Novel carboximidamide derivatives represented by the following formula (A) and acid adduct salts thereof are disclosed: ##STR1## wherein all the substituents have the same meanings as defined above. N-cyano-pyridinecarboximidate compounds represented by the following formula (II) which are the intermediates for preparing of N-cyano-N'-substituted-pyridinecarboximidamide derivatives wherein the substituent B in the above described formula (A) is pyridine is also disclosed: ##STR2## wherein all the substitutents have the same meanings as defined above. The process for preparing the compounds, the pharmaceutical agents comprising the compound having vasodilating effect, and the therapeutic method of dosing the compound on patients for therapy are also disclosed.

TECHNICAL FIELD 
The present invention relates to novel carboximidamide derivatives having 
vasodilating effect, more particularly N-cyano-N'-substituted 
pyridinecarboximidamide derivatives and N-cyano-N'-substituted 
carboximidamide derivatives in which N'-position is substituted by an 
alkyl substituent, or acid adduct salts thereof, intermediates for 
preparing them and a process for preparing them. 
The present invention also relates to potassium channel activating agents, 
hypotensors, therapeutic agents of ischemic heart disease, ameliorants of 
peripheral circulation, ameliorants of cerebral circulation, therapeutic 
agents of thrombosis and antasthmatics which contain as an active 
ingredient the above-described N-cyano-N'-substituted 
pyridinecarboximidamide derivative or an acid adduct salt thereof, and 
hypotensors which contain as an active ingredient the 
N-cyano-N'-substituted carboximidamide derivative wherein the N'-position 
is substituted by an alkyl group or an acid adduct salt thereof. The 
present invention further relates to the therapeutic methods for patients 
who need the treatments of potassium channel activation, the treatments of 
hypertension, the treatment of ischemic heart disease, the treatment of 
peripheral circulatory failure, the treatment of cerebral circulatory 
failure, the treatment of thrombosis and the asthma using the 
aforementioned N-cyano-N'-substituted pyridinecarboximidamide derivative 
or an acid adduct salt thereof, or the therapeutic method for patients who 
need hypotensive treatment using the N-cyano-N'-substituted 
carboximidamide derivative in which N'-position is substituted by an alkyl 
group or an acid adduct salt thereof. 
BACKGROUND ART 
As the well-known compounds among the N-cyanopyridinecarboximidamide 
compounds in relation to the present invention, there are mentioned 
N-cyano-3-pyridinecarboximidamide [see Journal of Medicinal Chemistry 23, 
690-692 (1980)], N-cyano-4-(2-ethylpyridine)carboximidamide (see Leprosy 
Review, 23-30, 1983) and N-cyano-4-pyridinecarboximidamide (see Bulletin 
des Societes Chimiques Belges, 78, 41-46, 1969). However, all of these 
compounds are the ones which have no substituent in N'-position and are 
reported only as the intermediates for producing of diuretics or as the 
agents for the treatment of Hansen's disease. There is no report of other 
utility. The syntheses of carboximidamides have been investigated from 
various aspects, and various synthetic methods mainly of 
benzenecarboximidamide compounds or alkylcarboximidamides are investigated 
(see, for example, "The Chemistry of amidines and imidates", Edited by 
Saul Patai, John Wiley and Sons, 1975). For example, in the case of an 
N-cyano-N'-substituted benzenecarboximidamide, a synthetic method which 
comprises converting cyanobenzene into an alkyl benzeneimidate, further 
reacting cyanamide (NH.sub.2 CN) with the alkyl benzeneimidate in pH 
6.5-7.0 to form an alkyl N-cyano-benzeneimidate and reacting an amine 
compound 25 with the aforementioned imidate has been proposed (see 
Synthesis, 263, 1971; Synthesis, 673-675, 1978; Journal of Organic 
Chemistry, 44, 1562-1563 (1979); Synthesis, 123-124, 1980; Synthesis, 
402-404, 1983). 
However, according to the conventional synthetic methods, particularly the 
synthesis within the above-described pH range, analkyl 
N-cyanopyridinecarboximidate is not produced, and thus an 
N-cyano-N'-substituted pyridinecarboximidamide compound could not be 
produced. 
On the other hand, as regards antihypertensive agents, a variety of 
pharmaceutical agents have been proposed, but, so far as the present 
inventor knows, none of these agents have satisfactory effects on the 
pathologies and patients of all kinds of hypertensions such as essential 
hypertension, secondary hypertension or the like. Also as regards the 
treatment of angina pectoris, calcium antagonists or .beta.-blockers and 
the like have hitherto been used, but the attack of angina pectoris is not 
completely suppressed by the use of these agents. There are reported no 
therapeutics having satisfactory cardioprotective effect after the 
reperfusion of coronary vessel when the pathology develops into myocardial 
infarction. New types of cardiovascular therapeutics with consideration 
for these points are continuously desired. 
For instance, as a cardiovascular therapeutic based on a new function 
mechanism, a compound having a potassium channel activating effect has 
recently been proposed. 
The potassium channel activating effect is an effect that potassium channel 
on cell membrane is opened and the permeability of potassium is enhanced 
so that hyperpolarization is caused and the contraction of smooth muscle 
or myocardium is suppressed. As compounds having potassium channel 
activating effect, there are known, for example, nicorandil, pinacidil and 
chromakalim (see Trends in Pharmacological Sciences, 8, 283, 1987). These 
exhibit vasodilating effect, antihypertensive effect, coronary blood flow 
increasing effect, cerebral vasodilative effect and bronchodilatative 
effect in animal experiments [see European Journal of Pharmacology, 152, 
331 (1988); The Journal of Pharmacology and Experimental Therapeutics, 
232, 369 (1985); Journal of Cardiovascular Pharmacology, 8, 798 (1986); 
Japan Heart Journal, 20, 881 (1979); European Journal of Pharmacology, 99, 
219 (1984); British Journal of Pharmacology, 95, 763 (1988)]. Furthermore, 
these agents clinically exhibit utilities as an antihypertensive drug [see 
Clinical Physiology, 1, 375 (1981); Journal of Hypertension, 4, S166 
(1986)] or as an antianginal drug [see RINSHO YAKURI, 13, 311 (1982)]. 
As the well-known carboximidamide compounds except the 
N-cyano-pyridinecarboximidamide compounds relating to the present 
invention, there are mentioned N-cyano-5-nitro-2-furamidine (Japanese 
Patent Publication No. 20453/68 and British Patent No. 1133950); 
N-cyano-2-thiophenecarboximidamide and N-cyano-3-thiophenecarboximidamide 
[Journal of Medicinal Chemistry, 23, 690-692 (1980)]; and 
N-(N-cyanoimidoyl)-sulfoximides [Chemisch Berichte, 121, 383-386 (1988)]. 
However, these compounds have been reported only as the intermediates in 
the production of anti-bacterial agents or diuretics and the intermediates 
in the production of thiatriazines, respectively, without descriptions of 
the vasodilating effect and hypotensive effect. Also, no carboximidamide 
compounds relating to the present invention which have an alkyl 
substituent in N'-position have hitherto been reported. 
SUMMARY OF THE INVENTION 
Summary 
The present invention has been done for the purpose of providing a new 
compound having vasodilating effect. The present inventor has discovered 
that N-cyano-N'-substituted pyridinecarboximidamide derivatives and 
N-cyano-N'-substituted carboximidamide derivatives in which the 
N'-position is substituted with an alkyl substituent have the 
aforementioned effect and find out from these novel carboximidamide 
derivatives the ones which are effective as a potassium channel activating 
agent, a hypotensor, a therapeutic for the treatment of ischemic heart 
disease, a therapeutic for the treatment of peripheral circulatory 
failure, an ameliorants of cerebral circulation, a therapeutic for the 
treatment of thrombosis and an antasthmatic. The present invention has 
been accomplished on the basis of these discoveries. 
In other words, the carboximidamide derivatives according to the present 
invention are represented by the following formula (A): 
##STR3## 
wherein when B is 
##STR4## 
wherein X represents a hydrogen atom or a chlorine atom, R"'represents 
--R.sup.1 or 
##STR5## 
wherein R.sup.1 represents an alkyl group, 
##STR6## 
or an alkyl group having a nitroxyl group, wherein R.sup.4 represents an 
alkyl group or an alkoxyl group and b denotes an integer of 0 or 1, and 
R.sup.2 represents one or more members selected from the group consisting 
of an alkyl group, an aryl group, a nitroxyl group, an arylalkoxyl group, 
a hydroxyl group and a hydrogen atom and a denotes an integer of 1-3, 
provided that when a is an integer of 2 or more, two or more R.sup.2' 's 
may be the same or different members in the aforementioned group, and 
R.sup.3 represents 
##STR7## 
wherein R.sup.5 represents one or more members selected from the group 
consisting of an alkyl group, an alkoxyl group, an arylalkoxyl group, a 
nitro group, an amino group, an alkylamino group, an arylalkylamino group, 
an alkylthio group, a perfluoroalkyl group or a halogen atom, and c 
denotes an integer of 0-5, provided that when c denotes an integer of 2 or 
more, two or more R.sup.5 's may be the same or different members in the 
aforementioned group; and 
##STR8## 
The present invention also relates to acid adduct salts thereof. 
The compound according to the present invention includes the compound which 
has pyridine as the substituent B in the formula (A) and the compound 
having no pyridine. 
The compound having pyridine as the substituent B is the 
pyridinecarboximidamide derivative represented by the following formula 
(I): 
##STR9## 
wherein 
X represents a hydrogen atom or a chlorine atom; R represents --R.sup.1 or 
##STR10## 
wherein R.sup.1 represents an alkyl group, 
##STR11## 
or an alkyl group having a nitroxyl group, wherein R.sup.4 represents an 
alkyl group or an alkoxy group and b denotes an integer of 0-1, R.sup.2 
represents one or more members selected from the group consisting of an 
alkyl group, an aryl group, a nitroxyl group, an arylalkoxyl group, a 
hydroxyl group and a hydrogen atom, and a denotes an integer of 1-3, 
provided that when a is an integer of 2 or more, two or more R.sup.2 's 
may be the same or different members in the aforementioned group, R.sup.3 
represents 
##STR12## 
wherein R.sup.5 represents one or more members selected from the group 
consisting of an alkyl group, an alkoxyl group, an arylalkoxyl group, a 
nitro group, an amino group, an alkylamino group, an arylalkylamino group, 
an alkylthio group, a perfluoroalkyl group or a halogen atom, c denotes an 
integer of 0-5, provided that when c denotes an integer of 2or more, two 
or more R.sup.5 's may be the same or different members in the 
aforementioned group; or an acid adduct salt thereof. 
The compound according to the present invention which has no pyridine as 
the substituent B is the carboximidamide derivative represented by the 
following formula (I'): 
##STR13## 
The present invention also relates to the intermediate obtained in the 
course of the production of the compound represented by the formula (I). 
The N-cyanopyuridinecarboximidate compound which is the intermediate 
obtained in the course of the production of the compound of the present 
invention is represented by the following formula (II): 
##STR14## 
wherein X represents a hydrogen atom or a chlorine atom, and R' represents 
an alkyl group. 
Furthermore, the present invention relates to the process for producing the 
compound represented by the formula (I). 
That is to say, the process for producing the pyridinecarboximidamide 
derivative represented by the formula (I) set forth above is characterized 
in that a cyanopyridine compound represented by the following formula 
(III) is reacted with an alcohol and sodium hydride or a sodium alkoxide 
to form a compound represented by the following formula (IV), which is 
reacted with cyanamide in a buffer solution having a pH in the range of 
5.0-6.0 to form an N-cyanopyridinecarboximidate compound represented by 
the above-described formula (II), which is further reacted with an amine 
compound represented by the formula NH.sub.2 --R, wherein R has the same 
meaning as defined above: 
##STR15## 
wherein X represents a hydrogen atom or a chlorine atom, and R' represents 
an alkyl group. 
The present invention also relates to the use of the carboximidamide 
derivatives represented by the above-described formula (A). In other 
words, the present invention relates to potassium channel activating 
agents, hypotensor, therapeutic agents of ischemic heat disease, 
therapeutic agents of peripheral circulatory failure, ameliorants of 
cerebral circulation, therapeutic agents of thrombosis and antasthmatics 
which contain the pyridinecarboximidamide derivative represented by the 
formula (I) or an acid adduct salt thereof as an effective ingredient, and 
hypotensors which contain as an active ingredient, and hypotensors which 
contain as an active ingredient the N-cyano-N'-substituted carboximidamide 
derivative wherein the N'-position is substituted by an alkyl group of an 
acid adduct salt thereof, and relates to the therapeutic methods for 
patients who need the treatments of potassium channel activation, the 
treatment of hypertension, the treatment of ischemic heart disease, the 
treatment of peripheral circulatory failure, the treatment of cerebral 
circulatory failure, the treatment of thrombosis and the asthma using the 
aforementioned N-cyano-N'-substituted pyridinecarboximidamide derivative 
or an acid adduct salt thereof, and the therapeutic method for patients 
who need hypotensive treatment using the N-cyano-N'-substituted 
carboximidamide derivative in which N'-position is substituted by an alkyl 
group or an acid adduct salts thereof. 
Effect of the Invention 
The carboximidamide derivatives according to the present invention have 
vasodilating effect and hypotensive effect, and the carboximidamide 
derivatives having a pyridine substituent have further potassium channel 
activating effect. 
The carboximidamide derivatives according to the present invention have 
vasodilative effect and hypotensive effect, and the 
pyridinecarboximidamide derivatives have further potassium channel 
activating effect as described above. They also have coronary vasodilative 
effect, cardioprotective effect, peripheral blood vessel resistance 
decreasing effect, cerebral vasodilative effect, platelet aggregation 
inhibiting effect and bronchodilatative effect. 
It should be extraordinary that the carboximidamide derivative according to 
the present invention has various physiological effects set forth above.

DETAILED DESCRIPTION OF THE INVENTION 
The carboximidamide derivatives according to the present invention are 
represented by the formula (A) set forth above and include the 
N-cyano-N'-substituted pyridinecarboximidamide derivatives having pyridine 
as the substituent B and the N-cyano-N'-substituted carboximidamide 
derivatives having no pyridine, wherein respective substituents have the 
same meanings as defined above. 
[I]N-cyano-N'-substituted-pyridinecarboximidamide derivatives 
The pyridinecarboximidamide derivative according to the present invention 
is the N-cyano-N'-substituted-pyridinecarboximidamide derivative 
represented by the formula (I) set forth above (wherein respective 
substituents have the same meanings as defined above). 
In the formula (I), the alkyl group of R.sup.1 has preferably 1-10 carbon 
atoms, particularly 5-8 carbon atoms. It may be the alkyl group in a 
straight chain or a branched chain, preferably in a branched chain. The 
alkyl group having a nitroxyl group of R.sup.1 is preferably the one 
having 1-5 carbon atoms, particularly 1-3 carbon atoms. In this case, one 
or more, preferably one or two, nitroxyl groups may be contained. The 
nitroxyl group may be bonded to either one of primary, secondary or 
tertiary carbon atoms, and particularly the nitroxyl group is desirably 
bonded to a primary carbon atom. 
The alkyl group of R.sup.2 has preferably 1-5 carbon atoms, particularly 
1-3 carbon atoms. The aryl group is preferably a tolyl group, a xylyl 
group or a phenyl group, more preferably a phenyl group. The arylalkoxyl 
group is preferably a phenethyloxy group, a 3-phenylpropyloxy group or a 
benzyloxy group, more preferably a benzyloxy group. 
When two or more R.sup.2 's are simultaneously contained, these plural 
R.sup.2 's may be the same or different members in the aforementioned 
group consisting of the groups and the atom set forth above. When R.sup.4 
is an alkyl group or an alkoxyl group, the alkyl or alkoxyl group 
preferably contains 1-5 carbon atoms, particularly 1-3 carbon atoms. 
R.sup.5 represents one or more members selected from the aforementioned 
group as defined above. When two or more R.sup.5 's are simultaneously 
contained, the R.sup.5 's may be the same or different members in the 
group. When R.sup.5 is an alkyl group or an alkoxyl group, the alkyl or 
alkoxyl group preferably contains 1-5 carbon atoms, particularly 1-3 
carbon atoms. When R.sup.5 is an arylalkoxyl group, the arylalkoxyl group 
is preferably a phenethyloxy group, a 3-phenylpropyloxy group or a 
benzyloxy group, particularly a benzyloxy group. The alkylamino group 
preferably contains 1-5 carbon atoms, preferably 1-3 carbon atoms. The 
arylalkylamino group is preferably a phenethylamino group, a 
3-phenylpropylamino group or a benzylamino group, more preferably a 
benzylamino group. When R.sup.5 is an alkylthio group or a perfluoroalkyl 
group, each of these groups preferably contains 1-5 carbon atoms, 
particularly 1-3 carbon atoms. 
The halogen atom may be any of halogen atoms, and it is preferably 
fluorine, chlorine or bromine. 
The aforementioned N-cyano-N'-substituted pyridinecarboximidamide 
derivative according to the present invention has a basic nitrogen atom 
and thus forms an acid adduct salt. Acids with which an acid adduct salt 
is formed include, for example, inorganic acids such as hydrochloric acid, 
sulfuric acid, nitric acid, phosphoric acid or the like; or organic acids 
such as acetic acid, propionic acid, maleic acid, oleic acid, palmitic 
acid, citric acid, succinic acid, tartaric acid, fumaric acid, glutamic 
acid, pantothenic acid, laurylsulfonic acid or the like. It is needless to 
say that when an acid adduct salt is used as a medicine, the acid must be 
the one which is pharmaceutically acceptable. 
As the representative examples of the 
N-cyano-N'-substituted-pyridinecarboximidamide derivative according to the 
present invention represented by the formula (I), there are mentioned the 
following compound [compound Nos. (1)-(53)]: 
______________________________________ 
Compound No. 
Name of Compound 
______________________________________ 
(1) N-cyano-N'-(2-nitroxyethyl)-2- 
pyridinecarboximidamide 
(2) N-cyano-N'-(2,2-dimethylpropyl)-2- 
pyridinecarboximidamide 
(3) N-cyano-N'-(1,2,2-trimethylpropyl)-2- 
pyridinecarboximidamide 
(4) N-cyano-N'-phenyl-2-pyridinecarboximidamide 
(5) N-cyano-N'-(4-methoxyphenyl)-2- 
pyridinecarboximidamide 
(6) N-cyano-N'-(4-methylbenzyl)-2- 
pyridinecarboximidamide 
(7) N-cyano-N'-(4-chlorobenzyl)-2- 
pyridinecarboximidamide 
(8) N-cyano-N'-[4-(trifluoromethyl)benzyl]-2- 
pyridinecarboximidamide 
(9) N-cyano-N'-[2-(4-methylphenyl)ethyl]-2- 
pyridinecarboximidamide 
(10) N-cyano-N'-[2-(4-chlorophenyl)ethyl]-2- 
pyridinecarboximidamide 
(11) N-cyano-N'-(2-hydroxy-1-methyl-2- 
phenylethyl)-2-pyridinecarboximidamide 
(12) N-cyano-N'-(2-thienylmethyl)-2- 
pyridinecarboximidamide 
(13) N-cyano-N'-(2-nitroxyethyl)-3- 
pyridinecarboximidamide 
(14) N-cyano-N'-(3-nitroxypropyl)-3- 
pyridinecarboximidamide 
(15) N-cyano-N'-(3,3-dimethylbutyl)-3- 
pyridinecarboximidamide 
(16) N-cyano-N'-(4-methylphenyl)-3- 
pyridinecarboximidamide 
(17) N-cyano-N'-benzyl-3-pyridinecarboximidamide 
(18) N-cyano-N'-(4-methylbenzyl)-3- 
pyridinecarboximidamide 
(19) N-cyano-N'-(4-methoxybenzyl)-3- 
pyridinecarboximidamide 
(20) N-cyano-N'-(4-dimethylaminobenzyl)-3- 
pyridinecarboximidamide 
(21) N-cyano-N'-[4-(trifluoromethyl)benzyl]-3- 
pyridinecarboximidamide 
(22) N-cyano-N'-(4-chlorobenzyl)-3- 
pyridinecarboximidamide 
(23) N-cyano-N'-(4-nitrobenzyl)-3- 
pyridinecarboximidamide 
(24) N-cyano-N'-(3,4-dichlorbenzyl)-3- 
pyridinecarboximidamide 
(25) N-cyano-N'-[3,5-bis(trifluoromethyl)benzyl]- 
3-pyridinecarboximidamide 
(26) N-cyano-N'-(3-benzyloxybenzyl)-3- 
pyridinecarboximidamide 
(27) N-cyano-N'-(2-phenylethyl)-3- 
pyridinecarboximidamide 
(28) N-cyano-N'-[2-(2-methoxyphenyl)ethyl]-3- 
pyridinecarboximidamide 
(29) N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3- 
pyridinecarboximidamide 
(30) N-cyano-N'-[2-(4-chlorophenyl)ethyl]-3- 
pyridinecarboximidamide 
(31) N-cyano-N'-[2-(4-benzylaminophenyl)ethyl]-3- 
pyridinecarboximidamide 
(32) N-cyano-N'-[2-(4-nitrophenyl)-2- 
nitroxyethyl]-3-pyridinecarboximidamide 
(33) N-cyano-N'-(3-phenylpropyl)-3- 
pyridinecarboximidamide 
(34) N-cyano-N'-diphenylmethyl-3- 
pyridinecarboximidamide 
(35) N-cyano-N'-(1,2-diphenylethyl)-3- 
pyridinecarboximidamide 
(36) N-cyano-N'-(2,2-diphenylethyl)-3- 
pyridinecarboximidamide 
(37) N-cyano-N'-(3,3-diphenylpropyl)-3- 
pyridinecarboximidamide 
(38) N-cyano-N'-(2-benzyloxy-2-phenylethyl)-3- 
pyridinecarboximidamide 
(39) N-cyano-N'-[2-(3,4-dibenzyloxyphenyl)ethyl]- 
3-pyridinecarboximidamide 
(40) N-cyano-N'-3-(2,6-dimethoxypyridine)-3- 
pyridinecarboximidamide 
(41) N-cyano-N'-(2-nitroxyethyl)-4- 
pyridinecarboximidamide 
(42) N-cyano-N'-(3-nitroxypropyl)-4- 
pyridinecarboximidamide 
(43) N-cyano-N'-phenyl-4-pyridinecarboximidamide 
(44) N-cyano-N'-(3,4-dichlorobenzyl)-4- 
pyridinecarboximidamide 
(45) N-cyano-N'-(4-methylthiobenzyl)-4- 
pyridinecarboximidamide 
(46) N-cyano-N'-(3-benzyloxybenzyl)-4- 
pyridinecarboximidamide 
(47) N-cyano-N'-[2-(4-chlorophenyl)ethyl]-4- 
pyridinecarboximidamide 
(48) N-cyano-N'-[2-(2-methoxyphenyl)ethyl]-4- 
pyridinecarboximidamide 
(49) N-cyano-N'-(2-phenylthioethyl)-4- 
pyridinecarboximidamide 
(50) N-cyano-N'-[2-(4-nitrophenyl)-2- 
nitroxyethyl]-4-pyridinecarboximidamide 
(51) N-cyano-N'-[1-methyl-2-(4-nitrophenyl)-2- 
nitroxyethyl]-4-pyridinecarboximidamide 
(52) N-cyano-N'-(2-nitroxyethyl)-3-(6- 
chloropyridine)carboximidamide 
(53) N-cyano-N'-(2-phenylethyl)-3-(6- 
chloropyridine)carboximidamide 
______________________________________ 
The substituents R of these compounds have the following structures: 
______________________________________ 
Compound 
No. R 
______________________________________ 
##STR16## 
(1) 
##STR17## 
(2) 
##STR18## 
(3) 
##STR19## 
(4) 
##STR20## 
(5) 
##STR21## 
(6) 
##STR22## 
(7) 
##STR23## 
(8) 
##STR24## 
(9) 
##STR25## 
(10) 
##STR26## 
(11) 
##STR27## 
(12) 
##STR28## 
##STR29## 
(13) 
##STR30## 
(14) 
##STR31## 
(15) 
##STR32## 
(16) 
##STR33## 
(17) 
##STR34## 
(18) 
##STR35## 
(19) 
##STR36## 
(20) 
##STR37## 
(21) 
##STR38## 
(22) 
##STR39## 
(23) 
##STR40## 
(24) 
##STR41## 
(25) 
##STR42## 
(26) 
##STR43## 
(27) 
##STR44## 
(28) 
##STR45## 
(29) 
##STR46## 
(30) 
##STR47## 
(31) 
##STR48## 
(32) 
##STR49## 
(33) 
##STR50## 
(34) 
##STR51## 
(35) 
##STR52## 
(36) 
##STR53## 
(37) 
##STR54## 
(38) 
##STR55## 
(39) 
##STR56## 
(40) 
##STR57## 
##STR58## 
(41) 
##STR59## 
(42) 
##STR60## 
(43) 
##STR61## 
(44) 
##STR62## 
(45) 
##STR63## 
(46) 
##STR64## 
(47) 
##STR65## 
(48) 
##STR66## 
(49) 
##STR67## 
(50) 
##STR68## 
(51) 
##STR69## 
##STR70## 
(52) 
##STR71## 
(53) 
##STR72## 
______________________________________ 
[II] N-cyano-pyridinecarboximidate compounds 
The N-cyano-pyridinecarboximidate compound is the alkyl 
N-cyano-pyridinecarboximidate compound represented by the formula (II) set 
forth above, and it is an intermediate for producing the compound of the 
present invention represented by the formula (I) or an acid adduct salt 
thereof (wherein the meanings of respective substituents are defined 
above). 
In the aforementioned formula (II), the alkyl group of R' has preferably 
1-8 carbon atoms, more preferably 1-5 carbon atoms, which may be the chain 
or cycle in form, particularly an isopropyl group. 
As the representative examples of the alkyl N-cyanopyridinecarboximidate 
compounds of the present invention represented by the formula (II), there 
are mentioned the following compounds [compound Nos. (54)-(58)]: 
______________________________________ 
Compound No. 
Name of Compound 
______________________________________ 
(54) Methyl N-cyano-2-pyridinecarboximidate 
(55) Isopropyl N-cyano-2-pyridinecarboximidate 
(56) Isopropyl N-cyano-3-pyridinecarboximidate 
(57) Isopropyl N-cyano-4-pyridinecarboximidate 
(58) Isopropyl N-cyano-3-(6-chloropyridine)- 
carboximidate 
______________________________________ 
These compounds have the following structures: 
______________________________________ 
Compound No. 
Structural Formula 
______________________________________ 
(54) 
##STR73## 
(55) 
##STR74## 
(56) 
##STR75## 
(57) 
##STR76## 
(58) 
##STR77## 
______________________________________ 
[III] Process for producing N-cyano-N'-substituted pyridinecarboximidamide 
derivatives 
(1) Summary 
The N-cyano-N'-substituted-pyridinecarboximidamide derivative according to 
the present invention can be produced by any methods suitable for the 
purpose, for example by the following two production methods. These 
production methods are illustrated by the reaction scheme (i) and the 
reaction scheme (ii), respectively. 
That is to say, there are mentioned a method for producing the object 
compound, N-cyano-N'-substituted-pyridinecarboximidamide derivative 
represented by the formula (I), as is illustrated in the reaction scheme 
(i), by leading the cyanopyridine compound represented by the formula 
(III) to the N-cyano-pyridinecarboximidate compound represented by the 
formula (II), which is further reacted with any of various amine compounds 
(method i), and a method for producing the object compound, as is 
illustrated in the reaction scheme (ii), by converting the amide compound 
represented by the formula (V) which is prepared by a well-known method to 
the thioamide compound represented by the formula (VI), which is reacted 
with cyanamide (NH.sub.2 CN) in the presence of phosphorus oxychloride and 
a tertiary amine (method ii). 
However, a compound containing a nitroxyl group in R cannot be produced by 
the method (ii). 
These methods (i) and (ii) are described in detail below. 
##STR78## 
Wherein R, R' and X have the same meanings as defined above. 
##STR79## 
Wherein R and X have the same meanings as defined above. 
(2) Method (i) 
The method (i) is, as described above, a method for producing the object 
compound according to the reaction scheme (i). 
(a) Compound (III).fwdarw.Compound (IV) 
The cyanopyridine compound represented by the formula (III) is reacted with 
sodium hydride or R'ONa corresponding to R'OH used, i.e. sodium alkoxide, 
in R'OH, i.e. an alcohol to form an imidate compound represented by the 
formula (IV). The amount of sodium hydride or R'ONa used in the reaction 
is a catalytic amount, and the reaction is generally carried out by using 
sodium hydride or R'ONa preferably in an amount of 0.01-0.5 mole, more 
preferably 0.02-0.2 mole in proportion to 1 mole of the cyanopyridine. 
Alcohols (R'OH) which can be used in the reaction include chain and cyclic 
alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 
isobutanol, t-butanol, cyclopentanol, cyclohexanol, n-octanol and the 
like. 
The alcohol can be used also as a reaction solvent and can be used as only 
a reagent in the presence of other solvents. When the alcohol is used as a 
reaction solvent, it is generally used in an amount of 10-50 moles in 
proportion to 1 mole of the cyanopyridine. When the alcohol is used in the 
presence of other solvents, it is preferably used in an amount of 1-5 
moles in proportion to 1 mole of the cyanopyridine. The solvents which can 
be used in the reaction desirably include aprotic solvents such as hexane, 
benzene, toluene, diethyl ether, petroleum ether, tetrahydrofuran, 
N,N-dimethylformamide and the like. The reaction temperature is preferably 
in the range of 0.degree.-50.degree. C., particularly around room 
temperature. 
Under the aforementioned reaction conditions, the reaction can be completed 
in 3-24 hours. 
The resulting imidate compound represented by the formula (IV) can 
immediately be used in the next reaction without purification by 
isolation. 
(b) Compound (IV).fwdarw.Compound (II) 
The imidate compound represented by the formula (IV) is reacted with 
cyanamide (NH.sub.2 CN) in a buffer solution, preferably in a phosphate 
buffer solution to be converted into the N-cyano-pyridinecarboximidate 
compound represented by the formula (II). 
The amount of the cyanamide is preferably at least 1 mole or more, 
particularly 2-3 moles in proportion to 1 mole of the imidate compound 
represented by the formula (IV). The reaction is conducted in a buffer 
solution, preferably in a phosphate buffer solution, and the pH is 
preferably in the range of 5.0-6.0, more preferably in the range of 
5.2-5.6. The concentration of the buffer solution is preferably in the 
range of 0.5-4 M. When a phosphate buffer solution is used, each of the 
components of the buffer solution, Na.sub.2 HPO.sub.4 and NaH.sub.2 
PO.sub.4 , is preferably used in an amount of at least 1 mole or more to 1 
mole of the imidate compound represented by the formula (IV) in order to 
maintain sufficient bufferizing ability. The reaction temperature is 
preferably in the range of 0.degree.-50.degree. C., particularly around 
room temperature. 
Under such reaction conditions as above, the imidate compound represented 
by the formula (IV) is generally converted into the 
N-cyano-pyridinecarboximidate compound represented by the formula (II) in 
2-12 hours. 
As the method for purification by isolation of the 
N-cyano-pyridinecarboximidate compound represented by the formula (II) 
thus obtained, there can be used purification methods which are well known 
in the art of organic synthetic chemistry such as a crystallization 
method, a distillation method, a column chromatography method with a 
carrier of silica gel and the like. (c) Compound (II).fwdarw.Compound (I) 
The N-cyano-N'-substituted-pyridinecarboximidamide compound represented by 
the formula (I) can be produced by reacting the 
N-cyano-pyridinecarboximidate compound represented by the formula (II) 
with any of various amine compounds. 
The amine compound is preferably used in an amount of at least 1 mole or 
more, more preferably in the range of 1-2 moles to 1 mole of the 
N-cyanopyridinecarboximidate compound represented by the formula (II). The 
reaction is usually conducted in a solvent. As the solvents which can be 
used in the reaction, there can be mentioned, for example, methanol, 
ethanol, dichloromethane, chloroform, carbon tetrachloride, dioxane, 
tetrahydrofuran, water and the like, particularly methanol. The reaction 
temperature is in the range from 0.degree. C. to the boiling point of the 
solvent, preferably around room temperature. 
Under such reaction conditions as above, the reaction can be completed in 5 
minutes-24 hours. 
The methods for purification by isolation of the compound represented by 
the formula (I) from the reaction mixture obtained in the aforementioned 
reaction are the same as those set forth in the stage of the purification 
by isolation of the N-cyano-pyridinecarboximidate compound represented by 
the formula (II). 
The compound of the present invention represented by the formula (I) can be 
converted into an acid adduct salt thereof according to a method which is 
well-known per se. The acids which can be converted into acid adduct salts 
are the same as defined above. 
(3) Method (ii) 
(a) Compound (V).fwdarw.Compound (VI) 
The amide compound represented by the formula (V) which is prepared by a 
well-known method is converted into the thioamide compound represented by 
the formula (VI) with a well-known thiocarbonylation reagent such as 
P.sub.2 S.sub.5 or a Lawesson's reagent in a well-known method [see 
Tetrahedron, 35, 2433 (1979)]. 
(b) Compound (VI).fwdarw.Compound (I) 
The thioamide compound represented by the formula (VI) can be reacted with 
cyanamide (NH.sub.2 CN) in the presence of phosphorus oxychloride and a 
tertiary amine to prepare the 
N-cyano-N'-substituted-pyridinecarboximidamide compound represented by the 
formula (I). In the reaction, cyanamide (NH.sub.2 CN) can be used in an 
amount of at least 1 mole or more, preferably 3 moles or more, more 
preferably in the range of 5-15 moles in proportion to 1 mole of the 
thioamide compound represented by the formula (VI). 
While the reaction is, as described above, conducted in the presence of 
phosphorus oxychloride, the reaction can be performed in the same manner 
not only with phosphorus oxychloride but also with phosphorus pentoxide, 
phosphorus pentachloride, thionyl chloride, sulfuryl chloride or the like. 
Such an reagent is desirably used in an amount of at least 1 mole or more, 
preferably in the range of 1-2 moles in proportion to 1 mole of the 
thioamide compound represented by the formula (VI). The reaction is also 
conducted in the coexistence of a tertiary amine. As the tertiary amine, 
triethylamine, diisopropylethylamine or the like is suitable. The tertiary 
amine is preferably used in an 
amount of 1-2 moles to 1 mole of the thioamide compound represented by the 
formula (VI). 
The reaction is usually carried out in a solvent, and the solvents which 
can be used include acetonitrile, benzene, hexane, toluene, 
dichloromethane, chloroform, carbon tetrachloride, dioxane, 
tetrahydrofuran, N,N-dimethylformamide and the like, and acetonitrile is 
particularly preferred. 
The reaction temperature is preferably in the range from room temperature 
to the boiling temperature of the solvent used, particularly in the range 
of 80.degree.-110.degree. C. 
Under such reaction conditions, the reaction can be completed in 6-24 
hours. 
The method of purifying the N-cyano-N'-substituted pyridinecarboximidamide 
compound as the object compound from the reaction mixture thus obtained 
and the method of forming an acid adduct salt are the same as those set 
forth in the description of the method (i). 
[IV] -Use of the Compound [Pyridinecarboximidamide Derivative Represented 
by the Formula (I)] 
(1) Potassium Channel Activating Agent 
The compound of the present invention represented by the formula (I) has, 
as shown in the result of Referential Example 1)-2 below, potassium 
channel activating effect and thus is useful as a potassium channel 
activating agent. 
(2) Hypotensor 
The compound of the present invention exhibited, as shown in the results of 
Referential Examples 1)-3 and 1)-4, strong hypotensive effect in either of 
the intravenous or oral administration of the compound in spontaneous 
hypertensive rats. Moreover, the compound decreased in the blood pressure 
even at a low dose to a dog, as shown in Referential Example 1)-5. Thus, 
the compound of the present invention is useful as a hypotensor. 
(3) Therapeutic agent for the treatment of ischemic heart disease 
The compound of the present invention significantly increased coronary 
blood flow in a heart isolated from a rat as compared with nicorandil as 
shown in Referential Example 1)-6. The compound of the present invention 
exhibited hypotensive effect and continuous coronary blood flow increasing 
effect by far stronger than nicorandil as shown in Referential Example 
1)-7. Moreover, these effects were continuously observed on 
intraduodenally administering the compound in Referential Example 1)-8. 
The compound represented by the formula (I) exhibited strong inhibitory 
effect on a rhythmic contraction induced by 3,4-DAP as a model of 
pseudoangina pectoris in Referential Example 1)-9, and it was also more 
effective than nicorandil in an angina pectoris model of rat, as shown in 
Referential Example 1)-10. Moreover, it was recognized from the result of 
Referential Example 1)-11 that the compound represented by the formula (I) 
also exhibited the cardioprotective effect after ischemia-reperfusion. 
As apparent from the above-described results, the compound of the present 
invention represented by the formula (I) is useful as a therapeutic agent 
for the treatment of ischemic heart diseases such as angina pectoris, 
myocardiac infarction or the like. 
(4) Therapeutic Agent for Ameliorant of Peripheral Circulation 
The compound represented by the formula (I) decreased the total peripheral 
resistance by intraduodenal administration, as shown in Referential 
Example 1)-8. As apparent from the result, the compound of the present 
invention represented by the formula (I) is useful as an ameliorant of 
peripheral circulation. 
(5) Therapeutic Agent for Ameliorant of Cerebral Circulation 
The compound represented by the formula (I) was found to exhibit cerebral 
vasodilatative effect from the result of Referential Example 1)-12 and the 
effect of prolonging the survival time in hypoxia from the result of 
Referential Example 1)-13. As apparent from these results, the compound of 
the present invention represented by the formula (I) is useful as an 
ameliorant of cerebral circulation. 
(6) Therapeutic Agent of Thrombosis 
The compound represented by the formula (I) inhibited the aggregation of 
platelets and promoted the dissociation thereof as shown in Referential 
Example 1)-14. As apparent from the result, the compound of the present 
invention represented by the formula (I) is useful as a therapeutic agent 
for the treatment of thrombosis. 
(7) Antasthmatic 
The compound represented by the formula (I) dilated not only the smooth 
muscle of blood vessel but also the smooth muscle of trachea as shown in 
Referential Example 1)-15. As apparent from the result, the compound of 
the present invention represented by the formula (I) is useful as an 
antasthmatic. 
When the compound represented by the formula (I) is administered as a 
hypotensor, a therapeutic agent for the treatment of ischemic heart 
diseases, an ameliorant of peripheral circulation, an ameliorant of 
cerebral circulation, a therapeutic agent for the treatment of thrombosis 
or an antasthmatic, it can be administered orally, parenterally 
(intramuscularly, intravenously, subcutaneously or percutaneously), or in 
the form of a sublingual tablet or a suppository. 
It is needless to say that the dose and the dosing way of the compound 
represented by the formula (I) vary depending on the states of a patient 
such as body weight, sex, sensitivity, dosage time, drugs to be used in 
combination, patients or the seriousness of the patients. The suitable 
dose and dosage times under a certain condition must be determined on the 
basis of the above-described principles by the suitable dose determining 
test by medical specialists. The dose is generally in the range of about 
0.1-200 mg, preferably 0.1-100 mg, particularly 0.5-30 mg per day for an 
adult patient. 
When the compound represented by the formula (I) is administered orally as 
a drug, it is administered in the form of tablets, granules, powder or 
capsules. When it is administered parenterally, it is administered in the 
form of injections or suspensions. In order to produce these 
pharmaceutical preparations, excipients, binding agents, disintegrating 
agents, lubricants, stabilizers and the like can be added. If necessary, 
other drugs can be mixed. 
The excipients include, for example, lactose, starch, crystalline 
cellulose, mannitol, maltose, calcium hydrogen phosphate, light anhydrous 
silicic acid, calcium carbonate and the like; binding agents include, for 
example, starch, polyvinylpyrrolidone, hdroxypropylcellulose, 
ethylcellulose, carboxymethylcellulose, gum arabic and the like; 
disintegrating agents include, for example, starch, calcium 
carboxymethylcellulose and the like; lubricants include, for example, 
magnesium stearate, talc, hardened oils and the like; and stabilizing 
agents include, for example, lactose, mannitol, maltose, Polysorbates, 
Macrogols, polyoxyethylene hardened castor oil or the like. 
The pharmaceutical preparations can be produced in the dosage forms of 
tablets, granules, capsules, injections or the like with these 
ingredients. 
[IV] N-Cyano-N'-Substituted-Carboximidamide Derivatives 
The carboximidamide derivative of the present invention which having no 
pyridine as the substituent B in the formula (A) set forth above is, as 
described above, the N-cyano-N'-substituted-carboximidamide derivative 
represented by the following formula (I') as described above: 
##STR80## 
the compound represented by the formula (I') can form its acid adduct 
salts. The acids with which acid adduct salts are formed include the same 
acids as in the case of the N-cyano-N'-substituted-pyridinecarboximidamide 
derivatives. In this connection, it is needless to say that when the acid 
adduct salt is used as a drug, the acid must be the one which is 
pharmaceutically acceptable. 
Representative examples of the N-cyano-N'-substituted-carboximidamide 
derivative of the present invention represented by the formula (I') 
include the following representative compounds [compound Nos. (59)-(70)]: 
______________________________________ 
Compound No. 
Name of Compound 
______________________________________ 
(59) N-cyano-N'-(2-nitroxyethyl)-3-quinoline- 
carboximidamide 
(60) N-cyano-N'-(2-phenylethyl)-3-quinoline- 
carboximidamide 
(61) N-cyano-N'-(2-nitroxyethyl)pyrazine- 
carboximidamide 
(62) N-cyano-N'-(2-nitroxyethyl)-2-furfan- 
carboximidamide 
(63) N-cyano-N'-(2-phenylethyl)-2-furan- 
carboximidamide 
(64) N-cyano-N'-(2-nitroxyethyl)-3-furan- 
carboximidamide 
(65) N-cyano-N'-(2-phenylethyl)-3-furan- 
carboximidamide 
(66) N-cyano-N'-(2-nitroxyethyl)-2-thiophene- 
carboximidamide 
(67) N-cyano-N'-(2-phenylethyl)-2-thiophene- 
carboximidamide 
(68) N-cyano-N'-(2-phenylethyl)-3-thiophene- 
carboximidamide 
(69) N-cyano-N'-(2-phenylethyl)-4-cyanobenzene- 
carboximidamide 
(70) 3-Cyano-2-methyl-1-(2-nitroxyethyl)- 
isothiourea 
______________________________________ 
These compounds have the following structures, respectively. 
______________________________________ 
Compound 
No. Structure 
______________________________________ 
(59) 
##STR81## 
(60) 
##STR82## 
(61) 
##STR83## 
(62) 
##STR84## 
(63) 
##STR85## 
(64) 
##STR86## 
(65) 
##STR87## 
(66) 
##STR88## 
(67) 
##STR89## 
(68) 
##STR90## 
(69) 
##STR91## 
(70) 
##STR92## 
______________________________________ 
[V] Process for Producing N-cyano-N'-Substituted-Carboximidamide 
Derivatives 
The N-cyano-N'-substituted-carboximidamide derivatives according to the 
present invention represented by the formula (I') can be prepared by any 
methods suitable for the purpose such as the methods (i') and (ii') 
described below. 
(1) Method (i') 
The carboximidamide derivatives of the present invention represented by the 
formula (I') except those in which X" is H.sub.3 C--S-- such as 
3-cyano-2-methyl-1-(2-nitroxyethyl)isothiourea can be obtained, as 
illustrated by the reaction scheme (i'), by converting the nitrile 
represented by the formula (II') into the cyanoimidate compound 
represented by the formula (IV'), which is then reacted with an amine 
compound. Thus, the N-cyano-N'-substituted-carboximidamide derivative 
represented by the formula (I') as the object compound can be obtained. 
##STR93## 
wherein R"" represents an alkyl group, and X" and R" have the same 
meanings as defined above. 
The production method is further described in detail below referring to the 
reaction scheme (i'). 
(a) Compound (II').fwdarw.Compound (III') 
The nitrile compound represented by the formula (II') is reacted with 
sodium hydride or R""ONa corresponding to R""OH used, i.e. sodium 
alkoxide, in R""OH, i.e. an alcohol to form the imidate compound 
represented by the formula (III'). The amount of sodium hydride or R""ONa 
used in the reaction is a catalytic amount, and the reaction is generally 
carried out by using sodium hydride or R""ONa preferably in an amount of 
0.01-0.5 mole, more preferably 0.02-0.2 mole in proportion to 1 mole of 
the nitrile. 
Alcohols (R""OH) which can be used in the reaction include either chain or 
cyclic alcohols such as methanol, ethanol, n-propanol, isopropanol, 
n-butanol, isobutanol, t-butanol, cyclopentanol, cyclohexanol, n-octanol 
and the like. The alcohol can be used also as a reaction solvent and can 
be used as only a reagent in the coexistence of other solvents. When the 
alcohol is used as a reaction solvent, it is generally used in an amount 
of 10-50 moles in proportion to 1 mole of the nitrile. When the alcohol is 
used in the presence of other solvents, it is preferably used in an amount 
of 1-5 moles in proportion to 1 mole of the nitrile. The solvents which 
can be used desirably include aprotic solvents such as hexane, benzene, 
toluene, diethyl ether, petroleum ether, tetrahydrofuran and the like. The 
reaction temperature is preferably in the range of 0.degree.-50.degree. 
C., particularly around room temperature. 
Under the aforementioned reaction conditions, the reaction can be completed 
usually in 0.5-28 hours. 
The resulting imidate compound represented by the formula (III') can be 
immediately used in the next reaction without purification by isolation. 
(b) Compound (III').fwdarw.Compound (IV') 
The imidate compound represented by the formula (III') is reacted with 
cyanamide (NH.sub.2 CN) in a buffer solution, preferably in a phosphate 
buffer solution to be converted into the cyanoimidate compound represented 
by the formula (IV'). 
The amount of the cyanamide is preferably at least 1 mole or more, 
particularly 2-3 moles in proportion to 1 mole of the imidate compound. 
The reaction is conducted in a buffer solution, preferably in a phosphate 
buffer solution, and the pH is preferably in the range of 5.0-6.5, more 
preferably in the range of 5.2-6.2. The concentration of the buffer 
solution is preferably in the range of 0.5-4 M, particularly 1-3 M. When a 
phosphate buffer solution is used, each of the components of the buffer 
solution, for example, Na.sub.2 HPO.sub.4 and NaH.sub.2 PO.sub.4, is 
preferably used in an amount of at least 1 mole or more to 1 mole of the 
imidate compound in order to maintain sufficient bufferizing ability. The 
reaction temperature is preferably in the range of 0.degree.-50.degree. 
C., particularly around room temperature. 
Under such reaction conditions as above, the imidate compound represented 
by the formula (III') is generally converted into the cyanoimidate 
compound represented by the formula (IV') in 2-75 hours. 
As the method for purification by isolation of the cyanoimidate compound 
represented by the formula (IV') thus obtained, there can be used 
purification methods which are well-known in the art of organic synthetic 
chemistry such as a crystallization method, a distillation method, a 
column chromatography method with a carrier of silica gel and the like. 
(c) Compound (IV').fwdarw.Compound (I') 
The N-cyano-N'-substituted-carboximidamide derivative represented by the 
formula (I') can be produced by reacting the cyanoimidate compound 
represented by the formula (IV') with one of various amine compounds. 
The amine compound is preferably used in an amount of at least 1 mole or 
more, more preferably in the range of 1-2 moles to 1 mole of the 
cyanoimidate compound represented by the formula (IV'). The reaction is 
usually conducted in a solvent. As the solvents which can be used in the 
reaction, there can be mentioned, for example, methanol, ethanol, 
dichloromethane, chloroform, carbon tetrachloride, dioxane, 
tetrahydrofuran and the like, particularly methanol. The reaction 
temperature is in the range from 0.degree. to the boiling point of the 
solvent, preferably around room temperature. 
Under such reaction conditions as above, the reaction generally can be 
completed in 5 minutes-50 hours. 
The methods for purification by isolation of the e compound represented by 
the formula (I') from the reaction mixture obtained in the aforementioned 
reaction are the same as those set forth in the stage of the purification 
by isolation of the cyanoimidate compound represented by the formula 
(IV'). 
(2) Method (ii') 
Among the compound of the present invention, 
3-cyano-2-methyl-1-(2-nitroxyethyl)isothiourea can be prepared by reacting 
the dimethyl N-cyanodithioiminocarbonate represented by the formula (V') 
with 2-nitroxyethylamine, as shown in the following reaction scheme (ii'). 
##STR94## 
The amount of 2-nitroxyethylamine which is used in the reaction is 
preferably at least 1 mole or more, particularly 1-2 moles per mole of 
dimethyl N-cyanodithioiminocarbonate represented by the formula (V'). The 
reaction is usually conducted in a solvent, and the solvents which can be 
used in the reaction preferably include alcohols such as methanol, 
ethanol, isopropanol and the like, and aprotic solvents such as 
chloroform, dichloromethane, tetrahydrofuran, benzene, toluene and the 
like. The reaction temperature is preferably in the range from the 
solidifying point of the solvent to 50.degree. C., preferably around room 
temperature. Under such reaction conditions set forth above, the reaction 
can be completed in 1-30 hours. 
The methods for purification by isolation of 
3-cyano-2-methyl-1-(2-nitroxyethyl)isothiourea from the reaction mixture 
obtained in the aforementioned reaction are the same as those set forth in 
the stage of the purification by isolation of the cyanoimidate compound 
represented by the formula (IV'), and purification methods well-known in 
the art of organic synthetic chemistry such as a crystallization method, a 
distillation method, a chromatographical method with a carrier of silica 
gel can be used. 
Among the compounds of the present invention represented by the formula 
(I'), the compound which has basic nitrogen atom can be converted into its 
acid adduct salt by a method which is well-known per se. The acids with 
which the acid adduct salts can be formed are the same as described above. 
[VI] Use of the Compounds [Carboximidamide Derivatives Represented by the 
Formula (I')] 
The compound of the present invention represented by the formula (I') has, 
as shown in the results of Referential Examples 2)-1 and 2)-2 below, 
vasodilative effect and hypotensive effect and thus is useful as a 
vasodilative agent and a hypotensor. 
When the compound represented by the formula (I') is administered as a 
vasodilator or a hypotensor, it can be administered orally, parenterally 
(intramuscularly, intravenously, subcutaneously or percutaneously), or in 
the form of a sublingual tablet or a suppository. 
It is needless to say that the dose and the dosing route of the compound 
represented by the formula (I') vary depending on the states of a patient 
such as body weight, sex, sensitivity, dosage time, drugs to be used in 
combination, patients or the seriousness of the patients. The suitable 
dose and dosage times under a certain condition must be determined on the 
basis of the above-described principles by the suitable dose determining 
test by medical specialists. The dose is generally in the range of about 
0.1-200 mg, preferably 0.5-100 mg per day for an adult patient. 
When the compound represented by the formula (I') is administered orally as 
a drug, it is administered in the form of tablets, granules, powder or 
capsules. When it is administered parenterally, it is administered in the 
form of injections or suspensions. In order to produce these 
pharmaceutical preparations, excipients, binding agents, disintegrating 
agents, lubricants, stabilizers and the like which are described in the 
explanation of the compound represented by the formula (I) can be added. 
If necessary, other drugs can be mixed. 
[VII] Experimental Examples 
The present invention is further described in detail with reference to the 
following Referential Examples and Examples, which are given for the 
purpose of merely illustrating the invention without limiting it. 
1) Compounds Represented by the Formula (I) 
Referential Example 1)-1 
Vasorelaxing Effect on the Isolated Rat Aortae 
(1) Method 
The compounds of the present invention were tested for their physiological 
activities by measuring the tension of isolated rat aortae isometrically. 
Thoracic aortae obtained from male Wistar rats (weighing 250-350 g) were 
cut into ring segments about 3 mm long. The ring preparation was placed in 
an organ bath filled with 10 ml of Krebs-Ringer solution that was 
maintained at 37.degree. C. and gassed with 95% O.sub.2 -5% CO.sub.2. 
The preparation in the organ bath was allowed to equilibrate under resting 
tension of 1 g. After equilibration period, the solution in the organ bath 
was replaced with an isotonic solution containing 40 mM KCl to contract 
the preparation. 
After the contraction induced by KCl had reached plateau, the 
concentration-response relationship for the test compound was determined 
by means of cumulative addition. 
The relaxation response of the test compounds was expressed as the percent 
inhibition of the contraction induced by KCl, and the IC.sub.50 value, 
which is a concentration required for inhibiting the contraction induced 
by KCl to an extent of 50%, was calculated by the Probit method from the 
concentration-response curve. 
(2) Results 
The IC.sub.50 values of the test compounds and the control compounds are 
shown in the following table. 
______________________________________ 
Test Compound No. 
IC.sub.50 Value (M) 
______________________________________ 
(1) 4.6 .times. 10.sup.-6 
(2) 6.0 .times. 10.sup.-5 
(3) 4.9 .times. 10.sup.-5 
(4) 3.1 .times. 10.sup.-5 
(5) 6.5 .times. 10.sup.-5 
(6) 5.1 .times. 10.sup.-5 
(7) 2.3 .times. 10.sup.-5 
(8) 5.7 .times. 10.sup.-5 
(9) 7.2 .times. 10.sup.-5 
(10) 4.0 .times. 10.sup.-5 
(11) 1.2 .times. 10.sup.-5 
(12) 2.4 .times. 10.sup.-5 
(13) 5.1 .times. 10.sup.-6 
(14) 2.0 .times. 10.sup.-5 
(15) 9.5 .times. 10.sup.-5 
(16) 1.7 .times. 10.sup.-5 
(17) 6.6 .times. 10.sup.-5 
(18) 2.2 .times. 10.sup.-5 
(19) 3.7 .times. 10.sup.-5 
(20) 7.8 .times. 10.sup.-5 
(21) 7.0 .times. 10.sup.-5 
(22) 2.2 .times. 10.sup.-5 
(23) 9.8 .times. 10.sup.-5 
(24) 2.1 .times. 10.sup.-5 
(25) 2.4 .times. 10.sup.-5 
(26) 2.3 .times. 10.sup.-5 
(27) 4.0 .times. 10.sup.-5 
(28) 7.0 .times. 10.sup.-5 
(29) 3.8 .times. 10.sup.-5 
(30) 4.3 .times. 10.sup.-5 
(31) 1.6 .times. 10.sup.-5 
(32) 7.8 .times. 10.sup.-5 
(33) 9.5 .times. 10.sup.-5 
(34) 3.8 .times. 10.sup.-5 
(35) 1.8 .times. 10.sup.-5 
(36) 1.6 .times. 10.sup.-5 
(37) 2.8 .times. 10.sup.-5 
(38) 6.8 .times. 10.sup.-5 
(39) 4.8 .times. 10.sup.-5 
(40) 4.0 .times. 10.sup.-5 
(41) 1.2 .times. 10.sup.-5 
(42) 2.0 .times. 10.sup.-5 
(43) 5.2 .times. 10.sup.-5 
(44) 1.9 .times. 10.sup.-5 
(45) 4.9 .times. 10.sup.-5 
(46) 3.0 .times. 10.sup.-5 
(47) 4.0 .times. 10.sup.-5 
(48) 7.3 .times. 10.sup.-5 
(49) 6.2 .times. 10.sup.-5 
(50) 1.4 .times. 10.sup.-5 
(51) 1.3 .times. 10.sup.-5 
(52) 1.1 .times. 10.sup.-5 
(53) 7.7 .times. 10.sup.-5 
______________________________________ 
Control Compounds 
IC.sub.50 Value (M) 
______________________________________ 
1. N-cyano-3-pyridine- 
4.0 .times. 10.sup.-2 
carboxyimidamide 
2. N-cyano-4-pyridine- 
1.8 .times. 10.sup.-4 
carboxyimidamide 
______________________________________ 
Referential Example 1)-2 
Potassium Channel Activating Effect 
(1) Method 
The compounds of the present invention 
(N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13)), 
N-cyano-N'-benzyl-3-pyridinecarboximidamide (compound (17)), 
N-cyano-N'-(2-phenylethyl)-3-pyridinecarboximidamide (compound (27)) and 
N-cyano-N'-(2-nitroxyethyl)-4-pyridinecarboximidamide (compound (41)) were 
tested for the potassium channel activating effect by using the .sup.86 
rubidium (referred to hereinafter as .sup.86 Rb) which is a radioisotope 
as a marker of potassium [See Journal of Physiology, 316, 33 (1981)]. 
Male Wistar rats (weighing 250-350 g) were dehematized to death, and 
thoracic aortae were rapidly isolated. The aorta was opened along the 
longitudinal axis to prepare a flat sheet. The preparation was loaded with 
.sup.86 Rb in the Krebs-Ringer solution which contained .sup.86 Rb in the 
concentration of 10 .mu.Ci/ml and was gassed with 95% O.sub.2 -5% CO.sub.2 
at 37.degree. C. for 2 hours. The preparation was then transferred to a 
Krebs-Ringer solution not containing .sup.86 Rb, and washed to remove 
excess radioactivity for 18 minutes by refreshing the solution every 2 
minutes. Finally the preparation was placed into a Krebs-Ringer solution 
containing each compound (10.sup.-4 M) for 8 minutes. 
The amount of .sup.86 Rb efflux from the preparation in each period was 
determined with a .gamma.-counter. 
The increment in efflux rate during the application of the compound was 
expressed as percent of the efflux before the application of the compound. 
(2) Results 
The increment in .sup.86 Rb efflux ratio (%) during the application of the 
test compounds are shown in the following table. 
______________________________________ 
Compound No. Increment of Efflux (%) 
______________________________________ 
(13) 213.53 
(17) 135.41 
(27) 206.61 
(41) 126.88 
______________________________________ 
Referential Example 1)-3 
Hypotensive effect on spontaneous hypertensive rats (intravenously) 
(1) Method 
The hypotensive effects of the compounds of the present invention [test 
compounds: N-cyano-N'-(2-nitroxyethyl)-2-pyridinecarboximidamide (compound 
(1)), N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound 
(13)), N-cyano-N'-benzyl-3 -pyridinecarboximidamide (compound (17)), 
N-cyano-N'-(2-phenylethyl)-3-pyridinecarboximidamide (compound (27)), 
pyridinecarboximidamide (compound (29)) and 
N-cyano-N'-(2-nitroxyethyl)-4-pyridinecarboximidamide (compound (41))] 
were observed in male spontaneous hypertensive rats (SHR). 
Rats were anesthetized with urethane-.alpha.-chloralose (1 g/kg-25 mg/kg; 
intraperitoneally). Mean blood pressure was measured by a pressure 
transducer through a cannula inserted into the carotid artery. The 
compound was cumulatively administered every 30 minutes through the 
cannula inserted into the jagular vein. The change in blood pressure was 
expressed as percent of the blood pressure before the administration of 
the compound. And the ED.sub.20 value, which was the dose required for 
descending blood pressure to an extent of 20%, was calculated from the 
dose-response curve. 
(2) Results 
The ED.sub.20 values of the test compounds are shown in the following 
table. 
______________________________________ 
Compound No. ED.sub.20 (mg/kg, i.v.) 
______________________________________ 
(1) 0.037 
(13) 0.010 
(17) 0.250 
(27) 0.074 
(29) 0.013 
(41) 0.130 
______________________________________ 
Referential Example 1)-4 
Hypotensive Effect on Spontaneous Hypertensive Rats (Orally) 
(1) Method 
The hypotensive effect by oral administration of the compound of the 
present invention [test compound: 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13))] was 
observed in male spontaneous hypertensive rats (SHR). 
Systolic pressure of the rats fasted for 24 hour was measured by using the 
tail cuff method before and 2 hours after administration of the compound. 
The compound was dissolved in a mixed solvent of polyethylene glycol 
200:physiological saline=1:1. The control group was administered the 
solvent alone. The change in blood pressure was expressed as percent of 
the blood pressure before the administration of the compound in respective 
groups. 
(2) Results 
The decreasing rates (%) of the blood pressure by the test compound are 
shown in the following table. 
______________________________________ 
Decreasing Rate of Blood 
Dose (mg/kg, p.o.) 
Pressure (%) 
______________________________________ 
Compound (13) 
0.3 6.76 .+-. 1.53 
0.5 9.12 .+-. 2.41 
1.0 27.31 .+-. 2.32 
3.0 49.99 .+-. 2.48 
Control Group -2.11 .+-. 3.21 
______________________________________ 
(mean .+-. S.E.M.) 
Referential Example 1)-5 
Hypotensive Effect on Beagles (Intravenously) 
(1) Method 
The hypotensive effect of the compound of the present invention [test 
compound: N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound 
(13))] was observed in beagles of either sex anesthetized with intravenous 
injection of sodium pentobarbital (35 mg/kg). 
Mean blood pressure was measured by means of a pressure transducer through 
a cannula inserted into the femoral artery. , The compound was 
administered into the femoral vein through the cannula. The change in 
blood pressure was expressed as percent changes from the pretreatment 
values. 
(2) Results 
The decreasing rates (%) of blood pressure by the test compound are 
illustrated in FIG. 1. 
Referential Example 1)-6 
Effect on Isolated Rat Heart 
(1) Method 
The effect of the compound of the present invention on heart of rats was 
examined by using the Langendorff's method [test compound: 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13))]. 
Hearts were excised from male rats (weighing 250-350 g) and perfused at 80 
cmH.sub.2 O in a Langendorff fashion. Krebs-Hensaleit bicarbonate solution 
(pH 7.4, 37.degree. C.) containing an 11 mM glucose which was oxygenated 
with 95% O.sub.2 -5% CO.sub.2 gas mixture was used as a perfusate. The 
left ventricular pressure was recorded by inserting a latex baloon into 
the left ventricle, and heart rate was determined from the pulse of it. 
Coronary perfusate flow was also measured with an electromagnetic 
flowmeter. The experiments were carried out by perfusing a perfusate 
containing the compound (13) for 10 minutes after an initial equilibration 
period for 30 minutes. As the control compound, nicorandil which has an 
effect opening potassium channel and is similar to the test compound in 
structure was used. The changes in the coronary perfusate flow and the 
cardiac function (heart rate x left ventricular pressure) caused by these 
compounds were expressed as percent changes from the preperfusion values 
of the compound (13) or nicorandil. 
(2) Results 
The effects of these compounds on coronary perfusate flow and cardiac 
function are shown in the following table. 
______________________________________ 
Concentra- The Number Coronary 
tion of Perfusate Flow 
Cardiac 
(mol/min) Experiments 
(% change) Function 
______________________________________ 
Nicor- 
1 .times. 10.sup.-8 
3 3.3 .+-. 5.6 
3.7 .+-. 6.7 
andil 
Com- 1 .times. 10.sup.-8 
3 51.3 .+-. 3.2** 
13.3 .+-. 6.5 
pound 
(13) 
______________________________________ 
(mean .+-. S.D.) 
**p &lt; 0.01 as compared with nicorandil (Student's ttest) 
Referential Example 1)-7 
Hemodynamic Profile of the Compound of the Present Invention in Beagles 
(Intravenously) 
(1) Method 
Hemodynamic profile of the compound of the present invention was 
investigated in beagles anesthetized with pentobarbital (30 mg/kg, 
intravenously) [test compound: 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13))]. 
The thorax was opened under artificial respiration. After administering 
heparin in an amount of 500 units/kg, a Moravitz's cannula was introduced 
into the coronary sinus via the right atrium. The coronary sinus outflow 
was returned to the right external jagular vein. The coronary sinus 
outflow was measured by an electromagnetic flowmeter (MFU-2100, 
manufactured by Nihon Kohden) connected to the Moravitz's cannula. A 
cannula was inserted into the aortic arch through the subclavian artery to 
measure aortic blood pressure. The aortic blood pressure was measured with 
a pressure transducer (Nihon Kohden, TP-200T). Heart rate was monitored 
with a heart rate counter with R waves of electrocardiogram. All 
parameters were recorded on a thermosensitive recorder (WT-685G, 
manufactured by Nihon Kohden). 
The compound was administered through the cannula inserted into the right 
femoral vein. Nicorandil was used as a control. As for respective 
measurement items, peak changes were expressed as percent change from the 
pretreatment values of the compound (13) or nicorandil. 
(2) Results 
The results obtained by the compound (13) and nicorandil are shown in the 
following table. 
______________________________________ 
Dose Mean Aortic Coronary 
(.mu.g/ 
Blood Heart Blood 
kg) Pressure Rate Flow 
______________________________________ 
Compound 3.0 -15.3 .+-. 2.5 
1.3 .+-. 1.4 
16.4 .+-. 1.8 
(13) 10.0 -38.5 .+-. 3.1 
-5.9 .+-. 2.8 
96.0 .+-. 17.6 
30.0 -50.7 .+-. 2.1 
-16.2 .+-. 3.3 
134.1 .+-. 9.2 
Nicorandil 
100.0 -21.3 .+-. 1.9 
0.2 .+-. 2.1 
20.3 .+-. 5.1 
300.0 -43.1 .+-. 5.4 
-20.7 .+-. 1.9 
84.9 .+-. 10.8 
______________________________________ 
mean .+-. S.E.M. (N = 5) 
Reference Example 1)-8 
Hemodynamic Profile of the Compound of the Present Invention in Beagles 
(Intraduodenally) 
(1) Method 
The aortic blood pressure, the heart rate and the coronary blood flow of 
the beagles anesthetized with pentobarbital were determined in the same 
manner as in the aforementioned Example 1)-7, and the aortic blood flow 
was measured with an electromagnetic flowmeter (MFV-3100, manufactured by 
Nihon Kohden) by attaching a probe at the origin of the aorta [test 
compound: N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound 
(13))]. A nelaton's tube was inserted into the duodenum via a small 
abdominal incision for administration of the compound (13) (100 .mu.g/kg). 
Time course changes in respective measurement items were expressed as 
percent changes from the pretreatment values. Total peripheral resistance 
was calculated by dividing the mean aortic blood pressure with the sum of 
the coronary blood flow and the aortic blood flow. 
(2) Results 
Time course of the changes after intraduodenal administration of the 
compound (13) (100 .mu.g/kg) are shown in the following table. 
__________________________________________________________________________ 
Time after dosage (min) 
1 2 3 5 7.5 10 20 30 60 
__________________________________________________________________________ 
Mean Aortic Blood 
-9.8 .+-. 
-14.3 .+-. 
-21.2 .+-. 
-35.0 .+-. 
-37.0 .+-. 
-42.0 .+-. 
-49.4 .+-. 
-49.0 .+-. 
-36.5 .+-. 
Pressure (3) 
1.0 1.3 1.2 2.0 2.9 2.9 3.1 3.7 7.3 
Heart Rate (3) 
0 1.6 .+-. 
0 -12.1 .+-. 
-17.5 .+-. 
-21.1 .+-. 
-26.1 .+-. 
-26.5 .+-. 
-10.0 .+-. 
1.6 5.1 4.1 4.4 5.5 4.6 1.4 
Coronary Blood Flow 
1.8 .+-. 
14.4 .+-. 
38.4 .+-. 
121.5 .+-. 
142.3 .+-. 
112.8 .+-. 
64.2 .+-. 
60.1 .+-. 
28.0 .+-. 
(3) 1.8 2.1 9.1 22.0 6.5 10.6 15.4 15.1 11.6 
Aortic Blood Flow 
10.0 12.2 15.1 27.0 25.5 15.0 10.7 8.3 0.5 
(2) 
Total Peripheral 
-17.8 
-24.1 
-33.7 
-49.5 
-50.3 
-51.1 
-55.3 
-55.8 
-44.3 
Resistance (2) 
__________________________________________________________________________ 
mean .+-. SEM; Numbers in parentheses denote sample numbers. 
Referential Example 1)-9 
Effect on 3,4-Diaminopyridine-Induced Rhythmic Contractions in Dog Coronary 
Artery 
(1) Method 
It is known that the attack of pseudoangina pectoris often appears and the 
spasms of the coronary artery occurs during the attack. It is considered 
that when 3,4-diaminopyridine (referred to hereinafter as 3,4-DAP) is 
administered to act on coronary artery in vitro, rhythmic contraction 
occurs, and this period of the contraction well accords with that of the 
attack of pseudoangina pectoris [see MYAKKAN-GAKU (Angiology), 24, 133 
(1984)]. The effect of the compound of the present invention on the 
rhythmic contraction caused by 3,4-DAP was tested in coronary arteries 
isolated from beagles [test compound: 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13))]. 
Beagles were anesthetized with pentobarbital and the heart was excised. The 
coronary arteries were dissected from the myocardium and cut into 3 mm 
long rings in the oxygenated Krebs-Ringer solution. The ring was suspended 
into an organ bath filled with the Krebs-Ringer solution that was 
maintained at 37.degree. C. and gassed with 95% O.sub.2 -5% CO.sub.2. 
Isometric contraction was recorded on a pen-writing recorder (FBR-252A, 
manufactured by TOA Denpa) through a FD pick-up (TB-611T, manufactured by 
Nihon Kohden) and a carrier amplifier (AP-621G, manufactured by Nihon 
Kohden). After equilibration period under 1 g resting tension, 3,4-DAP 
(10.sup.-2 M) was added to the organ bath. When the frequency and the 
amplitude of the oscillation became constant, the compound was added 
cumulatively to the bath. 
(2) Results 
Inhibitory effect of the compound (13) on the rhythmic contraction induced 
by 3,4-DAP in the coronary arteries of beagles is illustrated in FIG. 2. 
Referential Example 1)-10 
Effect of the Compound of the Present Invention on the Experimental Model 
of Angina Pectoris Induced by Vasopressin in Rats 
(1) Method 
It is known that when vasopressin is administered intravenously to a rat, 
myocardial ischemia accompanied with the depression of ST segment in the 
electrocardiogram can be induced. This phenomenon is very similar to the 
attack of pseudoangina pectoris which is observed clinically [see Japanese 
Journal of Pharmacology, 20, 313 (1970); OYO-YAKURI (Applied 
Pharmacology), 19, 311 (1980)]. The effect of the compound of the present 
invention on this model on the pseudoangina pectoris was examined [Test 
Compound: N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound 
(13))]. 
Male Donryu rats, weighing 200-500 g, were anesthetized with 
urethane-.alpha.-chloralose (1g/kg-25 mg/kg; intraperitoneally). 
Vasopressin at the dose of 1.0 IU/kg was administered 2 minutes after the 
administration of the test compound (100 .mu.g/kg). Vasopressin and test 
compound were intravenously administered into the femoral vein. The 
changes in the ST segment in Lead II electrocardiogram were observed after 
the administration of vasopressin. Nicorandil was used as a control. 
(2) Results 
The effect of the compound of the present invention on a 
vasopressin-induced angina pectoris model is shown in FIG. 3. 
Referential Example 1)-11 
Effect of the Compound of the present invention on the myocardiac injury 
inducted by re-perfusion after ischemia 
(1) Method 
The cardiac muscle protecting effect of the compound of the present 
invention was tested by using the isolated heat of rats [test compound: 
N-cyano-N'-(2-nitroxyethyl)- 3-pyridinecarboximidamide (compound (13))]. 
The Langendorff's method was used in the same manner as in the 
aforementioned Referential Example 1)-6. The isolated heart was perfused 
with a perfusate for 30 minutes and then with a perfusate containing the 
test compound for 10 minutes, and perfusion was stopped so that the heart 
was in the so-called "ischemic state". Pacing was performed during the 
ischemia. After 25 minutes, perfusion was stated again with the original 
perfusate which did not contain the test compound. Parameters of cardiac 
function after the onset of re-perfusion was monitored for 30 minutes, and 
the heart was quickly freezed. The amount of ATP in the heart muscle was 
extracted with perchloric acid and determined by HPLC. Nicorandil was used 
as a control. 
The recovery rate of the cardiac function (heart rate.times.left 
ventricular pressure) after onset of reperfusion was calculated based on 
the cardiac function prior to the perfusion of the compound (13) and 
nicorandil as 100%. The amount of ATP in the heart muscle was also 
determined. 
(2) Results 
Recovery rates of the cardiac function and amounts of ATP in the heart 
muscle are shown in the following table. 
______________________________________ 
Amount of ATP in 
Concentra- 
Recovery rate 
the heart muscle 
tion of cardiac (.mu.mole/g of dry 
(mole/min) 
function (%) 
weight) 
______________________________________ 
Physiological 0.5 .+-. 0.5 (11) 
5.76 .+-. 0.83 (5) 
saline 
Nicorandil 
1 .times. 10.sup.-6 
12.7 .+-. 8.2 (4) 
5.93 .+-. 0.49 (4) 
Compound 1 .times. 10.sup.-7 
67.5 .+-. 6.0 (3)** 
11.12 .+-. 1.12 (6) 
(13) 
______________________________________ 
(mean .+-. SD); 
Numbers within parentheses denote specimen numbers. 
**p &lt; 0.01 (comparison with the physiological saline group) (Student's 
ttest) 
Referential Example 1)-12 
Effect of the Compound of the Present Invention on the Isolated Beagle 
Basilar Artery 
(1) Method 
A beagle was anesthetized with pentobarbital and dehematized from common 
carotid artery to death. The basilar artery was isolated rapidly. The 
artery was removed fat and connective tissue carefully and was cut into 
ring segments about 3.5 mm long in the Krebs-Ringer solution under oxygen. 
The ring preparation was suspended into an organ bath filled with the 
Krebs-Ringer solution which was maintained at 37.degree. C. and gassed 
with 95% O.sub.2 -5% CO.sub.2. The preparation in the organ bath was 
allowed to equilibrate under resting tension of 0.5 g. After equilibration 
period, U-46619 (thromboxane A.sub.2 derivative, 10.sup.-7 M) was added to 
the organ bath in order to contract the preparation. After the contraction 
induced by U-46619 had reached plateau, the compound of the present 
invention was cumulatively added to the organ bath to relax the 
preparation [test compound: 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13))]. 
The relaxation response was expressed as the percent inhibition of the 
contraction induced by U-46619. 
(2) Results 
The concentration-response curve for the relaxing action of the compound 
(13) is illustrated in FIG. 4. 
Referential Example 1)-13 
Effect of the Compound of the Present Invention on Hypoxia 
(1) Method 
The effect of the compound of the present invention [test compound: 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13))] on 
hypoxia was examined in male ddY mice (4 week old). Mice were exposed to a 
gas mixture of 96% N.sub.2 -4% Oz that was streamed in a flow rate of 5 
l/min. 
The time from the onset of the gas stream till the stop of respiration 
[survival time (sec)] was measured. 
The test compound was orally administered in the dosage form of a 2% 
suspension in gum arabic 30 minutes before the onset of the gas streaming. 
The control group was administered a gum arabic suspension only. 
(2) Results 
Survival times of the control and the compound administered groups are 
shown in the following table. 
______________________________________ 
Survival Time 
Dose Number (sec) 
(mg/kg) of Mice mean .+-. S.E.M. 
______________________________________ 
Control group 15 129.47 .+-. 8.51 
Compound (13) 
0.3 15 130.27 .+-. 9.32 
1.0 14 201.00 .+-. 13.40*** 
3.0 13 523.15 .+-. 48.57*** 
______________________________________ 
***p &lt; 0.001 (Student's ttest) 
Referential Example 1)-14 
Inhibitory Effect of the Compound of the Present Invention on the Platelet 
Aggregation 
(1) Method 
Using platelets of a beagle, the inhibitory effect of the compound of the 
present invention on the platelet aggregation was examined [test compound: 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13))]. 
Blood was collected from the cephalic vein of a beagle (blood: 3.8% citric 
acid =9:1) and centrifuged at 1050 rpm for 10 minutes. The supernatant was 
collected as platelet-rich plasma (PRP). Platelet poor plasma (PPP) was 
obtained by further centrifugation of the residue at 3000 rpm for 15 
minutes. Platelets were adjusted to 3.times.10.sup.8 platelets/ml by 
diluting PRP with PPP. 
Adenosin diphosphate (ADP) was used as an aggregating agent. After 
preincubation stirred with or without the compound (13) for 2 minutes at 
37.degree. C, PRP was mixed with ADP. Platelet aggregation was measured 
photometrically in volume of 750 .mu.l of PRP by means of an aggregometer 
(CAF-100, manufactured by Japan Spectroscopic). 
(2) Results 
The inhibiting effect of the compound (13) on platelet aggregation was 
illustrated in FIG. 5. Vertical vibration state in this figure are 
diagrammatically illustrated. 
Referential Example 1)-15 
Relaxing Effect of the Compound of the Present Invention on the Isolated 
Guinea Pig Trachea 
(1) Method 
The relaxing effect of the compound of the present invention on the smooth 
muscle of trachea obtained from quinea pig was examined [test compound: 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13))]. A 
male Hartley guinea pig (weighing 250 g) was dehematized to death. The 
trachea was isolated and cut into a spiral strip in the Krebs-Ringer 
solution. The preparation was placed in an organ bath filled with the 
Krebs-Ringer solution which was maintained at 37.degree. C. and gassed 
with 95% O.sub.2 -5% CO.sub.2. The preparation in the organ bath was 
allowed to equilibrate under resting tension of 0.5 g. After equilibration 
period, the solution in the organ bath was replaced with an isotonic 
solution containing 40 mM KCl to contract the trachea preparation. 
After the contraction induced by KCl had reached plateau, the compound (13) 
was cumulatively added to the organ bath to relax the preparation. 
The relaxation response was expressed as the percent inhibition of the 
contraction induced by KCl. 
(2) Results 
The concentration-response curve for the relaxing effect of the compound 
(13) is illustrated in FIG. 6. 
Referential Example 1)-16 
Acute Toxicity 
(1) Method 
Using male ddY mice (4 week old), acute toxicity on the oral administration 
of the compound of the present invention was examined [test compound: 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compound (13))]. As 
a result, LD.sub.50 was about 400 mg/kg. 
Example 1)-1 
Preparation of N-cyano-N'-(2-nitroxyethyl)-2-pyridinecarboximidamide 
(Method i) 
a) 2-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in methanol (50 ml). 
Sodium methoxide (0.26 g, 4.8 mmol) was added to the solution, and 
reaction was conducted for 6 hours at room temperature. After the reaction 
was completed, acetic acid (0.32 g, 5.3 mmol) was added to neutralize the 
reaction solution, and the solution was concentrated under reduced 
pressure. Diethyl ether (50 ml) was added to the concentrated residue, and 
diethyl ether insoluble products were removed by filtration. The filtrate 
was concentrated under reduced pressure to give the crude product of 
methyl 2-pyridinecarboximidate as a pale yellow oil in a yield of 7.5 g. 
Next, cyanamide (4.64 g, 110 mmol) and a phosphate buffer (pH 5.4) (70 ml) 
of Na.sub.2 HPO.sub.4 (7.81 g, 55 mmol) and NaH.sub.2 PO.sub.4.2H.sub.2 O 
(34.3 g, 220 mmol) were added to the oil, and the mixture was stirred 
vigorously at room temperature for 4 hours. After the reaction was 
completed, extraction was carried out with dichloromethane (100 
ml.times.3), and the dichloromethane layer was dried over anhydrous sodium 
sulfate and then concentrated under reduced pressure. The concentrated 
residue thus obtained was subjected to chromatography on a silica gel 
column (WAKO GEL C-200, 40 g) by eluting with hexane : diethyl ether 
(1:2). The product obtained was further crystallized from 
dichloromethane-diethyl ether to give methyl 
N-cyano-2-pyridinecarboximidate (8.81 g, 54.7 mmol, yield: 57%) as 
colorless needles. 
Physico-chemical properties of methyl N-cyano-2-pyridinecarboximidate 
MP: 81.0.degree.-81.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2220, 1640, 1570, 1340; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.83 (1H, 
ddd, J=2.4, 3.4, 9.4Hz), , 7.98 (1H, dd, J=2.4, 7.3Hz), 7.94 (1H, d, 
J=3.4Hz), : 7.63 (1H, dd, J=7.3, 9.4Hz), 4.16 (3H, s). 
b) Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved 
in methanol (5 ml), 2-nitroxyethylamine nitrate (0.57 g, 3.4 mmol) was 
added, and sodium methoxide (0.18 g, 3.4 mmol) was further added 
gradually. The mixture was stirred at room temperature for 10 minutes. 
After the reaction was completed, the reaction solution was concentrated 
under reduced pressure, and the residue thus obtained was extracted with 
dichloromethane (50 ml.times.3). The dichloromethane layer was dried over 
anhydrous sodium sulfate and concentrated under reduced pressure. The 
concentrated residue was crystallized from dichloromethane-diethyl ether 
to give the title compound (0.44 g, 0.20 mmol, yield: 63%) as colorless 
needles. 
Physico-chemical properties of 
N-cyano-N'-(2-nitroxyethyl)-2-pyridinecarboximidamide 
MP: 53.5.degree.-54.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3280, 2180, 1640, 1630, 1600, 1580, 1560, 
1290; 
NMR spectrum: (100 MHz, CD.sub.3 OD) .delta. (ppm) 8.73 (1H, br d, 
J=3.4Hz), 8.3-7.9 (2H, m), 7.64 (1H, m), 4.77 (2H, t, J=5.5Hz), 3.92 (2H, 
t, J=5.5Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 45.96 3.86 29.78 
Found: 45.68 3.76 30.12 (%) 
(C.sub.9 H.sub.9 N.sub.5 O.sub.3) 
______________________________________ 
Example 1)-2 
Preparation of N-cyano-N'-(2,2-dimethylpropyl)-2-pyridinecarboximidamide 
(method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in 
methanol (10 ml), 2,2-dimethylpropylamine (0.30 g, 3.4 mmol) was added, 
and the resulting mixture was stirred at room temperature for 30 minutes. 
After the reaction was completed, the reaction solution was concentrated 
under reduced pressure, and the residue thus obtained was crystallized 
from dichloromethane-diethyl ether to give the title compound (0.63 g, 2.9 
mmol, yield: 94%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(2,2-dimethylpropyl)-2-pyridinecarboximidamide 
MP: 109.degree.-109.8.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3260, 2970, 2190, 1600, 1580, 1560; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.7-8.5 (3H, m), 
8.00-7.80 (1H, m), 7.6-7.4 (1H, m), 3.58 (2H, d, J=6.9Hz), 1.05 (9H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 66.64 7.46 25.90 
Found: 66.41 7.58 25.72 (%) 
(C.sub.12 H.sub.16 N.sub.4) 
______________________________________ 
Example 1)-3 
Preparation of N-cyano-N'-(1,2,2-trimethylpropyl)-2-pyridinecarboximidamide 
(method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in 
methanol (10 ml), 1,2,2-trimethylpropylamine (0.34 g, 3.4 mmol) was added, 
and the resulting mixture was stirred at room temperature for 30 minutes. 
After the reaction was completed, the reaction solution was concentrated 
under reduced pressure, and the residue thus obtained was crystallized 
from dichloromethane-diethyl ether to give the title compound (0.67 g, 2.9 
mmol, yield: 92%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(1,2,2-trimethylpropyl)-2-pyridinecarboximidamide 
MP: 96.5.degree.-97.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3230, 3100, 2960, 2180, 1590, 1580, 1560; 
NMR spectrum: (100 MHz, CD.sub.3 OD) .delta. (ppm) 8.60 (2H, m), 7.92 (1H, 
m), 7.50 (1H, m), 4.48 (1H, q, J=7.2Hz), 1.28 (3H, d, J=7.2Hz), 1.03 (9H, 
s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 67.80 7.88 24.33 
Found: 67.51 7.97 24.25 (%) 
(C.sub.13 H.sub.18 N.sub.4) 
______________________________________ 
Example 1)-4 
Preparation of N-cyano-N'-phenyl-2 -pyridinecarboximidamide (method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in 
methanol (10 ml), aniline (0.32 g, 3.4 mmol) was added, and the resulting 
mixture was stirred at room temperature for 40 minutes. After the reaction 
was completed, the reaction solution was concentrated under reduced 
pressure, and the residue thus obtained was crystallized from 
dichloromethane-diethyl ether to give the title compound (0.63 g, 2.8 
mmol, yield: 91%) as colorless needles. 
Physico-chemical properties of N-cyano-N'-phenyl-2-pyridinecarboximidamide 
MP: 103.0.degree.-104.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1620, 1610, 1580, 1560; 
NMR spectrum: (100 MHz, CD.sub.3 OD) .delta. (ppm) 8.80 (1H, br s), 8.4-8.0 
(2H, m), 7.9-7.2 (6H, m); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 70.26 4.54 25.21 
Found: 70.09 4.57 25.14 (%) 
(C.sub.13 H.sub.10 N.sub.4) 
______________________________________ 
Example 1)-5 
Preparation of N-cyano-N'-(4-methoxyphenyl)-2-pyridinecarboximidamide 
(method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in 
methanol (10 ml), 4-methoxyaniline (0.36 g, 3.4 mmol) was added, and the 
resulting mixture was stirred at room temperature for 30 minutes. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the residue thus obtained was crystallized from 
dichloromethane-diethyl ether to give the title compound (0.74 g, 2.9 
mmol, yield: 94%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(4-methoxyphenyl)-2-pyridinecarboximidamide 
MP: 116.5.degree.-117.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 
NMR spectrum: (100 MHz, CD.sub.3 OD) .delta. (ppm) 8.77 (1H, br d, 
J=5.8Hz), 8.25 (1H, d, J=7.2Hz), 8.06 (1H, t, J=7.2Hz), 7.8-6.9 (3H, m), 
6.98 (2H, br d, J=10.3Hz), 3.83 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 66.66 4.79 22.21 
Found: 66.41 4.83 22.12 (%) 
(C.sub.14 H.sub.12 N.sub.4 O) 
______________________________________ 
Example 1)-6 
Preparation of N-cyano-N'-(4-methylbenzyl)-2-pyridinecarboximidamide 
(method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.30 g, 1.9 mmol) was dissolved in 
methanol (10 ml), p-methylbenzylamine (0.25 g, 2.1 mmol) was added, and 
the resulting mixture was stirred at room temperature for 2 hours. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the residue thus obtained was crystallized from 
diethyl ether to give the title compound (0.41 g, 1.6 mmol, yield: 91%) as 
colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(4-methylbenzyl)-2-pyridinecarboximidamide 
MP: 104.2.degree.-104.8.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1600, 1570; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.8-8.5 (2H), 7.91 (1H, 
dt, J=2.7, 7.5Hz), 7.49 (1H, dd, J=4.8, 7.5Hz), 7.35-7.15 (4H), 4.84 (2H, 
d, J=7.3Hz), 2.37 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 71.98 5.64 22.38 
Found: 71.87 5.59 22.11 (%) 
(C.sub.15 H.sub.14 N.sub.4) 
______________________________________ 
Example 1)-7 
Preparation of N-cyano-N'-(4-chlorobenzyl)-2-pyridinecarboximidamide 
(method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in 
methanol (10 ml), 4-chlorobenzylamine (0.48 g, 3.4 mmol) was added, and 
the resulting mixture was stirred at room temperature for 5 hours. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the residue thus obtained was crystallized from 
diethyl ether to give the title compound (0.13 g, 0.5 mmol, yield: 16%) as 
colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(4-chlorobenzyl)-2-pyridinecarboximidamide 
MP: 93.5.degree.-94.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1610, 1560; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.75-8.55 (2H), 7.92 (1H, 
dt, J=2.4, 7.5Hz), 7.50 (1H, dd, J=5.1, 7.5Hz), 7.36 (4H, s), 4.85 (2H, d, 
J=6.8Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 62.11 4.10 20.70 
Found: 62.08 4.00 20.43 (%) 
(C.sub.14 H.sub.11 N.sub.4 Cl) 
______________________________________ 
Example 1)-8 
Preparation of 
N-cyano-N'-[4-(trifluoromethyl)benzyl]-2-pyridinecarboximidamide (method 
i) 
Methyl N-cyano-2 pyridinecarboximidate (0.30 g, 1.9 mmol) was dissolved in 
methanol (10 ml), 4-(trifluoromethyl)benzylamine (0.36 g, 2.1 mmol) was 
added, and the resulting mixture was stirred at room temperature for 30 
minutes. After the reaction was completed, the reaction solution was 
concentrated under reduced pressure, and the residue thus obtained was 
crystallized from diethyl ether to give the title compound (0.47 g, 1.5 
mmol, yield: 84%) as colorless crystals. 
Physico-chemical properties of N 
cyano-N'-[4-(trifluoromethyl)benzyl]-2-pyridinecarboximidamide 
MP: 127.0.degree.-127.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1570, 1330; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.80-8.55 (2H), 7.95 (1H, 
dt, J=2.7, 7.2Hz), 7.70-7.40 (5H), 4.92 (2H, d, J=6.1Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 59.21 3.64 18.41 
Found: 59.15 3.63 18.25 (%) 
(C.sub.15 H.sub.11 N.sub.4 F.sub.3) 
______________________________________ 
Example 1)-9 
Preparation of 
N-cyano-N'-[2-(4-methylphenyl)ethyl]-2-pyridinecarboximidamide (method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in 
methanol (10 ml), 2-(p-tolyl)ethylamine (0.47 g, 3.5 mmol) was added, and 
the resulting mixture was stirred at room temperature for 1 hour. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the residue thus obtained was crystallized from 
methanol-diethyl ether to give the title compound (0.76 g, 2.9 mmol, 
yield: 93%) as colorless crystals. 
Physico-chemical properties of N 
cyano-N'-[2-(4-methylphenyl)ethyl]-2-pyridinecarboximidamide 
MP: 91.0.degree.-91.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1600, 1580, 1560; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 8.62-8.55 (2H), 8.41 (1H, 
br s), 7.89 (1H, dt, J=1.8, 7.8Hz), 7.48 (1H, dd, J=5.2, 7.8Hz), 7.15 (4H, 
dd, J=7.6, 14.0Hz), 3.97 (2H, br s), 2.99 (2H, t, J=7.6Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 72.70 6.10 21.20 
Found: 72.44 5.98 21.01 (%) 
(C.sub.16 H.sub.16 N.sub.4) 
______________________________________ 
Example 1)-10 
Preparation of 
N-cyano-N'-[2-(4-chlorophenyl)ethyl]-2-pyridinecarboximidamide (method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in 
methanol (10 ml), 4-chlorophenethylamine (0.53 g, 3.4 mmol) was added, and 
the resulting mixture was stirred at room temperature for 30 minutes. 
After the reaction was completed, the reaction solution was concentrated 
under reduced pressure, and the residue thus obtained was crystallized 
from dichloromethane-diethyl ether to give the title compound (0.43 g, 1.5 
mmol, yield: 49%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-[2-(4-chlorophenyl)ethyl]-2-pyridinecarboximidamide 
MP: 112.7.degree.-113.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3280, 2170, 1620, 1550, 1440; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.7-8.3 (3H), 7.90 (1H, 
m), 7.84 (1H, m), 7.3-7.1 (4H), 3.95 (2H, q, J=6.8Hz), 3.00 (2H, t, 
J=6.8Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 63.27 4.60 19.68 
Found: 63.17 4.71 19.70 (%) 
(C.sub.15 H.sub.13 N.sub.4 Cl) 
______________________________________ 
Example 1)-11 
Preparation of 
N-cyano-N'-(2-hydroxy-1-methyl-2-phenylethyl)-2-pyridinecarboximidamide 
(method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.24 g, 1.5 mmol) was dissolved in 
methanol (5 ml), DL-phenylpropanolamine hydrochloride (0.31 g. 1.7 mmol, 
supplied by Tokyo Chemical Industry Co., Ltd.) and triethylamine (0.17 g, 
1.7 mmol) were added, and the resulting mixture was stirred at room 
temperature for 5 solution was concentrated under reduced pressure, and 
the residue thus obtained was extracted with ethyl acetate (30 
ml.times.3). The ethyl acetate layer was washed with water (100 ml), dried 
over anhydrous sodium sulfate and concentrated under reduced pressure. The 
concentrated residue thus obtained was crystallized from diethyl ether to 
give the title compound (0.23 g, 0.8 mmol, yield: 54%) as colorless 
crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-hydroxy-1-methyl-2-phenylethyl)-2-pyridinecarboximidamide 
MP: 135.2.degree.-135.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1580, 1560; 
NMR spectrum: (500 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.68 (1H, 
d, J=4.8Hz), 8.42 (1H, d, J=8.0Hz), 7.97 (1H, dt, J=2.0, 8.0Hz), 8.57 (1H, 
dd, J=5.6, 8.0Hz), 7.46 (2H, d, J=7.8Hz), 7.38 (2H, t, J=7.8Hz), 7.29 (1H, 
t, J=7.8Hz), 5.05 (1H, d, J=3.6Hz), 4.70 (1H, br s), 1.17 (3H, d, 
J=7.6Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 68.55 5.75 19.99 
Found: 68.56 5.66 19.72 (%) 
(C.sub.16 H.sub.16 N.sub.4 O) 
______________________________________ 
Example 1)-12 
Preparation of N-cyano-N'-(2-thienylmethyl)-2-pyridinecarboximidamide 
(method i) 
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in 
methanol (10 ml), 2-thiophenemethylamine (0.38 g, 3.4 mmol) was added, and 
the resulting mixture was stirred at room temperature for 40 minutes. 
After the reaction was completed, the reaction solution was concentrated 
under reduced pressure, and the residue thus obtained was crystallized 
from dichloromethane-diethyl ether to give the title compound (0.40 g, 1.7 
mmol, yield: 54%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(2-thienylmethyl)-2-pyridinecarboximidamide 
MP: 87.0.degree.-88.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3220, 2160, 1600, 1580, 1560; 
NMR spectrum: (500 MHz, CDC13) .delta. (ppm) 8.72 (1H, br s), 8.60 (1H, d, 
J=4.0Hz), 8.51 (1H, br s), 7.93 (1H, t, J=8.6Hz), 7.52 (1H, dd, J=5.1, 
8.6Hz), 7.31 (1H, d, J=4.9Hz), 7.14 (1H, d, J=3.4Hz), 7.02 (1H, dd, J=3.7, 
5.4Hz), 5.05 (2H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 59.49 4.16 23.12 
Found: 59.76 4.14 23.21 (%) 
(C.sub.12 H.sub.10 N.sub.4 S) 
______________________________________ 
Example 1)-13 
Preparation of N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide 
(method i) 
a) 3-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in isopropanol (50 
ml). Sodium hydride (0.23 g, 9.6 mmol) from which oily matters had been 
removed by washing with ether was added to the solution, and the mixture 
was stirred at room temperature for 3 hours. After the reaction was 
completed, acetic acid (0.64 g, 10.7 mmol) was added to neutralize the 
reaction solution, and the solution was concentrated under reduced 
pressure. After concentrating the solution, diethyl ether (80 ml) was 
added to the concentrated residue, and insoluble products were removed by 
filtration. The filtrate was concentrated under reduced pressure, and 
hexane (80 ml) was added to the concentrated residue, and depositing 
unreacted 3-cyanopyridine was removed by filtration. The hexane solution 
was then concentrated under reduced pressure to give the crude product of 
isopropyl 3-pyridinecarboximidate as a pale yellow oil in a yield of 5.68 
g. 
Next, cyanamide (2.91 g, 69.2 mmol) and a phosphate buffer (pH 5.4, 30 ml) 
of Na.sub.2 HPO.sub.4 (4.91 g, 34.6 mmol) and NaH.sub.2 PO.sub.4.2H.sub.2 
O (21.59 g, 138.4 mmol) were added to the oil, and the mixture was stirred 
at room temperature for 6 hours. After the reaction was completed, the 
reaction solution was extracted with dichloromethane (100 ml.times.3), and 
the dichloromethane layer was dried over anhydrous sodium sulfate and then 
concentrated under reduced pressure. The concentrated residue thus 
obtained was subjected to chromatography on a silica gel column (WAKO GEL 
C-200, 250 g) by eluting with hexane : diethyl ether (1:2). The eluted 
fractions were concentrated to give isopropyl 
N-cyano-3-pyridinecarboximidate (4.84 g, 25.6 mmol, yield: 26%) as pale 
yellow oil. 
Physico-chemical properties of isopropyl N-cyano-3-pyridinecarboximidate 
IR spectrum: (cm.sup.-1, neat) 3240, 2250, 2180, 1610, 1380, 1310, 1100; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 9.15 (1H, d, J=2.6Hz), 
8.83 (1H, dd, J=1.7, 4.9Hz), 8.48 (1H, ddd, J=1.7, 2.6, 8.1Hz), 7.50 (1H, 
dd, J=4.9, 8.1Hz), 5.42 (1H, m, J=7.2Hz), 1.48 (6H, d, J=7.2Hz). 
b) Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was 
dissolved in methanol (10 ml), and 2-nitroxyethylamine nitrate (0.49 g, 
2.9 mmol) and sodium methoxide (0.16 g, 2.9 mmol) were added. The mixture 
was stirred at room temperature for 10 minutes. After the reaction was 
completed, the reaction solution was concentrated under reduced pressure, 
and the residue was extracted with dichloromethane (50 ml.times.3). The 
dichloromethane layer was dried over anhydrous sodium sulfate and 
concentrated under reduced pressure. The concentrated residue was 
crystallized from dichloromethane-diethyl ether to give the title compound 
(0.48 g, 2.1 mmol, yield: 79%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide 
MP: 99.5.degree.-100.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1640, 1590, 1280; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.73 (1H, d, J=4.9Hz), 
8.71 (1H, s), 8.16 (1H, d, J=7.9Hz), 7.51 (1H, dd, J=4.9, 7.9Hz), 4.72 
(2H, t, J=4.9Hz), 3.84 (2H, t, J=4.9Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 45.96 3.86 29.78 
Found: 45.77 3.78 30.01 (%) 
(C.sub.9 H.sub.9 N.sub.5 O.sub.3) 
______________________________________ 
Example 1)-14 
Preparation of N-cyano-N'-(3-nitroxypropyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 3-nitroxypropylamine nitrate (0.53 g, 2.9 mmol) 
and sodium methoxide (0.16 g, 2.9 mmol) were added. The mixture was 
stirred at room temperature for 18 hours. After the reaction was 
completed, the reaction solution was concentrated under reduced pressure, 
and the residue was extracted with chloroform (30 ml.times.3). The 
chloroform layer was washed with water (100 ml), dried over anhydrous 
sodium sulfate and concentrated under reduced pressure. The concentrated 
residue thus obtained was subjected to chromatography on a silica gel 
column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (60:1). 
Eluted fractions were concentrated under reduced pressure and crystallized 
from methanol-diethyl ether to give the title compound (0.26 g, 1.0 mmol, 
yield: 39%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(3-nitroxypropyl)-3-pyridinecarboximidamide 
MP: 124.9.degree.-125.8.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1620, 1600, 1560, 1280; 
NMR spectrum: (500 MHz, CDCl.sub.3 -CD.sub.3 OD) .delta. (ppm) 8.75-8.70 
(2H), 8.10 (1H, dt, J=2.4, 7.8Hz), 7.54 (1H, dd, J=5.2, 7.8Hz), 4.59 (2H, 
t, J=6.0Hz), 3.61 (2H, t, J=6.0Hz), 2.14 (2H, quint, J=6.0Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 48.19 4.45 28.10 
Found: 48.16 4.29 27.93 (%) 
(C.sub.10 H.sub.11 N.sub.5 O.sub.3) 
______________________________________ 
Example 1)-15 
Preparation of N-cyano-N'-(3,3-dimethylbutyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved 
in methanol (10 ml), and 3,3-dimethylbutylamine (0.36 g, 3.6 mmol) was 
added. The mixture was stirred at room temperature for 20 minutes. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the concentrated residue was crystallized from 
dichloromethane-diethyl ether to give the title compound (0.46 g, 2.0 
mmol, yield: 63%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(3,3-dimethylbutyl)-3-pyridinecarboximidamide 
MP: 168.0.degree.-168.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3250, 2970, 2190, 1590, 1560, 720; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 10 8.70 (2H, m), 7.96 
(1H, d, J=8.6Hz), 7.42 (1H, dd, J=5.5, 8.6Hz), 6.88 (1H, br s), 3.50 (2H, 
m), 1.58 (2H, m), 1.00 (9H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 67.80 7.88 24.32 
Found: 67.69 7.95 24.36 (%) 
(C.sub.13 H.sub.18 N.sub.4) 
______________________________________ 
Example 1)-16 
Preparation of N-cyano-N'-(4-methylphenyl) 3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 4-methylaniline (0.31 g, 2.9 mmol) was added. The 
mixture was stirred at room temperature for 30 minutes. After the reaction 
was completed, the reaction solution was concentrated under reduced 
pressure, and the concentrated residue thus obtained was crystallized from 
dichloromethane-diethyl ether to give the title compound (0.56 g, 2.4 
mmol, yield: 90%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(4-methylphenyl)-3-pyridinecarboximidamide 
MP: 202.5.degree.-203.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3200, 2180, 1580, 1550, 710; 
NMR spectrum: (100 MHz, CDCl.sub.3 -CD.sub.3 OD) .delta. (ppm) 8.86 (1H, 
s), 8.78 (1H, br s), 8.18 (1H, br s), 7.60 (3H, br s), 7.22 (2H, m), 2.39 
(3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 71.17 5.12 23.71 
Found: 71.06 5.15 23.65 (%) 
(C.sub.14 H.sub.12 N.sub.4) 
______________________________________ 
Example 1)-17 
Preparation of N-cyano-N'-benzyl-3 -pyridinecarboximidamide (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and benzylamine (0.31 g, 2.9 mmol) was added. The 
mixture was stirred at room temperature for 30 minutes. After the reaction 
was completed, the reaction solution was concentrated under reduced 
pressure, and the concentrated residue thus obtained was crystallized from 
methanoldiethyl ether to give the title compound (0.44 g, 1.8 mmol, yield: 
72%) as colorless needles. 
Physico-chemical properties of N-cyano-N'-benzyl-3-pyridinecarboximidamide 
MP: 104.degree.-104.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3230, 3100, 2170, 1580, 1550, 710; 
NMR spectrum: (100 MHz, CDCl.sub.3 -CD.sub.3 OD) .delta. (ppm) 8.70 (2H, br 
s), 8.08 (1H, dt, J=2.9, 7.9Hz), 25 7.50 (1H, dd, J=4.8, 7.9Hz), 7.36 (5H, 
s), 4.62 (2H, t, J=3.4Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 71.17 5.12 23.71 
Found: 71.00 5.16 23.62 (%) 
(C.sub.14 H.sub.12 N.sub.4) 
______________________________________ 
Example 1)-18 
Preparation of N-cyano-N'-(4-methylbenzyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (5 ml), and 4-methylbenzylamine (0.35 g, 2.9 mmol) was added. 
The mixture was stirred at room temperature for 30 minutes. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the concentrated residue thus obtained was 
crystallized from diethyl ether to give the title compound (0.60 g, 2.4 
mmol, yield: 91%) as colorless powder. 
Physico-chemical properties of N 
cyano-N'-(4-methylbenzyl)-3-pyridinecarboximidamide 
MP: 150.0.degree.-150.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3270, 2180, 1580, 1560; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.72 (2H, 
m), 8.05 (1H, m), 7.57 (1H, dd, J=6.2, 7.5Hz), 7.20 (4H, s), 4.59 (2H, s), 
2.30 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 71.98 5.64 22.38 
Found: 71.72 5.78 22.24 (%) 
(C.sub.15 H.sub.14 N.sub.4) 
______________________________________ 
Example 1)-19 
Preparation of N-cyano-N'-(4-methoxybenzyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 4-methoxybenzylamine (0.40 g, 2.9 mmol) was 
added. The mixture was stirred at room temperature for 40 minutes. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the concentrated residue thus obtained was 
crystallized from methanol-diethyl ether to give the title compound (0.50 
g, 2.1 mmol, yield: 80%) as colorless powder. 
Physico-chemical properties of 
N-cyano-N'-(4-methoxybenzyl)-3-pyridinecarboximidamide 
MP: 160.5.degree.-162.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3230, 1590, 1550, 1510, 1250; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.73 (2H, 
m), 8.08 (1H, m), 7.58 (1H, m), 7.32 (2H, d, J=9.2Hz), 6.91 (2H, d, 
J=9.2Hz), 4.59 (2H, s), 3.78 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 67.65 5.30 21.04 
Found: 67.88 5.28 21.04 (%) 
(C.sub.15 H.sub.14 N.sub.4 O) 
______________________________________ 
Example 1)-20 
Preparation of N-cyano-N'-(4-dimethylaminobenzyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (5 ml), and a solution of p-(dimethylamino)benzylamine 
dihydrochloride (0.65 g, 2.9 mmol) and triethylamine (0.64 g, 6.4 mmol) in 
methanol (5 ml) were added. The mixture was stirred at room temperature 
for 6 hours. After the reaction was completed, the reaction solution was 
concentrated under reduced pressure, and the concentrated residue thus 
obtained was extracted with ethyl acetate (50 ml.times.3). The ethyl 
acetate layer was washed with water (50 ml), dried over anhydrous sodium 
sulfate and concentrated under reduced pressure. The residual concentrate 
thus obtained was subjected to chromatography on a silica gel column (WAKO 
GEL C-200, 30 g) eluting with chloroformmethanol (100:1). The eluted 
fractions were concentrated under reduced pressure and then crystallized 
from methanol-diethyl ether to give the title compound (0.63 g, 2.3 mmol, 
yield: 85%) as colorless powder. 
Physico-chemical properties of 
N-cyano-N'-(4-dimethylaminobenzyl)-3-pyridinecarboximidamide 
MP: 148.8.degree.-152.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1580, 1550, 1530; 
NMR spectrum: (100 MHz, CDCl.sub.3 -CD.sub.3 OD) .delta. (ppm) 8.70 (2H, 
m), 8.06 (1H, m), 7.57 (1H, dd, J=5.2, 7.5Hz), 7.25 (2H, d, J=9.2Hz), 6.76 
(2H, d, J=9.2Hz), 4.53 (2H, s), 2.92 (6H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 68.80 6.13 25.07 
Found: 68.56 6.09 24.97 (%) 
(C.sub.16 H.sub.17 N.sub.5) 
______________________________________ 
Example 1)-21 
Preparation of N-cyano-N'-[4 
(trifluoromethyl)benzyl]-3-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 4-(trifluoromethyl)benzylamine (0.51 g, 2.9 mmol) 
was added. The mixture was stirred at room temperature for 1 hour. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the concentrated residue thus obtained was 
crystallized from diethyl ether to give the title compound (0.53 g, 1.7 
mmol, yield: 66%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-[4-(trifluoromethyl)benzyl]-3-pyridinecarboximidamide 
MP: 201.0.degree.-201.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2170, 1590, 1580, 1550, 1330; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.80-8.70 
(2H), 8.11 (1H, d, J=7.8Hz), 7.75-7.40 (5H), 4.70 (2H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 59.21 3.64 18.41 
Found: 59.14 3.62 18.17 (%) 
(C.sub.15 H.sub.11 N.sub.4 F.sub.3) 
______________________________________ 
Example 1)-22 
Preparation of N-cyano-N'-(4-chlorobenzyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 4-chlorobenzylamine (0.41 g, 2.9 mmol) was added. 
The mixture was stirred at room temperature for 1.5 hours. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the concentrated residue thus obtained was 
crystallized from methanol-diethyl ether to give the title compound (0.65 
g, 2.4 mmol, yield: 91%) as colorless powder. 
Physico-chemical properties of 
N-cyano-N'-(4-chlorobenzyl)-3-pyridinecarboximidamide 
MP: 163.5.degree.-166.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3250, 2180, 1580, 1550; 
NMR spectrum (100 MHz, CDCl.sub.3 -CD.sub.3 OD) .delta. (ppm) 8.75 (2H, m), 
8.10 (1H, m), 7.59 (1H, dd, J=5.5, 7.9Hz), 7.40 (4H, s), 4.54 (2H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 62.11 4.10 20.70 
Found: 61.94 4.11 20.65 (%) 
(C.sub.14 H.sub.11 N.sub.4 Cl) 
______________________________________ 
Example 1)-23 
Preparation of N-cyano-N'-(4-nitrobenzyl)-3-pyridinecarboximidamide (method 
i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (5 ml), and a solution of p-nitrobenzylamine hydrochloride 
(0.55 g, 2.9 mmol) and triethylamine (0.32 g, 3.2 mmol) in methanol (5ml) 
was added. The mixture was stirred at room temperature for 2 hours. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the concentrated residue thus obtained was 
crystallized from methanol-diethyl ether to give the title compound (0.70 
g, 2.5 mmol, yield: 95%) as colorless powder. 
Physico-chemical properties of 
N-cyano-N'-(4-nitrobenzyl)-3-pyridinecarboximidamide 
MP: 206.2.degree.-207.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1580, 1550, 1520, 1350, 1340; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.83 (2H, 
m), 8.4-8.0 (3H), 7.8-7.5 (3H), 4.75 (2H, d, J=6.2Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 59.78 3.94 24.90 
Found: 59.50 4.06 24.88 (%) 
(C.sub.14 H.sub.11 N.sub.5 O.sub.2) 
______________________________________ 
Example 1)-24 
Preparation of N-cyano-N'-(3,4-dichlorobenzyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 3,4-dichlorobenzylamine (0.51 g, 2.9 mmol) was 
added. The mixture was stirred at room temperature for 3 hours. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the concentrated residue thus obtained was 
crystallized from diethyl ether to give the title compound (0.42 g, 1.4 
mmol, yield: 52%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(3,4-dichlorobenzyl)-3-pyridinecarboximidamide 
MP: 149.5.degree.-150.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2170, 1590, 1550; 
NMR spectrum: (500 MHz, CDCl.sub.3 -CD.sub.3 OD) .delta. (ppm) 8.75-8.72 
(2H), 8.11 (1H, dt, J=2.0, 8.2Hz), 7.54 (1H, dd, J=5.2, 8.2Hz), 7.48 (1H, 
d, J=2.0Hz), 7.46 (1H, d, J=8.4Hz), 7.25 (1H, dd, J=2.0, 8.4Hz), 4 60 (2H, 
s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 55.10 3.30 18.36 
Found: 54.99 3.01 18.09 (%) 
(C.sub.14 H.sub.10 N.sub.4 Cl.sub.2) 
______________________________________ 
Example 1)-25 
Preparation of N-cyano-N'-[3,5 
-bis(trifluoromethyl)benzyl]-3-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 3,5-bis(trifluoromethyl)benzylamine (0.71 g, 2.9 
mmol) was added. The mixture was stirred at room temperature for 1 hour. 
After the reaction was completed, the reaction solution was concentrated 
under reduced pressure, and the concentrated residue thus obtained was 
crystallized from diethyl ether to give the title compound (0.34 g, 0.91 
mmol, yield: 35%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-[3,5-bis(trifluoromethyl)benzyl]-3-pyridinecarboximidamide 
MP: 172.0.degree.-172.1.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1580, 1280, 1180, 1120; 
NMR spectrum: (500 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.76-8.72 
(2H), 8.12 (1H, dt, J=2.0, 8.2Hz), 7.90-7.83 (3H), 7.54 (1H, dd, J=5.0, 
8.2Hz), 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 51.64 2.71 15.05 
Found: 51.49 2.56 14.95 (%) 
(C.sub.16 H.sub.10 N.sub.4 F.sub.6) 
______________________________________ 
Example 1)-26 
Preparation of N-cyano-N'-(3-benzyloxybenzyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.30 g, 1.6 mmol) was dissolved 
in methanol (10 ml), and 3-benzyloxybenzylamine (0.41 g, 1.9 mmol) was 
added. The mixture was stirred at room temperature for 2 hours. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure. The concentrated residue was subjected to chromatography 
on a silica gel column (WAKO GEL C-200, 30 g). Elution with 
chloroform-methanol (100:1) was conducted, the eluted fractions were 
concentrated under reduced pressure, and the concentrated residue thus 
obtained was crystallized from methanol-diethyl ether to give the title 
compound (0.48 g, 1.4 mmol, yield: 88%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(3-benzyloxybenzyl)-3-pyridinecarboximidamide 
MP: 122.0.degree.-122.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2170, 1590; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 8.66-8.62 (2H), 7.98 (1H, 
dt, J=2.0, 7.9Hz), 7.44-7.26 (6H), 6.96-6.86 (4H), 5.06 (2H, s), 4.61 
(2H, d, J=5.8Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 73.67 5.30 16.36 
Found: 73.54 5.19 16.11 (%) 
(C.sub.21 H.sub.18 N.sub.4 O) 
______________________________________ 
Example 1)-27 
Preparation of N-cyano-N'-(2-phenylethyl)-3-pyridinecarboximidamide (method 
i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 2-phenylethylamine (0.35 g, 2.9 mmol) was added. 
The mixture was stirred at room temperature for 40 minutes. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the concentrated residue thus obtained was 
crystallized from methanol-diethyl ether to give the title compound (0.45 
g, 1.8 mmol, yield: 68%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(2-phenylethyl)-3-pyridinecarboximidamide 
MP: 149.5.degree.-150.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3220, 3120, 2180, 1590, 1550, 710; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.70 (1H, 
dd, J=2.0, 5.1Hz), 8.61 (1H, dd, J=1.0, 2.4Hz), 8.00 (1H, ddd, J=2.0, 2.4, 
8.2Hz), 7.50 (1H, ddd, J=1.0, 5.1, 8.2Hz), 7.26 (5H, br s), 3 74 (2H, t, 
J=7.8Hz), 2.98 (2H, t, J=7.8Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 71.98 5.64 22.38 
Found: 71.70 5.68 22.30 (%) 
(C.sub.15 H.sub.14 N.sub.4) 
______________________________________ 
Example 1)-28 
Preparation of 
N-cyano-N'-[2-(2-methoxyphenyl)ethyl]-3-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 2-(2-methoxyphenyl)ethylamine (0.44 g, 2.9 mmol) 
was added. The mixture was stirred at room temperature for 6 hours. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the residue thus obtained was subjected to 
chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure, and the concentrated residue thus obtained was 
crystallized from chloroformhexane to give the title compound (0.50 g, 1.8 
mmol, yield: 68%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-[2-(2-methoxyphenyl)ethyl]-3-pyridinecarboximidamide 
MP: 123.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2170, 1580, 1550; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 8.76 (1H, d, J=4.4Hz), 
8.63 (1H, s), 8.03 (1H, d, J=9.6Hz), 7.44 (1H, dd, J=4.4, 9.6Hz), 7.28 
(1H, t, J=8.7Hz), 7.19 (1H, d, J=8.7Hz), 6.98 (1H, t, J=8.7Hz), 6.92 (1H, 
d, J=8.7Hz), 6.70 (1H, br s), 3.82 (3H, s), 3.75 (2H, m), 3.03 (2H, t, 
J=7.1Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 68.55 5.75 19.99 
Found: 68.72 5.71 19.91 (%) 
(C.sub.16 H.sub.16 N.sub.4 O) 
______________________________________ 
Example 1)-29 
Preparation of 
N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 2-(2-chlorophenyl)ethylamine (0.45 g, 2.9 mmol) 
was added. The mixture was stirred at room temperature for 7 hours. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure. The residual concentrate was subjected to chromatography 
on a silica gel column (WAKO GEL C-200, 30 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure, and the concentrated residue thus obtained was 
crystallized from methanolhexane to give the title compound (0.56 g, 2.0 
mmol, yield: 75%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide 
MP: 138.5.degree.-140.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1590; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.77 (1H, 
dd, J=1.7, 4.8Hz), 8.68 (1H, d, J=2.0Hz), 8.12 (1H, m), 7.60-7.25 (5H), 
3.76 (2H, t, J=7.6Hz), 3.14 (1H, t, J=7.6Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 63.27 4.60 19.68 
Found: 63.17 4.64 19.45 (%) 
(C.sub.15 H.sub.13 N.sub.4 Cl) 
______________________________________ 
Example 1)-30 
Preparation of 
N-cyano-N'-[2-(4-chlorophenyl)ethyl]-3-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved 
in methanol (10 ml), and 2-(4-chlorophenyl)ethylamine (0.55 g, 3.5 mmol) 
was added. The mixture was stirred at room temperature for 2.5 hours. 
After the reaction was completed, the reaction solution was concentrated 
under reduced pressure. The residual concentrate was subjected to 
chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure, and the concentrated residue thus obtained was further 
crystallized from methanol-diethyl ether to give the title compound (0.71 
g, 2.5 mmol, yield: 79%) as colorless powder. 
Physico-chemical properties of 
N-cyano-N'-[2-(4-chlorophenyl)ethyl]-3-pyridinecarboximidamide 
MP: 121.8.degree.-122.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3240, 3100, 2180, 1590, 1550, 710; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.8-8.5 (2H), 7.97 (1H, 
d, J=9.9Hz), 7.5-7.1 (5H), 6.70 (1H, br s), 3.78 (2H, q, J=6.8Hz), 2.99 
(2H, t, J=6.8Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 63.27 4.60 19.68 
Found: 63.14 4.68 19.61 (%) 
(C.sub.15 H.sub.13 N.sub.4 Cl) 
______________________________________ 
Example 1)-31 
Preparation of 
N-cyano-N'-[2-(4-benzylaminophenyl)ethyl]-3-pyridinecarboximidamide 
(method i) 
a) Isopropyl N-cyano-3-pyridinecarboximidate (1.0 g, 5.3 mmol) was 
dissolved in methanol (15 ml), and 2-(4-aminophenyl)ethylamine (0.80 g, 
5.8 mmol) was added. The mixture was stirred at room temperature for 1 
hour. After the reaction was completed, the reaction solution was 
concentrated under reduced pressure. The residual concentrate was 
crystallized from methanol-diethyl ether pyridinecarboximidamide (0.88 g, 
3.3 mmol, yield: 63%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-[2-(4-aminophenyl)ethyl]-3-pyridinecarboximidamide 
MP: 154.5.degree.-155.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2160, 1580, 1540; 
NMR spectrum: (500 MHz, CDCl.sub.3 -CD.sub.3 OD) .delta. (ppm) 8.70 (1H, 
dd, J=1.8, 5.4Hz), 8.62 (1H, d, J=1.8Hz), 8.01 (1H, dt, J=1.8, 8.6Hz), 
7.51 (1H, dd, J=5.4, 8.6Hz), 7.03 (2H, d, J=8.4Hz), 6.70 (2H, d, J=8.4Hz), 
3.67 (2H, t, J=7.4Hz), 2.87 (2H, t, J=7.4Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 67.91 5.70 26.40 
Found: 67.80 5.66 26.17 (%) 
(C.sub.15 H.sub.15 N.sub.5) 
______________________________________ 
b) N-cyano-N'-[2-(4-aminophenyl)ethyl]-3-pyridinecarboximidamide (0.20 g, 
0.75 mmol) was dissolved in methanol (15 ml), and benzaldehyde (0.12 g, 
1.13 mmol) and sodium cyanoborohydride (0.10 g, 1.59 mmol) were added. The 
mixture was stirred at room temperature for 2 hours. After the reaction 
was completed, the reaction solution was concentrated under reduced 
pressure. The residue thus obtained was extracted with chloroform (50 
ml.times.3). The chloroform layer was washed with water (100 ml), dried 
over anhydrous sodium sulfate and concentrated under reduced pressure. The 
residual concentrate was subjected to chromatography on a silica gel 
column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). 
The eluted fractions were concentrated under reduced pressure and 
crystallized from methanol-diethyl ether to give the title compound (0.12 
g, 0.34 mmol, yield: 75%) as colorless needles. 
Physico-chemical properties of N-cyano-N'-[2 
(4-benzylaminophenyl)ethyl]-3-pyridinecarboximidamide 
MP: 131.5.degree.-132.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1590, 1550; 
NMR spectrum: (500 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.70 (1H, 
dd, J=2.0, 5.2Hz), 8.62 (1H, d, J=2.0Hz), 8.00 (1H, dt, J=2.0, 8.0Hz), 
7.49 (1H, dd, J=5.2, 8.0Hz), 7.38-7.25 (5H), 7.04 (2H, d, J=8.2Hz), 6.63 
(2H, d, J=8.2Hz), 4.32 (2H, s), 3.66 (2H, t, J=7.4Hz), 2.86 (2H, t, 
J=7.4Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 74.34 5.96 19.70 
Found: 74.21 6.11 19.48 (%) 
(C.sub.22 H.sub.21 N.sub.5) 
______________________________________ 
Example 1)-32 
Preparation of 
N-cyano-N'-[2-(4-nitrophenyl)-2-nitroxyethyl]-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.22 g, 1.2 mmol) was dissolved 
in methanol (10 ml), and 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate 
(0.40 g, 1.4 mmol) and sodium methoxide (0.14 g, 2.6 mmol) were added. The 
mixture was stirred at room temperature for 17 hours. After the reaction 
was completed, the reaction solution was concentrated under reduced 
pressure. The residual concentrate was extracted with chlofororm (100 
ml.times.3). The chloroform layer was washed with water (150 ml), dried 
over anhydrous sodium sulfate and concentrated under reduced pressure. The 
residual concentrate was subjected to chromatography on a silica gel 
column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (50:1). The 
eluted fractions were concentrated under reduced pressure and crystallized 
from methanol-diethyl ether to give the title compound (0.13 g, 0.36 mmol, 
yield: 31%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-[2-(4-nitrophenyl)-2-nitroxyethyl]-3-pyridinecarboximidamide 
MP: 86.5.degree.-89.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1640, 1590, 1520, 1380, 1350; 
NMR spectrum: (500 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.33 (2H, 
d, J=8.7Hz), 8.14 (1H, dd, J=4.0, 8.7Hz), 7.69 (2H, d, J=8.7Hz), 6.32 (1H, 
d, J=3.5, 9.3Hz), 3.76 (2H, m); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 50.57 3.39 23.59 
Found: 50.50 3.49 23.33 (%) 
(C.sub.15 H.sub.12 N.sub.6 O.sub.5) 
______________________________________ 
Example 1)-33 
Preparation of N-cyano-N'-(3-phenylpropyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved 
in methanol (10 ml), and 3-phenylpropylamine (0.47 g, 3.5 mmol) was added. 
The mixture was stirred at room temperature for 50 minutes. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure. The residual concentrate thus obtained was subjected to 
chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure and crystallized from methanol-diethyl ether to give the 
title compound (0.67 g, 2.5 mmol, yield: 80%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(3-phenylpropyl)-3-pyridinecarboximidamide 
MP: 98.5.degree.-99.1.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3240, 2180, 1590, 1550, 1440, 710; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.7-8 4 (2H), 7.80 (1H, 
m), 7.4-7.0 (7H), 3.49 (2H, q, J=7.4Hz), 2.70 (2H, t, J=7.4Hz), 1.98 (2H, 
quint, J=7.4Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 72.70 6.10 21.20 
Found: 72.58 6.21 21.17 (%) 
(C.sub.16 H.sub.16 N.sub.4) 
______________________________________ 
Example 1)-34 
Preparation of N-cyano-N'-diphenyl methyl-3-pyridinecarboximidamide 
hydrochloride (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and aminodiphenylmethane (0.54 g, 2.9 mmol) was 
added. The mixture was stirred at room temperature for 1 hour. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure. The residual concentrate thus obtained was subjected to 
chromatography on a silica gel column (WAKO GEL C-200, 40 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure to give 
N-cyano-N'-diphenylmethyl-3-pyridinecarboximidamide (0.48 g, 1.5 mmol, 
yield: 58%) as colorless syrup. Next, to this syrup was added a solution 
of 5% hydrogen chloride in methanol (2 ml) to form a solution. The 
solution was further crystallized from methanol-diethyl ether to give 
N-cyano-N'-diphenylmethyl-3-pyridinecarboximidamide hydrochloride as 
colorless powder. 
Physico-chemical properties of 
N-cyano-N'-diphenylmethyl-3-pyridinecarboximidamide hydrochloride 
MP: 164.0.degree.-165.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3020, 2180, 1580, 700; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.95 (2H, 
m), 8.58 (1H, m), 8.00 (1H, m), 7.4-7.2 (12H), 6.50 (1H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 68.86 4.91 16.23 
Found: 68.61 5.04 16.15 (%) 
(C.sub.20 H.sub.16 N.sub.4.HCl) 
______________________________________ 
Example 1)-35 
Preparation of N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide 
hydrochloride (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved 
in methanol (10 ml), and 1,2-diphenylethylamine (0.69 g, 3.5 mmol) was 
added. The mixture was stirred at room temperature for 45 minutes. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure. The residual concentrate thus obtained was subjected to 
chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure to give 
N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide (0.60 g, 1.8 
mmol, yield: 58%) as colorless syrup. Next, to this syrup was added a 5% 
hydrogen chloride solution in methanol (2.5 ml). The solution was 
crystallized from a methanol-diethyl ether to give 
N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride as 
colorless powder. 
Physico-chemical properties of 
N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride 
MP: 140.5.degree.-143.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1570, 700; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.90 (1H, 
d, J=5.8Hz), 8.72 (1H, s), 8.48 (1H, d, J=9.6Hz), 8.10 (1H, dd, J=5.8, 
9.6Hz), 7.6-7.2 (10H), 5.46 (1H, t, J=8.6Hz), 3.29 (2H, d, J=8.6Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 69.51 5.28 15.44 
Found: 69.32 5.25 15.43 (%) 
(C.sub.21 H.sub.18 N.sub.4.HCl) 
______________________________________ 
Example 1)-36 
Preparation of N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide 
hydrochloride (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 2,2-diphenylethylamine (0.58 g, 2.9 mmol) was 
added. The mixture was stirred at room temperature for 2 hours. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure. The residual concentrate thus obtained was subjected to 
chromatography on a silica gel column (WAKO GEL C 200, 30 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure to give 
N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide (0.61 g, 1.9 
mmol, yield: 71%) as colorless syrup. Next, to this syrup was added a 5% 
hydrogen chloride solution in methanol (2.5 ml). The solution was 
crystallized from methanol-diethyl ether to give 
N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride as 
colorless powder. 
Physico-chemical properties of 
N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride 
MP: 139.5.degree.-142.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3040, 2170, 1610, 1580, 700; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.94 (1H, 
d, J=6.2Hz), 8.70 (1H, s), 8.41 (1H, d, J=8.6Hz), 8.08 (1H, dd, J=6.2, 
8.6Hz), 4.60 (1H, t, J=8.9Hz), 4.19 (2H, d, J=8.9Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 69.51 5.28 15.44 
Found: 69.19 5.46 15.20 (%) 
(C.sub.21 H.sub.18 N.sub.4.HCl) 
______________________________________ 
Example 1)-37 
Preparation of N-cyano-N'-(3,3-diphenylpropyl)-3-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved 
in methanol (10 ml), and 3,3-diphenylpropylamine (0.74 g, 3.5 mmol) was 
added. The mixture was stirred at room temperature for 1 hour. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure. The residual concentrate thus obtained was subjected to 
chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure and crystallized from methanol-diethyl ether to give the 
title compound (0.68 g, 2.0 mmol, yield: 63%) as colorless powder. 
Physico-chemical properties of 
N-cyano-N'-(3,3-diphenylpropyl)-3-pyridinecarboximidamide 
MP: 150.9.degree.-151.3.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1590, 1550, 700; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.68 (1H, m), 8.50 (1H, 
s), 7.82 (1H, d, J=7.5Hz), 7.4-7.0 (11H), 6.54 (1H, br s), 4.00 (1H, t, 
J=8.6Hz), 3.51 (2H, q, J=8.6Hz), 2.43 (2H, q, J=8.6Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 77.62 5.92 16.46 
Found: 77.60 5.92 16.43 (%) 
(C.sub.22 H.sub.20 N.sub.4) 
______________________________________ 
Example 1)-38 
Preparation of 
N-cyano-N'-(2-benzyloxy-2-phenylethyl)-3-pyridinecarboximidamide 
hydrochloride (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.20 g, 1.1 mmol) was dissolved 
in methanol (5 ml), and 2-benzyloxy-2-phenylethylamine (0.26 g, 1.1 mmol) 
was added. The mixture was stirred at room temperature for 3 hours. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure. The residual concentrate thus obtained was subjected to 
chromatography on a silica gel column (WAKO GEL C-200, 20 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure to give 
N-cyano-N'-(2-benzyloxy-2-phenylethyl)-3-pyridinecarboximidamide (0.24 g, 
0.7 mmol, yield: 64%) as colorless syrup. Next, to this syrup was added a 
5% hydrogen chloride in methanol (2 ml). The solution was crystallized 
from methanol-diethyl ether to give 
N-cyano-N'-(2-benzyloxy-2-phenylethyl)-3-pyridinecarboximidamide 
hydrochloride as colorless powder. 
Physico-chemical properties of 
N-cyano-N'-(2-benzyloxy-2-phenylethyl]-3-pyridinecarboximidamide 
hydrochloride 
MP: 163.0.degree.-165.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2550, 2200, 1710, 1680; 
NMR spectrum: (100 MHz, CDC13) .delta. (ppm) 9.00 (2H), 8.60 (1H, d, 
J=8.3Hz), 8.19 (1H, m), 7.60-7.20 (11H), 4.82 (1H, m), 4.42 (2H, m), 3.79 
(2H, d, J=6.3Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 67.26 5.13 14.26 
Found: 67.07 4.99 13.97 (%) 
(C.sub.22 H.sub.20 N.sub.4 O.HCl) 
______________________________________ 
Example 1)-39 
Preparation of N-cyano-N'-[2-(3 
,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide hydrochloride 
(method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.25 g, 1.3 mmol) was dissolved 
in methanol (10 ml), and 3,4-(dibenzyloxy)phenethylamine hydrochloride 
(0.54 g, 1.5 mmol) and triethylamine (0.15 g, 1.5 mmol) were added. The 
mixture was stirred at room temperature for 45 minutes. After the reaction 
was completed, the reaction solution was concentrated under reduced 
pressure. The residual concentrate thus obtained was extracted with ethyl 
acetate (100 ml.times.3). The ethyl acetate layer was washed with water 
(100 ml), dried over anhydrous sodium sulfate and concentrated under 
reduced pressure. The residual concentrate was subjected to chromatography 
on a silica gel column (WAKO GEL C-200, 50 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure to give 
N-cyano-N'-[2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide 
(0.13 g, 0.3 mmol, yield: 21%) as colorless syrup. Next, to this syrup was 
added a 5% hydrogen chloride in methanol (2 ml). The solution was 
crystallized from methanol-diethyl ether to give N-cyano-N'-[ 
2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide hydrochloride as 
colorless powder. 
Physico-chemical properties of 
N-cyano-N'-[2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide 
hydrochloride 
MP: 84.8.degree.-85.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3400, 2180, 1610, 1590, 1260, 700; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.90 (2H), 
8.60 (1H, m) 8.06 (1H, m), 7.5 7.3 (10H), 7.0-6.7 (3H), 5.16 (4H, m), 3.75 
(2H, t, J=7.2Hz), 2.94 (2H, t, J=7.2Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 69.80 5.45 11.23 
Found: 70.01 5.48 11.25 (%) 
(C.sub.29 H.sub.26 N.sub.4 O.sub.2.HCl) 
______________________________________ 
Example 1)-40 
Preparation of 
N-cyano-N'-3-(2,6-dimethoxypyridine)-3-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 3-amino-2,6-dimethoxypyridine (0.45 g, 2.9 mmol) 
was added. The mixture was stirred at room temperature for 2 hours. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure and crystallized from methanol-diethyl ether to give the 
title compound (0.35 g, 1.2 mmol, yield: 47%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-3-(2,6-dimethoxypyridine)-3-pyridinecarboximidamide 
MP: 162.5.degree.-163.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1580, 1550, 1490, 1470, 1390, 1330; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 9.0-8 7 
(2H, m), 8.3-7.9 (2H, m), 7.57 (1H, dd, J=4.8, 7.9Hz), 6.40 (1H, d, 
J=8.9Hz), 4.02 (3H, s), 3.96 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 59.36 4.63 24.72 
Found: 59.06 4.68 24.48 (%) 
(C.sub.14 H.sub.13 N.sub.5 O.sub.2) 
______________________________________ 
Example 1)-41 
Preparation of N-cyano-N'-(2-nitroxyethyl)-4-pyridinecarboximidamide 
(method i) 
a) 4 cyanopyridine (10.0 g, 96.1 mmol) was dissolved in isopropanol (50 
ml), and sodium hydride (0.23 g, 9.6 mmol) from which oily matters had 
been removed by washing with ether was added. The mixture was stirred at 
room temperature for 6 hours. After the reaction was completed, the 
reaction solution was neutralized by adding acetic acid (0.64 g, 10.7 
mmol) and concentrated under reduced pressure. To the residual concentrate 
was added diethyl ether (50 ml). Insolubles were removed by filtration, 
and the filtrate was concentrated under reduced pressure. To this 
concentrate was added hexane (80 ml), and deposited unreacted 
4-cyanopyridine was removed by filtration. The filtrate was concentrated 
under reduced pressure to give crude isopropyl 4-pyridinecarboximidate 
(11.0 g) as a pale yellow oil. 
Next, cyanamide (5.63 g, 133.9 mmol) and a phosphate buffer solution (pH 
5.4, 60 ml) of Na.sub.2 HPO.sub.4 (9.51 g, 67.0 mmol) and NaH.sub.2 
PO.sub.4.2H.sub.2 O (41.8 g, 267.9 mmol) were added to the oil, and the 
mixture was stirred at room temperature for 8 hours. After the reaction 
was completed, the reaction solution was extracted with dichloromethane 
(100 ml.times.3), and the dichloromethane layer was dried over anhydrous 
sodium sulfate and concentrated under reduced pressure. The residual 
concentrate thus obtained was subjected to chromatography on a silica gel 
column (WAKO GEL C-200, 200 g). Eluting with hexane-diethyl ether (1:2) 
gave isopropyl N-cyano-4-pyridinecarboximidate (11.2 g, 59.2 mmol, yield: 
62%) as pale yellow oil. 
Physico-chemical properties of isopropyl N-cyano-4-pyridinecarboximidate 
IR spectrum: (cm.sup.-1, neat) 3250, 3000, 2250, 2200, 1620, 1590, 1380, 
1310, 1100; 
NMR spectrum: (100 MHz, CD.sub.3 OD) .delta. (ppm) 30 8.9-8.7, 8.0-7.7 
(4H), 5.42 (1H, m, J=6.1Hz), 1.50 (6H, d, J=6.1Hz). 
b) Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was 
dissolved in methanol (10 ml), and 2-nitroxyethylamine nitrate (0.57 g, 
2.9 mmol) and sodium methoxide (0.18 g, 2.9 mmol) were added. The mixture 
was stirred at room temperature for 10 minutes. After the reaction was 
completed, the reaction solution was concentrated under reduced pressure. 
The residue thus obtained was extracted with dichloromethane (50 
ml.times.3). The dichloromethane layer was dried over anhydrous sodium 
sulfate and concentrated under reduced pressure. The residual concentrate 
was crystallized from dichloromethane-diethyl ether to give the title 
compound (0.37 g, 1.6 mmol, yield: 61%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-(2-nitroxyethyl)-4-pyridinecarboximidamide 
MP: 102.5.degree.-103.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1640, 1580, 1540, 1290, 1280; 
NMR spectrum: (100 MHz, CDC13) .delta. (ppm) 8.72 (2H, s), 7.48 (2H, s), 
4.70 (2H, s), 3.80 (2H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 45.96 3.86 29.78 
Found: 45.68 3.64 29.99 (%) 
(C.sub.9 H.sub.9 N.sub.5 O.sub.3) 
______________________________________ 
Example 1)-42 
Preparation of N-cyano-N'-(3-nitroxypropyl)-4-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 3-nitroxypropylamine nitrate (0.53 g, 2.9 mmol) 
and sodium methoxide (0.22 g, 4.1 mmol) were added. The mixture was 
stirred at room temperature for 18 hours. After the reaction was 
completed, the reaction solution was concentrated under reduced pressure. 
The residual concentrate was extracted with chloroform (50 ml.times.3). 
The chloroform layer was washed with water (100 ml), dried over anhydrous 
sodium sulfate and concentrated under reduced pressure. The residual 
concentrate was subjected to chromatography on a silica gel column (WAKO 
GEL C-200, 50 g) eluting with chloroform-methanol (60:1). The eluted 
fractions were concentrated under reduced pressure and crystallized from 
methanol-diethyl ether to give the title compound (0.27 g, 1.08 mmol, 
yield: 41%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(3-nitroxypropyl)-4-pyridinecarboximidamide 
MP: 112.5.degree.-112.8.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1600, 1280; 
NMR spectrum: (500 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.75 (2H, 
dd, J=1.6, 4.4Hz), 7.54 (2H, dd, J=1.6, 4.4Hz), 4.57 (2H, t, J=6.0Hz), 
3.59 (2H, t, J=6.0Hz), 2.13 (2H, quint, J=6.0Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 48.19 4.45 28.10 
Found: 48.01 4.33 27.91 (%) 
(C.sub.10 H.sub.11 N.sub.5 O.sub.3) 
______________________________________ 
Example 1)-43 
Preparation of N cyano-N'-phenyl-4-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (5 ml), and aniline (0.27 g, 2.9 mmol) dissolved in methanol 
(5 ml) was added. The mixture was stirred at room temperature for 20 
minutes. After the reaction was completed, the reaction solution was 
concentrated under reduced pressure. The residual concentrate was 
subjected to chromatography on a silica gel column (WAKO GEL C-200, 40 g). 
Elution with chloroform-methanol (100:1) gave the object compound, which 
was further crystallized from methanol-diethyl ether to give 
N-cyano-N'-phenyl-4-pyridinecarboximidamide (0.32 g, 1.4 mmol, yield: 54%) 
as colorless needles. 
Physico-chemical properties of N-cyano-N'-phenyl-4-pyridinecarboximidamide 
MP: 220.degree.-222.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3060, 2180, 1610, 1580, 1530, 1450; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.80 (2H, 
brs), 7.8-7.5 (4H, m), 7.42 (2H, brs), 7.27 (1H, brs); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 70.26 4.54 25.21 
Found: 70.50 4.54 25.14 (%) 
(C.sub.13 H.sub.10 N.sub.4) 
______________________________________ 
Example 1)-44 
Preparation of N-cyano-N'-(3,4-dichlorobenzyl)-4-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 3,4-dichlorobenzylamine (0.52 g, 3.0 mmol) was 
added. The mixture was stirred at room temperature for 3 hours. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure. The residual concentrate was crystallized from 
methanol-diethyl ether to give the title compound (0.42 g, 1.4 mmol, 
yield: 52%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(3,4-dichlorobenzyl)-4-pyridinecarboximidamide 
MP: 164.8.degree.-165.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2190, 1590; 
NMR spectrum: (500 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.74 (2H, 
dd, J=1.8, 5.8Hz), 7.52 (2H, dd, J=1.8, 5.8Hz), 7.46 (1H, d, J=2.2Hz), 
7.45 (1H, d, J=8.2Hz), 7.23 (1H, dd, J=2.2, 8.2Hz), 4.59 (2H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 55.10 3.30 18.36 
Found: 55.02 3.19 18.23 (%) 
(C.sub.14 H.sub.10 N.sub.4 Cl.sub.2) 
______________________________________ 
Example 1)-45 
Preparation of N-cyano-N'-(4-methylthiobenzyl)-4-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano 4-pyridinecarboximidate (0.40 g, 2.1 mmol) was dissolved 
in methanol (15 ml), and 4-methylthiobenzylamine hydrochloride (0.60 g, 
3.2 mmol) and triethylamine (0.43 g, 4.2 mmol) were added. The mixture was 
stirred at room temperature for 1 hour. After the reaction was completed, 
the reaction solution was then concentrated under reduced pressure. The 
residual concentrate was extracted with ethyl acetate (50 ml.times.3). The 
ethyl acetate layer was washed with water (100 ml), dried over anhydrous 
sodium sulfate and concentrated under reduced pressure. The residual 
concentrate was crystallized from methanol-diethyl ether to give the title 
compound (0.29 g, 1.0 mmol, yield: 49%) as colorless crystals. 
Physico-chemical properties of N-cyano 
N'-(4-methylthiobenzyl)-4-pyridinecarboximidamide 
MP: 165.5.degree.-166.8.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1580; 
NMR spectrum: (500 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.72 (2H, 
dd, J=2.0, 4.4Hz), 7.52 (2H, dd, J=2.0, 4.4Hz), 7.30 (2H, d, J=8.2Hz), 
7.26 (2H, d, J=8.2Hz), 4.59 (2H, s), 2.50 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 63.81 5.00 19.84 
Found: 63.69 5.19 19.66 (%) 
(C.sub.15 H.sub.14 N.sub.4 S) 
______________________________________ 
Example 1)-46 
Preparation of N-cyano-N'-(3-benzyloxybenzyl)-4-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-4-pyridinecarboximidate (0.30 g, 1.6 mmol) was dissolved 
in methanol (10 ml), and 3-benzyloxybenzylamine (0.42 g, 2.0 mmol) was 
added. The mixture was stirred at room temperature for 2 hours. After the 
reaction was completed, the reaction solution was then concentrated under 
reduced pressure. The residual concentrate was crystallized from 
methanol-diethyl ether to give the title compound (0.26 g, 0.8 mmol, 
yield: 48%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(3-benzyloxybenzyl)-4-pyridinecarboximidamide 
MP: 123.8.degree.-124.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2190, 1580; 
NMR spectrum: (500 MHz, CDC13) .delta. (ppm) 8.69 (2H, dd, J=1.4, 5.0Hz), 
7.50-7.25 (8H), 7.00-6.90 (3H), 6.80 (1H, brs), 5.09 (2H, s), 4.60 (2H, d, 
J=6.0Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 73.67 5.30 16.36 
Found: 73.55 5.40 16.31 (%) 
(C.sub.21 H.sub.18 N.sub.4 O) 
______________________________________ 
Example 1)-47 
Preparation of 
N-cyano-N'-[2-(4-chlorophenyl)ethyl]-4-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-4-pyridinecarboximidate (0.5 g, 2.6 mmol) was dissolved 
in methanol (5 ml), and 2-(4 chlorophenyl)ethylamine (0.46 g, 3.0 mmol) 
having been diluted with methanol (5 ml) was added. The mixture was 
stirred at room temperature for 40 minutes. After the reaction was 
completed, the reaction solution was then concentrated under reduced 
pressure. The residual concentrate was further crystallized from 
methanol-diethyl ether to give the title compound (0.44 g, 1.5 mmol, 
yield: 58%) as colorless needles. 
Physico-chemical properties of 
N-cyano-N'-[2-(4-chlorophenyl)ethyl]-4-pyridinecarboximidamide 
MP: 164.0.degree.-165.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1590, 1540, 1500; 
NMR spectrum: (100 MHz, CDCl.sub.3) .delta. (ppm) 8.68 (2H, m), 7.4-7.1 
(6H), 6.56 (1H, brs), 3.74 (2H, q, J=6.8Hz), 2.97 (2H, t, J=6.8Hz) 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 63.27 4.60 19.68 
Found: 63.02 4.66 19.56 (%) 
(C.sub.15 H.sub.13 N.sub.4 Cl) 
______________________________________ 
Example 1) 48 
Preparation of 
N-cyano-N'-[2-(2-methoxyphenyl)ethyl]-4-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (10 ml), and 2-(2-methoxyphenyl)ethylamine (0.44 g, 2.9 mmol) 
was added. The mixture was stirred at room temperature for 1 hour. After 
the reaction was completed, the reaction solution was concentrated under 
reduced pressure. The residual concentrate was subjected to chromatography 
on a silica gel column (WAKO GEL C-200, 40 g) eluting with 
chloroform-methanol (100:1). The eluted fractions were concentrated under 
reduced pressure and crystallized from chloroform-diethyl ether to give 
the title compound (0.45 g, 1.6 mmol, yield: 61%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-[2-(2-methoxyphenyl)ethyl]-4-pyridinecarboximidamide 
MP: 141.2.degree.-141.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2190, 1580; 
NMR spectrum: (500 MHz, CDC13) .delta. (ppm) 8.78 (2H, d, J=5.4Hz), 7.39 
(2H, d, J=5.4Hz), 7.28 (1H, t, J=7.1Hz), 7.18 (1H, d, J=7.1Hz), 6.97 (1H, 
t, J=7.1Hz), 6.91 (1H, d, J=7.1Hz), 6.66 (1H, brs), 3.80 (3H, s), 3.72 
(2H, m), 3.01 (2H, t, J=7.1Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 68.55 5.75 19.99 
Found: 68.46 5.49 19.71 (%) 
(C.sub.16 H.sub.16 N.sub.4 O) 
______________________________________ 
Example 1)-49 
Preparation of N-cyano-N'-(2-phenylthioethyl)-4-pyridinecarboximidamide 
(method i) 
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved 
in methanol (5 ml), and 2-phenylthioethylamine (0.49 g, 3.2 mmol) was 
added. The mixture was stirred at room temperature for 2 hours. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the residual concentrate was subjected to 
chromatography on a silica gel column (WAKO GEL C-200, 10 g) eluting with 
chloroform-methanol (50:1). The eluted fractions were concentrated under 
reduced pressure and crystallized from diethyl ether to give the title 
compound (0.49 g, 1.7 
Physico-chemical properties of 
N-cyano-N'-(2-phenylthioethyl)-4-pyridinecarboximidamide 
MP: 114.0.degree.-114.3.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2190, 1590; 
NMR spectrum: (500 MHz, CDC13) .delta. (ppm) 8.73 (2H, dd, J=1.5, 4.6Hz), 
7.42-7.23 (8H), 3.71 (2H, t, J=6.2Hz), 3.23 (2H, t, J=6.2Hz) 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 63.81 5.00 19.84 
Found: 63.80 4.89 19.71 (%) 
(C.sub.15 H.sub.14 N.sub.4 S) 
______________________________________ 
Example 1)-50 
Preparation of N-cyano-N'-[2-(4-nitrophenyl) 
2-nitroxyethyl]-4-pyridinecarboximidamide (method i) 
Isopropyl N-cyano-4-pyridinecarboximidate (0.22 g, 1.2 mmol) was dissolved 
in methanol (10 ml), and 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate 
(0.40 g, 1.4 mmol) and sodium methoxide (0.14 g, 2.6 mmol) were added. The 
mixture was stirred at room temperature for 16 hours. After the reaction 
was completed, the reaction solution was concentrated under reduced 
pressure, and the residue was extracted with chloroform (50 ml.times.3). 
The chloroform layer was washed with water (100 ml), dried over anhydrous 
sodium sulfate and concentrated under reduced pressure. The residual 
concentrate thus obtained was subjected to chromatography on a silica gel 
column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (50:1). The 
eluted fractions were concentrated under reduced pressure and crystallized 
from methanol-diethyl ether to give the title compound (0.13 g, 0.4 mmol, 
yield: 31%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-[2-(4-nitrophenyl)-2-nitroxyethyl]-4-pyridinecarboximidamide 
MP: 127.5.degree.-129.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2190, 1640, 1590, 1530, 1350; 
NMR spectrum: (500 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.78 (2H, 
d, J=4.4Hz), 8.33 (2H, d, J=8.4Hz), 7.68 (2H, d, J=8.4Hz), 7.52 (2H, d, 
J=4.4Hz), 6.31 (1H, dd, J=3.8, 9.4Hz), 3.80 (2H, m); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 50.57 3.39 23.59 
Found: 50.46 3.58 23.36 (%) 
(C.sub.15 H.sub.12 N.sub.6 O.sub.5) 
______________________________________ 
Example 1)-51 
Preparation of 
N-cyano-N'-[1-methyl-2-(4-nitrophenyl)-2-nitroxyethyl]-4-pyridinecarboximi 
damide (method i) 
Isopropyl N-cyano-4-pyridinecarboximidate (0.31 g, 1.6 mmol) was dissolved 
in methanol (15 ml), and 1-methyl-2-(4-nitrophenyl)-2-nitroxyethylamine 
nitrate (0.50 g, 1.8 mmol) and sodium methoxide (0.09 g, 1.7 mmol) were 
added. The mixture was stirred at room temperature for 16 hours. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the residue was extracted with chloroform (50 
ml.times.3). The chloroform layer was washed with water (100 ml), dried 
over anhydrous sodium sulfate and concentrated under reduced pressure. The 
residue thus obtained was subjected to chromatography on a silica gel 
column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (60:1). The 
eluted fractions were concentrated under reduced pressure and crystallized 
from diethyl ether to give the title compound (0.03 g, 0.08 mmol, yield: 
5%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-[1-methyl-2-(4-nitrophenyl)-2-nitroxyethyl]-4-pyridinecarboximi 
damide 
MP: 153.0.degree.-153.1.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2200, 1650, 1580, 1530, 1350, 1290; 
NMR spectrum: (500 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 8.77 (2H, 
d, J=5.9Hz), 8.35 (2H, d, J=8.9Hz), 7.69 (2H, d, J=8.9Hz), 7.49 (2H, d, 
J=5.9Hz), 1.32 (3H, d, J=9.4Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 51.89 3.80 22.69 
Found: 51.62 3.99 22.57 (%) 
(C.sub.16 H.sub.14 N.sub.6 O.sub.5) 
______________________________________ 
Example 1)-52 
Preparation of 
N-cyano-N'-(2-nitroxyethyl)-3-(6-chloropyridine)carboximidamide (method i) 
a) 6-chloro-3-cyanopyridine (3.63 g, 26.2 mmol) was suspended in 
isopropanol (40 ml), and sodium hydride (0.1 g, 4.2 mmol) from which oily 
matters had been removed by washing with ether was added. The mixture was 
stirred at room temperature for 18 hours. After the reaction was 
completed, the reaction solution was neutralized by adding acetic acid 
(0.27 g, 4.5 mmol) and then concentrated under reduced pressure. The 
residual concentrate was diluted with ether (100 ml), and ether insolubles 
were removed by filtration. The filtrate was concentrated under reduced 
pressure. The residual concentrate was diluted with hexane (100 ml), and 
the deposited unreacted 6-chloro-3-cyanopyridine was removed by 
filtration. The filtrate was concentrated under reduced pressure to give 
the crude product of isopropyl 3-(6-chloropyridine)carboximidate (1.88 g) 
as colorless oil. Next, to this oil were added cyanamide (0.80 g, 19.0 
mmol) and a phosphate buffer (pH 5.4, 60 ml) of Na.sub.2 HPO.sub.4 (1.34 
g, 9.4 mmol) and NaH.sub.2 PO.sub.4.2H.sub.2 O (5.90 g, 37.8 mmol), and 
the mixture was stirred at room temperature for 24 hours. After the 
reaction was completed, the reaction solution was extracted with 
dichloromethane (100 ml.times.4), and the dichloromethane layer was dried 
over anhydrous sodium sulfate and concentrated under reduced pressure. The 
residue thus obtained was subjected to chromatography on a silica gel 
column (WAKO GEL C-200, 70 g, eluting with hexane-dichloromethane-methanol 
(50:50:1). The eluted fractions were concentrated under reduced pressure 
to give isopropyl N-cyano-3-(6-chloropyridine)carboximidate (0.83 g, 3.7 
mmol, yield: 14%) as colorless syrup. 
Physico-chemical properties of isopropyl 
N-cyano-3-(6-chloropyridine)carboximidate 
IR spectrum: (cm.sup.-1, neat) 2200, 1610, 1580, 1310, 1110; 
NMR spectrum: (100 MHz, CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm) 9.13 (1H, 
d, J=3.0Hz), 8.61 (1H, dd, J=3.0, 8.6Hz), 7.52 (1H, d, J=8.6Hz), 5.43 (1H, 
m, J=6.1Hz), 1.49 (6H, d, J=6.1Hz). 
b) Isopropyl N-cyano-3-(6 -chloropyridine)carboximidate (0.20 g, 0.9 mmol) 
was dissolved in methanol (8 ml), and 2-nitroxyethylamine nitrate (0.23 g, 
1.4 mmol) and sodium methoxide (0.1 g, 1.9 mmol) were added. The mixture 
was stirred at room temperature for 5 hours. After the reaction was 
completed, the reaction solution was concentrated under reduced pressure. 
The residue thus obtained was extracted with chloroform (50 ml.times.3). 
The chloroform layer was washed with water (100 ml), dried over anhydrous 
sodium sulfate and concentrated under reduced pressure. The residual 
concentrate was subjected to chromatography on a silica gel column (WAKO 
GEL C-200, 25 g) eluting with chloroform-methanol (50:1). The eluted 
fractions were concentrated under reduced pressure and crystallized from 
diethyl ether to give the title compound (0.04 g, 0.1 mmol, yield: 17%) as 
colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-nitroxyethyl)-3-(6-chloropyridine)carboximidamide 
MP: 139.0.degree.-140.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1630, 1580, 1280; 
NMR spectrum: (500 MHz, CD.sub.3 OD) .delta. (ppm) 8.62 (1H, d, J=3.0Hz), 
8.08 (1H, dd, J=3.0, 9.1Hz), 7.65 (1H, d, J=9.1Hz), 4.75 (2H, t, J=7.1Hz), 
3.86 (2H, t, J=7.1Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 40.09 2.99 25.97 
Found: 39.95 2.88 25.69 (%) 
(C.sub.9 H.sub.8 N.sub.5 O.sub.3 Cl) 
______________________________________ 
Example 1)-53 
Preparation of 
N-cyano-N'-(2-phenylethyl)-3-(6-chloropyridine)carboximidamide (method i) 
Isopropyl N-cyano-3-(6-chloropyridine)carboximidate (0.30 g, 1.3 mmol) was 
dissolved in methanol (8 ml), and 2-phenylethylamine (0.18 g, 1.5 mmol) 
was added. The mixture was stirred at room temperature for 30 minutes. 
After the reaction was completed, the reaction solution was concentrated 
under reduced pressure, and the residue was crystallized from diethyl 
ether to give the title compound (0.24 g, 0.8 mmol, yield: 63%) as 
colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-phenylethyl)-3-(6-chloropyridine)carboximidamide 
MP: 168.8.degree.-169.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1590; 
NMR spectrum: (500 MHz, CD.sub.3 OD) .delta. (ppm) 8.47 (1H, d, J=3.0Hz), 
7.96 (1H, dd, J=3.0, 9.3Hz), 7.61 (1H, d, J=9.3Hz), 7.36-7.20 (5H), 3.72 
(2H, t, J=7.2Hz), 2.99 (2H, t, J=7.2Hz) 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 63.27 4.60 19.68 
Found: 63.25 4.38 19.37 (%) 
(C.sub.15 H.sub.13 N.sub.4 Cl) 
______________________________________ 
Example 1) 54 
Preparation of N-cyano-N'-benzyl-3 -pyridinecarboximidamide (method ii) 
a) N-benzylnicotinamide (1.0 g, 4.7 mmol) was dissolved in toluene (90 ml). 
Lawesson's reagent (2.3 g, 5.7 mmol) was added, and the mixture was heated 
under reflux in argon stream for 3 hours. After the reaction was 
completed, the reaction mixture was cooled to room temperature and 
concentrated under reduced pressure. The concentrate thus obtained was 
extracted with a 2N aqueous hydrochloric acid solution (200 ml.times.3), 
and the aqueous layer was washed with chloroform (500 ml). After washing, 
the aqueous hydrochloric acid layer was neutralized with NaOH and 
extracted with chloroform (200 ml.times.3). The chloroform layer was dried 
over anhydrous sodium sulfate and concentrated under reduced pressure. The 
concentrate was further crystallized from chloroform-hexane to give 
N-benzylnicotinethioamide (0.83 g, 3.6 mmol, yield: 77%) as pale yellow 
needles. 
Physico-chemical properties of N-benzylnicotinethioamide 
MP: 136.0.degree.-136.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 3170, 1540, 1420, 1390, 1340, 760, 700; 
NMR spectrum: (100 MHz, CDC13) .delta. (ppm) 8.81 (1H, brs), 8.57 (1H, d, 
J=4.1Hz), 8.14 (1H, dt, J=2.7, 10.0Hz), 8.00 (1H, brs), 7.40 (5H, s), 7.35 
(1H, m), 5.00 (2H, d, J=6.2Hz); 
b) N-benzylnicotinethioamide (0.5 g, 2.2 mmol) was dissolved in 
acetonitrile (20 ml), and phosphorus oxychloride (0.4 g, 2.6 mmol) was 
added. The mixture was stirred at room temperature for 9 hours. Cyanamide 
(0.92 g, 21.9 mmol) and triethylamine (0.27 g, 2.6 mmol) were added, and 
the mixture was heated under reflux in argon stream for 4 hours. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure. Chloroform (50 ml) was added to the residual 
concentrate, and insolubles were removed by filtration. The filtrate was 
concentrated under reduced pressure. The concentrate thus obtained was 
subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g). 
Elution with chloroform-methanol (100:1) gave the title compound, which 
was further crystallized from methanol-diethyl ether to give 
N-cyano-N'-benzyl-3-pyridinecarboximidamide (0.085 g, 0.3 mmol, yield: 
16%) as colorless needles. 
Physico-chemical properties including mp, IR spectrum and 
NMR spectrum of the crystal thus obtained well accorded with those obtained 
in 
Example 1)-17. 
Example 1)-55 
______________________________________ 
(Tablet/formulation in one tablet) 
______________________________________ 
Compound of the present invention 
2 mg 
Lactose 75.5 
Corn starch 18 
Talc 4 
Magnesium stearate 0.5 
Total 100 mg 
______________________________________ 
Components set forth above are blended and pressed into a tablet. 
Example 1)-56 
______________________________________ 
(Capsule/formulation in one capsule) 
______________________________________ 
Compound of the present invention 
5 mg 
Lactose 94 
Magnesium stearate 1 
Total 100 mg 
______________________________________ 
Components set forth above are blended and pressed into a capsule. 
Example 1)-57 
______________________________________ 
(Injection/formulation in one vial) 
______________________________________ 
Compound of the present invention 
1 mg 
Maltose 25 mg 
Distilled water for injection 
q.v. 
Total 2 mg 
______________________________________ 
Components set forth above are blended, filtrated and then charged into a 
vial. They are lyophilized in a usual manner and stoppered to make an 
injection. 
2) Compounds Represented by the Formula (I') 
Referential Example 2)-1 
Vasorelaxing effect on the isolated rat aortae 
(1) Method 
The compounds of the present invention were tested for their physiological 
activities by measuring the tension of isolated rat aortae isometrically. 
Thoracic aortae obtained from male Wistar rats (weighing 250-350 g) were 
cut into ring segments about 3 mm long. The ring preparation was placed in 
an organ bath filled with 10 ml of Krebs-Ringer solution which was 
maintained at 37.degree. C. and gassed with 95% O.sub.2 -5% CO.sub.2. 
The preparation in the organ bath was allowed to equilibrate under resting 
tension 1 g. After equilibration period, the solution in the organ bath 
was replaced with an isotonic solution containing 40 mM KCl to contract 
the preparation. 
After the contraction induced by KCl had reached plateau, the 
concentration-response relationship for the test compound was determined 
by means of cumulative addition. 
The relaxation response of the test compounds was expressed as the percent 
inhibition of the contraction induced by KCl, and the IC.sub.50 value, 
which is a concentration required for inhibiting the contraction induced 
by KCl to an extent of 50%, was calculated by the Probit method from the 
concentration-response curve. 
(2) Results 
The IC.sub.50 values of the test compounds are shown in the following 
table. 
______________________________________ 
Test Compound No. 
IC.sub.50 Value (M) 
______________________________________ 
(59) 2.4 .times. 10.sup.-5 
(60) 6.1 .times. 10.sup.-6 
(61) 5.3 .times. 10.sup.-5 
(62) 2.6 .times. 10.sup.-5 
(63) 1.8 .times. 10.sup.-5 
(64) 8.0 .times. 10.sup.-6 
(65) 9.4 .times. 10.sup.-5 
(66) 9.6 .times. 10.sup.-6 
(67) 1.9 .times. 10.sup.-5 
(68) 9.2 .times. 10.sup.-5 
(69) 4.0 .times. 10.sup.-5 
(70) 4.3 .times. 10.sup.-6 
______________________________________ 
Referential Example 2)-2 
Hypotensive effect on spontaneous hypertensive rats (intravenously) 
(1) Method 
The hypotensive effects of the compounds of the present invention [test 
compounds: N-cyano-N'-(2-nitroxyethyl)-2-furancarboximidamide (compound 
(62)) and N-cyano-N'-(2-nitroxyethyl)-2-thiophenecarboximidamide (compound 
(66))] were observed in male spontaneous hypertensive rates (SHR). 
Rats were anesthetized with urethane-.alpha.-chloralose (1 g/kg-25 mg/kg; 
intraperitoneally). Mean blood pressure was measured by a pressure 
transducer through a cannula inserted into the carotid artery. The 
compound was cumulatively administered every 30 minutes through the 
canulla inserted into the jagular vein. The change in blood pressure was 
expressed as percent of the blood pressure before the administration of 
the compound. And the ED.sub.20 value, which was the dose required for 
decreasing blood pressure to an extent of 20%, was calculated from the 
dose-response curve. 
(2) Results 
The ED.sub.20 values of the test compounds are shown in the following 
table. 
______________________________________ 
Compound No. ED.sub.20 (mg/kg, i.v.) 
______________________________________ 
(62) 0.025 
(66) 0.115 
______________________________________ 
i.v.: intravenously. 
Example 2)-1 
Preparation of N-cyano-N'-(2-nitroxyethyl)-3-quinolinecarboximidamide 
a) 3-cyanoquinoline (1.58 g, 10.2 mmol) was dissolved in methanol (20 ml), 
and sodium methoxide (0.06 g, 1.1 mmol) was added. The reaction was 
conducted at room temperature for 22 hours. After the reaction was 
completed, acetic acid (0.07 g, 1.1 mmol) was added to neutralize the 
reaction solution, and the solution was concentrated under reduced 
pressure. Diethyl ether (60 ml) was added to the concentrated residue, and 
insolubles were removed by filtration. The filtrate was concentrated under 
reduced pressure to give the crude product of methyl 
3-quinolinecarboximidate. 
Next, cyanamide (0.84 g, 20 mmol) and a phosphate buffer (pH 5.4, 10 ml) of 
Na.sub.2 HPO.sub.4 (1.42 g, 10 mmol) and NaH.sub.2 PO.sub.4.2H.sub.2 O 
(6.24 g, 40 mmol) were added, and the mixture was stirred at room 
temperature for 6 hours. After reaction was completed, insolubles in the 
reaction mixture were removed by filtration, and the filtrate was 
extracted with dichloromethane (50 ml.times.3), and the dichloromethane 
layer was washed with saturated saline, dried over anhydrous sodium 
sulfate and then concentrated under reduced pressure. The residue thus 
obtained was subjected to chromatography on a silica gel column (WAKO GEL 
C-200, 25 g) eluting with dichloromethane-hexane (3:2). The eluted 
fractions were concentrated under reduced pressure, crystallized from 
diethyl ether to give methyl N-cyano-3-quinolinecarboximidate (1.14 g, 5.4 
mmol, yield: 53%) as pale brown crystals. 
Physico-chemical properties of methyl N-cyano-3-quinolinecarboximidate 
MP: 113.5.degree.-113.8.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2190, 1610, 1310; 
NMR spectrum: (500 MHz, CDC13) .delta. (ppm) 9.35 (1H, d, J=2.6Hz), 9.17 
(1H, d, J=2.6Hz), 8.17 (1H, d, J=8.0Hz), 8.00 (1H, d, J=8.0Hz), 7.90 (1H, 
dt, J=1.8, 8.0Hz), 7.68 (1H, t, J=8.0Hz), 4.18 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 68.24 4.29 19.89 
Found: 68.01 4.23 19.67 (%) 
(C.sub.12 H.sub.9 N.sub.3 O) 
______________________________________ 
b) Methyl N-cyano-3-quinolinecarboximidate (0.32 g, 1.5 mmol) was dissolved 
in methanol (3 ml), 2-nitroxyethylamine nitrate (0.42 g, 2.5 mmol) and 
sodium methoxide (0.12 g, 2.2 mmol) were added. The mixture was stirred at 
room temperature for 18 hours. After the reaction was completed, the 
reaction solution was concentrated under reduced pressure, and the residue 
thus obtained was subjected to chromatography on a silica gel column (WAKO 
GEL C-200, 30 g) eluting with dichloromethane-methanol (50:1). The eluted 
fractions were concentrated under reduced pressure and crystallized from 
dichloromethane-diethyl ether to give the title compound (0.23 g, 0.80 
mmol, yield: 54%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-nitroxyethyl)-3-quinolinecarboximidamide 
MP: 126.5.degree.-127.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2190, 1620, 1580, 1560, 1280; 
NMR spectrum: (500 MHz, CD.sub.3 OD) .delta. (ppm) 9.05 (1H, s), 8.71 (1H, 
s), 8.13 (1H, d, J=8.0Hz), 8.10 (1H, d, J=8.0Hz), 7.93 (1H, t, J=7.7Hz), 
7.74 (1H, t, J=7.7Hz), 4.80 (2H, t, J=5.7Hz), 3.92 (2H, t, J=5.7Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 54.74 2.46 24.55 
Found: 54.66 2.34 24.29 (%) 
(C.sub.13 H.sub.11 N.sub.5 O.sub.3) 
______________________________________ 
Example 2)-2 
Preparation of N-cyano-N'-(2-phenylethyl)-3-quinoline-carboximidamide 
Methyl N-cyano-3-quinolinecarboximidate (0.32 g, 1.5 mmol) was dissolved in 
methanol (3 ml), 2-phenylethylamine (0.20 g, 1.65 mmol) was added. The 
mixture was stirred at room temperature for 30 minutes. After the reaction 
was completed, the reaction solution was concentrated under reduced 
pressure, and the residue thus obtained was crystallized from diethyl 
ether to give the title compound (0.41 g, 1.36 mmol, yield: 91%) as pale 
yellow crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-phenylethyl)-3-quinolinecarboximidamide 
MP: 165.0.degree.-167.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2190, 1580, 1560; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 8.84 (1H, s), 8.47 (1H, 
s), 8.11 (1H, d, J=8.5Hz), 7.90 (1H, d, J=8.6Hz), 7.84 (1H, t, J=7.3Hz), 
7.65 (1H, t, J=8.0Hz), 7.37 (2H, t, J=7.3Hz), 7.32-7.25 (3H), 6.05 (1H, 
brs), 3.87 (2H, dd, J=6.7, 12.8Hz), 3.06 (2H, t, J=6.7Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 75.98 5.37 18.65 
Found: 75.86 5.32 18.42 (%) 
(C.sub.19 H.sub.16 N.sub.4) 
______________________________________ 
Example 2)-3 
Preparation of N-cyano-N'-(2-nitroxyethyl)pyrazinecarboximidamide 
a) Cyanopyrazine (5.26 g, 50 mmol) was dissolved in methanol (40 ml), and 
sodium methoxide (0.27 g, 5.0 mmol) was added. The reaction mixture was 
stirred at room temperature for 45 minutes. After the reaction was 
completed, acetic acid (0.33 g, 5.5 mmol) was added to neutralize the 
reaction solution, and the solution was concentrated under reduced 
pressure. Dichloromethane (50 ml) and diethyl ether (50 ml) were added to 
the concentrated residue, and insolubles were removed by filtration. The 
filtrate was concentrated under reduced pressure to give the crude product 
of methyl pyrazinecarboximidate (6.87 g) as colorless powder. 
Next, cyanamide (3.15 g, 75 mmol) and a phosphate buffer (pH 5.4, 40 ml) of 
Na.sub.2 HPO.sub.4 (7.10 g, 50 mmol) and NaHzPO.sub.4.2H.sub.2 O (31.22 g, 
200 mmol) were added, and the mixture was stirred at room temperature for 
48 hours. After the reaction was completed, the reaction solution was 
extracted with dichloromethane (100 ml.times.4), and the dichloromethane 
layer was washed with saturated saline (300 ml), dried over anhydrous 
sodium sulfate and then concentrated under reduced pressure. The residue 
thus obtained was crystallized from diethyl ether to give methyl 
N-cyanopyrazinecarboximidate (4.53 g, 27.9 mmol, yield: 56%) as colorless 
crystals. 
Physico-chemical properties of methyl N-cyanopyrazinecarboximidate 
MP: 47.5.degree.-49.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2190, 1630, 1330; 
NMR spectrum: (500 MHz, CDC13) .delta. (ppm) 9.33 (1H, s), 8.78 (1H, d, 
J=2.2Hz), 8.74 (1H, brs), 4.07 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 51.85 3.73 34.55 
Found: 51.71 3.69 34.29 (%) 
(C.sub.7 H.sub.6 N.sub.4 O) 
______________________________________ 
b) Methyl N-cyanopyrazinecarboximidate (0.49 g, 3.0 mmol) was dissolved in 
methanol (6 ml), 2-nitroxyethylamine nitrate (1.01 g, 6.0 mmol) and 
triethylamine (1.01 g, 10.0 mmol) were added. The mixture was stirred at 
room temperature for 46 hours. After the reaction was completed, the 
reaction solution was concentrated under reduced pressure, and the residue 
thus obtained was subjected to chromatography on a silica gel column (WAKO 
GEL C 200, 30 g) eluting with chloroform-methanol (300:1). The eluted 
fractions were concentrated under reduced pressure and crystallized from 
diethyl ether to give the title compound (0.18 g, 0.78 mmol, yield: 26%) 
as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-nitroxyethyl)pyrazinecarboximidamide 
MP: 102.8.degree.-103.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1630, 1620, 1290; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 9.83 (1H, brs), 8.88 (1H, 
s), 8.64 (1H, s), 8.28 (1H, brs), 4.78 (2H, t, J=4.9Hz), 4.15 (2H, brs); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 40.68 3.41 35.58 
Found: 40.66 3.27 35.30 (%) 
(C.sub.8 H.sub.8 N.sub.6 O.sub.3) 
______________________________________ 
Example 2)-4 
Preparation of N-cyano-N'-(2-nitroxyethyl)-2-furancarboximidamide 
a) 2-Cyanofuran (4.50 g, 48.3 mmol) was dissolved in methanol (25 ml), and 
sodium methoxide (130 mg, 2.4 mmol) was added under ice-cooling. The 
mixture was stirred while the temperature is slowly raised up to room 
temperature for 2 hours. After the reaction was completed, acetic acid 
(0.16 g, 2.6 mmol) was added to neutralize the reaction solution, and the 
solution was concentrated under reduced pressure. Diethyl ether (100 ml) 
was added to the concentrated residue, and insolubles were removed by 
filtration. The filtrate was concentrated under reduced pressure to give 
the crude product of methyl 2-furancarboximidate (6.0 g) as a pale yellow 
oil. 
Next, cyanamide (4.06 g, 96.6 mmol) and a phosphate buffer (pH 6.0, 30 ml) 
of Na.sub.2 HPO.sub.4 (6.86 g, 48.3 mmol) and NaH.sub.2 PO.sub.4.2H.sub.2 
O (15.08 g, 96.6 mmol) were added, and the mixture was stirred at room 
temperature for 24 hours. After the reaction was completed, the reaction 
solution was extracted with dichloromethane (70 ml.times.4), and the 
dichloromethane layer was dried over anhydrous sodium sulfate and then 
concentrated under reduced pressure. The residue thus obtained was 
crystallized from diisopropyl ether-hexane to give methyl 
N-cyano-2-furancarboximidate (4.83 g, 32.2 mmol, yield: 67%) as colorless 
crystals. 
Physico-chemical properties of methyl N-cyano-2-furancarboximidate 
MP: 58.5.degree.-59.2.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2200, 1600, 1480, 1350; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 7.78 (1H, d, J=3.8Hz), 
7.69 (1H, d, J=1.8Hz), 6.64 (1H, dd, J=1.8, 3.8Hz), 4.05 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 56.00 4.03 18.66 
Found: 55.82 4.04 18.40 (%) 
(C.sub.7 H.sub.6 N.sub.2 O.sub.2) 
______________________________________ 
b) Methyl N-cyano-2 furancarboximidate (0.32 g, 2.09 mmol) was dissolved in 
methanol (3 ml), 2-nitroxyethylamine nitrate (0.37 g, 2.19 mmol) and 
triethylamine (0.22 g, 2.19 mmol) were added. The mixture was stirred at 
room temperature for 16 hours. After the reaction was completed, the 
reaction solution was concentrated under reduced pressure, and the residue 
thus obtained was subjected to chromatography on a silica gel column (WAKO 
GEL C-200, 25 g) eluting with dichloromethane. The eluted fractions were 
concentrated under reduced pressure and crystallized from dichloromethane 
to give the title compound (0.20 g, 0.89 mmol, yield: 45%) as colorless 
crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-nitroxyethyl)-2-furancarboximidamide 
MP: 77.0.degree.-77.8.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1630, 1600, 1570; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 8.04 (1H, d, J=3.7Hz), 
7.57 (1H, d, J=1.2Hz), 6.79 (1H, brs), 6.66 (1H, dd, J=1.2, 3.7Hz), 4.69 
(2H, t, J=5.5Hz), 3.87 (2H, dd, J=5.5Hz, 10.4Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 42.86 3.60 24.99 
Found: 42.92 3.48 24.72 (%) 
(C.sub.8 H.sub.8 N.sub.4 O.sub.4) 
______________________________________ 
Example 2)-5 
Preparation of N-cyano-N'-(2-phenylethyl)-2-furancarboximidamide 
Methyl N-cyano-2-furancarboximidate (0.30 g, 2.0 mmol) was dissolved in 
methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The 
mixture was stirred at room temperature for 1 hour. After the reaction was 
completed, the reaction solution was concentrated under reduced pressure, 
and the residue thus obtained was crystallized from diethyl ether-hexane 
to give the title compound (0.46 g, 1.93 mmol, yield: 97%) as colorless 
crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-phenylethyl)-2-furancarboximidamide 
MP: 88.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1600, 1570; 
NMR spectrum: (500 MHz, CDC13) .delta. (ppm) 8.00 (1H, d, J=3.7Hz), 7.48 
(1H, d, J=1.2Hz), 7.4-7.2 (5H), 6.61 (1H, dd, J=1.2, 3.7Hz), 6.43 (1H, 
brs), 3.75 (2H, dd, J=7.3, 13.4Hz), 2.96 (2H, t, J=7.3Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 70.28 5.48 17.56 
Found: 70.12 5.54 17.41 (%) 
(C.sub.14 H.sub.13 N.sub.3 O) 
______________________________________ 
Example 2)-6 
Preparation of N-cyano-N'-(2-nitroxyethyl)-3-furancarboximidamide 
a) 3-cyanofuran (3.76 g, 40.1 mmol) was dissolved in methanol (30 ml), and 
sodium methoxide (0.1 g, 1.9 mmol) was added. The mixture was stirred at 
room temperature for 18 hours. After the reaction was completed, acetic 
acid (0.14 g, 2.3 mmol) was added to neutralize the reaction solution, and 
the solution was concentrated under reduced pressure. Diethyl ether was 
added to the concentrated residue, and insolubles were removed by 
filtration. The filtrate was concentrated under reduced pressure to give 
the crude product of methyl 3-furancarboximidate as a pale yellow oil. 
Next, cyanamide (3.37 g, 80.2 mmol) and a phosphate buffer (pH 5.4, 50 ml) 
of Na.sub.2 HPO.sub.4 (5.69 g, 40.1 mmol) and NaH.sub.2 PO.sub.4.2H.sub.2 
O (25.0 g, 160.2 mmol) were added to the oil, and the mixture was stirred 
at room temperature for 18 hours. After the reaction was completed, the 
reaction solution was extracted with chloroform (100 ml.times.3), and the 
chloroform layer was dried over anhydrous sodium sulfate and then 
concentrated under reduced pressure. The residue thus obtained was 
subjected to chromatography with chloroform. The eluted fractions were 
concentrated under reduced pressure to give methyl N 
cyano-3-furancarboximidate (1.09 g, 7.3 mmol, yield: 18%) as a colorless 
oil. 
Physico-chemical properties of methyl N-cyano-3-furancarboximidate 
IR spectrum: (cm.sup.-1, neat) 2190, 1610, 1590; 
NMR spectrum: (100 MHz, CDC13) .delta. (ppm) 8.59 (1H, t, J=1.1Hz), 7.57 
(1H, t, J=2.2Hz), 7.06 (1H, dd, J=1.1, 2.2Hz), 4.00 (3H, s). 
b) Methyl N-cyano-3-furancarboximidate (0.5 g, 3.3 mmol) was dissolved in 
methanol (10 ml), and 2 nitroxyethylamine nitrate (0.84 g, 5.0 mmol) and 
sodium methoxide (0.27 g, 5.0 mmol) were added. The mixture was stirred at 
room temperature for 26 hours. After the reaction was completed, the 
reaction solution was concentrated under reduced pressure, and the residue 
thus obtained was extracted with chloroform (60 ml.times.3). The 
chloroform layer was washed with water (100 ml), dried over anhydrous 
sodium sulfate and concentrated under reduced pressure. The residual 
concentrate was subjected to chromatography on a silica gel column (WAKO 
GEL C 200, 20 g) eluting with chloroform-methanol (100:1). The eluted 
fractions were concentrated under reduced pressure and crystallized from 
methanol-diethyl ether to give the title compound (0.06 g, 0.27 mmol, 
yield: 8%) as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-nitroxyethyl)-3-furancarboximidamide 
MP: 107.1.degree.-107.9.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1640, 1600, 1550; 
NMR spectrum: (500 MHz, CDC13) .delta. (ppm) 8.44 (1H, s), 7.53 (1H, s), 
6.83 (1H, s), 4.68 (2H, t, J=4.9Hz), 3.80 (2H, t, J=4.9Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 42.86 3.60 24.99 
Found: 42.61 3.53 24.73 (%) 
(C.sub.8 H.sub.8 N.sub.4 O.sub.4) 
______________________________________ 
Example 2)-7 
Preparation of N-cyano-N'-(2-phenylethyl)-3-furancarboximidamide 
Methyl N-cyano-3-furancarboximidate (0.30 g, 2.0 mmol) was dissolved in 
methanol (10 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The 
mixture was stirred at room temperature for 2 hours. After the reaction 
was completed, the reaction solution was concentrated under reduced 
pressure, and the residue thus obtained was crystallized from diethyl 
ether to give the title compound (0.38 g, 1.59 mmol, yield: 79%) as 
colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-phenylethyl)-3-furancarboximidamide 
MP: 132.5.degree.-133.1.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2170, 1610, 1560; 
NMR spectrum: (100 MHz, CDC13) .delta. (ppm) 8.28 (1H, s), 7.45 (1H, t, 
J=1.9Hz), 7.4-7.1 (5H), 6.69 (1H, s), 6.54 (1H, brs), 3.68 (2H, q, 
J=6.6Hz), 2.95 (2H, t, 6.6Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 70.28 5.48 17.56 
Found: 70.22 5.41 17.37 (%) 
(C.sub.14 H.sub.13 N.sub.3 O) 
______________________________________ 
Example 2)-8 
Preparation of N-cyano-N'-(2-nitroxyethyl)-2-thiophenecarboximidamide 
a) 2-cyanothiophene (5.46 g, 50 mmol) was dissolved in methanol (25 ml), 
and sodium methoxide (0.27 g, 5 mmol) was added. The mixture was stirred 
at room temperature for 18 hours. After the reaction was completed, acetic 
acid (0.33 g, 5.5 mmol) was added to neutralize the reaction solution, and 
the solution was concentrated under reduced pressure. Diethyl ether (40 
ml) was added to the concentrated residue, and insolubles were removed by 
filtration. The filtrate was concentrated under reduced pressure to give 
the crude product of methyl 2-thiophenecarboximidate (6.35 g) as a yellow 
oil. 
Next, cyanamide (2.52 g, 60 mmol) and a phosphate buffer (pH 6.0, 20 ml) of 
Na.sub.2 HPO.sub.4 (4.26 g, 30 mmol) and NaH.sub.2 PO.sub.4.2H.sub.2 O 
(9.36 g, 60 mmol) were added to the oil, and the mixture was stirred at 
room temperature for 14 hours. After the reaction was completed, the 
reaction solution was extracted with dichloromethane (50 ml.times.4), and 
the dichloromethane layer was dried over anhydrous sodium sulfate and then 
concentrated under reduced pressure. The residue thus obtained was 
crystallized from dichloromethane-hexane to give methyl 
N-cyano-2-thiophenecarboximidate (4.48 g, 27.0 mmol, yield: 54%) as 
colorless crystals. 
Physico-chemical properties of methyl N-cyano-2-thiophenecarboximidate 
MP: 66.9.degree.-67.1.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2200, 1580; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 8.64 (1H, d, J=4.8Hz), 
7.77 (1H, d 7.27 (1H, t, J=4.8Hz), 4.10 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 50.59 3.64 16.86 
Found: 50.46 3.52 16.61 (%) 
(C.sub.7 H.sub.6 N.sub.2 OS) 
______________________________________ 
b) Methyl N-cyano-2-thiophenecarboximidate (0.32 g, 1.9 mmol) was dissolved 
in methanol (3 ml), and 2-nitroxyethylamine nitrate (0.34 g, 2.0 mmol) and 
triethylamine (0.20 g, 2.0 mmol) were added. The mixture was stirred at 
room temperature for 17 hours. After the reaction was completed, the 
reaction solution was concentrated under reduced pressure, and the residue 
thus obtained was subjected to chromatography on a silica gel column (WAKO 
GEL C-200, 25 g) eluting with ethyl acetate. The eluted fractions were 
concentrated under reduced pressure and crystallized from ethyl 
acetate-hexane to give the title compound (0.18 g, 0.77 mmol, yield: 40%) 
as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-nitroxyethyl)-2-thiophenecarboximidamide 
MP: 101.5.degree.-102.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2180, 1630, 1570, 1280; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 7.96 (1H, d, J=3.7Hz), 
7.61 (1H, d, J=3.7Hz), 7.19 (1H, t, J=3.7Hz), 4.70 (2H, t, J=4.9Hz), 3.82 
(2H, t, J=4.9Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 40.00 3.36 23.32 
Found: 39.88 3.42 23.22 (%) 
(C.sub.8 H.sub.8 N.sub.4 O.sub.3 S) 
______________________________________ 
Example 2)-9 
Preparation of N-cyano-N'-(2-phenylethyl)-2-thiophenecarboximidamide 
Methyl N-cyano-2-thiophenecarboximidate (0.33 g, 2.0 mmol) was dissolved in 
methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The 
mixture was stirred at room temperature for 1 hour. After the reaction was 
completed, the reaction solution was concentrated under reduced pressure, 
and the residue thus obtained was crystallized from diethyl ether-hexane 
to give the title compound (0.50 g, 1.97 mmol, yield: 98%) as colorless 
crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-phenylethyl)-2-thiophenecarboximidamide 
MP: 106.8.degree.-107.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2200, 1580; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 7.89 (1H, s), 7.51 (1H, 
d, J=4.9Hz), 7.4-7.2 (5H), 7.14 (1H, t, J=4.9Hz), 5.98 (1H, brs), 3.76 
(2H, dd, J=6.7, 12.8Hz), 2.97 (2H, t, J=6.7Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 65.85 5.13 16.46 
Found: 65.67 5.11 16.36 (%) 
(C.sub.14 H.sub.13 N.sub.3 S) 
______________________________________ 
Example 2)-10 
Preparation of N-cyano-N'-(2-phenylethyl) 3-thiophenecarboximidamide 
a) 3-cyanothiophene (0.66 g, 6.0 mmol) was dissolved in methanol (6 ml), 
and sodium methoxide (0.03 g, 0.6 mmol) was added. The mixture was stirred 
at room temperature for 28 hours. After the reaction was completed, acetic 
acid (0.03 g, 0.6 mmol) was added to neutralize the reaction solution, and 
the solution was concentrated under reduced pressure. Diethyl ether (50 
ml) was added to the concentrated residue, and insolubles were removed by 
filtration. The filtrate was concentrated under reduced pressure to give 
the crude product of methyl 3-thiophenecarboximidate. 
Next, cyanamide (0.5 g, 12 mmol) and a phosphate buffer (pH 6.0, 10 ml) of 
Na.sub.2 HPO.sub.4 (0.86 g, 6 mmol) and NaH.sub.2 P04 2H.sub.2 O (1.89 g, 
12 mmol) were added to the oil, and the mixture was stirred at room 
temperature for 74 hours. After the reaction was completed, the reaction 
solution was extracted with dichloromethane (10 ml.times.4), and the 
dichloromethane layer was washed with water (50 ml), dried over anhydrous 
sodium sulfate and then concentrated under reduced pressure. The residue 
thus obtained was subjected to chromatography on a silica gel column (WAKO 
GEL C-200, 30 g) eluting with chloroform. The eluted fractions were 
concentrated under reduced pressure to give methyl 
N-cyano-3-thiophenecarboximidate (0.70 g, 4.2 mmol, yield: 70%) as a 
colorless oil. 
Physico-chemical properties of methyl N-cyano-3-thiophenecarboximidate 
IR spectrum: (cm.sup.-1, neat) 2200, 1590, 1300; 
NMR spectrum: (500 MHz, CDC13) .delta. (ppm) 8.69 (1H, dd, J=2.0, 3.4Hz), 
7.82 (1H, dd, J=2.0, 5.6Hz), 7.41 (1H, dd, J=3.4, 5.6Hz), 4.03 (3H, s). 
b) Methyl N-cyano-3-thiophenecarboximidate (0.33 g, 2.0 mmol) was dissolved 
in methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. 
The mixture was stirred at room temperature for 40 minutes. After the 
reaction was completed, the reaction solution was concentrated under 
reduced pressure, and the residue thus obtained was crystallized from 
diethyl ether to give the title compound (0.48 g, 1.89 mmol, yield: 95%) 
as colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-phenylethyl)-3-thiophenecarboximidamide 
MP: 156.9.degree.-157.7.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2170, 1550; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 7.96 (1H, s), 7.45-7.20 
(7H), 6.20 (1H, brs), 3.73 (2H, dd, J=6.7, 13.4Hz), 2.97 (2H, t, J=6.7Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 65.85 5.13 16.46 
Found: 65.77 5.01 16.29 (%) 
(C.sub.14 H.sub.13 N.sub.3 S) 
______________________________________ 
Example 2)-11 
Preparation of N-cyano-N'-(2-phenylethyl)-4-cyanobenzene-carboximidamide 
a) 1,4-dicyanobenzene (6.41 g, 50 mmol) was suspended in methanol (100 ml), 
and sodium methoxide (0.27 g, 5.0 mmol) was added. The mixture was stirred 
at room temperature for 22 hours. After the reaction was completed, acetic 
acid (0.31 g, 5.1 mmol) was added to neutralize the reaction solution, and 
the solution was concentrated under reduced pressure. Dichloromethane (50 
ml) and diethyl ether (50 ml) were added to the concentrated residue, and 
insolubles were removed by filtration. The filtrate was concentrated under 
reduced pressure to give the crude product of methyl 
4-cyanobenzenecarboximidate (5.77 g) as colorless powder. 
Next, cyanamide (3.03 g, 72 mmol) and a phosphate buffer (pH 6.0, 20 ml) of 
Na.sub.2 HPO.sub.4 (5.11 g, 36 mmol) and NaH.sub.2 PO.sub.4.2H.sub.2 O 
(11.23 g, 72 mmol) were added to the powder, and the mixture was stirred 
at room temperature for 23 hours. After the reaction was completed, the 
reaction solution was concentrated under reduced pressure. Chloroform (200 
ml) and methanol (200 ml) were added to the residue, and insolubles were 
removed by filtration through celite. The filtrate was concentrated. The 
concentrate was crystallized by adding diethyl ether (100 ml). Deposited 
crystals were collected by filtration and washed with diethyl ether. The 
filtrate and the wash liquid were collected together and concentrated 
under reduced pressure to give methyl N-cyano-4-cyanobenzenecarboximidate 
(3.63 g, 19.6 mmol, yield: 39%) as colorless powder. 
Physico-chemical properties of methyl N-cyano-4-cyanobenzenecarboximidate 
MP: 94.5.degree.-95.0.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2200, 1600, 1350; 
NMR spectrum: (500 MHz, CDCl.sub.3) .delta. (ppm) 8.18 (2H, d, J=8.6Hz), 
7.83 (2H, d, J=8.6Hz), 4.13 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 64.86 3.81 22.69 
Found: 64.81 3.77 22.41 (%) 
(C.sub.10 H.sub.7 N.sub.3 O) 
______________________________________ 
b) Methyl N-cyano-4-cyanobenzenecarboximidate (0.37 g, 2.0 mmol) was 
suspended in methanol (4 ml), and 2-phenylethylamine (0.25 g, 2.1 mmol) 
was added. The mixture was stirred at room temperature for 1 hour. After 
the reaction was completed, methanol (6 ml) and diethyl ether (10 ml) were 
added to the reaction solution, and deposited crystals were collected by 
filtration to give the title compound (0.51 g, 1.87 mmol, yield: 94%) as 
colorless crystals. 
Physico-chemical properties of 
N-cyano-N'-(2-phenylethyl)-4-cyanobenzenecarboximidamide 
MP: 261.0.degree.-261.8.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2170, 1550; 
NMR spectrum: (500 MHz, CD.sub.3 OD) .delta. (ppm) 7.84 (2H, d, J=8.5Hz), 
7.64 (2H, d, J=8.5Hz), 7.36-7.22 (5H), 3.73 (2H, t, J=7.3Hz), 3.00 (2H, t, 
J=7.3Hz); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 74.43 5.14 20.42 
Found: 74.13 5.35 20.21 (%) 
(C.sub.17 H.sub.14 N.sub.4) 
______________________________________ 
Example 2)-12 
Preparation of 3-cyano-2-methyl-(2-nitroxyethyl)isothiourea 
a) 2-Nitroxyethylamine nitrate (0.56 g, 3.3 mmol) was dissolved in methanol 
(2 ml), and sodium methoxide (0.18 g, 3.3 mmol) was added. 
Dimethyl-N-cyanodithioiminocarbonate (0.44 g, 3.0 mmol) dissolved in 
methanol (4 ml) was added further to the solution. The mixture was stirred 
at room temperature for 24 hours. After the reaction was completed, the 
reaction solution was concentrated under reduced pressure, and the residue 
obtained was crystallized from diethyl ether to give colorless powder. The 
powder thus obtained was washed with water and recrystallized from 
methanol to give the title compound (0.26 g, 1.3 mmol, yield: 43%) as 
colorless crystals. 
Physico-chemical properties of 
3-cyano-2-methyl-1-(2-nitroxyethyl)isothiourea 
MP: 135.degree.-135.5.degree. C.; 
IR spectrum: (cm.sup.-1, KBr) 2170, 1640, 1560, 1280; 
NMR spectrum: (500 MHz, CD.sub.3 OD) .delta. (ppm) 4.63 (2H, s), 3.74 (2H, 
s), 2.60 (3H, s); 
______________________________________ 
Elementary Analysis: 
C H N 
______________________________________ 
Calculated: 29.41 3.95 27.44 
Found: 29.33 3.77 27.15 (%) 
(C.sub.5 H.sub.8 N.sub.4 O.sub.3 S) 
______________________________________ 
BRIEF DESCRIPTION OF THE DRAWINGS 
FIG. 1 is a graph which illustrates the change in blood pressure in a 
beagle upon the intravenous administration of the compound of the present 
invention represented by the formula (I) [compound (13)]. 
FIG. 2 is a graph which illustrates the inhibitory effect of the compound 
of the present invention represented by the formula (I) [compound (13)] on 
the rhythmic contraction of a coronary artery of a dog induced by 3.4-DAP. 
FIG. 3 is a graph which illustrates the effects of the compound of the 
present invention represented by the formula (I) [compound (13)] and 
nicorandil on an angina pectoris model induced by vasopressin. 
FIG. 4 is a graph which illustrates the relaxation effect of the compound 
of the present invention represented by the formula (I) [compound (13)] on 
the basilar artery of a beagle. 
FIG. 5 is a graph which illustrates the inhibitory effect of the compound 
of the present invention represented by the formula (I) [compound (13)] on 
platelet aggregation. 
FIG. 6 is a graph which illustrates the relaxation effect of the compound 
of the present invention represented by the formula (I) [compound (13)] on 
the smooth muscle of a trachea.