, 1H), 3.42 (q, J=7 Hz, 2H), 3.60-3.71 (m, 4H), 4.44 (t, J=7 Hz, 2H), 
5.85-5.93 (bm, 1H), 6.62 (d, J=9 Hz, 1H), 7.89 (dd, J=2 Hz, 9 Hz, 1H), 
8.53 (d, J=2 Hz, 1H) 
EXAMPLE 12 
N-(16-Nitroxyhexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide 
##STR23## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(16-hydroxyhexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide to afford 
the title compound. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.25-1.50 (m, 24H), 1.59-1.67 (m, 2H), 
1.72 (quint, J=7 Hz, 2H), 2.98 (t, J=5 Hz, 4H), 3.42 (q, J=7 Hz, 2H), 3.62 
(t, J 5 Hz, 4H), 4.44 (t, J=7 Hz, 2H), 5.83-5.96 (brm, 1H), 6.62 (d, J=9 
Hz, 1H), 7.90 (dd, J=2, 9 Hz, 1H), 8.53 (d, J=2 Hz, 1H) 
EXAMPLE 13 
N-(18-Nitroxyoctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
##STR24## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(18-hydroxyoctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
to afford the title compound as a colorless crystal. 
mp 88.5-89.5.degree. C. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.22-1.41 (m, 28H), 1.59 (quint, J=7.3 
Hz, 2H), 1.67-1.75 (m, 2H), 2.34 (s, 3H), 2.51 (t, J=4.8 Hz, 4H), 3.42 (q, 
J=7.3 Hz, 2H), 3.66 (t, J=4.8 Hz, 4H), 4.44 (t, J=6.8 Hz, 2H), 5.90 (brs, 
1H), 6.62 (d, J=8.7 Hz, 1H), 7.90 (dd, J=2.4, 8.7 Hz, 1H), 8.53 (d, J=2.4 
Hz, 1H) 
EXAMPLE 14 
N-(18-Nitroxyoctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide 
##STR25## 
Synthesis was carried out in the same manner as described in Example 1 
using as a starting material 
N-(18-hydroxyoctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide to afford 
the title compound as colorless crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.18-1.44 (m, 28H), 1.60 (quint, J=7 Hz, 
2H), 1.71 (quint, J=7 Hz, 2H), 3.00 (t, J=5 Hz, 4H), 3.43 (q, J=7 Hz, 2H), 
3.64 (t, J=5 Hz, 4H), 4.44 (t, J=7 Hz, 2H), 5.86-5.96 (b, 1H), 6.62(d, J=9 
Hz, 1H), 7.91 (dd, J=2 Hz, 9 Hz, 1H), 8.53 (d, J=2 Hz, 1H) 
PREATION EXAMPLE 1 
N-(14-Hydroxytetradecyl)-6-(4-methyl--piperazinyl)pyridine-3-carboxamide 
##STR26## 
To 1.0 g of N-(14-hydroxytetradecyl)-6-chloropyridine-3-carboxamide was 
added 5 ml of 1-methylpiperazine and the mixture was heated at 160.degree. 
C. for 30 minutes. The reaction solution was diluted with chloroform and 
washed with water, dried over anhydrous sodium sulfate and then distilled 
off under reduced pressure. The residue thus obtained was chromatographed 
over a silica gel column to afford the title compound as crystals. 
mp 118.5-120.degree. C. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.25-1.32 (m, 20H), 1.53-1.61 (m, 4H), 
2.34 (s,3H), 2.51 (t, J=4.8 Hz, 4H), 3.39-3.44 (m, 2H), 3.62-3.67 (m, 6H), 
5.91 (brs, 1H), 6.62 (d, J=9.2 Hz, 1H), 7.90 (dd, J=2.4, 9.2 Hz, 1H), 8.52 
(d, J=2.4 Hz, 1H). 
PREATION EXAMPLE 2 
N-(14-Hydroxytetradecyl)-6-chloropyridine-3-carboxamide 
##STR27## 
To a suspension of 1.0 g of 14-aminotetradecanol and 0.68 g of 
6-chloronicotinic acid in 20 ml of dichloromethane was added 0.83 g of 
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCl) and 
then the mixture was stirred overnight. The precipitate was recovered by 
filtration with chloroform and washed with water to afford the title 
compound as a colorless crystal. The crystal thus obtained was used for 
the subsequent reaction without purification. 
PREATION EXAMPLE 3 
N-(14-Hydroxytetradecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
##STR28## 
Synthesis was carried out in the same manner as described in Preparation 
Example 1 using as a starting material 
N-(14-hydroxytetradecyl)-6-chloropyridine-3-carboxamide and 
1-ethylpiperazine to afford the title compound as a crystal. The crystal 
thus obtained was used for the subsequent reaction without purification. 
PREATION EXAMPLE 4 
N-(14-Hydroxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide 
##STR29## 
To a suspension of 2.50 g of 
N-(14-hydroxytetradecyl)-6-chloropyridine-3-carboxamide in 50 ml of 
toluene was added 3.0 g of piperazine and the mixture was heated under 
reflux for 10 hours. Then, the reaction solution was distilled under 
reduced pressure. The crystal thus obtained was used for the subsequent 
reaction without purification. 
PREATION EXAMPLE 5 
N-(14-Hydroxytetradecyl)-6-(4-propyl-1-piperazinyl)pyridine-3-carboxamide 
##STR30## 
A solution of 
N-(14-hydroxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 
1-bromopropane and potassium carbonate in dimethylformamide was heated at 
100.degree. C. for 3 hours. The reaction solution was diluted with 
chloroform and washed successively with water and a saturated aqueous 
solution of sodium chloride. It was dried over anhydrous sodium sulfate 
and the solvent was distilled off under reduced pressure. The residue thus 
obtained was chromatographed over a silica gel column to afford the title 
compound as a crystal. The crystal thus obtained was used for the 
subsequent reaction without purification. 
PREATION EXAMPLE 6 
N-(14-Hydroxytetradecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamid 
e 
##STR31## 
Synthesis was carried out in the same manner as described in Preparation 
Example 5 using as a starting material 
N-(14-hydroxytetradecyl)-6-(1-piperazinyl)pyridine-3-carboxamide and 
2-bromopropane to afford the title compound as a crystal. The crystal thus 
obtained was used for the subsequent reaction without purification. 
PREATION EXAMPLE 7 
N-(16-Hydroxyhexadecyl)-6-chloropyridine-3-carboxamide 
##STR32## 
Synthesis was carried out in the same manner as described in Preparation 
Example 2 using as starting materials 16-aminohexadecanol and 
6-chloronicotinic acid to afford the title compound as a colorless 
crystal. The crystal thus obtained was used for the subsequent reaction 
without purification. 
PREATION EXAMPLE 18 
N-(16-Hydroxyhexadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
##STR33## 
Synthesis was carried out in the same manner as described in Preparation 
Example 1 using as starting materials 
N-(16-hydroxyhexadecyl)-6-chloropyridine-3-carboxamide and 
1-methylpiperazine to afford the title compound as a crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.38 (m, 24H), 1.53-1.62 (m, 4H), 
2.34 (s,3H), 2.50 (t, J=4.8 Hz, 4H), 3.42 (q, J=6.8 Hz, 2H), 3.62-3.67 
(m,6H), 5.94 (brs, 1H), 6.62 (d, J=8.7 Hz, 1H), 7.90 (dd, J=2.4, 8.7 Hz, 
1H), 8.53 (d, J=2.4 Hz, 1H) 
PREATION EXAMPLE 9 
N-(16-Hydroxyhexadecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide 
##STR34## 
Synthesis was carried out in the same manner as described in Preparation 
Example 1 using as starting materials 
N-(16-hydroxyhexadecyl)-6-chloropyridine-3-carboxamide and 
1-ethylpiperazine to afford the title compound as a crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.13 (t, J=7 Hz, 3H), 1.19-1.41 (m, 24H), 
1.50-1.64 (m, 4H), 2.46 (q, J=7 Hz, 2H), 2.54 (t, J=5 Hz, 4H), 3.42 (q, 
J=7 Hz, 2H), 3.64 (t, J=7 Hz, 2H), 3.67 (t, J=5 Hz, 4H), 5.86-5.95 
(bm,1H), 6.63 (d, J=9 Hz, 1H), 7.90 (dd, J=2 Hz, 9 Hz, 1H), 8.53 (d, J=2 
Hz, 1H) 
PREATION EXAMPLE 10 
N-(16-Hydroxyhexadecyl)-6-(4-isopropyl-1-piperazinyl)pyridine-3-carboxamide 
##STR35## 
Synthesis was carried out in the same manner as described in Preparation 
Example 1 using as starting materials 
N-(16-hydroxyhexadecyl)-6-chloropyridine-3-carboxamide and 
1-isopropylpiperazine to afford the title compound as a crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.08 (d, J=6 Hz, 6H), 1.19-1.45 (m, 24H), 
1.49-1.69 (m, 4H), 2.62 (t, J=5 Hz, 4H), 2.73 (sept, J=6 Hz, 1H), 3.42 
(q,J=7 Hz, 2H), 3.57-3.73 (m, 6H), 5.91 (bt, J=6 Hz, 1H), 6.62 (d, J=9 Hz, 
1H), 7.89 (dd, J=2 Hz, 9 Hz, 1H), 8.53 (d, J=2 Hz, 1H) 
PREATION EXAMPLE 11 
N-(16-Hydroxyhexadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide 
##STR36## 
To a suspension of N-(16-hydroxyhexadecyl)-6-chloropyridine-3-carboxamide 
in toluene was added piperazine and the mixture was heated under reflux 
for 10 hours. Then, the reaction solution was distilled off under reduced 
pressure. The residue was chromatographed over a silica gel column to 
afford the title compound as a crystal. 
PREATION EXAMPLE 12 
N-(18-Hydroxyoctadecyl)-6-chloropyridine-3-carboxamide 
##STR37## 
Synthesis was carried out in the same manner as described in Preparation 
Example 2 using as starting materials 18-aminooctadecanol and 
6-chloronicotinic acid to afford the title compound as a crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.13-1.39 (m, 28H), 1.55-1.66 (m, 4H), 
3.46 (q, J=7.3 Hz, 2H), 3.64 (t, J=6.8 Hz, 2H), 6.08 (brs, 1H), 7.41 (d, 
J=8.3 Hz, 1H), 8.07 (dd, J=2.4, 8.3 Hz, 1H), 8.71 (d, J=2.4 Hz, 1H) 
PREATION EXAMPLE 13 
N-(18-Hydroxyoctadecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide 
##STR38## 
Synthesis was carried out in the same manner as described in Preparation 
Example 1 using as starting materials 
N-(18-hydroxyoctadecyl)-6-chloropyridine-3-carboxamide and 
1-methylpiperazine to afford the title compound as a crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.38 (m, 28H), 1.54-1.62 (m, 4H), 
2.35 (s, 3H), 2.51 (t, J=4.8 Hz, 4H), 3.42 (q, J=6.8 Hz, 2H), 3.63 (t, 
J=6.8 Hz, 2H), 3.66 (t, J=4.8 Hz, 4H), 6.91 (brs, 1H), 6.62 (d, J=8.7 Hz, 
1H), 7.90 (dd, J=2.4, 8.7 Hz, 1H), 8.52 (d, J=2.4 Hz, 1H) 
PREATION EXAMPLE 14 
N-(18-Hydroxyoctadecyl)-6-(1-piperazinyl)pyridine-3-carboxamide 
##STR39## 
To a suspension of 2.00 g of 
N-(18-hydroxyoctadecyl)-6-chloropyridine-3-carboxamide in 60 ml of toluene 
was added 4.00 g of piperazine and the mixture was heated under reflux for 
5 hours. Then, it was allowed to stand over 3 nights. The crystal thus 
precipitated out was dispersed in water and recovered by filtration. After 
washing with water, the crystal was dried under reduced pressure to afford 
a crude crystal of the title compound. It was dissolved in hot chloroform 
and insolubles were filtered off. The filtrate was distilled off at 
ordinary pressure, hexane was added, the crystal thus precipitated out was 
recovered by filtration and then dried under reduced pressure to afford 
1.47 g of the title compound as a crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.18-1.42 (28H, m, 14.times.CH2), 
1.47-1.65 (4H, m,2.times.CH2), 2.97 (4H, t, J=5 Hz, Piperaz 3, 5-H), 3.42 
(2H, q, J=7 Hz, 1-CH2), 3.61 (4H, t, J=5 Hz, Piperaz 2, 6 - H), 3.64 (2H, 
t, J=7 Hz, 18 - CH2), 5.86-5.95 (1H, b, CONH), 6.62 (1H, d, J=9 Hz, Py 5 - 
H), 7.90 (1H, dd, J=2 Hz, 9 Hz, Py 4 - H), 8.53 (1H, d, J=2 Hz, Py 2 - H) 
PREATION EXAMPLE 15 
Diethyl tetradecanedioate 
##STR40## 
To a solution of 5.0 g of tetradecanedioic acid in 100 ml of ethanol was 
added 0.2 ml of sulfuric acid and the mixture was heated under reflux for 
one hour. The reaction solution was distilled under reduced pressure and 
the residue was diluted with ethyl acetate and washed successively with 
water, a saturated aqueous solution of sodium hydrogen carbonate and a 
saturated aqueous solution of sodium chloride and dried over anhydrous 
sodium sulfate to afford the title compound as a pale yellow oily 
substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.28 (m, 22H), 1.59-1.63 (m, 4H), 
2.38 (t,J=7.8 Hz, 4H), 4.12 (q, J=7.3 Hz, 4H) 
PREATION EXAMPLE 16 
1,14-Tetradecanediol 
##STR41## 
To a solution of 6.0 g of diethyl tetradecanedioate in 80 ml of 
tetrahydrofuran was added 1.5 g of lithium aluminum hydride and the 
mixture was stirred for one hour. After addition of a saturated aqueous 
solution of sodium sulfate, the insolubles thus precipitated out was 
filtered off and the filtrate was distilled under reduced pressure to 
afford the title compound. 
.sup.1 H NMR (CD.sub.3 OD) .delta. 1.30-1.38 (m, 20H), 1.48-1.53 (m, 4H), 
3.52 (t, J=6.8 Hz, 4H) 
PREATION EXAMPLE 17 
N-(14-Hydroxytetradecyl)phthalimide 
##STR42## 
To a suspension of 4.0 g of 1,14-tetradecanediol, 4.56 g of 
triphenylphosphine and 2.25 g of phthalimide in 150 ml of tetrahydrofuran 
was added dropwise at 0.degree. C. a solution of 7.59 ml of diethyl 
azodicarboxylate (40%/toluene) in 10 ml of tetrahydrofuran and the mixture 
was stirred at room temperature overnight. The reaction solution was 
distilled under reduced pressure, diethyl ether was added to the residue 
and the precipitate thus separated was filtered off. The filtrate was 
distilled under reduced pressure and chromatographed over a silica gel 
column to afford the title compound as a crystal. The crystal thus 
obtained was used for the subsequent reaction without purification. 
PREATION EXAMPLE 18 
N-(14-Hydroxytetradecyl)phthalimide 
To 19.5 g of 1,14-tetradecanediol were added 200 ml of toluene and 29.5 ml 
of 48% hydrobromic acid and the mixture was heated under reflux for 2 
hours. After completion of the reaction, the reaction solution was washed 
with an aqueous solution of sodium hydrogen carbonate and the solvent was 
distilled off. 
The reaction solution was distilled and to the residue thus obtained were 
added 30 g of potassium phthalimide and 200 ml of DMF and the mixture was 
allowed to react at 100.degree. C. for 3 hours. After the reaction 
solution was distilled, the residue was chromatographed over silica gel 
column to afford the title compound as a colorless crystal. 
PREATION EXAMPLE 19 
14-Aminotetradecanol 
EQU HO(CH.sub.2).sub.14 NH.sub.2 
To a suspension of N-(14-hydroxytetradecyl)phthalimide in 100 ml of 
methanol was added 0.87 g of hydrazine monohydrate and the mixture was 
heated under reflux for 3 hours. The reaction solution was distilled under 
reduced pressure and the residue was diluted with a 1N aqueous solution of 
sodium hydroxide and then extracted twice with chloroform. The organic 
layers were combined, washed with a saturated aqueous solution of sodium 
chloride, dried over anhydrous sodium sulfate and then distilled under 
reduced pressure. Chromatography over silica gel afforded the title 
compound as a colorless crystal. 
PREATION EXAMPLE 20 
Ethyl 16-hydroxyhexadecanoate 
EQU HO(CH.sub.2).sub.15 COOEt 
To a solution of 5.0 g of 16-hydroxyhexadecanoic acid in 100 ml of ethanol 
was added 0.2 ml of sulfuric acid and the mixture was heated under reflux 
for one hour. The reaction solution was distilled off under reduced 
pressure. The residue was diluted with ethyl acetate and washed 
successively with water, a saturated aqueous solution of sodium hydrogen 
carbonate and a saturated aqueous solution of sodium chloride, dried over 
anhydrous sodium sulfate and then distilled under reduced pressure to 
afford the title compound. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.27 (m, 27H), 1.54-1.61 (m, 2H), 
2.28 (t, J=7.3 Hz, 2H), 3.64 (t, J=6.3 Hz, 2H), 4.12 (q, J=7.3 Hz, 2H) 
PREATION EXAMPLE 21 
Ethyl 16-methoxymethoxyhexadecanoate 
EQU MOMO(CH.sub.2).sub.15 COOEt 
To a solution of 5.44 g of ethyl 16-hydroxyhexadecanoate in 80 ml of 
dichloromethane was added under ice-cooling 1.63 ml of methoxymethyl 
chloride, 4.1 ml of diisopropylethylamine was added dropwise and then the 
mixture was stirred overnight. The reaction solution was diluted with 
chloroform, washed with water, dried over anhydrous sodium sulfate and 
distilled under reduced pressure. The residue was chromatographed over a 
silica gel column to afford the title compound as a colorless oily 
substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.27 (m, 27H), 1.55-1.63 (m, 2H), 
2.28 (t, J=7.3 Hz, 2H), 3.36 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 4.12 (q, 
J=7.3 Hz, 2H), 4.62 (s, 2H) 
PREATION EXAMPLE 22 
16-Methoxymethoxyhexadecanol 
EQU MOMO(CH.sub.2).sub.16 OH 
To a solution of 3.0 g of ethyl 16-methoxymethoxyhexadecanoate in 50 ml of 
tetrahydrofuran was added under ice-cooling 1.5 g of lithium aluminum 
hydride and the mixture was stirred for one hour. After a saturated 
aqueous solution of sodium sulfate was added, the insolubles precipitated 
out were filtered off and distilled under reduced pressure. The residue 
was chromatographed over a silica gel column to afford the title compound 
as a colorless oily substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.36 (m, 24H), 1.53-1.62 (m, 4H), 
3.36 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 3.63-3.64 (m, 2H), 4.62 (s, 2H) 
PREATION EXAMPLE 23 
N-(16-Methoxymethoxyhexadecyl)phthalimide 
##STR43## 
To a solution of 1.0 g of 16-methoxymethoxyhexadecanol, 0.86 g of 
triphenylphosphine and 0.48 g of phthalimide in 25 ml of tetrahydrofuran 
was added dropwise under ice-cooling a solution of diethyl 
azodicarboxylate in 5 ml of tetrahydrofuran and the mixture was stirred 
overnight. The reaction solution was distilled under reduced pressure and 
chromatographed over a silica gel column to afford the title compound as a 
colorless crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.22-1.36 (m, 24H), 1.54-1.68 (m, 4H), 
3.36 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 3.67 (t, J=7.3 Hz, 2H), 4.62 (s, 
2H), 7.69-7.71 (m, 2H), 7.83-7.85 (m, 2H) 
PREATION EXAMPLE 24 
16-Methoxymethoxyhexadecylamine 
EQU MOMO(CH.sub.2).sub.16 NH.sub.2 
To a suspension of 0.97 g of N-(16-methoxymethoxyhexadecyl)phthalimide in 
50 ml of ethanol was added 0.4 ml of hydrazine monohydrate and the mixture 
was heated under reflux for 2 hours. The reaction solution was distilled 
under reduced pressure. The residue was diluted with chloroform, washed 
with a 1N aqueous solution of sodium hydroxide, dried over anhydrous 
sodium sulfate and then distilled under reduced pressure. The residue was 
chromatographed over a silica gel column to afford the title compound as a 
colorless oily substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.46 (m, 26H), 1.55-1.62 (m, 2H), 
2.68 (t, J=6.8 Hz, 2H), 3.36 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 4.62 (s, 2H) 
PREATION EXAMPLE 25 
16-Aminohexadecanol 
EQU HO(CH.sub.2).sub.16 NH.sub.2 
To a suspension of 0.65 g of 16-methoxymethoxyhexadecylamine in 40 ml of 
methanol was added 1 ml of conc. hydrochloric acid and the mixture was 
heated under reflux for one hour. The reaction solution was distilled 
under reduced pressure. The residue was diluted with a 1N aqueous solution 
of sodium hydroxide, extracted with chloroform, dried over anhydrous 
sodium sulfate and distilled under reduced pressure to afford the title 
compound as a colorless crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.28 (m, 24H), 1.41-1.46 (m, 2H), 
1.53-1.60 (m, 2H), 2.67 (t, J=6.8 Hz, 2H), 3.63 (t, J=6.3 Hz, 2H) 
PREATION EXAMPLE 26 
N-(16-Hydroxyhexadecyl)phthalimide 
##STR44## 
Synthesis was carried out in the same manner as described in Preparation 
Example 18 using as a starting material 1,16-hexadecanediol to afford the 
title compound. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.17-1.40 (m, 24H), 1.50-1.61 (m, 2H), 
1.61-1.70 (m, 2H), 3.63 (t, J=6 Hz, 2H), 3.67 (t, J=7 Hz, 2H), 7.70 (dd, 
J=3, 5 Hz, 2H), 7.84 (dd, J=3, 5 Hz, 2H) 
PREATION EXAMPLE 27 
16-Aminohexadecanol 
EQU HO(CH.sub.2).sub.16 NH.sub.2 
Synthesis was carried out in the same manner as described in Preparation 
Example 19 using as a starting material N-(16-hydroxyhexadecyl)phthalimide 
to afford the title compound. 
PREATION EXAMPLE 28 
Methyl 16-hydroxyhexadecanoate 
Synthesis was carried out in the same manner as described in Preparation 
Example 20 from 16-hydroxyhexadecanoic acid and methanol to afford the 
title compound. 
PREATION EXAMPLE 29 
Methyl 16-phthalimidehexadecanoate 
##STR45## 
Synthesis was carried out in the same manner as described in Preparation 
Example 23 using as a starting material methyl 16-hydroxyhexadecanoate to 
afford the title compound. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.19-1.37 (m, 22H), 1.54-1.71 (m, 4H), 
2.30 (t, J=8 Hz, 2H), 3.66 (s, 3H), 3.67 (t, J=7 Hz, 2H), 7.70 (dd, J=3 
Hz, 5 Hz, 2H), 7.84 (dd, J=3 Hz, 5 Hz, 2H) 
PREATION EXAMPLE 30 
Methyl 16-aminohexadecanoate 
EQU H.sub.2 N(CH.sub.2).sub.15 COOMe 
To a suspension of 3.08 g of methyl 16-phthalimidehexadecanoate in 100 ml 
of ethanol was added 3 ml of hydrazine monohydrate and the mixture was 
stirred overnight. The reaction solution was filtered, the filtrate was 
distilled. The residue thus obtained was extracted thrice with hot 
chloroform. The combined organic layer was distilled off to afford the 
title compound as a colorless crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.20-1.36 (m, 22H), 1.43 (quint, J=7 Hz, 
2H), 1.62 (quint, J=7 Hz, 2H), 2.30 (t, J=8 Hz, 2H), 2.67 (t, J=7 Hz, 2H), 
3.67 (s, 3H) 
PREATION EXAMPLE 31 
16-Aminohexadecanol 
EQU HO(CH.sub.2).sub.16 NH.sub.2 
In a mixed solvent of 75 ml of isopropyl ether and 25 ml of tetrahydrofuran 
was suspended 1.0 g of lithium aluminum hydride and to the suspension was 
added with stirring at room temperature 2.45 g of crystalline methyl 
16-aminohexadecanoate and the mixture was stirred overnight. To the 
reaction solution were added successively 1 ml of water, 1 ml of a 10% 
aqueous solution of sodium hydroxide and 3 ml of water and the insolubles 
thus precipitated out were filtered off. The insolubles were extracted 
with a mixed solvent of chloroform and methanol. Then, the extract was 
combined with the filtrate and the mixture was distilled to afford the 
title compound as a colorless crystal. 
PREATION EXAMPLE 32 
16-Methoxymethoxyhexadecanal 
EQU MOMO(CH.sub.2).sub.15 CHO 
To a solution of 1.23 ml of oxalyl chloride in 60 ml of dichloromethane was 
added dropwise at -78 .degree. C. a solution of 2.0 ml of dimethyl 
sulfoxide in 2 ml of dichloromethane. After stirring for 10 minutes, a 
solution of 2.13 g of 16-methoxymethoxyhexadecanol in 30 ml of 
dichloromethane was added dropwise and the mixture was allowed to slowly 
rise up to -20.degree. C. and then stirred for 15 minutes. 5.9 ml of 
triethylamine was added and the mixture was stirred at 0.degree. C. for 
one hour. To the reaction solution was added a saturated aqueous solution 
of ammonium chloride and extracted with chloroform. The extract was dried 
over anhydrous sodium sulfate, distilled under reduced pressure and 
chromatographed over a silica gel column to afford the title compound as a 
colorless oily substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.22-1.29 (m, 22H), 1.37-1.66 (m, 4H), 
2.42 (dt, J=1.9, 7.3 Hz, 2H), 3.36 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 4.62 
(s, 2H), 9.76 (t, J=1.9 Hz, 1H) 
PREATION EXAMPLE 33 
Ethyl (E)-18-methoxymethoxy-2-octadecenoate 
##STR46## 
To a suspension of 0.31 g of sodium hydride in 50 ml of tetrahydrofuran was 
added dropwise at 0.degree. C. a solution of 1.73 ml of diethyl 
phosphonacetic acid ethyl ester in 5 ml of tetrahydrofuran. After stirring 
for one hour, a solution of 2.17 g of 16-methoxymethoxyhexadecanal in 30 
ml of tetrahydrofuran was added dropwise and then the mixture was stirred 
for 1.5 hours. To the reaction solution was added a saturated aqueous 
solution of ammonium chloride and extracted with ethyl acetate. The 
extract was washed with a saturated aqueous solution of sodium chloride, 
dried over anhydrous sodium sulfate and distilled off under reduced 
pressure. Chromatography over a silica gel afforded the title compound as 
a colorless oily substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.30 (m, 25H), 1.37-1.48 (m, 2H), 
1.55-1.62 (m, 2H), 2.18 (dq, J=1.4, 7.3 Hz, 2H), 3.36 (s, 3H), 3.51 (t, 
J=6.3 Hz, 2H), 4.18 (q, J=7.3 Hz, 2H), 4.62 (s, 2H), 5.80 (dt, J=1.4,15.6 
Hz, 1H), 6.96 (dt, J=6.8, 15.6 Hz, 1H) 
PREATION EXAMPLE 34 
Ethyl 18-methoxymethoxyoctadecanoate 
##STR47## 
To a solution of 0.51 g of ethyl (E)-18-methoxymethoxy-2-octadecenoate in 
30 ml of ethanol was added 0.06 g of 10% palladium carbon and the mixture 
was stirred overnight under hydrogen atmosphere. After filtering off the 
catalyst, the filtrate was distilled under reduced pressure to afford the 
title compound as a colorless oily substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.23-1.37 (m, 29H), 1.55-1.65 (m, 4H), 
2.28 (t, J=7.3 Hz, 2H), 3.36 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 4.12 (q, 
J=7.8 Hz, 2H), 4.62 (s, 2H) 
PREATION EXAMPLE 35 
18-Methoxymethoxyoctadecanol 
EQU MOMO(CH.sub.2).sub.18 OH 
Synthesis was carried out in the same manner as described in Preparation 
Example 22 using as a starting material ethyl 
18-methoxymethoxyoctadecanoate to afford the title compound as a colorless 
crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.22-1.38 (m, 28H), 1.53-1.62 (m, 4H), 
3.36 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 3.61-3.66 (m, 2H), 4.62 (s, 2H) 
PREATION EXAMPLE 36 
N-(18-Methoxymethoxyoctadecyl)phthalimide 
##STR48## 
Synthesis was carried out in the same manner as described in Preparation 
Example 23 using as a starting material 18-methoxymethoxyoctadecanol to 
afford the title compound as a colorless crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.22-1.36 (m, 28H), 1.55-1.70 (m, 4H), 
3.36 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 3.67 (t, J=7.3 Hz, 2H), 4.62 (s, 
2H), 7.69-7.71 (m, 2H), 7.83-7.85 (m, 2H) 
PREATION EXAMPLE 37 
18-Methoxymethoxyoctadecylamine 
EQU MOMO(CH.sub.2).sub.18 NH.sub.2 
Synthesis was carried out in the same manner as described in Preparation 
Example 24 using as a starting material 
N-(18-methoxymethoxyoctadecyl)phthalimide to afford the title compound as 
a colorless waxy substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.22-1.35 (m, 28H), 1.37-1.47 (m, 2H), 
1.55-1.62 (m, 2H), 2.68 (t, J=6.8 Hz, 2H), 3.36 (s, 3H), 3.51 (t, J=6.8 
Hz, 2H), 4.62 (s, 2H) 
PREATION EXAMPLE 38 
18-Aminooctadecanol 
EQU HO(CH.sub.2).sub.18 NH.sub.2 
Synthesis was carried out in the same manner as described in Preparation 
Example 25 using as a starting material 18-methoxymethoxyoctadecylamine to 
afford the title compound as a colorless crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.24-1.46 (m, 30H), 1.56 (quint, J=6.8 
Hz, 2H), 2.67 (t, J=6.8 Hz, 2H), 3.63 (t, J=6.8 Hz, 2H) 
PREATION EXAMPLE 39 
Dimethyl 1,18-octadecanedioate 
##STR49## 
To a suspension of 10.18 g of 1,18-octadecanedioic acid in 200 ml of 
methanol was added dropwise at room temperature with stirring 1 ml of 
thionyl chloride and the mixture was stirred for 50 minutes. The reaction 
solution was stirred at 60.degree. C. for a further one hour and then 
allowed to cool. The crystal thus precipitated out was recovered by 
filtration to afford 10.78 g of the title compound. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.17-1.37 (m, 24H), 1.62 (quint, J=7 Hz, 
4H), 2.30 (t, J=8 Hz, 4H), 3.67 (s, 6H) 
PREATION EXAMPLE 40 
1,18-Octadecanediol 
##STR50## 
Synthesis was carried out in the same manner as described in Preparation 
Example 16 using as a starting material dimethyl 1,18-octadecanedioate to 
afford the title compound as a colorless crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.16-1.40 (m, 28H), 1.57 (quint, J=7 Hz, 
4H), 3.64 (t, J=7 Hz, 4H) 
PREATION EXAMPLE 41 
N-(18-Hydroxyoctadecyl)phthalimide 
##STR51## 
Synthesis was carried out in the same manner as described in Preparation 
Example 17 using as a starting material 1,18-octadecanediol to afford the 
title compound as a crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.16-1.41 (m, 28H), 1.50-1.62 (m, 2H), 
1.67 (quint, J=7 Hz, 2H), 3.64 (q, J=6 Hz, 2H), 3.67 (t, J=7 Hz, 2H), 
7.70(dd, J=3 Hz, 5 Hz, 2H), 7.84 (dd, J=3 Hz, 5 Hz, 2H) 
PREATION EXAMPLE 42 
18-Aminooctadecanol 
EQU HO(CH.sub.2).sub.18 NH.sub.2 
Synthesis was carried out in the same manner as described in Preparation 
Example 19 using as a starting material N-(18-hydroxyoctadecyl)phthalimide 
to afford the title compound as a crystal. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.18-1.39 (m, 28H), 1.43 (quint, J=7 Hz, 
2H), 1.56 (quint, J=7 Hz, 2H), 2.68 (q, J=7 Hz, 2H), 3.64 (t, J=7 Hz, 2H) 
PREATION EXAMPLE 43 
1-Isopropylpiperazine 
##STR52## 
PREATION EXAMPLE 43-1 
1-Acetyl-4-isopropylpiperazine 
To a mixture of 12.95 g of piperazine, 0.75 g of sodium iodide and 3.46 g 
of potassium carbonate were added successively 25 ml of methanol and 6.15 
g of 2-bromopropane and the mixture was stirred at 60.degree. C. for 4 
hours. Chloroform was added, washed with a saturated aqueous solution of 
sodium chloride, and dried over anhydrous magnesium sulfate. The solvent 
was distilled off under reduced pressure, 12 ml of acetic anhydride was 
added gradually and the mixture was stirred at room temperature for 2.5 
hours. The reaction solution was poured into ice, chloroform was added and 
then it was neutralized with sodium carbonate. After extracted with 
chloroform, the extract was dried over anhydrous magnesium sulfate and the 
solvent was distilled off under reduced pressure. The residue thus 
obtained was chromatographed over a silica gel column and the solvent was 
distilled off. The residue thus precipitated out was allowed to stand 
overnight and the diacetylpiperazine was filtered off to afford 7.26 g of 
the title compound as an oily substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.04 (d, J=6 Hz, 6H), 2.08 (s, 3H), 2.47 
(t, J=5 Hz, 2H), 2.51 (t, J=5 Hz, 2H), 2.71 (sept, J=6 Hz, 1H), 3.46 (t, 
J=5 Hz, 2H), 3.62 (t, J=5 Hz, 2H) 
PREATION EXAMPLE 43-2 
1-Isopropylpiperazine 
A mixture of 7.26 g of 1-acetyl-4-isopropylpiperazine, 100 ml of methanol 
and 10 g of potassium hydroxide was heated under reflux for 17 hours. 
After the solvent was distilled off, water and chloroform were added to 
perform extraction with chloroform and the extract was dried over 
anhydrous magnesium sulfate. The solvent was distilled off under reduced 
pressure to afford 5.78 g of the title compound as an oily substance. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.05 (d, J=6 Hz, 6H), 2.49 (bt, J=5 Hz, 
4H), 2.75 (sept, J=6 Hz, 1H), 2.90 (t, J=5 Hz, 4H) 
PREATION EXAMPLE 44 
Sodium 6-(4-methyl-1-piperazinyl)pyridine-3-carboxylate 
##STR53## 
To a solution of 1.48 g of sodium hydroxide in 4 ml of water were added 40 
ml of methanol and 8.70 g of methyl 
6-(4-methyl-1-piperazinyl)pyridine-3-carboxylate and the mixture was 
heated under reflux for 2 hours. Then, 0.20 g of sodium hydroxide was 
added and the mixture was heated under reflux for a further one hour and 
the solvent was distilled off. The residue was dispersed in acetone, 
recovered by filtration and dried under reduced pressure to afford the 
title compound as a crystal. This product was used for the subsequent 
reaction without purification. 
PREATION EXAMPLE 45 
Methyl 6-(4-methyl-1-piperazinyl)pyridine-3-carboxylate 
##STR54## 
To 10.2 g of methyl 6-chloronicotinate were added 6.24 g of 
methylpiperazine, 6 g of diisopropylamine, 6.1 g of sodium iodide and 60 
ml of DMF and the mixture was stirred at 120.degree. C. for 4 hours. After 
water was added, the reaction solution was extracted with ethyl acetate 
and the extract was washed with a saturated aqueous solution of sodium 
chloride and then distilled under reduced pressure to afford the title 
compound as a crystal. 
Pharmacological test results of the pyridinecarboxamide derivatives (I) of 
the present invention will be shown below. 
For comparison, the compound of Example 10 and the compound of Example 2 of 
JP-A-5-32630 were used, namely, 
N-(11-nitroxy-1-undecanyl)-6-(4-methyl-1-piperazinyl)nicotinamide 
(hereinafter referred to as "Comparative Compound 1"), and 
N-(12-nitroxy-1-dodecanyl)-6-(4-methyl-1-piperazinyl)nicotinamide 
(hereinafter referred to as "Comparative Compound 2"). 
The compounds of the present invention will be shown below in terms of the 
corresponding Example numbers. For example, "Compound 1" is meant to 
indicate the compound obtained by the present Example 1. 
1. Behavior suppressing action 
The effect of the present pyridinecarboxamide derivatives on general 
behaviors of mice was studied. 
Using ddY-strain mice of 7 weeks old, test substance was administered at 
100.mu.11/10 sec to the tail vein and behavior of the animal was observed 
over one hour. After the administration, sedative animal was evaluated as 
sedated, while animal with behavioral suppression was evaluated as 
suppressed. 
TABLE 1 
______________________________________ 
Behavioral suppression 
Test substance 
R n (10 mg/kg) 
______________________________________ 
Compound 1 Me 14 Non 
Compound 5 Et 14 Non 
Compound 6 H 14 Non 
Compound 7 n-Pr 14 Non 
Compound 8 i-Pr 14 Non 
Compound 9 Me 16 Non 
Compound 10 Et 16 Non 
Compound 11 i-Pr 16 Non 
Compound 13 Me 18 Non 
Comparative Me 11 Sedated 
Compound 1 
______________________________________ 
No abnormalities were observed in general behaviors with Compounds 1, 5, 6, 
7, 8, 9, 10, 11 and 13. However, it has become apparent that Comparative 
Compound 1 is not desirable as a therapeutic agent for cerebrovascular 
disorders because of the suppression of behavior being shown. 
2. Cerebral protective action 
Cerebral protective action of the pyridinecarboxamide derivatives of this 
invention (an anti-anoxia action) were studied using a hypoxic model of 
mice. 
Using ddY-strain male mice of 6 weeks old, the test substance of Compound 
1, Compound 10 or Compound 11 was intravenously administered to the tail 
vein at the dose of 1.0 mg/kg. After 30 minutes from the administration, 
animals were decapitated to measure a gasping duration. This measurement 
was made by two persons who had not been informed of the test substances 
and the measured values were averaged to obtain the data. Also, the test 
was carried out in the same manner as described above except that 
Comparative Compound 1 was administered instead of the test substances. 
The action of each substance will be shown in Table 2, with the gasping 
time of Comparative Compound 1 being defined as 1. 
TABLE 2 
______________________________________ 
Test substance 
R n Gasping duration 
______________________________________ 
Compound 1 Me 14 2.6 
Compound 10 Et 16 1.7 
Compound 11 i-Pr 16 1.4 
Comparative Me 11 1 
Compound 1 
______________________________________ 
The pyridinecarboxamide derivatives of this invention had a 1.4 to 2.6 
times higher cerebral protective action than Comparative Compound 1. 
It is believed that grasping after decapitation is controlled by the 
respiratory center and, if the nervous functions are maintained by the 
respiratory center, the gasping duration would be prolonged. Moreover, it 
is suggested that the ischemia with decapitation is related to the 
decrease in the intracerebral glucose which is believed to be essential as 
a nutrition component in the brain. In view of the foregoing, the 
pyridinecarboxamide derivatives of this invention can prolong the gasping 
duration and then are useful as a cerebral protective agent. 
3. Anti-cerebral edema action (Obstructive cerebral ischemia model using 
polyvinyl acetate) 
Inhibiting action on cerebral ischemia was studied in an obstructive 
cerebral ischemia model using polyvinyl acetate. 
The obstructive model was prepared as described below. (Hiroyoshi Nishi et 
al., Stroke 1989, 20:1236-1240) 
Wistar-strain male rats weighing 200-350 g were used and fixed at the 
dorsal position under anesthesia of ether and then the left common carotid 
artery, internal carotid artery, external carotid artery were isolated. 
The external carotid artery was ligated, the pterylgopalatine artery was 
fastened with clamp and a cannula was inserted from the external carotid 
artery toward the branch between the internal carotid artery and the 
common carotid artery. 5 .mu.l of a 3% polyvinyl acetate/52% ethanol 
solution in water was injected. After 30 seconds, the clamp was removed 
from the artery and then the wound was sutured. After 24 hours, animal was 
decapitated and the cerebrum was isolated, within 120 seconds from which 
wet weights of the left cerebrum and the right cerebrum were measured. The 
left and right cerebra were dried in an oven at 105.degree. C. for 24 
hours and then the dry weights were measured. A cerebral water content was 
calculated according to the following equation: 
##EQU1## 
Compound 1 or Compound 9 was intravenously injected to the tail vein at the 
doses of 1.0 mg/kg and 3.0 mg/kg before 5 minutes from the administration 
of polyvinyl acetate. 
Inhibitory rate of cerebral edema in the cerebral edema model using 
polyvinyl acetate are shown in Table 3. 
TABLE 3 
______________________________________ 
Test substance R n 1 mg/kg 
______________________________________ 
Compound 1 Me 14 44.0% 
Compound 9 Me 16 33.3% 
______________________________________ 
Compounds 1 and 9 inhibited cerebral edema at 44.0% and 33.3%, 
respectively. 
4. Anti-cerebral edema action (Ischemic reperfusion model using SHR-SP) 
The pyridinecarboxamide derivatives of this invention were studied for the 
inhibitory action on cerebral edema with the model using SHR-SP 
(Spontaneous hypertensive rats which are vulnerable to cerebral 
hemorrhage). 
Male SHR-SP of 15-17 weeks old were measured for the blood pressure one day 
before the testing and classified into groups. Both common carotid 
arteries were separated under pentobarbital anesthesia at 35 mg/kg and 
common carotid arteries were fastened by clamp to cause ischemia. After 2 
hours, the clamp was removed from the common carotid artery to reperfuse. 
After a further 2 hours, the animal was decapitated and the cerebrum 
excised under ether anesthesia. The cerebrum was dried in an oven at 
105.degree. C. for 24 hours and the cerebral water content (%) was 
calculated. 
##EQU2## 
Compound 1 and Comparative Compound 2 were intravenously administered 
twice, that is, immediately after the ischemia and immediately before the 
reperfusion at the dose of 1 mg/kg, respectively. 
Inhibitory rates of cerebral ischemia by Compound 1 and Comparative 
Compound 2 are shown in Table 3-2. 
TABLE 3-2 
______________________________________ 
Test substance R n 
______________________________________ 
Compound 1 Me 14 63% 
Comparative Me 12 -90% 
Compound 2 
______________________________________ 
Compound 1 showed a potent anti-cerebral edema activity, whereas 
Comparative Compound 2 made cerebral edema worse. 
5. Inhibitory rate of delayed neuronal death 
MON/Jms/Gbs-strain male jirds (weighing 60-80 g) were fixed at the dorsal 
position under 1.5-2.0% halothane anesthesia and the common carotid artery 
was isolated. Ischemia was caused by fastening the common carotid artery 
with clamp for 3 minutes and then reperfused. After 7 days, the brain was 
excised under ether anesthesia and fixed with 10% formalin for 2 days and 
then tissue slices of the hippocampus were prepared. The hippocampus CA1 
cells were stained using HE staining and the survival rate of the CA1 
cells was evaluated. 
Compound 1 was administered to the carotid artery at the dose of 0.5 mg/kg 
immediately after ischemia. Using as a control the case wherein the drug 
was not administered, inhibitory rate was calculated according to the 
following equation: 
##EQU3## 
TABLE 4 
______________________________________ 
R n Inhibitory rate 
______________________________________ 
Compound 1 Me 14 47% 
______________________________________ 
6. Hypotensive activity 
The action on blood pressure was studied using rats. 
Using Wistar-strain male rats, animals were anesthetized by intraperitoneal 
administration of thiopental and then a tracheal cannula, a cannula for 
measuring blood pressure into the right femoral artery, a cannula for 
continuous anesthesia into the right femoral vein and a cannula for 
administering Compound 1, Compound 5, Compound 8 and Compound 9 into the 
left femoral vein were inserted. In the right femoral artery cannula, 
blood pressure was measured by means of an amplifier for measuring blood 
pressure (Nihon Koden Co., Ltd., AP-601G) via a transducer (Gould, CA930). 
.alpha.-Chloralose was administered at 40 mg/kg/hr via the right femoral 
vein cannula to maintain anesthesia. The tracheal cannula was connected to 
a respirator (Haward, MODEL 683) and controlled respiration was applied at 
50 strokes/min., 1 ml/100 g b.w. And, 100% oxygen was charged to the 
inspiratory port of the respirator and an oxygen rate was adjusted to 50 
ml/min. by means of a flow meter. A rectum temperature was maintained at 
37.degree. C. by means of a heating pad. 
After blood pressure was stabilized, test substance was administered at 1.0 
mg/kg via the vein cannula. Also, Comparative Compound 2 was administered 
as a control substance in the same manner as described above. The blood 
pressure was measured after one minute from the administration of the test 
substance and a percent to the blood pressure value before the 
administration was calculated. 
TABLE 5 
______________________________________ 
Test substance 
R n Decrease in blood pressure (%) 
______________________________________ 
Compound 1 
Me 14 11.2 
Compound 5 
Et 14 15.2 
Compound 8 
i-Pr 14 10.2 
Compound 9 
Me 16 7.7 
Comparative 
Me 12 43.9 
Compound 2 
______________________________________ 
It is shown from Table 5 that the pyridinecarboxamide derivatives of this 
invention do hardly affect blood pressure. However, it is believed that 
the compound of Comparative Compound 2 could make worse the ischemic 
condition derived from cerebrovascular disorders and then is not desirable 
as a therapeutic agent for cerebral edema in view of the decrease of the 
blood pressure of 44%. 
7. Inhibitory action on lipid peroxidation 
Inhibitory action on lipid peroxidation was studied in rat brain 
homogenate. 
Wistar-strain male rats (weighing 230-300 g) were decapitated and the 
cerebrum was quickly excised. A 4 times volume of a solution of 50 mM 
phosphoric acid and 0.142 mM NaCl (pH 7.4) was added and the mixture was 
homogenated and then centrifuged at 3000 rpm for 10 minutes. The 
supernatant thus obtained was prepared to give a protein level of 2 mg/ml. 
Determination of lipid peroxide was carried out using TBA method 
(thiobarbituric acid). To the brain homogenate was added each of Compound 
1, Compound 5, Compound 6, Compound 8, Compound 9, Compound 11 and 
Compound 14 as a test substance to give a final concentration of 10.sup.-4 
M, thereby initiating the reaction. After incubation at 37.degree. C. for 
15 minutes, the reaction was stopped in ice by adding a 35% perchloric 
acid solution. The reaction mixture was centrifuged at 4.degree. C. and 
1000 rpm for 5 minutes and to the supernatant thus obtained was added a 
0.5% TBA solution. The mixture was boiled at 100.degree. C. for 15 
minutes. After cooling, absorbance was determined at 532 nm. 
1,1,3,3-Tetraethoxypropane as a standard was subjected to the reaction in 
the same manner as above and an amount of lipid peroxide, that is, an 
amount of the malondialdehyde (MDA) produced was determined from the 
absorbance. 
Inhibitory rate of lipid peroxidation was calculated according to the 
following equation: 
##EQU4## 
TABLE 6 
______________________________________ 
Inhibitory rate of lipid 
Test substance 
R n peroxidation (%) 
______________________________________ 
Compound 1 Me 14 91 
Compound 5 Et 14 69 
Compound 6 H 14 59 
Compound 8 i-Pr 14 70 
Compound 9 Me 16 72 
Compound 11 i-Pr 16 53 
Compound 14 H 18 75 
______________________________________ 
It was observed from the results of Table 6 that the pyridinecarboxamide 
derivatives of this invention have an inhibitory action on lipid 
peroxidation.