KR970005907B1 - Novel carboximidamide derivatives - Google Patents

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Description

Novel Carboxyimidamide Derivatives and Methods for Making the Same

1 is a graph showing changes in blood pressure upon intravenous administration of a compound of the present invention (Compound No. (13) represented by Structural Formula (I)) to a Beagle dog.

2 is a graph showing the inhibitory effect of the compound of the present invention (Compound No. (13) represented by Structural Formula (I)) on the periodic contraction of the coronary artery of the dog by 3,4-DAP,

3 is a graph showing the action of the compound of the present invention (Compound No. (13) represented by Structural Formula (I)) and nicorandil on a vasoflegin-induced angina pectoris model,

4 is a graph showing the relaxation action of the compound of the present invention (Compound No. (13) represented by Structural Formula (I)) on the basal artery of the dog,

5 is a graph showing the platelet aggregation inhibitory effect of the compound of the present invention (Compound No. (13) represented by Structural Formula (I)),

6 is a graph showing the relaxation action of the compound of the present invention (Compound No. (13) represented by Structural Formula (I)) on tracheal smooth muscle.

The present invention relates to a novel carboxyimidamide derivative having a vasodilating action and a preparation method thereof, and more particularly, to an N-cyano-N'-substituted pyridinecarboximidamide derivative and an N-cyano-N '. A derivative in which the N 'position is substituted with an alkyl substituent in the -substituted-carboxyimidamide derivative, or an acid addition salt thereof, an intermediate for its preparation, and a method for producing the same.

The present invention also provides a potassium channel activator, a coercive agent, an ischemic heart disease treatment agent, and a peripheral circulation using the N-cyano-N'-substituted pyridinecarboximidamide derivative or an acid addition salt thereof as an active ingredient. Insufficiency drugs, brain circulation improvement drugs, thrombosis therapy drugs, and asthma therapy drugs, and N-cyano-N'-substituted carboxyimidamide derivatives whose N 'positions are substituted with alkyl groups or acid addition salts thereof as active ingredients It is about.

The present invention also provides potassium channel activation of the N-cyano-N'-substituted pyridinecarboximidamide derivatives or acid addition salts thereof, coercion, ischemic heart disease treatment, peripheral circulation insufficiency treatment, brain circulation improvement, thrombosis treatment and asthma A treatment method for patients in need of treatment and a treatment method for patients in need of coercion of N-cyano-N'-substituted carboxyimidamide derivatives having N 'positions substituted with alkyl groups or acid addition salts thereof will be.

Known compounds among the N-cyano-N'-substituted pyridine carboximidamide compounds related to the present invention include N-cyano-3-pyridinecarboximidamide (Journal of Medicinal Chemistry, Vol. 23, 690-692). Page, 1980), N-cyano-4- (2-ethylpyridine) carboxyimidamide (Leprosy Review, pages 23-30, 1983), and N-cyano-4-pyridine carboxyimide Damids (Bullentin des Societes Chimiques Belges, vol. 78, pp. 41-46, 1969) are known, all of which are compounds that do not have a substituted N 'position and are intermediates in the manufacture of diuretics or Hansen's disease, respectively. It is reported only as a medicament and no other usefulness has been described. In addition, various studies have been made on the synthesis method of the carboxyimidamide compound, and in particular, various synthesis methods have been studied, focusing on benzene carboxyimidide compounds or alkylcarboxyimidamides. (See The chemistry of amidines and imwdates Edited by Saul Patai, John Wiley and Sons, 1975). For example, in the case of N-cyano-N'-substituted-benzinecarboxamidamide, cyanobenzene is alkyl = benzeneimidate, and cyanamide (NH ₂ CN) is reacted in pH 6.5 to 7.0. A synthesis method is proposed in which alkyl = N-cyano-benzeneimidate and an amine compound (Synthesis, page 263, 1971; Synthesis, pages 673-667, 1978; Journal of Organic Chemistry , Vol. 44, pp. 1562-1563, 1979; Synthesis, pp. 123-124, 1980; Synthesis, pp. 402-404, 1983). However, in the conventional synthesis method, in particular, the synthesis method subject to the above range, alkyl-n-cyano-pyridinecarboxyimidate is not produced, and an n-cyano-n'-substituted pyridine carboximidamide compound is produced. It was impossible.

On the other hand, various types of drugs have been proposed to the coercion until now, but as far as the present inventors and the like are aware, the conditions of all hypertension symptoms such as essential hypertension and secondary hypertension, and satisfactory effects on patients. The drug that brings it has not been reported yet.

In addition, regarding the treatment of angina pectoris, calcium antagonists, β-blockers, and the like have been conventionally used, but the use of these agents did not completely suppress angina attacks, and when the condition progressed due to myocardial infarction. However, no satisfactory therapeutic agents have been reported, such as myocardial protection after vasculogenesis. There has been a constant demand for new types of circulatory therapeutics to address these issues.

For example, as a drug for circulatory therapy based on the order of new functional groups, a compound having potassium channel activating action has recently been proposed. Here, the potassium channel activating action is to open the potassium channel on the cell membrane and increase the permeability of potassium ions, causing hyperpolarization of the membrane to suppress smooth muscle and myocardial contraction. Examples of the compound having a potassium channel activating action include nicorandil, pinassidyl, chromatin and potassium (see Trends in Pharmacological Sciences, Vol. 8, page 283, 1987). They show vasodilating, coercive, vascular-increasing, cerebrovascular and bronchial expansion in animal experiments (Europen Journal of Pharma-cology, Vol. 152, page 331, 1988; The Journal of Pharmacology and Experimental Therapeutics, Vol. 232, pp. 369, 1985; Journal of Cadiovascular Pharcology, Vol. 8, pp. 798, 1986; Japan Heart Journal, Vol. 20, pp. 881, 1979; European Journal of Pharmacology , Volume 99, page 219, 1984; British Journal of Pharmacology, volume 95, page 763, 1988).

Known carboxyimidamide compounds other than the N-cyano-pyridinecarboximidamide compound related to the present invention include N-cyano-5-nitro-2-furamidine (Japanese Patent Application No. 43-20453, British Patent No. 1,133,950), N-cyano-2-thiophenecarboximidamide, N-cyano-3-thiophenecarboximidamide (both in Journal of Medicinal Chemistry, Vol. 23, pp. 690-692, 1980) Years) and N- (N-cyanoimidoyl) -sulfoxyimides (see Chemisch Berichte, Vol. 121, pp. 383-386, 1988). However, these compounds have been reported as antimicrobial agents, diuretics, intermediates for the preparation and intermediates for the preparation of thytoriadines, respectively, and there are no reports of vasodilating and coercive action. In addition, what has an alkyl substituent at the N 'position in the carboxyimidamide compound which concerns on this invention is currently unknown at all.

The present invention aims to provide a novel compound having vasodilating action, that is, N-cyano-N'-substituted pyridine carboximidamide derivative and N-cyano-N'-substituted carboxyimida Based on the discovery that derivatives in which the N 'position is substituted with alkyl substituents in the mid derivatives have the same effect as above, and among these novel carboxyimidimide derivatives, potassium channel activators, coercive agents, ischemic heart disease therapeutic agents, and peripheral circulation The present invention has been completed by discovering that it is effective as a drug for treating insufficiency, an agent for improving brain circulation, an agent for treating thrombosis, and an agent for treating nephropathy.

Hereinafter, the present invention will be described in detail.

The present invention is a carboxyimidamide derivative represented by the following structural formula (A) or an acid addition salt thereof.

In the above formula, B is (Where X represents a hydrogen atom or a chlorine atom) or

Or H ₃ CS.

(여기서 X는 수소원자 또는 염소원자를 나타냄)인 경우, -R¹또는

R 'is B

(Where X represents a hydrogen atom or a chlorine atom), -R ¹ or

또는

을 나타낸다(여기서 R⁴은 알킬기 또는 알콕시기를 나타내며, b는 0 내지 1중의 어느 하나의 정수를 나타낸다)[Wherein R1 is an alkyl group, an alkyl group having a nitroxyl group,

or

(Wherein R ⁴ represents an alkyl group or an alkoxy group, b represents an integer of 0 to 1)

R ² is selected from the group consisting of alkyl group, aryl group, nitroxyl group, arylalkoxy group, hydroxyl group and hydrogen atom, a represents an integer of 1 to 3 (where a is 2 or more, 2 or more are R <^2> to be mentioned may be any 1 type, or multiple types may be sufficient as said group and atom atom).

또는

를 나타낸다.R ³ is

or

Indicates.

R ⁵ represents an alkyl group, an alkoxyl group, an aryl alkoxyl group, an aryl alkoxyl 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 is a 0-5 compound. When c is 2 or more, R ⁵ to be 2 or more may be any one of the above-described groups and atoms, or may be two or more kinds).

Some compounds according to the present invention may or may not have pyridine as substituent B in the above formula (A).

Having pyridine as the substituent B is a pyridinecarboxyimidamide derivative represented by the following structural formula (I) or an acid addition salt thereof.

In the above formula, X represents a hydrogen atom or a chlorine atom.

[여기서, R¹은 알킬기, 니트록실기를 갖는 알킬기,R is -R ¹ or

[Wherein R ¹ is an alkyl group, an alkyl group having a nitroxyl group,

을 나타낸다(여기서, R⁴는 알킬기 또는 알콕실기를 나타내며, b는 0 내지 1 중의 어느 하나의 정수를 나타낸다), R²는 알킬기, 아릴기, 니트록실기, 아릴알콕실기, 수산기 및 수소원자로 된 군중에서 선택된 것을 나타내며, a는 1 내지 3중 어느 하나의 정수를 나타낸다(여기서, a가 2이상인 경우, 2이상이 되는 R²는 상기한 기와 원자중에서 어느 1종이어도 좋고 복수종이어도 좋다).or

(Wherein R ⁴ represents an alkyl group or an alkoxyl group, b represents an integer of 0 to 1), and R ² represents an alkyl group, an aryl group, a nitoxyl group, an arylalkoxyl group, a hydroxyl group and a hydrogen atom. It represents what was selected from the crowd, and a represents the integer in any one of 1-3 (wherein, when a is 2 or more, two or more R <^2> may be any of the above-mentioned group and atom, and may be multiple types).

또는

를 나타낸다. (여기서 R⁵는 알킬기, 알콕실기, 아릴알콕실기, 니트로기, 아미노기, 알킬아미노기, 아릴알킬아미노기, 알킬티오기, 퍼플루오로알킬기 또는 할로겐원자를 나타내며, c는 0 내지 5중 어느 하나의 정수를 나타낸다. 또한 c가 2이상인 경우, 2이상이 되는 R⁵는 상기한 기와 원자중에서 어느 1종이어도 좋고 복수종이어도 좋다.)]을 나타낸다.R ³ is

or

Indicates. R ⁵ represents an alkyl group, an alkoxyl group, an aryl alkoxyl 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 is an integer of any one of 0 to 5. In addition, when c is 2 or more, any one of R ⁵ and two or more of the above-described groups and atoms may be used.

The compound of the present invention having no pyridine as the substituent B is a carboxyimidamide derivative represented by the following structural formula (I ').

또는

을 나타낸다Or H ₃ CS- and R is

or

Indicates

The present invention also relates to intermediates for the preparation of compounds represented by the above structural formula (I). The N-cyano-pyridinecarboxyimidate compound which is the manufacturing intermediate according to the present invention is represented by the following structural formula (II).

Wherein X represents a hydrogen atom or a chlorine atom and R 'represents an alkyl group.

The present invention also relates to intermediates for the preparation of compounds represented by the above structural formula (I). That is, in the method for preparing the pyridinecarboximidamide derivative represented by the above formula (I) according to the present invention, alcohol, sodium hydride or sodium alkoxide is reacted with a cyanopyridine compound represented by the following formula (III) After obtaining the compound represented by (IV), the compound was reacted with cyanamide in a pH 5.0 to 6.0 buffer to produce an N-cyano-pyridinecarboxyimide compound represented by the above formula (II), The compound is characterized by reacting an amine compound represented by NH ₂ -R (wherein R is as described above).

In the above formula, X represents a hydrogen atom or a chlorine atom, and R 'represents an alkyl group.

In addition, the present invention relates to the use of the carboxyimidamide derivative represented by the above structural formula (A), that is, potassium having a pyridine carboximidamide derivative represented by the above structural formula (I) or an acid addition salt thereof as an active ingredient. A channel activator, coercive agent, ischemic heart disease treatment agent, peripheral circulation failure treatment agent, brain circulation improvement agent, thrombosis treatment drug and asthma treatment drug or carboxyimidamide derivative represented by the above formula (I ') or acid addition salt thereof as an active ingredient Potassium channelization, coercion, ischemic heart disease treatment, peripheral circulation insufficiency treatment, cerebral circulation improvement, thrombosis treatment and asthma treatment of hypertensive and N-cyano-N'-substituted pyridinecarboximidamide derivatives or acid addition salts thereof Therapeutic methods for patients in need and N-cyano-N'-substituted carboxyimidamide derivatives in which the N 'position is substituted with an alkyl group or its acid moiety It relates to treatment for patients in need of salt coercion.

The carboxyimidamide derivative according to the present invention has vasodilating action and hypotensive action, and the carboxyimidamide derivative having a pyridine substituent also has a potassium channel activating action.

In addition, the carboxyimidamide derivative according to the present invention has such vasodilating and coercive action, and in the case of the pyridine carboxyimidamide derivative, it also has a potassium channel activating action and at the same time, vasodilatation and myocardial protective action. It has peripheral blood vessel resistance reduction, cerebrovascular expansion, platelet aggregation inhibition and bronchial expansion.

The carboxyimidamide derivative according to the present invention could not be considered a characteristic having various physiological actions as described above.

The carboxyimidamide derivative according to the present invention is represented by the above structural formula (A), and N-cyano-N'-substituted-pyridine carboxyimidamide derivative having pyridine as substituent B and N-cyano without pyridine -N'-substituted-carboxyimidamide derivatives (the definition of each substituent is as described above).

[I] N-cyano-N'-substituted-pyridinecarboximidamide derivatives

The pyridinecarboximidamide derivatives according to the present invention are N-cyano-N'-substituted pyridinecarboximidamide derivatives represented by the above structural formula (I) (the definition of each substituent is as described above).

In the above structural formula (I), the alkyl group of R 'is preferably 1 to 10 carbon atoms, particularly 5 to 8 carbon atoms, and may be linear or branched chain, particularly preferably a branched alkyl group. Moreover, it is preferable that C1-C5 has the alkyl group which has the niroxyl group of R ', and it is especially preferable that it is 1-3. In this case, although several nitroxyl groups may be contained, 1-2 are especially preferable. In addition, although the coupling | bonding position of a nitroxyl group may be couple | bonded with any of 1st-3rd grade carbon, it is preferable to bind to primary carbon especially.

The alkyl group of R ² preferably has 1 to 5 carbon atoms, particularly 1 to 3 carbon atoms, and an aryl group is preferably a tolyl group, a xylyl group or a phenyl group, and more preferably a phenyl group. In addition, the arylalkoxy group is preferably a phenethyloxyl group, 3-phenylpropyloxyl group, or benzyloxyl group, and among these, a benzyloxyl group is more preferable.

In addition, when several R <^2> contains several at the same time, several R <^2> may be any one of said group and atom, and may be multiple types.

In the case where R ⁴ is an alkyl group or an alkoxyl group, the alkyl group or alkoxyl group preferably has 1 to 5 carbon atoms, particularly 1 to 3 carbon atoms.

The definition of R ⁵ is gateuna described above, R ⁵ is intended to mean also a plurality of kinds, in addition to these means gatneun any one kind of these groups or atoms. Moreover, when R <^5> is an alkyl group or an alkoxyl group, this alkyl group or alkoxyl group has 1-5 carbons, especially 1-3 are preferable. In the case of an aryl alkoxyl group, a phenethyloxyl group, 3-phenylpropyloxyl group, and benzyloxyl group are preferable, and a benzyloxyl group is more preferable among these. In addition, the alkylamino group preferably has 1 to 5 carbon atoms, particularly 1 to 3 carbon atoms, and an arylalkylamino group is preferably a phenethylamino group, 3-phenylpropylamino group, or benzylamino group, and more preferably a benzylamino group.

In the case of an alkylthio group or a pifluoroalkyl group, carbon atoms are preferably 1 to 5, particularly 1 to 3, respectively.

In addition, although a halogen atom may be freezing, fluorine, chlorine, and a cancellation are more preferable.

Since the N-cyano-N'-substituted pyridinecarboximidamide derivative according to the present invention has a basic nitrogen atom, its acid addition salt is present. That is, examples of the acid that can form an acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, or acetic acid, propionic acid, maleic acid, oleic acid, palmitic acid, citric acid, succinic acid, tin acid, And organic acids such as fumaric acid, glutamic acid, pantothenic acid and laurylsulfonic acid. In addition, it is needless to say that when acid addition salt is used as a medicament, the acid must be pharmaceutically acceptable.

As typical examples of the N-cyano-N'-substituted-pyridinecarboximidamide derivatives represented by the above structural formula (I) according to the present invention, compounds (1) to (53) shown below can be given.

Compound Number Compound Name

(1) N-cyano-N '-(2-nitoxyethyl) -2-pyridinecarboxyimidamide,

(2) N-cyano-N '-(2,2-dimethylpropyl) -2-pyridinecarboxyimidamide,

(3) N-cyano-N '-(1,2,2-trimethylpropyl) -2-pyridinecarboxyimidamide,

(4) N-cyano-N'-phenyl-2-pyridinecarboxyimidamide,

(5) N-cyano-N '-(4-methoxyphenyl) -2-pyridinecarboxyimidamide,

(6) N-cyano-N '-(4-methylbenzyl) -2-pyridinecarboximidamide,

(7) N-cyano-N '-(4-chlorobenzyl) -2-pyridinecarboximidamide,

(8) N-cyano-N '-[4- (trifluoromethyl) benzyl] -2-pyridinecarboxyimidamide,

(9) N-cyano-N '-[2- (4-methylphenyl) ethyl] -2-pyridinecarboxyimidamide,

(10) N-cyano-N '-[2- (4-chlorophenyl) ethyl] -2-pyridinecarboxyimidamide,

(11) N-cyano-N '-[2- (4-chlorophenyl) ethyl] -2-pyridinecarboxyimidamide,

(12) N-cyano-N '-(2-thienylmethyl) -2-pyridinecarboximidamide,

(13) N-cyano-N '-(2-nitroethylethyl) -3-pyridinecarboxyimidamide,

(14) N-cyano-N '-(3-nitoxypropyl) -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-pyridinecarboxyimidamide,

(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-dichlorobenzyl) -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- (4-nitrophenyl) -2-nitoxyethyl] -3-pyridinecarboximidamide,

(33) N-cyano-N '-(3-phenylpropyl) -3-pyridinecarboximidamide,

(34) N-cyano-N'-diphenylphenyl-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 '-(2,6-dimethoxypyridine) -3-pyridinecarboximidamide,

(41) N-cyano-N '-(2-nitroethylethyl) -4-pyridinecarboximidamide,

(42) N-cyano-N '-(3-nitropropyl) -4-pyridinecarboximidamide,

(43) N-cyano-N'-phenyl-4-pyridinecarboxyimidamide,

(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-nitroethylethyl] -4-pyridinecarboximidamide,

(52) N-cyano-N '-(2-nitoxyethyl) -3- (6-chloropyridine) -carboxyimidamide,

(53) N-cyano-N '-(2-phenylethyl) -3- (6-chloropyridine) -carboxyimido.

The structure of the substituent R of these compounds was as follows.

[II] N-cyano-pyridinecarboxyimidate compound

The N-cyano-pyridinecarboxyimidate compound according to the present invention is an alkyl = N-cyano-pyridinecarboxyimidate compound represented by the above formula (II), and the compound according to the present invention represented by the formula (I) or It is an intermediate for preparing the acid addition salt thereof (the definition of each substituent is as described above). In the structural formula (II), the alkyl group of R 'is preferably 1 to 8 carbon atoms, more preferably 1 to 5 carbon atoms, and may be linear or cyclic, and particularly preferably isopropyl group.

As a typical example of the alkyl = N-cyano-pyridinecarboxyimidate compound represented by the structural formula (II) according to the present invention, the compounds (54) to (58) shown below may be mentioned.

Compound Number Compound Name

(54) methyl = N-2-pyridinecarboxyimidate

(55) isopropyl = N-2-pyridinecarboxyimidate,

(56) isopropyl = N-3-pyridinecarboxyimidate,

(57) isopropyl = N-4-pyridinecarboxyimidate,

(58) isopropyl = N-3- (6-chloropyridine) carboxyimidate.

The structural formula of these compounds is as follows.

Method of preparing [III] N-cyano-N'-substituted-pyridinecarboxyimidamide derivatives

(1) Overview

The N-cyano-N'-substituted-pyridinecarboximidamide derivatives according to the present invention can be prepared by either of the following two methods. This method can be represented by the following schemes (A) and (B).

That is, as represented by the reaction formula (A), the cyanopyridine compound represented by the structural formula (III) induces the N-cyano-pyridinecarboxyimidate compound of the structural formula (II), and various kinds of amine compounds And (a) a method of obtaining an N-cyano-N'-substituted-pyridine carboximidamide derivative of the desired structural formula (I), and an amide compound represented by the structural formula (V) prepared by a known method. The target compound of formula (I) was prepared by converting to a thioamide compound of (IV) and reacting it with cyanamide (NH ₂ CN) in the presence of a tertiary amine which is phosphorus oxychloride. However, according to the method (b), it is impossible to produce a compound having a nitroxyl group in R.

The following is a detailed description of the methods (a) and (b).

Wherein R, R 'and X are as described above.

In the above formula, R and X are as described above.

(2) (a) Method

As described above, the method (a) is a method for preparing the target compound according to the reaction formula (a).

화합물(Ⅳ)(a) Compound (III)

Compound (IV)

The cyanopyridine compound represented by formula (III) is already represented by formula (IV) by reacting R'Na, i.e. sodium alkoxide, in R'OH, i.e., sodium hydride in alcohol or the corresponding R'OH. Induced by a dating compound. The amount of sodium hydride or R'ONa used in this reaction is a catalytic amount, and it is usually carried out within the range of 0.01 mol to 0.5 mol, more preferably 0.02 mol to 0.2 mol with respect to 1 mol of cyanopyridine. good.

Alcohols (R'OH) which may be used in this reaction include linear and cyclic alcohols, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, cyclopentanol , Cyclohexanol, n-octanol and the like.

These alcohols may also be used as reaction solvents, or may be used only as reaction reagents in the presence of another solvent. In general, when used as a reaction solvent, it is usually changed within the range of 10 to 50 moles with respect to 1 mole of cyanopyridine, and 1 to 5 moles with respect to 1 mole of cyanopyridine when used in the presence of another solvent. It is preferable to use within the range of. As a solvent that can be used in this reaction, for example, an aprotic solvent, ie, hexane, benzene, toluene, diethyl ether, petroleum ether, tetrahydrofuran, N, N-dimethylformamide, or the like is preferable. Moreover, reaction temperature is especially preferable in room temperature within the range of 0-50 degreeC.

Under the above reaction conditions, this reaction can usually be completed within 3 to 24 hours.

The imitate compound represented by the obtained structural formula (IV) is provided to the next reaction without being isolated and purified.

화합물(Ⅱ)(b) Compound (IV)

Compound (II)

The imidate compound represented by the formula (IV) is converted into the N-cyano-pyridine-carboximidate compound represented by the formula (II) by acting cyanamide (NH ₂ CN) in a buffer, preferably in a phosphate buffer. do.

The amount of cyanamide used is preferably at least 1 mole, particularly 2 to 3 moles, relative to 1 mole of the imidate compound of the formula (IV). The reaction can also be carried out in the same buffer, preferably in a phosphate buffer solution, but its pH range is advantageously in the range of 5.0 to 6.0, preferably in the range of 5.2 to 5.6. Moreover, the density | concentration of a buffer solution is suitable in the range of 0.5-4M. In addition, in order to maintain sufficient buffering capacity, the buffer is composed of one component, i.e., in the case of phosphate buffer, for example, Na ₂ HPO ₄ and NaH ₂ PO ₄ are either 1 mole with respect to 1 mole of the imidate compound of formula (IV). It is preferable to use more than that. The reaction temperature is preferably in the range of 0 to 50 ° C, particularly near room temperature.

Under these reaction conditions, the imidate compound represented by the formula (IV) is usually converted to the N-cyano-pyridinecarboximitate compound represented by the formula (II) within 2 to 12 hours. The method for isolating and purifying the N-cyano-pyridinecarboximidate compound represented by Structural Formula (II) thus obtained is known in the field of organic synthesis chemistry such as crystallization, distillation, column chromatography using silica gel as a carrier. You can use the law.

화합물(Ⅰ)(c) Compound (II)

Compound (I)

The N-cyano-pyridinecarboximitate compound represented by Structural Formula (II) is reacted with various kinds of amine compounds to form the N-cyano-N'-substituted pyridinecarboximidamide derivative represented by Structural Formula (I). It can manufacture.

The amount of the amine compound used is preferably at least 1 mole or more, preferably 1 to 2 moles with respect to 1 mole of the N-cyano-pyridinecarboxyimitate compound represented by Structural Formula (II). This reaction is usually carried out in a solvent, and solvents that can be used include, for example, methanol, ethanol, dichloromethane, chloroform, carbon tetrachloride, dioxane, tetrahydrofuran, water, and the like. desirable. The reaction temperature is particularly preferably in the vicinity of room temperature within the range of 0 ° C to the boiling point of the solvent. Under the above reaction conditions, this reaction can be completed within 5 minutes to 24 hours.

The method for isolating and purifying the compound represented by the structural formula (I) from the reaction mixture obtained in the above reaction is the same as the method for isolating and purifying the N-cyano-pyridinecarboxyimide compound represented by the structural formula (II).

The compound represented by Structural Formula (I) according to the present invention may itself be an acid addition salt thereof by a public office method, and the acid necessary to make the addition salt is as described above.

(3) (b) method

화합물(Ⅵ)(a) Compound (V)

Compound (VI)

Amide compounds represented by formula (V) prepared by known methods are known thiocarbonylated reagents, namely P ₂ S ₅ or Lawesson's reagent (Tetrahedron, Vol. 35, p. 2433, 1979). And the like to convert a thioamide compound of formula (VI) by a known method.

화합물(Ⅰ)(b) Compound (IV)

Compound (I)

The thioamide compound represented by formula (VI) is N-cyano-N'-substituted-pyridinecarboxyl represented by formula (I) by acting cyanamide (NH ₂ CN) in the presence of a tertiary amine which is oxychloride. Imidamide derivatives can be prepared. In this reaction, the amount of cyanamide (NH ₂ CN) used is at least 1 mole, preferably at least 3 moles, more preferably 5 to 15 moles per mole of thioamide compound represented by the formula (VI). It is preferable to use within.

The reaction is carried out in the presence of phosphorus oxychloride as described above, but the reaction proceeds in the same manner not only with phosphorus oxychloride but also with phosphorus pentoxide, phosphorus thionyl chloride, or sulfyl chloride as the reagent for advancing the reaction. You can. Moreover, it is preferable to use the usage-amount at least 1 mol or more with respect to 1 mol of thioamide compounds of structural formula (VI), Preferably it is 1-2 mol. Similarly, this reaction may proceed in the presence of a tertiary amine. As the tertiary amine, triethylami, diisopropylethylamine and the like are suitable, and the amount of the tertiary amine is 1 to 2 based on 1 mole of the thioamide compound of the formula (VI). It is suitable to use in the range of mole. This reaction can be carried out in a common solvent, solvents which may be used include acetonitrile, benzene, hexane, toluene, dichloromethane, chloroform, carbon tetrachloride, dioxane, tetrahydrofuran, N, N-dimethylformamido Etc., and acetonitrile is particularly preferable. The reaction temperature is suitably within the boiling point range of the solvent used, from room temperature to 80 to 110 ° C.

As the above reaction conditions, the reaction may be terminated within 6 to 24 hours.

The method for purifying the desired N-cyano-N'-substituted-pyridinecarboximidamide mixture from the reaction mixture thus obtained, and the method for making an acid addition salt are all as described in the method (a).

[VI] Use of the compound (pyridinecarboximidamide derivative represented by formula (I))

(1) potassium channel activator

As shown in the results of the following Reference Examples 1-3 and 4, the compound of the present invention represented by Structural Formula (I) exhibits strongly coercive action in either intravenous administration or oral administration in hypertensive rats. In addition, as shown in Reference Example 1-5, the blood pressure was also reduced in dogs at low concentration. These results show that the compound of the present invention is useful as a coercive agent.

(3) Treatment of fever heart disease

The compound of the present invention represented by Structural Formula (I) significantly increased the amount of blood flow in the heart of the extract in Reference Example 1-6, compared with nicolandil. In addition, in Reference Example 1-7, the compound of the present invention had a continuous blood flow increasing action in addition to the strong coercive action significantly exceeding nicorandil. This effect was also observed continuously in the duodenal administration of Reference Examples 1-8.

In addition, the compound represented by Structural Formula (I) shows a strong inhibitory effect on the periodic contraction of 3,4-DAP, which is a model of heteroangular angina attack, in Reference Example 1-9. It was also more effective than nicorandil in angina model rats. In addition, the compound represented by Structural Formula (I) in Reference Example 1-11 was confirmed to have a myocardial protective action after ischemia reperfusion.

From the above results, it can be seen that the compound of the present invention represented by Structural Formula (I) is useful as a therapeutic agent for ischemic heart disease such as angina pectoris and myocardial infarction.

(4) Drugs for peripheral circulation insufficiency

Compound represented by formula (IV) reduced peripheral vascular resistance by intraduodenal administration in Reference Examples 1-8. Accordingly, it can be seen that the compound of the present invention represented by Structural Formula (I) is useful as a therapeutic agent for peripheral circulatory insufficiency.

(5) Brain circulation improving drug

It was confirmed that the compound represented by Structural Formula (I) had cerebrovascular expansion from Reference Examples 1-12, and from the results of Inclusion Examples 1-13, it was confirmed that there was an extension of production time in the hypoxic state. From these results, it can be seen that the compound of the present invention represented by structural formula (I) is useful as a brain circulation improving drug.

(6) thrombosis medicine

The compound represented by Structural Formula (I) inhibited platelet aggregation and promoted its dissociation in Reference Examples 1-14. These results show that the compound of the present invention represented by the structural formula (I) is useful as a therapeutic drug.

(7) asthma medicine

The compound represented by Structural Formula (I) expanded not only vascular smooth muscle but also organ smooth muscle in Reference Example 1-15. Therefore, it turns out that the compound of this invention represented by structural formula (I) is useful as a therapeutic agent of asthma.

The compound represented by Structural Formula (I) is a coercive drug, an agent for treating ischemic heart disease, an agent for treating peripheral circulation failure, an agent for improving brain circulation, an agent for treating thrombosis, and an agent for asthma. , Subcutaneous absorption) or sublingual tablets, suppositories, and the like.

The dosage and method of administration of the compound represented by Structural Formula (I) may of course vary depending on the situation of the patient, for example, body weight, sex, sensitivity, time of administration, drug used in combination, patient, or stage thereof. In addition, the dosage and the number of doses under the previous conditions should be determined according to the expert's quantitative determination test based on the above-mentioned guidelines. In general, the amount administered daily is about 0.1 to 200 mg, preferably 0.1 to 100 mg based on an adult. Especially preferably, it is about 0.5-30 mg.

When the compound represented by the structural formula (I) is orally administered as a medicament, it is administered by tablets, granules, powders, capsules, and parenteral administration by injection or suspension. To prepare such a tablet, the compound of the present invention may be used alone, or an excipient, a binder, a disintegrant, a lubricant, a stabilizer, or the like may be added. Moreover, you may combine other drugs as needed. Examples of the excipient include lactose, starch, crystalline cellulose, mannitol, maltose, calcium hydrogen phosphate, hard silicic anhydride, calcium carbonate, and the like, for example, starch, polyvinylpyrrolidone, and hydroxypropyl. Cellulose, ethyl cellulose, carboxymethyl cellulose, gum arabic, and the like, and disintegrating agents include starch, carboxymethyl cellulose calcium, and the like. Examples thereof include lactose, mannitol, maltose, polysorbates, macrogols, polyoxyethylene, hardened rice oil and the like. These ingredients can be used in the formulation of tablets, granules, capsules, injections and the like.

[IV] N-cyano-N'-substituted-carboxyimidamide derivatives

Carboxylimidamide derivatives according to the present invention having no pyridine as a substituent B in the above formula (A) are represented by the following formula (I '), which is as described above, which is N-cyano-N'-substituted-carboxy Imidamide derivatives.

또는

를 나타낸다.R is

or

Indicates.

또는

인 경우에는, 구조식(Ⅰ')의 화합물은 산부가염을 형성할 수 있는 산은, 구조식(Ⅰ')으로 표시되는 N-시아노-N'-치환-피리딘가르복시이미다미드 유도체의 경우와 동일하다.Where X is

or

In the case of the compound of formula (I '), the acid capable of forming an acid addition salt is the same as that of the N-cyano-N'-substituted-pyridinegarboximidamide derivative represented by the formula (I'). Do.

It goes without saying that acid addition salts should be medically acceptable when used as a medicine.

Representatives of the N-cyano-N'-substituted-carboxyimidamide derivatives represented by Structural Formula (I ') according to the present invention include those shown below (Compound Nos. 59 to 70).

Compound Number Compound Name

(59) N-cyano-N '-(2-nitoxyethyl) -3-quinolinecarboxyimidamide,

(60) N-cyano-N '-(2-phenylethyl) -3-quinolinecarboxyimidamide,

(61) N-cyano-N '-(2-nitoxyethyl) -pyrazinecarboxyimidamide,

(62) N-cyano-N '-(2-nitoxyethyl) -2-furancarboxyimidamide,

(63) N-cyano-N '-(2-phenylethyl) -2-furancarboxyimidamide,

(64) N-cyano-N '-(2-nitroethylethyl) -3-furancarboxyimidamide,

(65) N-cyano-N '-(2-phenylethyl) -3-furancarboxyimidamide,

(66) N-cyano-N '-(2-nitoxyethyl) -2-thiophenecarboximidamide,

(67) N-cyano-N '-(2-phenylethyl) -2-thiophenecarboxyimidamide,

(68) N-cyano-N '-(2-phenylethyl) -3-thiophenecarboximidamide,

(69) N-cyano-N '-(2-phenylethyl) -4-cyanobenzenecarboxyimidamide,

(70) 3-cyano-2-methyl-1- (2-nitoxyethyl) isothiourea.

The structure of these compounds is as follows.

[V] Method for Preparing N-Cyano-N'-Substituted-Carboximidamide Derivatives

The N-cyano-N'-substituted-carboxyimidamide derivative represented by Structural Formula (I ') according to the present invention can be prepared by any suitable method, for example, It can be produced by two methods, (b) method and (b) method.

(1) (a) Method

Among the N-cyano-N'-substituted-carboxyimidamide derivatives represented by Structural Formula (I ') according to the present invention, ⅩⅩ HC-S- (for example, 3-cyano-2-methyl-1- ( Compounds other than 2-nithoxyethyl) isothiourea) induce nitrile represented by the formula (II ') to the cyanoimidate compound of the formula (IV'), as shown in Scheme (ga ') By reacting this with the amine compound, an N-cyano-N'-substituted-carboxyimidamide derivative represented by the desired structural formula (I ') can be obtained.

Scheme (a ')

Wherein R represents an alkyl group and X and R are as defined above.

Next, this preparation method will be described in more detail according to the reaction formula (a).

(2) (a) Method

화합물(Ⅲ')(a) Compound (II ')

Compound (III ')

Natrils represented by the formula (II ') are derived from the imidate compound represented by the formula (III') by reacting sodium hydride in ROH, ie, sodium hydride in alcohol or RONa, ie sodium alkoxide, to be used. The amount of sodium hydride or RONa used in this reaction is a catalytic amount, usually in the range of 0.01 mol to 0.5 mol, more preferably in the range of 0.02 mol to 0.2 mol relative to 1 mol of nitrile represented by Structural Formula (II '). It is good to carry out.

Alcohols (ROH) which can be used in this reaction are both linear and cyclic alcohols, for example methanol, ethanol, n-furopanol, isopropanol, n-butanol, isobutanol, t-butanol, cyclopentanol, Cyclohexanol, n-octanol, etc. are mentioned.

These alcohols may also be used as reaction solvents, or may be used only as reaction reagents in the presence of another solvent. In general, when used as a reaction solvent, it is usually used in the range of 10 to 50 moles with respect to 1 mole of nitrile, and when used in the presence of other solvent, within the range of 1 to 5 moles with respect to 1 mole of nitrile. It is preferable to use. As a solvent which can be used in this reaction, an aprotic solvent, ie, hexane, benzene, toluene, diethyl ether, petroleum ether, tetrahydrofuran, etc. is preferable. The reaction temperature is preferably in the range of 0 to 50 ° C, particularly near room temperature.

Under the above reaction conditions, this reaction can usually be completed in 0.5 to 28 hours. The imitate compound represented by the obtained structural formula (III ') is to be provided to the next reaction without isolation and purification.

화합물(Ⅳ')(b) Compound (III ')

Compound (IV ')

The imidate compound represented by the formula (III) is preferably converted into a cyanoimide compound represented by the formula (IV ') by acting cyanamide (NH ₂ CN) in a buffer solution, preferably in a phosphate buffer.

The amount of cyanamide used is preferably at least 1 mole, particularly 2 to 3 moles, per 1 mole of imidate compound. The reaction can also be carried out in the same buffer (preferably phosphate buffer), but its pH range is advantageously in the range of 5.0 to 6.5, preferably in the range of 5.2 to 6.2. Moreover, the density | concentration of a buffer solution is suitable in the range of 0.5-4 M, especially 1-3 M. In order to maintain sufficient buffering capacity, for example, in the case of a phosphate buffer solution, ie, phosphate buffer, Na ₂ HPO ₄ and NaH ₂ PO ₄ are preferably used at least one mole with respect to one mole of imidate compound. Do. The reaction temperature is preferably in the range of 0 to 5 ° C, particularly near room temperature.

Under these reaction conditions, the imidate compound represented by Structural Formula (III ′) is usually converted to cyanoimate compound represented by Structural Formula (IV ′) within 2 to 75 hours.

As a method for isolating and purifying the cyanoimitate compound represented by Structural Formula (IV ′) thus obtained, purification methods known in the field of organic synthesis chemistry such as crystallization, distillation, and column chromatography using silica gel can be used. have.

화합물(Ⅰ')(c) Compound (IV ')

Compound (I ')

The cyanoimitate compound represented by Structural Formula (IV ') can be prepared by reacting various kinds of amine compounds with N-cyano-N'-substituted-carboxamidamide derivatives represented by Structural Formula (I'). .

The amount of the amine compound to be used is preferably in the range of at least 1 mole or more, preferably 1 to 2 moles, per 1 mole of the cyanoimitate compound represented by Structural Formula (IV ′). In addition, this reaction is usually exerted in a solvent, and examples of the solvent that can be used include methanol, ethanol, dichloromethane, chloroform, carbon tetrachloride, dioxane and tetrahydrofuran, and methanol is particularly preferable. Do. The reaction temperature is particularly preferably in the vicinity of room temperature within the range of 0 ° C to the boiling point of the solvent. Under the above reaction conditions, the reaction can be completed within 5 hours to 24 hours to 50 hours.

The method for isolating and purifying the compound represented by structural formula (I ') from the reaction mixture obtained from the above reaction is the same as the method for isolating and purifying cyanoimidate compounds represented by structural formula (IV').

(2) (b) method

Among the compounds of the present invention, 3-cyano-2-methyl-1- (2-nitroethylethyl) thiourea is dimethyl-N-sia represented by the structural formula (V '), as shown in the following reaction formula (Na'). It can be prepared by acting 2-nitroxylethylamine on nodithioiminocarbonate.

Scheme (I ')

The amount of 2-nitoxyethylamine to be used in this reaction is at least 1 mole, in particular in the range of 2 moles to 1 mole of dimethyl-N-cyanodithioiminocarbonate represented by the formula (V '). It is preferable. In addition, this reaction is usually carried out in a solvent, and as a solvent which can be used, alcohols such as methanol, ethanol and isopropanol, aprotic solvents such as chloroform, dichloromethane, tetrahydrofuran, benzene and toluene are preferable. The reaction temperature is preferred within the range of the freezing point of the solvent to 50 ° C, particularly near room temperature. Under the above reaction conditions, this reaction can be completed in 1 to 30 hours.

The method for isolating and purifying 3-cyano-2-methyl-1- (2-nitroethylethyl) isothiourea from the reaction mixture obtained in the above reaction is isolated and purified of the cyanoimidate compound represented by the formula (IV '). As described in the method, purification methods known in the field of organic synthesis chemistry such as crystallization method, distillation method and column chromatography using silica gel as carriers can be used.

About the compound which has basic nitrogen in the compound represented by Structural formula (I ') by this invention, it can be set as the acid addition salt by itself according to a well-known method. The acid for making acid addition salt is as above-mentioned.

[VI] Use of a compound (carboxyimidamide derivative represented by structural formula (I ')).

The compounds of the present invention represented by the structural formula (I ') are useful as vasodilators or suppressors having vasodilatation and coercive action, as can be seen from the results of Reference Examples 2-1 and 2-2.

Compound represented by Structural Formula (I ') When administered as a vasodilator or coercive agent, oral administration or parenteral administration (intramuscular, intravenous, subcutaneous, transdermal absorption), as with the compound represented by Structural Formula (I') Or sublingual tablets, suppositories, or the like.

The dosage and method of administration of the compound of the present invention may vary depending on the situation of the patient, for example, body weight, sex, sensitivity, administration time, drug used in combination, the degree of the patient or the stage thereof, and under certain conditions. An appropriate amount and frequency of administration may be determined according to a specialist's titration determination test based on the above guidelines. Usually, the amount administered per day is about 0.1 to 200 mg, preferably 0.5 to 100 mg, based on an adult.

When the compound of the present invention is orally administered as a medicament, it is administered by tablets, granules, powders, or capsules, and when administered parenterally, it is administered by injection or suspension. To prepare such a formulation, the compound of the present invention may be used as it is, or an excipient, a binder, a disintegrant, a lubricant, a stabilizer, or the like described in the description of the compound represented by the above structural formula (I) may be added. If necessary, other drugs may be combined.

(Iii) Experimental example

The following reference examples and examples are intended to illustrate the present invention in more detail, but the present invention is not limited thereto.

1) Compound represented by structural formula (I)

Reference Example 1-1 Vasorelaxation Effects on Aortic Samples in Rats

(1) test method

The physiological activity of the compound of the present invention was tested by the method of using the isolated aorta.

A chest aorta was quickly extracted from a blood-sucked, 250-350 g Wister male rat and cut into rounds of 3 mm in width to prepare a specimen.

The specimen is suspended in an engine bath filled with Krebs-Ringer liquid, vented with a mixture of 95% O ₂ -5% CO ₂ gas.

After 1 g of static tension was loaded to stabilize the tension of the specimen, the inside of the trachea bath was exchanged with a solution of equal tension containing 40 mM KCl, and the tension of the specimen was increased.

After the development tension by KCl was constant, test compounds were cumulatively added into the glass bath and the specimens were relaxed.

The tension by KCl was set to 100%, and the relaxation reaction was determined as the inhibition rate. The IC ₅₀ value (the concentration at which 50% of the tension was suppressed by KCl) was calculated according to the Probit method in the mean dose-action curve.

(2) results

IC ₅₀ values of the test and control compounds are shown in the following table.

Reference Example 1-2 Potassium Channel Activation Activity

(1) test method

Potassium channel activating action of the compound of the present invention was carried out using N-cyano-N '-(2-nitoxyethyl) -3-pyridinecarboximidamide (Compound No. 13) and N-cyano-N'-benzyl-3- Pyridinecarboximidamide (Compound No. 17), N-cyano-N '-(2-phenylethyl) -3-pyridinecarboximidamide (Compound No. 27) and N-cyano-N'-(2- Nitrooxyethyl) -4-pyridinecarboximidamide (Compound No. 41) was tested using the radioactive isotope, ⁸⁶ rubidium (hereinafter referred to as ⁸⁶ Rb), which is an indicator of potassium. (Manufactured by Joel of Physiolosy) 316, page 33, 1981).

The thoracic aorta was quickly taken out of the blood-killed, 250-350 g of Wister male male rats, and cut in the longitudinal direction to form a piece. The sample of the Krebs 37 ℃ was vented to 95% O ₂ -5% CO ₂ gas mixture containing ⁸⁶ Rb for 10μCi.㎖ - in the Ringer solution, handing it with the ⁸⁶ Rb into the cells by dipping. Thereafter, the sample was washed for 18 minutes by transferring to Krebs-ring gel solution containing no ⁸⁶ Rb and changing the solution every 2 minutes, and then 18 minutes to Krebs-ring gel solution to which each compound (10 ^-4 M) was added. I hung it. The hourly ⁸⁶ Rb effluent was measured using the * -counter intracellularly.

Before the compound was reacted, the amount of effluent per minute for 6 minutes was 100%, and the amount of effluent increase per minute for 8 minutes was obtained.

(2) results

The ⁸⁶ % Rb runoff of the test compound is shown in the following table.

Reference Example 1-3 Hypotensive Action (Intravenous Administration) in Hypertensive Rats

(1) test method

The hypotensive action of the compound of the present invention was observed in male hypertensive rats (SHR) (Test compound: N-cyano-N '-(2-nitroethylethyl) -2-pyridinecarboximidamide (compound) No. 1), N-cyano-N '-(2-nitroethylethyl) -3-pyridinecarboximidamide (Compound No. 13), N-cyano-N'-benzyl-3-pyridinecarboximidamide (Compound No. 17), N-cyano-N '-(2-phenylethyl) -3-pyridinecarboxyimidamide (Compound No. 27), N-cyano-N'-[2- (2-chlorophenyl ) Ethyl-3-pyridinecarboximidamide (Compound No. 29) and N-cyano-N '-(2-nitroethylethyl) -4-pyridinecarboximidamide (Compound No. 41)).

Cannula was inserted into the carotid artery of rats anesthetized with urethane-α-chlorarose (1 g / kg-25 mg / kg intraperitoneally) to measure average blood pressure through a transducer.

Compounds were cumulatively administered every 30 minutes via cannula inserted into the jugular vein. The blood pressure before administration was 100%, and the change in blood pressure was calculated from the drop rate to calculate an ED ₂₀ value (a dose dropping blood pressure by 20%) in the dose-action curve.

(2) results

Test compound ED ₂₀ values are shown in the following table.

Reference Example 1-4 Blood pressure lowering effect in spontaneously hypertensive rats (oral administration)

(1) Experimental method

The hypotensive effect of oral administration of the compound of the present invention was observed in male hypertensive rats (SHR) of male (test compound N-cyano-N '-(2-nitroethylethyl) -3-pyridinecarboxyimida) Mead (Compound No. 13)). Systolic blood pressure 2 hours after administration of the compound fasted for 24 hours after the compound was measured by a non-invasive method using the tail cuff method. The compound was dissolved in a solvent of polyethylene glycol 200: saline = 1: 1, and only the solvent was administered as a control. In each group, the blood pressure before administration was 100%, and the change in blood pressure was calculated from the drop rate.

(2) results

The blood pressure drop rate (%) of the test compound is shown in the following table.

Reference Example 1-5 Lowering Blood Pressure in Beagle Dog (Intravenous Administration)

(1) test method

The hypotensive action of the compound of the present invention was observed in non-eagle dogs anesthetized for intravenous administration of pentobarbital sodium (35 mg / kg) (test compound; N-cyano-N'-). (2-nitroethylethyl) -3-pyridinecarboxyimidamide (Compound No. 13)). The cannula was inserted into the femoral artery and the mean blood pressure was measured through a pressure transducer. Compounds were administered via cannula inserted into the femoral vein. The blood pressure before administration was 100%, and the change rate of blood flow was calculated | required.

(2) results

The blood pressure strengthening rate (%) of the test compound is shown in FIG.

Reference Example 1-6 Action on Rat Low Cardiac Heart

(1) test method

The action of the compound of the present invention on the heart was tested using the ringgendorf method (test compound; N-cyano-N '-(2-nitroethylethyl) -3-pyridinecarboximidamide (Compound No. 13) )). Hearts were extracted from male rats weighing 250-350 g and perfused with an Lingogendorf loop at 80 cm water pressure. The perfusion solution was oxygenated using a Krebs-Hensaleit Bicarbonate liquid (37 ° C, pH 7.4) containing 11 mM glucose with 95% O ₂ -5% CO ₂ mixed gas. It was. Left ventricular pressure was measured by inserting latex varene into the left ventricle, and heart rate was measured by the pulsation thereof. In addition, the perfusion amount was measured using the electronic meter. The test was carried out by perfusion for 30 minutes with the perfusion solution, followed by perfusion for 10 minutes with the perfusion solution containing the compound number (13), and as a reference, nicorandil having a potassium channel activation action and having a similar structure. Was used. Compound number (13) and the rate of change in the perfusion amount and nicotine function (heart rate * left ventricular pressure) before nicorandil and perfusion were determined.

(2) results

The effects on perfusion increase and cardiac function are shown in the following table.

(Mean ± S.D.)

** p 0.01 Comparison with Nicorandin Group (Student's t-test)

Reference Example 1-7 Action on Circulatory Status in Beagle Dog (Intravenous Administration)

(1) test method

The action of the compound of the present invention on the circulating state was tested using a Beagle dog anesthetized with pentobarbital (30 mg / kg, intravenously) (Test compound N-cyano-N '-(2-nit). Oxyethyl) -3-pyridinecarboxyimidamide (Compound No. 13)).

After opening the chest in the state of ventilation and administering 500 units / kg of heparin, Moravit's cannula was inserted into the coronary sinus in the right ventricle, and the blood from there was returned to the right jugular vein. The blood flow probe was attached on the way, and the coronary sinus blood flow was measured by the electronic blood flow meter (Japan Electron MFV-2100). Aortic pressure was measured by inserting a cannula into the left subclavian artery, fixing the tip at the start of the aorta, and connecting it to a pressure transducer (Nippon Density TP-200T). The heart rate was measured by driving an instantaneous heart rate monitor by the R wave of the electrocardiogram. All records were shown on a thermographic recorder (Japanese Electronic WT-685G). Administration was carried out in a cannula inserted into the right femoral vein. In addition, nicorandil was used as a reference drug. For each measurement item, the maximum change rate against compound number (13) and just before administration of nicorandil was obtained.

(2) results

The test results of the compound number (13) and nicorandil are shown in the following table.

Reference Example 1-8 Action on the Circulatory State by the Nasal Gallbladder (Intraduodenal)

(1) test method

Aortic pressure, heart rate, and blood flow rate of non-eagle dogs anesthetized with pentobarbital were measured as described in 1-7 above, and the aortic blood flow rate was set with a blood flow probe at the beginning of the aorta, Number 13)). For administration, the dog was abdominalized, and the neratone chip was inserted into the duodenum, and compound number 13 (100 µg / kg) was administered thereto. The maximum rate of change for each measurement item immediately before administration was measured over time. Total peripheral vascular resistance was calculated by dividing the mean aortic pressure by the sum of the perfusion and the aortic blood flow.

(2) results

The change over time of intraduodenal administration of Compound No. 13 (100 μg / kg) is shown in the following table.

Reference Example 1-9 Effects on Periodic Contraction of Coronary Samples of Isolated Dogs by 3,4-Diaminopyridine

(1) test method

It is known that seizures of dysentery cardiac disease often occur periodically, with spasm of the coronary arteries. When 3,4-diaminopyridine (hereinafter referred to as 3,4-DAP) is applied to the coronary artery in vitro, it causes periodic contraction, and this cycle is known to coincide with the seizure cycle of heterophagia (脈). See Gwan-gwan, vol. 24, p. 133, 1984).

The effect on the periodic contraction by 3,4-DAP of the inventive compound was tested using an isolated canine artery (test compound; N-cyano-N '-(2-nitroethylethyl) -3-pyridinecarboxy) Imidamide (Compound No. 13)). Beagle dogs were bled into the total carotid artery under anesthesia with pentobarbital. The coronary artery was removed and rounded to a width of 3 mm in a Krebs-ringgel solution under oxygen to prepare a specimen. The sample is suspended in an engine bath filled with 37 ° C Krebs-ring gel fluid with a 95% O ₂ -5% CO ₂ mixed gas, and an FD peak pressure (TB-611T) and strain amplifier (AP) -621G) isotropic shrinkage was recorded on a pen writing recorder (FBR-252A). After loading of 1 g of static tension to stabilize the specimen, 3,4-DAP (10 ^-2 M) was applied, and after the periodic contraction in the specimen became constant, the compound number 13 was accumulated cumulatively. It was added to the bath to measure the cyclic contraction inhibitory action.

(2) results

The inhibitory effect of compound No. 13 on the periodic contraction of the canine artery by 3,4-DAP is shown in FIG.

Reference Example 1-10 Actions on Vasopressin-Induced Rat Angina Model

(1) test method

Administration of vasopressin intravenously in rats is known to cause myocardial ischemia with ST drop on ECG. This phenomenon is very similar to the clinically visible seizure of heteroangular angina (see Japanese Journal of Pharmacology, Volume 20, page 313, 1980). The effect of the compound of the present invention on this type angina model was examined. A male rat of 200-500 g body weight was anesthetized with urethane-α-chlorarose (1 g / kg-25 mg / kg intraperitoneally), followed by administration of a test compound (100 µg / kg) into the femoral vein. Two minutes later 1.0 IU / kg vasopressin was administered in the same femoral vein. The electrocardiogram was measured by the second induction, and the ST drop change amount (mV) after vasopressin administration was measured.

In addition, nicorandil was used for the reference drug.

(2) results

The action on the vasopressin-induced angina model is shown in FIG.

Reference Example 1-11 Action on Myocardial Inhibition by Reperfusion Following Ischemia

(1) test method

Cardioprotective action of the compound of the present invention in rat extraction heart No. 13)). This method used the Langendorf loop method as in Reference Example 1-6. The harvested heart was perfused for 30 minutes in the perfusion solution, and then perfused for 10 minutes in the perfusion solution containing compound number (13), and the so-called ischemic state was completely stopped. In addition, ischemic basing was performed. After 25 minutes, reperfusion was started using the original perfusate containing no test compound. After initiation of reperfusion, cardiac function parameters were monitored for 30 minutes, after which the heart was quickly frozen, extracted with perchloric acid and the amount of ATP in myocardial tissue was quantified using high performance liquid chromatography. Nitorandil was used as a reference. The cardiac function recovery rate after reperfusion was determined by adjusting the compound function (13) and nicorandil's preperfusion cardiac function (heart rate * left ventricular pressure) to 100%. The amount of ATP in myocardial tissue was also determined.

(2) results

Cardiac function recovery rate and APT amount in myocardial tissue are shown in the following table.

(Mean ± S.D.)

** p 0.01 Comparison with saline group (Student's t-test)

Reference Example 1-12 Effects on the Lower Arteries of the Isolated Open Brain

(1) Test method

Beagle dogs were bled from the total jugular vein under pentobarbital anesthesia. The basal artery was removed, the adipose connective tissue was carefully removed under a stereoscopic microscope in a crab-ring gel solution under oxygen, and rounded to a width of 3.5 mm to prepare a specimen. The specimen is suspended in an engine bath filled with 37 ° C. Krems-ringgel fluid, vented with 95% O ₂ -5% CO ₂ mixed gas.

Loading a stop 0.5g tension, and then stabilize the tension of the sample, by applying a view of the discussion in the sample A ₂ acid derivative U46619 (16-7) increased the tension of the specimen. After constant developmental tension, the compound of the present invention was added cumulatively to the inside of the organ bath to relax the specimen (Test compound: N-cyano-N '-(2-nitroethylethyl) -3-pyridinecarboximime Damid (compound number 13)). The relaxation reaction was determined as the inhibition rate by setting the generating tension by U46619 to 100%.

(2) results

The dose-action curve of the relaxation of compound No. (13) is shown in FIG.

Reference Example 1-13 Action on Hypoxic Load Conditions

(1) test method

The action of the compound of the present invention on the hypoxic load state using ddY male rat (4th week) is number 13)). The rats were placed in a constant pressure vessel and the 96% N ₂ -4% O ₂ mixed gas was vented at 5 L / min. The time from the start of aeration to the respiratory stop state (survival time (seconds)) was measured. The test compound was a 2% gum arabic suspension, administered orally 30 minutes before the aeration of the mixed gas, and the arabic rubber suspension as a control. Only dose was administered.

(2) results

The survival time of the control group for the control group and the compound number (13) is shown in the following table.

** p 0.001 (Student's t-test)

Reference Example 1-14 Platelet Aggregation Inhibitory Activity

(1) Test method

The platelet aggregation inhibitory effect of the compound of the present invention was tested using platelets from dogs (test compound: N-cyano-N '-(2-nitroethylethyl) -3-pyridinecarboximidamide (Compound No. 13)). Blood was collected from the vein of the Beagle dog's anterior leg (blood 9: 3.8% citric acid 1), centrifuged at 1050 rpm for 10 minutes, and the supernatant was collected with platelet-rich plasma (PRP). The precipitate was further centrifuged at 300 rpm for 15 minutes to obtain supernatant as low platelet plasma (PPP). PRP was diluted with PPP such that platelet count was 300,000 / ul.

Adenosine diphosphate (ADP) was used as a platelet aggregation inducing substance. 750 µl of prepared PRP was placed in a cuebed, compound No. 13 was added while maintaining a temperature of 37 ° C, and platelet aggregation ability by ADP was observed after 2 minutes. For this measurement, an intracellular calcium measuring apparatus (日本 minute light CAF-100) capable of measuring platelet aggregation ability was used.

(2) results

The platelet aggregation inhibitory effect of Compound No. (13) is shown in FIG. This figure briefly shows the up and down vibration state.

Reference Example 1-15 Extraction Mormot Organ Expansion

(1) test method

The organ smooth muscle relaxation effect of the compound of the present invention was tested using an extraction mormot organ. (Test compound: N-cyano-N '-(2-nitroethylethyl) -3-pyridinecarboximidamide (Compound No. 13) ). Body weight 250g Heart-ley male mormorts were bleeded, and organs were removed, connective tissue was removed from Krebs-ringgel solution, and a spiral specimen was prepared. The specimens were suspended in an engine bath filled with 37 ° C. Krebs-ring gel fluid vented with 95% O ₂ -5% CO ₂ mixed gas.

After 0.5 g of static tension was loaded and the tension of the specimen was stabilized, the nutrient solution of tension was exchanged in the tracheal bath containing 40 mM KCl, and the tension of the specimen was increased. After constant development of KCl, compound No. 13 was added cumulatively into the organ bath to relax the specimen.

Relaxation reaction was calculated from the inhibition rate of KCl as 100%.

(2) results

The organ smooth muscle relaxation effect of compound No. (13) is shown in FIG.

Reference Example 10-16 Acute Toxicity

Acute toxicity upon oral administration of the compound of the present invention using ddY male rats (4 weeks old) is 13)). As a result, the LD ₅₀ value was about 400 mg / kg.

EXAMPLE

Example 1-1

N-cyano-N '-(2-nitoxyethyl) -3-pyridinecarboximidamide (additional method)

a. 2-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in methanol (50 mL), sodium methoxide (0.26 Gg, 4.8 mmol) was added, and the mixture was allowed to react at room temperature for 6 hours. After the reaction was completed, acetic acid (0.32 g, 5.3 mmol) was added to neutralize the reaction solution, and the resultant was concentrated under reduced pressure. Diethyl ether (50 mL) was added to the concentrated residue, and diethyl ether insolubles were filtered off, and the filtrate was concentrated under reduced pressure to obtain 7.5 g of methyl = 2-pyridinecarboxyimitate crude product as a dark yellow oil. Subsequently, phosphate buffer (pH 5.4, 70 ml) of cyanamide (4.64 g, 110 mmol) and Na ₂ HPO ₄ (7.81 g, 55 mmol) and NaH ₂ PO ₄ .2H ₂ O (34.3 g, 220 mmol) was added to the oil. Was added and stirred vigorously for 4 hours at room temperature. After the reaction, the mixture was extracted with dichloromethane (100 ml * 3 times), and the dichloromethane layer was dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 40 g), eluted with nucleic acid: diethyl ether (1: 2), and crystallized as dichloromethane / diethyl ether to give methyl = N-sia. No-2-pyridinecarboxyimidate (8.81 g, 54.7 mmol, yield 57%) was obtained as colorless needles.

Physicochemical Properties of Methyl-N-cyano-2-pyridinecarboxyimidate

Melting Point: 81.0 ~ 81.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2220, 1640, 1570, 1340

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (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 = 3.4 Hz), 7.63 (1H, dd, J = 7.3, 9.4 Hz), 4.16 (3H, s).

b. Methyl = N-cyano-2-pyridinecarboximidate (0.05 g, 3.1 mmol) is dissolved in methanol (5 mL), 2-nitoxyethylamine nitrate (0.57, 3.4 mmol) is added, and sodium Methoxide (0.28 g, 3.4 mmol) was added in small portions and stirred at room temperature for 10 minutes. After the reaction, the reaction solution was concentrated under reduced pressure and extracted with dichloromethane (50 mL * 3 times). The dichloromethane layer was concentrated under reduced pressure after dehydration of anhydrous sodium sulfate. The concentrated residue was crystallized as dichloromethane / diethyl ether to give the title compound (0.44 g, 0.20 mmol, yield 63%) as colorless needles.

Physicochemical Properties of N-Cyano- (2-nitroethylethyl) -2-pyridinecarboxyimidamide

Melting Point: 53.5 ~ 54.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3280, 2180, 1640, 1630, 1600, 1580, 1560, 1290

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.73 (1H, brd, J = 3.4Hz), 8.3 ~ 7.9 (2H, m), 4.77 (2H, t, J = 5.5 Hz), 3.92 (2H, t, J = 5.5 Hz)

Elemental Analysis:

Calculated 45.96 3.86 29.78

Found 45.68 3.76 30.12 (%)

(C ₉ H ₉ N ₅ O ₃ )

Example 1-2

Preparation of N-cyano-N '-(2, 2-dimethylpropyl) -2-pyridinecarboxyimidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 mL), 2, 2-dimethylpropylamine (0.30 g, 3.4 mmol) was added, and 30 at room temperature was added. Stirred for a minute. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized from dichloromethane / diethyl ether to give the title compound (0.63 g, 2.9 mmol, yield 94%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(2, 2-dimethylpropyl) -2-pyridinecarboximidamide

Melting Point: 109-109.8 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3260, 2970, 2190, 1600, 1580, 1560

Nuclear Magnetic Resonance Spectrum: (100MHz, CD ₃ Cl ₃ increase) δ (ppm) 8.7 ~ 8.5 (3H, m), 8.00 ~ 7.80 (1H, m), 7.6 ~ 7.4 (1H, m), 3.58 (2H, d , J = 6.7 Hz), 1.05 (9H, s).

Elemental Analysis:

Calculation 66.64 7.46 25.90

Found 66.41 7.58 25.72 (%)

(C ₁₂ H ₁₆ N ₄ )

Example 1-3

Preparation of N-cyano-N '-(1, 2, 2-trimethylpropyl) -2-pyridinecarboxyimidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (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 room temperature Stir for 30 minutes. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized from dichloromethane / diethyl ether to give the title compound (0.67 g, 2.9 mmol, yield 92%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(1, 2, 2-trimethylpropyl) -2-pyridinecarboximidamide

Melting Point: 109-109.8 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3230, 3100, 2960, 2180, 1590, 1580, 1560

Nuclear Magnetic Resonance Spectrum: (100MHz, in CD3OD) δ (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 = 7.2 Hz), 1.03 (9H, s).

Elemental Analysis:

Calculation 67.80 7.88 24.33

Found 67.51 7.97 24.25 (%)

(C ₁₃ H ₁₈ N ₄ )

Example 1-4

Preparation of N-cyano-N'-phenyl-2-pyridinecarboxyimidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 mL), aniline (0.32 g, 3.4 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. After the reaction, the concentrated residue obtained by concentrating the reaction solution under reduced pressure was crystallized with dichloromethane / diethyl ether to give the title compound (0.63 g, 2.8 mmol, yield 91%) as colorless needles.

Physicochemical Properties of N-Cyano-N'-phenyl-2-pyridinecarboxyimidamide

Melting Point: 103.0 to 104.0 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1620, 1610, 1580, 1560

Nuclear magnetic resonance spectra: (100 MHz, in CD ₃ OD) δ (ppm) 8.80 (1H, brs), 8.4 to 8.0 (2H, m), 7.9 to 7.2 (6H, m).

Elemental Analysis:

Calculated 70.26 4.54 25.21

Found 70.09 4.97 25.14 (%)

(C ₁₃ H ₁₀ N ₄ )

Example 1-5

Preparation of N-cyano-N '-(4-methoxyphenyl) -2-pyridinecarboxyimidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (1.50 g, 3.1 mmol) was dissolved in methanol (10 mL), 4-methoxyaniline (0.36 g, 3.4 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Stirred. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized with dichloromethane / diethyl ether to give the title compound (0.74 g, 2.9 mmol, 94% yield) as colorless needles.

Physical Properties of N-Cyano-N '-(4-methoxyphenyl) -2-pyridinecarboxyimidamide

Melting Point: 116.5 ~ 117.2 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3.80, 2190, 1590, 1550, 1520, 1250

Nuclear Magnetic Resonance Spectrum: (100MHz, in CD3OD) δ (ppm) 8.77 (1H, brd, 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, brd, J = 10.3 Hz), 3.83 (3H, s).

Elemental Analysis:

Calculation 66.66 4.79 22.21

Found 66.41 4.83 22.12 (%)

(C ₁₄ H ₁₂ N ₄ O)

Example 1-6

Preparation of N-cyano-N '-(4-methylbenzyl) -2-pyridinecarboximidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (0.30 g, 1.9 mmol) was dissolved in methanol (10 mL), p-methylbenzylamine (0.25 g, 2.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. It was. After the reaction, the concentrated residue obtained by concentration under reduced pressure was crystallized with diethyl ether to give the title compound (0.41 g, 1.6 mmol, yield 91%) as a colorless needle.

Physical Properties of N-Cyano-N '-(4-methylbenzyl) -2-pyridinecarboxyimidamide

Melting Point: 104.2 to 104.8 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1600, 1570

Nuclear Magnetic Resonance Spectrum: (100Hz, in CDCl) δ (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 = 7.3 Hz), 2.37 (3H, s).

Elemental Analysis:

Calculated 71.98 5.64 22.38

Found 71.87 5.59 22.11 (%)

(C ₁₅ H ₁₄ N ₄ )

Example 1-7

Preparation of N-cyano-N '-(4-chlorobenzyl) -2-pyridinecarboxyimidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 mL), 4-chlorobenzylamine (0.48 g, 3.4 mmol) was added, and the mixture was stirred at room temperature for 5 hours. It was. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized with diethyl ether to obtain the title compound (0.13 g, 0.5 mmol, yield 16%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(4-chlorobenzyl) -2-pyridinecarboximidamide

Melting Point: 93.5 ~ 94.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1610, 1560

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCL) δ (ppm) 8.75 ~ 8.55 (2H), 7.92 (1H, dt, J = 2.4, 7.5Hz), 7.70 (1H, dd, J = 5.1, 7.5Hz), 7.36 (4H, s), 4.85 (2H, d, J = 6.8 Hz)

Elemental Analysis:

Calc 62.11 4.10 20.70

Found 65.08 4.00 20.43

(C ₁₄ H ₁₁ N ₄ Cl)

Example 1-8

Preparation of N-cyano-N '-[4- (trifluoromethyl) benzyl] -2-pyridinecarboxyimidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (0.30 g, 1.9 mmol) was dissolved in methanol (10 mL) and 4- (trifluoromethyl) benzylamine (0.36 g, 2.1 mmol) was added, Stir at room temperature for 30 minutes. After the reaction, the residue was concentrated under reduced pressure, and the residue was crystallized with diethyl ether to obtain the title compound (0.47 g, 1.5 mmol, yield 84%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-[4- (trifluoromethyl) benzyl] -2-pyridinecarboxyimidamide

Melting Point: 127.0-127.2 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1570, 1330

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDC ₃ ) δ (ppm) 8.80 ~ 8.55 (2H), 7.92 (1H, dt, J = 2.7, 7.2Hz), 7.70 ~ 7.40 (5H), 4.92 (2H, d, J = 6.1z)

Elemental Analysis:

Calculated 59.21 3.64 18.41

Analysis 59.15 3.63 18.15 (%)

(C ₁₅ H ₁₁ N ₄ F ₃ )

Example 1-9

Preparation of N-cyano-N '-[2- (4-methylphenyl) ethyl] -2-pyridinecarboxyimidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 mL) and 2- (p-tolyl) ethylamine (0.47 g, 3.5 mmol) was added to room temperature. Stirred for 1 hour. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized with methylol / diethyl ether to give the title compound (0.76 g, 2.9 mmol, 93% yield) as colorless crystals.

Physicochemical Properties of N-cyano-N '-[2- (4-methylphenyl) ethyl] -2-pyridinecarboximidamide

Melting Point: 91.0 to 91.5

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1600, 1580, 1560

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl3) δ (ppm) 8.62 ~ 8.55 (2H), 8.41 (1H, brs), 7.89 (1H, dt, J = 1.8, 7.8Hz), 7.48 (1H, dd, J = 5.2, 7.8 Hz), 7.15 (4H, dd, J = 7.6, 14.0 Hz), 3.97 (2H, brs), 2.99 (2H, t, J = 7.6 Hz).

Elemental Analysis:

Calculated 72.70 6.10 21.20

Category 72.44 5.98 21.01 (%)

(C ₁₆ H ₁₆ N ₄ )

Example 1-10

Preparation of N-cyano-N '-[2- (4-chlorophenyl) ethyl] -2-pyridinecarboximidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 mL), 4-chlorophenethylamine (0.53 g, 3.4 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Stirred. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized with dichloromethane / diethyl ether to give the title compound (0.43 g, 1.5 mmol, yield 49%) as colorless needles.

Physicochemical Properties of N-cyano-N '-[2- (4-chlorophenyl) ethyl] -2-pyridinecarboximidamide

Melting Point: 112.7 ~ 113.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3280, 2170, 1620, 1550, 1440

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl3) δ (ppm) 8.7 ~ 8.3 (3H), 7.90 (1H, m), 7.84 (1H, m), 7.3 ~ 7.1 (4H), 3.95 (2H, q, J = 6.8 Hz), 3.00 (2H, t, J = 6.8 Hz).

Elemental Analysis:

Calculated 63.27 4.60 19.68

Found 63.17 4.71 19.70 (%)

(C ₁₅ H ₁₃ N ₄ Cl)

Example 1-11

Preparation of N-cyano-N '-(2-hydroxy-1-methyl-2-phenylethyl) -2-pyridinegarboxylimidamide stomach (additional method)

Methyl = N-cyano-2-pyridinecarboximidate (0.24 g, 1.5 mmol) was dissolved in methanol (5 mL), and DL-phenylpropanolamine hydrochloride (0.31 g, 1.7 mmol) was used. Viii) and triethylamine (1.17 g, 1.7 mmol) were added and the mixture was stirred at room temperature for 5 hours. After the reaction, the residue obtained by concentrating the reaction solution under reduced pressure was extracted with ethyl acetate (30 ml * 3 times). The ethyl acetate layer was washed with water (100 ml), dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrated residue was crystallized with diethyl ether to give the title compound (0.23 g 0.8 mmol, yield 54%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-hydroxy-1-methyl-2-phenylethyl-2-pyridinecarboxyimidamide

Melting Point: 135.2 ~ 135.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1580, 1560

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 8.68 (1H, d, J = 4.8 Hz), 8.42 (1H, d, J = 8.0 Hz), 7.97 (1H, dt, J = 2.0, 8.0 Hz), 8.57 (1H, dd, J = 5.6, 8.0 Hz), 7.46 (2H, d, J = 7.8 Hz), 7.38 (2H, t, J = 7.8 Hz), 7.29 (1H, t, J = 7.8 Hz), 5.05 (1H, d, J = 3.6 Hz), 4.70 (1H, brs), 1.17 (3H, d, J = 7.64.8 Hz)

Elemental Analysis:

Calculation 68.55 5.75 19.99

Found 68.56 5.66 19.72 (%)

(C ₁₆ H ₁₆ N ₄ O)

Example 1-12

Preparation of N-cyano-N '-(2-thienylmethyl) -2-pyridinecarboxyimidamide (additional method)

Methyl = N-cyano-2-pyridinecarboxyimidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 mL) and 2-thiophene methylamine (0.83 g, 3.4 mmol) was added, followed by 40 minutes at room temperature. Stirred. After the reaction, the concentrated residue obtained by concentration under reduced pressure was crystallized with dichloromethane / diethyl ether to give the title compound (0.40 g, 1.7 mmol, yield 54%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-thienylmethyl) -2-pyridinecarboximidamide

Melting Point: 87.0 ~ 88.0 ℃

Melting Point: 135.2 ~ 135.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1580, 1560

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 8.72 (1H, brs), 8.60 (1H, d, J = 4.0Hz), 8.51 (1H, brs), 7.93 (1H, t, J = 8.6 Hz), 7.52 (1H, dd, J = 5.1, 8.6 Hz), 7.52 (1H, dd, J = 5.1, 8.6 Hz), 7.31 (1H, d, J = 4.9 Hz), 7.14 (1H, d, J = 3.4 Hz), 7.02 (1H, doublet of doublets, J = 3.7, 5.4 Hz), 5.05 (2H, s).

Elemental Analysis:

Calculated 59.49 4.16 23.12

Found 59.76 4.14 23.21 (%)

(C ₁₂ H ₁₀ N ₄ S)

Example 1-13

Preparation of N-cyano-N '-(2-nitoxyethyl) -3-pyridinecarboxyimidamide (additional method)

a. 3-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in isopropanol (50 mL), and sodium hydride (0.23 g, 9.6 mmol) from which oil was removed by ether washing was added, followed by stirring 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 resultant was concentrated under reduced pressure. After concentration, diethyl ether (80 ml) was added to the residue, the insolubles were separated by filtration, the filtrate was concentrated under reduced pressure, and nucleic acid (80 ml) was added to the concentrate to precipitate the unreacted 3-cyano. After pyridine was separated by filtration, the nucleic acid solution was concentrated under reduced pressure to obtain 5.68 g of a crude product of isopropyl = 3-pyridinecarboxyimidate as a pale yellow oil.

Next, phosphoric acid of cyanamide (2.91 g, 69.2 mmol) and Na ₂ HPO ₄ (4.91 g, 34.6, mmol) and Na ₂ H ₂ PO ₄ .2H ₂ O (21.59 g, 138.4, mmol) was added to the oil. Buffer (pH, 5.4, 4.30 mL) was added and stirred at room temperature for 6 hours. After the reaction, the reaction solution was extracted with dichloromethane (100 ml * 3 times), the dichloromethane layer was dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 250 g), and eluted with nucleic acid: diethyl ether (1: 2). The eluted fractions were concentrated to give isopropyl = N-cyano-3-pyridinecarboxyimitate (4.84 g, 25.6 mmol, yield 26%) as pale yellow oil.

Physicochemical Properties of Isopropyl = N-cyano-3-pyridinecarboxyimidamide

Infrared absorption spectrum: (cm ^-1 , neat) 3240, 2250, 2180, 1610, 1380, 1310, 1100,

Nuclear Magnetic Resonance Spectrum: (100 MHz, in CDCl ₃ ) δ (ppm) 9.15 (1H, d, J = 2.6 Hz), 8.83 (1H, dd, J = 1.7 Hz), 8.48 (1H, ddd, J = 1.7, 2.6, 8.1 Hz), 7.50 (1H, dd, J = 4.9, 8.1 Hz), 5.42 (1H, m, J = 7.2 Hz), 1.48 (6H, d, J = 7.2 Hz).

b. Isopropyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), 2-nitoxyethylamine nitrate (0.49, 2.9 mol) and sodium meroxide (0.16 g) , 2.9 mmol) was added and stirred at room temperature for 10 minutes. After the reaction, the reaction solution was concentrated under reduced pressure and extracted with dichloromethane (50 mL * 3 times). The dichloromethane layer was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained concentrate was crystallized from dichloromethane / diethyl ether to give the title compound (0.48 g, 2.1 mmol, yield 79%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(2-nitroethylethyl) -3-pyridinecarboximidamide

Melting Point: 99.5-100.2 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2181, 1640, 1590, 1280

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ ) δ (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, 7.9 Hz), 4.72 (2H, t, J = 4.9 Hz), 3.84 (2H, t, J = 4.9 Hz).

Elemental Analysis:

Calculated 45.96 3.86 29.78

Found 45.77 3.78 30.01 (%)

(C ₉ H ₉ N ₅ O ₃ )

Example 1-14

Preparation of N-cyano-N '-(3-nitoxypropyl) -3-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), 2-nitoxypropyl nitrate (0.53 g, 2.9 mmol) and sodium methoxide (0.16 g) , 2.9 mmol) was added and stirred at room temperature for 18 hours. After the reaction, the residue obtained by concentrating the reaction solution under reduced pressure was extracted with chloroform (30 ml * 3 times). The chloroform layer was washed with water (100 mL), dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure.

The obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 30 g), and eluted with chloroform: methanol (60: 1). The eluted fractions were concentrated under reduced pressure, and then crystallized with methanol / diethyl ether to obtain the title compound (0.26 g, 1.0 mmol, yield 39%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(3-nitropropyl) -3-pyridinecarboximidamide

Melting Point: 124.9-125.8 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1620, 1600, 1560, 1280

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (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 = 6.0 Hz), 3.61 (2H, t, J = 6.0 Hz), 2.14 (2H, quint, J = 6.0 Hz).

Elemental Analysis:

Calculation 48.19 4.45 28.10

Found 48.16 4.29 27.93 (%)

(C ₁₉ H ₁₁ N ₅ O ₃ )

Example 1-15

Preparation of N-cyano-N '-(3, 3-dimethylbutyl) -3-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 mL), and 3,3-dimethylbutylamine (0.36 g, 3.6 mmol) was added at room temperature. Stir for 30 minutes. After the reaction, the reaction solution was concentrated and the concentrate was crystallized with dichloromethane / diethyl ether to give the title compound (0.46 g, 2.0 mmol, yield 63%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(3, 3-dimethylbutyl) -3-pyridinecarboximidamide

Property

Melting Point: 168.0 to 168.2 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3250, 2970, 2190, 1590, 1560, 720

Nuclear magnetic resonance spectrum: (100 MHz, in CDCl ₃ ) δ (ppm) 8.70 (2H, m), 7.96 (1H, d, J = 8.6 Hz), 6.88 (1H, brs), 3.50 (2H, m), 1.58 (2H, m), 1.00 (9H, s).

Elemental Analysis:

Calculation 67.80 7.88 24.32

Found 67.69 7.95 24.36 (%)

(C ₁₃ H ₁₈ N ₄ )

Example 1-16

Preparation of N-cyano-N '-(4-methylphenyl) -3-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL), 4-methylaniline (0.31 g, 2.9 mmol) was added and stirred at room temperature for 30 minutes. It was. After the reaction, the residue was concentrated under reduced pressure, and the residue was crystallized with dichloromethane / diethyl ether to obtain the title compound (0.56 g, 2.4 mmol, yield 90%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(4-methylphenyl) -3-pyridinecarboxyimidamide

Melting Point: 202.5 ~ 203.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3200, 2180, 1580, 1550, 7100

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.86 (1H, s), 8.78 (1H, brs), 8.18 (1H, brs), 7.60 (3H, brs), 7.22 ( 2H, m), 2.39 (3H, s).

Elemental Analysis:

Calculated 71.17 5.12 23.71

Found 71.06 5.15 23.65 (%)

(C ₁₄ H ₁₂ N ₄ )

Example 1-17

Preparation of N-cyano-N'-benzyl-3-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL), benzylamine (0.31 g, 2.9 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized with methanol / diethyl ether to give the title compound (0.44 g, 1.8 mmol, yield 72%) as colorless needles.

Physical Properties of N-Cyano-N'-benzyl-3-pyridinecarboxyimidamide

Melting Point: 104 ~ 104.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3230, 3100, 2170, 1580, 1550, 710

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₂ OD) δ (ppm) 8.70 (2H, brs), 8.08 (1H, dt, J = 2.9, 7.9Hz), 7.50 (1H, dd, J = 4.8 , 7.9 Hz), 7.35 (5H, s), 4.62 (2H, t, J = 3.4 Hz).

Elemental Analysis:

Calculated 71.17 5.12 23.71

Found 71.00 5.16 23.62 (%)

(C ₁₄ H ₁₂ N ₄ )

Example 1-18

Preparation of N-cyano-N '-(4-methylphenyl) -3-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 mL), 4-methylbenzylamine (0.35 g, 2.9 mmol) was added, and 30 minutes at room temperature. Stirred. After the reaction, the concentrated residue obtained by concentration under reduced pressure was crystallized with diethyl ether to obtain the title compound (0.06 g, 2.4 mmol, yield 91%) as colorless powder.

Physicochemical Properties of N-Cyano-N '-(4-methylphenyl) -3-pyridinecarboxyimidamide

Melting Point: 150.0 ~ 105.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3270, 2180, 1580, 1560

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (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).

Elemental Analysis:

Calculated 71.98 5.64 22.38

Found 71.72 5.78 22.24 (%)

(C ₁₅ H ₁₄ N ₄ )

Example 1-19

Preparation of N-cyano-N '-(4-methoxybenzyl) -3-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL), 4-methoxybenzylamine (0.40 g, 2.9 mmol) was added to form 40 at room temperature. Stirred to min. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized with methanol / diethyl ether to obtain the title compound (0.50 g, 2.1 mmol, yield 80%) as colorless powder.

Physicochemical Properties of N-Cyano-N '-(4-methoxybenzyl) -3-pyridinecarboximidamide

Melting Point: 160.5 ~ 162.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3230, 1590, 1550, 1510, 1250

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.73 (2H, m), 8.08 (1H, m), 7.58 (1H, m), 7.32 (2H, d, J = 9.2 Hz), 6.91 (2H, d, J = 9.2 Hz), 4.59 (2H, s).

Elemental Analysis:

Calculated 67.65 5.30 21.04

Found 67.88 5.28 21.04 (%)

(C ₁₅ H ₁₄ N ₄ O)

Example 1-20

Preparation of N-cyano-N '-(4-dimethylamibenzyl) -3-pyridinecarboximidamide (the easy method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 mL), and hydrochloric acid p-dimethylaminobenzylamine (0.65 g, 2.9 mmol) and triethylamine (0.64 g, 6.4 mmol) was dissolved in methanol (5 mL) and added and stirred at room temperature for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (50 mL * 3 times). The ethyl acetate layer was washed with water (50 ml), dehydrated with sodium sulfate, and then concentrated under reduced pressure. The obtained concentrated residue was provided on silica gel column chromatography (Waco gel C-200, 60 g), and eluted with chloroform: methanol (100: 1). The eluted fractions were concentrated under reduced pressure, and then crystallized with methanol / diethyl ether to obtain the title compound (0.63 g, 2.3 mmol, yield 85%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(4-dimethylamibenzyl) -3-pyridinecarboxyimidamide

Melting Point: 148.8 ~ 152.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1580, 1550, 1530

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.70 (1H, m), 8.06 (1H, m), 7.57 (1H, dd, J = 5.2, 7.5Hz), 7.25 ( 2H, d, J = 9.2 Hz). 6.76 (2H, d, J = 9.2 Hz), 4.53 (2H, s), 2.92 (6H, s).

Elemental Analysis:

Calculation 68.80 6.13 25.07

Found 68.56 6.09 24.97 (%)

(C ₁₆ H ₁₇ N ₅ )

Example 1-21

Preparation of N-cyano-N '-[4- (trifluoromethyl) benzyl] -3-pyridinecarboxyimidamide

Isopropyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL) and 4- (triple solmethyl) benzylamine (0.51 g, 2.9 mmol) was dissolved. Add and stir at room temperature for 1 hour. After the reaction, the residue obtained by concentrating the reaction solution under reduced pressure was crystallized with diethyl ether to obtain the title compound (0.53 g, 1.7 mmol, 66% yield) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-[4- (trifluoromethyl) benzyl] -3-pyridinecarboxyimidamide

Melting Point: 202.5 ~ 203.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2170, 1590, 1580, 1580, 1330

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.80 ~ 8.70 (2H), 8.11 (1H, d, J = 7.8Hz), 7.75 ~ 7.40 (5H), 4.70 (2H, s).

Elemental Analysis:

Calculated 59.21 3.64 18.41

Found 59.14 3.62 18.17 (%)

(C ₁₅ H ₁₁ N ₄ F ₃ )

Example 1-22

Preparation of N-cyano-N '-(4-chlorobenzyl) -3-pyridinecarboximidamide (additional method)

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 for 1.5 hours at room temperature. Was stirred. After the reaction, the concentrate of the reaction solution was concentrated under reduced pressure, and the obtained concentrate was crystallized with methanol / diethyl ether to obtain the title compound (0.65 g, 2.4 mmol, yield 91%) as colorless powder.

Physicochemical Properties of N-cyano-N '-(4-chlorobenzyl) -3-pyridinecarboximidamide

Melting Point: 163.5 ~ 166.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3250, 2180, 1580, 1550

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (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).

Elemental Analysis:

Calc 62.11 4.10 20.70

Found 61.94 4.11 20.65 (%)

(C ₁₄ H ₁₁ N ₄ Cl)

Example 1-23

Preparation of N-cyano-N '-(4-nitrobenzyl) -3-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 mL), hydrochloric acid-p-nitrobenzylamine (0.55 g, 2.9 mmol) and triethylamine ( 0.32 g, 3.2 mmol) was added dissolved in methanol (5 mL) and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure and crystallized with methanol / diethyl ether to obtain the title compound (0.70 g, 2.5 mmol, yield 95%) as colorless powder.

Physicochemical Properties of N-Cyano-N '-(4-nitrobenzyl) -3-pyridinecarboximidamide

Melting Point: 206.2 to 207.5 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1580, 1550, 1520, 1350, 1340

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl3-CD3OD) δ (ppm) 8.83 (2H, m), 8.4 ~ 8.0 (3H), 7.8 ~ 7.5 (3H), 4.75 (2H, d, J = 6.2Hz)

Elemental Analysis:

Calculated 59.78 3.94 24.90

Found 59.50 4.06 24.88 (%)

(C ₁₄ H ₁₁ N ₅ O)

Example 1-24

Preparation of N-cyano-N '-(3, 4-dichlorobenzyl) -3-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL) and 3,4-dichlorobenzylamine (0.51 g, 2.9 mmol) was added to add 3 at room temperature. Stir for hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized with diethyl ether to obtain the title compound (1.42 g, 1.4 mmol, yield 52%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(3, 4-dichlorobenzyl) -3-pyridinecarboxyimidamide

Melting Point: 149.5 ~ 150.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2170, 1590, 1550

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.75 ~ 8.72 (2H), 8.11 (1H, dt, J = 2.0, 8.2Hz), 7.54 (1H, dd, J = 5.2 , 8.2 Hz), 7.48 (1H, d, J = 2.0 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.25 (1H, dd, J = 2.0, 8.4 Hz), 4.60 (2H, s).

Elemental Analysis:

Calculated 55.10 3.30 18.36

Found 54.99 3.01 18.09 (%)

(C ₁₄ H ₁₀ N ₄ Cl ₁₃ )

Example 1-25

Preparation of N-cyano-N '-[3,5-bis (trifluoromethyl) benzyl] -3-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL) and 3, 5-bis (trifluoromethyl) benziamine (0.71 g, 2.9 mmol) ) Was added and stirred for 1 hour at room temperature. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized with diethyl ether to give the title compound (0.34 g, 0.91 mmol, yield 35%) as colorless crystals.

Physicochemical Properties of N-cyano-N '-[3,5-bis (trifluoromethyl) benzyl] -3-pyridinecarboximidamide

Melting Point: 172.0 to 172.1 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1580, 1280, 1180, 1120

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (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, 8.2 Hz), 4.77 (2H, s).

Elemental Analysis:

Calculated 51.64 2.71 15.05

Found 51.49 2.56 14.95 (%)

(C ₁₄ H ₁₀ N ₄ F ₆ )

Example 1-26

Preparation of N-cyano-N '-(3-benzyloxybenzyl) -3-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.30 g, 1.6 mmol) was dissolved in methanol (10 mL) and 3-benzyloxybenzylamine (0.41 g, 1.9 mmol) was added at room temperature to 2 Stir for hours. After the reaction, the concentrated residue obtained by concentrating the reaction solution under reduced pressure was provided in silica gel column chromatography (Wakogel C-200, 30 g). Chloroform: eluted with methanol (100: 1), and the eluted fraction was concentrated under reduced pressure, and then crystallized with methanol / diethyl ether to obtain the title compound (0.48 g, 1.4 mmol, yield 88%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(3-benzyloxybenzyl) -3-pyridinecarboximidamide

Melting Point: 122.0 ~ 122.2 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2170, 1590

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl3) δ (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, doublet, J = 5.8 Hz).

Elemental Analysis:

Calc 73.67 5.30 16.36

Found 73.54 5.19 16.11 (%)

(C ₂₁ H ₁₈ N ₄ O)

Example 1-27

Preparation of N-cyano-N '-(2-phenylethyl) -3-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL), 2-phenylethylamine (0.35 g, 2.9 mmol) was added and 40 minutes at room temperature. Stirred. After the reaction, the concentrated residue obtained by concentrating the reaction solution under reduced pressure was crystallized with methanol / diethyl ether to obtain the title compound (0.45 g, 1.8 mmol, yield 68%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(2-phenylethyl) -3-pyridinecarboxyimidamide

Melting Point: 149.5 ~ 150.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3220, 3120, 2180, 1590, 1550, 710

Nuclear Magnetic Resonance Spectrum: (in 100MHz, CDCl ₃ -CD ₃ OD) δ (ppm) 8.70 (1H, dd, J = 2.0, 5.1Hz0, 8.61 (1H, dd, J = 1.0, 2.4Hz), 8.00 (1H , ddd, J = 2.0, 2.4, 8.2 Hz), 7.50 (1H, ddd, J = 1.0, 5.1, 8.2 Hz), 7.26 (5H, brs), 3.74 (2H, t, J = 7.8 Hz), 2.98 ( 2H, t, J = 7.8 Hz).

Elemental Analysis:

Calculation: 71.98 5.64 22.38

Analytical Value: 71.70 5.68 22.30 (%)

(C ₁₅ H ₁₄ N ₄ )

Example 1-28

Preparation of N-cyano-N '-[2- (2-methoxyphenyl) ethyl] -3-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (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. Add and stir at room temperature for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was provided on silica gel column chromatography (Wakogel C-200, 30 g), and eluted with chloroform: methanol (100: 1). The eluted fractions were concentrated under reduced pressure, and then crystallized with chloroform / hexane to give the title compound (0.56 g, 1.8 mmol, yield 68%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-[2- (2-methoxyphenyl) ethyl] -3-pyridinecarboximidamide

Melting Point: 123.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2170, 1580, 1550

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 8.76 (1H, d, J = 4.4Hz), 8.63 (1H, s), 8.03 (1H, d, J = 4.4, 9.6Hz), 7.44 (1H, dd, J = 4.4, 9.6 Hz), 7.28 (1H, t, J = 8.7 Hz), 7.19 (1H, d, J = 8.7 Hz), 6.98 (1H, t, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 6.70 (1H, brs), 3.82 (3H, s), 3.75 (2H, m), 3.03 (2H, t, J = 7.1 Hz).

Elemental Analysis:

Calculation 68.55 5.75 19.99

Found 68.72 5.71 19.91 (%)

(C ₁₆ H ₁₆ N ₄ O)

Example 1-29

Preparation of N-cyano-N '-[2- (2-chlorophenyl) ethyl) -3-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (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. And stirred at room temperature for 7 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The concentrated residue was provided on silica gel column chromatography (Wakogel C-200, 30 g), and eluted with chloroform: methanol (100: 1). The eluted fractions were concentrated under reduced pressure, and then crystallized from methanol / hexane to give the title compound (0.56 g, 2.0 mmol, yield 75%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-[2- (2-chlorophenyl) ethyl] -3-pyridinecarboximidamide

Melting Point: 138.5 ~ 140 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1590

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ -CD ₃ OD) δ (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 = 7.6 Hz), 3.14 (1H, t, J = 7.6 Hz).

Elemental Analysis:

Calculated 63.27 4.60 19.68

Found 63.17 4.64 19.45 (%)

(C ₁₅ H ₁₃ N ₄ Cl)

Example 1-30

Preparation of N-cyano-N '-[2- (4-chlorophenyl) ethyl-3-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (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. And stirred at room temperature for 2.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The concentrated residue was provided on silica gel column chromatography (Wakogel C-200, 50 g), eluted with chloroform: methanol (100: 1), and the elution fraction was concentrated under reduced pressure, and then crystallized with methanol / diethyl ether. Compound (0.71 g, 2.5 mmol, yield 79%) was obtained as a colorless powder.

Physicochemical Properties of N-Cyano-N '-[2- (4-chlorophenyl) ethyl-3-pyridinecarboximidamide

Melting Point: 121.8-122.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr), 3240, 3100, 2180, 1590, 1550, 710

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 8.8 ~ 8.5 (2H), 7.97 (1H, d, J = 9.9Hz), 7.5 ~ 7.7 (5H), 6.70 (1H, brs), 3.78 (2H, q, J = 6.8 Hz), 2.99 (2H, t, J = 6.8 Hz).

Elemental Analysis:

Calculated 63.27 4.60 19.68

Found 63.14 4.68 19.61 (%)

(C ₁₅ H ₁₃ N ₄ Cl)

Example 1-31

Preparation of N-cyano-N '-[2- (4-benzylaminophenyl) ethyl) -3-pyridinecarboximidamide (additional method)

a. Isopropyl = N-cyano-3-pyridinecarboxyimidate (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. And stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was determined by methanol / diethyl ether to obtain (0.088 g, 3.3 of N-cyano-N '-[2- (4-aminophenyl] -3-pyridinecarboxyimide). mmol, yield 63%) was obtained as colorless needles.

Physicochemical Properties of N-Cyano-N '-[2- (4-aminophenyl) ethyl] -3-pyridinecarboximidamide

Melting Point: 154.5 ~ 155.2 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2160, 1580, 1540

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.70 (1H, dd, J = 1.8, 5.4Hz), 8.62 (1H, d, J = 1.8Hz), 8.10 (1H, dt, J = 1.8, 8.6 Hz), 7.51 (1H, dd, J = 5.4, 8.6 Hz), 7.03 (2H, d, J = 8.4 Hz), 6.70 (2H, d, J = 8.4 Hz), 3.67 ( 2H, t, J = 7.4 Hz), 2.87 (2H, t, J = 7.4 Hz).

Elemental Analysis:

Calculation 67.91 5.70 26.40

Found 67.80 5.66 26.17 (%)

(C ₁₅ H ₁₅ N ₅ )

b. N-cyano-N '-[2- (4-aminophenyl) ethyl) -3-pyridinecarboximidamide (0.20 g, 0.75 mmol) was dissolved in methanol (15 mL), and benzoaldehyde (0.12 g, 1.13 mmol) and sodium cyanoborohydride (0.01 g, 1.59 mmol) were added and stirred at room temperature for 2 hours. After the reaction, the residue obtained by concentrating the reaction solution under reduced pressure was extracted with chloroform (50 ml * 3 times). The chloroform layer was washed with water (100 mL), dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrated residue was provided on silica gel column chromatography (waco gel C-200, 50 g) and eluted with chloroform: methanol (100: 1). The eluted fractions were concentrated under reduced pressure, and then crystallized with methanol / diethyl ether to give the title compound (0.12 g, 0.34 mmol, yield 75%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-[2- (4-benzylaminophenyl) ethyl] -3-pyridinecarboximidamide

Melting Point: 131.5 ~ 132.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1590, 1550

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ -CD ₃ OD) δ (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 = 8.2 Hz), 4.32 (2H, s), 3.66 (2H, t, J = 7.4 Hz), 2.86 (2H, t, J = 7.4 Hz).

Elemental Analysis:

Calculated 74.34 5.96 19.70

Found 74.21 6.11 19.48 (%)

(C ₂₂ H ₂₁ N ₅ )

Example 1-32

Preparation of N-cyano-N '-[2- (4-nitrophenyl) -2-nitoxyethyl] -3-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.22 g, 1.2 mmol) was dissolved in methanol (10 mL) and 2- (4-nitrophenyl) -2-nitroethylamine-nitrate (0.40) g, 1.4 mmol) and sodium methoxide (0.41 g, 2.6 mmol) were added and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (100 mL * 3 times). The chloroform layer was washed with water (150 mL), dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 30 g), and eluted with chloroform: methanol (50: 1). The eluted fraction was concentrated under reduced pressure, methanol / diethyl ether, to obtain the title compound (0.13 g, 0.36 mmol, yield 31%) as colorless crystals.

Physicochemical Properties of N-cyano-N '-[2- (4-nitrophenyl) -2-nitoxyethyl] -3-pyridinecarboxyimidamide

Melting Point: 86.5 ~ 89.0 ℃

Infrared absorption spectrum: (cm ^-1 , KBr) 2180, 1640, 1590, 1520, 1380, 1350

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.66 (2H), 8.51 (1H, d, J = 8.1Hz), 8.33 (2H, d, J = 8.7Hz), 8.14 (1H, dd, J = 4.0, 8.7 Hz), 7.69 (2H, d, J = 8.7 Hz), 6.32 (1H, d, J = 3.5, 9.3 Hz), 3.76 (2H, m).

Elemental Analysis:

Calculation 50.57 3.39 23.59

Analysis 50.50 3.49 23.33 (%)

(C ₁₆ H ₁₆ N ₄ )

Example 1-33

Preparation of N-cyano-N '-(3-phenylpropyl) -3-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 mL), 3-pinylpropylamine (0.47 g, 3.5 mmol) was added and 50 minutes at room temperature. Stirred. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 30 g), and eluted with chloroform: methanol (100: 1). The eluted fractions were concentrated under reduced pressure, and then crystallized with methanol / diethyl ether to obtain the title compound (0.67 g, 2.5 mmol, yield 80%) as colorless needles.

Physicochemical Properties of N-Cyano-N '-(3-phenylpropyl) -3-pyridinecarboximidamide

Melting Point: 98.5 ~ 99.1 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3240, 2180, 1590, 1550, 1440, 710

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ ) δ (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 = 7.4 Hz) 1.98 (2H, quint, J = 7.4 Hz).

Elemental Analysis:

Calculated 72.70 6.10 21.20

Found 72.58 6.21 21.17 (%)

(C ₁₆ H ₁₆ N ₄ )

Example 1-34

Production of N-cyano-N'-diphenylmethyl-3-pyridinecarboxyimidamide hydrochloride (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL) and added to aminodiphenylmethane (0.50 g, 2.9 mmol) for 1 hour at room temperature. Stirred. After the reaction, the reaction solution was concentrated under reduced pressure, the obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 40 g), eluted with chloroform: methanol (100: 1), and the elution fraction was concentrated under reduced pressure. Compound (0.48 g, 1.5 mmol, yield 58%) was obtained as a colorless syrup. Subsequently, a 5% hydrogen chloride methanol solution (2 ml) was added to this syrup to dissolve it, and crystallized with methanol / diethyl ether to give N-cyano-N'-diphenylmethyl-3-pyridinecarboximidamide hydrochloride. To a colorless powder.

Physicochemical Properties of N-Cyano-N'-diphenylmethyl-3-pyridinecarboxyimidamide Hydrochloride

Melting Point: 164.0-165.2 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3020, 2180, 1580, 700

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.95 (2H, m), 8.58 (1H, m), 8.00 (1H, m), 7.4 ~ 7.2 (12H), 6350 ( 1H, s).

Elemental Analysis:

Calculation 68.86 4.91 16.23

Found 68.61 5.04 16.15 (%)

_{(C 20 H 16 N 4 ·} HCl)

Example 1-35

Production of N-cyano-N '-(1,2-diphenylmethyl-3-pyridinecarboximidamide hydrochloride (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 mL), added to 1, 2-diphenylethylamine (0.69 g, 3.5 mmol) to room temperature. Stirred for 45 min. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting concentrate was subjected to silica gel column chromatography (Wacogel C-200, 50 g), eluted with chloroform: methanol (100: 1), and the elution fraction was concentrated under reduced pressure to obtain N. -Cyano-N '-(1,2-diphenylmethyl-3-pyridinecarboximidamide (0.60 g, 1.8 mmol, yield 58%) was obtained as a colorless syrup, which was then added to the syrup by 5% hydrogen chloride methanol. A solution (2.5 mL) was added and crystallized with methanol / diethyl ether to obtain N-cyano-N '-(1,2-diphenylmethyl) -3-pyridinecarboximidamide hydrochloride as a colorless powder.

Physicochemical Properties of N-Cyano-N '-(1,2-diphenylmethyl) -3-pyridinecarboxyimidamide Hydrochloride

Melting Point: 140.5 ~ 143.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1570, 700

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (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, 9.6 Hz), 7.4-7.2 (10H), 5.46 (1H, t, J = 8.6 Hz), 3.29 (2H, d, J = 8.6 Hz).

Elemental Analysis:

Calculated 69.51 5.28 15.44

Found 69.32 5.25 15.43 (%)

(C ₂₀ H ₁₈ N ₄ HCl)

Example 1-36

Production of N-cyano-N '-(2,2-diphenylmethyl-3-pyridinecarboximidamide hydrochloride (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL) and added to 2,2-diphenylethylamine (0.58 g, 2.9 mmol) to room temperature. Stirred for 2 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting concentrate was subjected to silica gel column chromatography (Wacogel C-200, 30 g), eluted with chloroform: methanol (100: 1), and the elution fraction was concentrated under reduced pressure to obtain N. -Cyano-N '-(2,2-diphenylmethyl-3-pyridinecarboximidamide (0.61 g, 1.9 mmol, yield 71%) was obtained as a colorless syrup, followed by 5% hydrogen chloride and methanol in this syrup. A solution (2.5 ml) was added and crystallized with methanol / diethyl ether to obtain N-cyano-N '-(2,2-diphenylmethyl) -3-pyridinecarboximidamide hydrochloride as a colorless powder.

Physicochemical Properties of N-Cyano-N '-(2,2-diphenylmethyl) -3-pyridinecarboxyimidamide Hydrochloride

Melting Point: 139.5 ~ 142.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3040, 2170, 1610, 1580, 700

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.94 (1H, d, J = 6.2Hz), 8.70 (1H, s), 8.41 (1H, d, J = 8.6Hz) , 8.08 (1H, doublet of doublets, J = 8.9 Hz), 4.19 (2H, doublet of d, J = 8.9 Hz).

Elemental Analysis:

Calculated 69.51 5.28 15.44

Found 69.19 5.46 15.20 (%)

(C ₂₀ H ₁₈ N ₄ HCl)

Example 1-37

Preparation of N-cyano-N '-(3, 3-diphenylmethyl) -3-pyridinecarboximidamide hydrochloride (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 mL), added to 3, 3-diphenylethylamine (0.74 g, 3.5 mmol) to room temperature. Stirred for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g). Chloroform: eluted with methanol (100: 1), the eluted fraction was concentrated under reduced pressure, and crystallized with methanol / diethyl ether to obtain the title compound (0.68 g, 2.0 mmol, 63% yield) as a colorless powder.

Physicochemical Properties of N-Cyano-N '-(3, 3-diphenylmethyl) -3-pyridinecarboxyimidamide Hydrochloride

Melting Point: 150.9 ~ 151.3 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1590, 1550, 700

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.68 (1H, m), 8.50 (1H, s), 7.82 (1H, d, J = 7.5Hz), 7.4 ~ 7.0 ( 11H), 6.54 (1H, brs), 4.00 (1H, t, J = 8.6 Hz), 3.51 (2H, q, J = 8.6 Hz), 2.43 (2H, q, J = 8.6 Hz)

Elemental Analysis:

Calculated 77.62 5.92 16.46

Found 77.60 5.92 16.43 (%)

(C ₂₂ H ₂₀ N ₄ )

Example 1-38

Preparation of N-cyano-N '-(2-benzyloxy-2-phenylethyl) -3-pyridinecarboximidamide hydrochloride (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (0.20 g, 1.1 mmol) was dissolved in methanol (5 mL) and added to 2-benzyloxy-phenylethylamine (0.26 g, 1.1 mmol) to room temperature. Stirred for 3 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (Wacogel C-200, 20 g), eluted with chloroform: methanol (100: 1), and the elution fraction was concentrated under reduced pressure to obtain N-. Cyano-N '-(2-benzyloxy-phenylethyl) -3-pyridinecarboximidamide (0.24 g, 0.7 mmol, yield 64%) was obtained as a colorless syrup. Subsequently, 5% hydrogen chloride methanol solution (2.5 ml) was added to the syrup, and crystallized with methanol / diethyl ether to give N-cyano-N '-(2-benzyloxy-2-phenylethyl) -3-pyridine. Carboxylimide hydrochloride was obtained as a colorless powder.

Physicochemical Properties of N-Cyano-N '-(2-benzyloxy-2-phenylethyl) -3-pyridinecarboxyimidamide Hydrochloride

Melting Point: 163.0 ~ 165.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2550, 2200, 1710, 1680

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ ) δ (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 = 6.3 Hz).

Elemental Analysis:

Calculated 67.26 5.13 14.26

Found 67.07 4.99 13.97 (%)

_{(C 22 H 20 N 4 ·} HCl)

Example 1-39

Preparation of N-cyano-N '-[2- (3,4-dibenzyloxyphenyl) ethyl] -3-pyridinecarboximidamide hydrochloride (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (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 and stirred at room temperature for 45 minutes. After the reaction, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (100 ml x 3 times). The ethyl acetate layer was washed with water (100 mL), dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained concentrate was subjected to silica gel column chromatography (Wakogel C-200, 50 g) to be eluted with chloroform: methanol (100: 1), and the elution fraction was concentrated under reduced pressure to give N-cyano-N '-[2- ( 3, 4-dibenzyloxyphenyl) ethyl] -3-pyridinecarboxyimidamide (0.13 g, 0.3 mmol), yield 21%) was obtained as a colorless syrup. Subsequently, 5% hydrogen chloride methanol solution (2 ml) was added to this syrup to dissolve it, and crystallized with methanol / diethyl ether to give N-cyano-N '-[2- (3,4-dibenzyloxyphenyl). Ethyl] -3-pyridinecarboximidamide hydrochloride was obtained as a colorless powder.

Physicochemical Properties of N-cyano-N '-[2- (3,4-dibenzyloxyphenyl) ethyl] -3-pyridinecarboximidamide hydrochloride

Melting Point: 84.8 ~ 85.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3400, 2180, 1610, 1590, 1260, 700

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (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 = 7.2 Hz), 2.94 (2H, t, J = 7.2 Hz).

Elemental Analysis:

Calculated 69.80 5.45 11.23

Found 70.01 5.48 11.25 (%)

(C ₂₉ H ₂₆ N ₂ HCl)

Example 1-40

Preparation of N-cyano-N'-3- (2, 6-dimethoxypyridine) -3-pyridinecarboximidamide hydrochloride (additional method)

Isopropyl = N-cyano-3-pyridinecarboxyimidate (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 and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure and crystallized with methanol / diethyl ether to obtain the title compound (0.35 g, 1.2 mmol, yield 47%) as colorless needles.

Physicochemical Properties of N-Cyano-N'-3- (2, 6-dimethoxypyridine) -3-pyridinecarboxyimidamide Hydrochloride

Melting Point: 162.5 ~ 163.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1580, 1550, 1490, 1470, 1390, 1330

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (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 = 8.9 Hz), 4.02 (3H, s).

Elemental Analysis:

Calculated 59.36 4.63 24.72

Analysis 59.06 4.68 24.48 (%)

(C ₁₄ H ₁₃ N ₅ O ₂ )

Example 1-41

Preparation of N-cyano-N '-(2-nitoxyethyl) -4-pyridinecarboxyimidamide (additional method)

a. 4-cyanopyridine (10.1 g, 96.1 mmol) was dissolved in isopropanol (50 mL), washed with ether to remove the oil component, sodium hydride (0.23 g, 9.6 mmol) was added and stirred at room temperature for 6 hours. I was. After the reaction, acetic acid (0.64 g, 10.7 mmol) was added to neutralize the reaction solution and concentrated under reduced pressure. After concentration, diethyl ether (50 mL) was added to the residue, the insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure. Hexane (80 ml) was added to the concentrate, the precipitated unreacted 4-cyanopyridine was filtered off, the filtrate was concentrated under reduced pressure, and 11.0 g of isopropyl = 4-fildinecarboxyimide crude product was concentrated. Obtained as a yellow oil.

Subsequently, phosphate buffer solution (pH, 5.4, 60 mL) with cyanamide (5.63 g, 133.9 mmol) and Na ₂ H ₂ PO ₄ .2H ₂ O (41.8 g, 267.9 mmol) was added to the oil. Stir for hours. After the reaction, the mixture was extracted with dichloromethane (100 ml * 3 times), and the dichloromethane layer was dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 30 g), eluted with hexane: diethyl ether (1: 2) to give isopropyl = N-cyano-4-pyridinecarboxyimide (11.2 g). , 59.2 mmol, yield 62%) was obtained as a pale yellow oil.

Physicochemical Properties of Isopropyl = N-Cyano-4-pyridinecarboxyimitate

Infrared absorption spectrum: (cm ^-1 , neat) 3250, 3000, 2250, 2200, 1620, 1590, 1380, 1310, 1100

Nuclear Magnetic Resonance Spectrum: (100MHz, in CD ₃ OD) δ (ppm) 8.9 ~ 8.7, 8.0 ~ 7.0 (4H), 5.42 (1H, m, J = 6.1Hz), 1.50 (6H, d, J = 6.1Hz ).

b. Isopropyl = N-cyano-4-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL), 2-nitoxyethylamine nitrate (0.57 g, 2.9 mmol) and sodium methoxide ( 0.18 g, 2.9 mmol) was added and stirred at room temperature for 10 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue obtained was extracted with dichloromethane (50 mL * 3 times). The dichloromethane layer was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained concentrated residue was crystallized from dichloromethane / diethyl ether to give a colorless needle of the title compound (0.37 g, 1.6 mmol, yield 67%).

N-Cyano-N '-(2-nitroethylethyl) -4-pyridinecarboximidamide Physicochemical Properties

Melting Point: 102.5 ~ 103.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1640, 1580, 1540, 1290, 1280

Nuclear magnetic resonance spectra: (100 MHz, in CDCl ₃ ) δ (ppm) 8.72 (2H, s), 7.48 (2H, s), 4.70 (2H, s), 3.80 (2H, s).

Elemental Analysis:

Calculated 45.96 3.86 29.78

Found 45.68 3.64 29.99 (%)

(C ₉ H ₉ N ₅ O ₃ )

Example 1-42

Preparation of N-cyano-N '-(3-nitropropyl) -4-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL), 3-nitoxypropylamine nitrate (0.53 g, 2.9 mmol) and sodium meroxide ( 0.22 g, 4.1 mmol) was added and stirred at room temperature for 18 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (50 mL * 3 times). The chloroform was washed with water (100 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was provided on silica gel column chromatography (waco gel C-200, 50 g), and eluted with chloroform: methanol (60: 1). The eluted fractions were concentrated under reduced pressure, and then crystallized with methanol / diethyl ether to obtain the title compound (0.27 g, 1.08 mmol, yield 41%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(3-nitropropyl) -4-pyridinecarboximidamide

Melting Point: 112.5 ~ 112.8 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1600, 1280

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.75 (2H, dd, J = 1.6, 4.4Hz), 7.54 (2H, dd, J = 1.6, 4.4Hz), 4.57 ( 2H, t, J = 6.0 Hz, 3.59 (2H, t, J = 6.0 Hz), 2.13 (2H, quint, J = 6.0 HZ).

Elemental Analysis:

Calculation 48.19 4.45 28.10

Found 48.01 4.33 27.91 (%)

(C ₁₀ H ₁₁ N ₅ O ₃ )

Example 1-43

Preparation of N-cyano-N'-phenyl-4-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-4-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was diluted with methanol (5 mL) and stirred at room temperature for 20 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained concentrate was subjected to silica gel column chromatography (Wacogel C-200, 40 g) to elute chloroform: methanol (100: 1) to obtain a target compound. Crystallization with methanol / diethyl ether gave N-cyano-N'-phenyl-4-pyridinecarboxyimidamide (0.32 g, 1.4 mmol, yield 54%) as colorless needles.

Physicochemical Properties of N-Cyano-N'-phenyl-4-pyridinecarboxyimidamide

Melting Point: 220 ~ 222 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3060, 2180, 1610, 1580, 1530, 1450

Nuclear magnetic resonance spectra: (100 MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.80 (2H, brs), 7.8-7.5 (4H, m), 7.42 (2H, brs), 7.27 (1H, brs).

Elemental Analysis:

Calculated 70.26 4.54 25.21

Found 70.50 4.54 25.14 (%)

(C1 ₃ H ₁₀ N ₄ )

Example 1-44

Preparation of N-cyano-N '-(3, 4-dichlorobenzyl) -4-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-4-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL), and 3,4-dichlorobenzylamine (0.52 g, 3.0 mmol) was added at room temperature. Stir for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained transcription was crystallized with methanol / diethyl ether to obtain the title compound (0.42 g, 1.4 mmol, yield 52%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(3, 4-dichlorobenzyl) -4-pyridinecarboxyimidamide

Melting Point: 164.8-165.2 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2190, 1590

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.74 (2H, dd, J = 1.8, 5.8Hz), 7.52 (2H, dd, J = 1.8, 5.8Hz), 7.46 ( 1H, d, J = 2.2 Hz, 7.45 (1H, d, J = 8.2 Hz), 7.23 (1H, dd, J = 2.2, 8.2 Hz), 4.59 (2H, s).

Elemental Analysis:

Calculated 55.10 3.30 18.36

Found 55.02 3.19 18.23 (%)

(C ₁₄ H ₁₀ N ₄ C _l2 )

Example 1-45

Preparation of N-cyano-N '-(4-methylthiobenzyl) -4-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-4-pyridinecarboxyimidate (0.40 g, 2.1 mmol) was dissolved in methanol (15 mL), 4-methylthiobenzylamine hydrochloride (0.60 g, 3.2 mmol) and triethylamine ( 0.43 g, 4.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 mL * 3 times). The ethyl acetate layer was washed with water (100 ml), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was crystallized from methanol / diethyl ether to give the title compound (0.29 g, 1.0 mmol, yield 49%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(4-methylthiobenzyl) -4-pyridinecarboximidamide

Melting Point: 165.5 ~ 166.8 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1580

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.72 (2H, dd, J-2.0, 4.4Hz), 7.52 (2H, dd, J = 20, 4.4Hz), 7.30 ( 2H, d, J = 8.2 Hz, 7.26 (2H, d, J = 8.2 Hz), 4.59 (2H, s), 2.50 (3H, s).

Elemental Analysis:

Calculated 63.81 5.00 19.84

Found 63.69 5.19 19.66 (%)

(C ₁₅ H ₁₄ N ₄ S)

Example 1-46

Preparation of N-cyano-N '-(3-benzyloxybenzyl) -4-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-4-pyridinecarboxyimidetate (0.30 g, 1.6 mmol) was dissolved in methanol (10 mL) and 3-benzyloxybenzylamine (0.42 g, 2.0 mmol) was added at room temperature. Stir for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was crystallized from methanol / diethyl ether to obtain the title compound (0.26 g, 0.8 mmol, yield 48%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(3-benzyloxybenzyl) -4-pyridinecarboxyimidamide

Melting Point: 123.8-124.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2190, 1580

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 88.69 (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 = 6.0 Hz).

Elemental Analysis:

Calc 73.67 5.30 16.36

Found 73.55 5.40 16.31 (%)

(C ₂₁ H ₁₈ N ₄ O)

Example 1-47

Preparation of N-cyano-N '-[2- (4-chlorophenyl) ethyl] -4-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-4-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 mL) and 2- (4-chlorophenyl) ethylamine (0.46 g, 3.0 mmol) was methanol. After dilution with (5 mL), the mixture was stirred at room temperature for 40 minutes. After the reaction, the reaction solution was concentrated under reduced pressure and crystallized with methanol / diethyl ether to obtain the title compound (0.44 g, 1.5 mmol, yield 58%) as colorless needles.

Physicochemical Properties of N-cyano-N '-[2- (4-chlorophenyl) ethyl] -4-pyridinecarboximidamide

Melting Point: 164.0-165.2 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1590, 1540, 1500

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ ) δ (ppm) 8.68 (2H, m), 7.4 ~ 7.1 (6H), 6.56 (H, brs), 3.74 (2H, q, J = 6.8Hz), 2.97 (2H, t, J = 6.8 Hz).

Elemental Analysis:

Calculated 63.27 4.60 19.68

Found 63.02 4.66 19.56 (%)

(C ₁₅ H ₁₃ N ₄ Cl)

Example 1-48

Preparation of N-cyano-N '-[2- (2-methoxyphenyl) ethyl] -4-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-4-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 mL) and 2- (2-methoxyphenyl) ethylamine (0.44 g, 2.9 mmol) was dissolved. Add and stir at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Wacogel C-200, 50 g) to elute with chloroform: methanol (100: 1). The eluted fraction was concentrated under reduced pressure and crystallized with chloroform / diethyl ether to give the title compound (0.45d, 1.6mmol, 61% yield) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-[2- (2-methoxyphenyl) ethyl] -4-pyridinecarboximidamide

Melting Point: 141.2 ~ 141.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2190, 1580

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (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 = 7.1 Hz), 6.97 (1H, t, J = 7.1 Hz), 6.91 (1H, d, J = 7.1 Hz), 6.66 (1H, brs), 3.80 (3H, s ), 3.72 (2H, m), 3.01 (2H, t, J = 7.1 Hz).

Elemental Analysis:

Calculation 68.55 5.75 19.99

Found 68.46 5.49 19.71 (%)

(C ₁₆ H ₁₆ N ₄ O)

Example 1-49

Preparation of N-cyano-N '-(2-phenylthioethyl) -4-pyridinecarboximidamide (additional method)

Isopropyl = N-cyano-4-pyridinecarboxyimidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 mL) and 2-phenylthioethylamine (0.49 g, 3.2 mmol) was added to methanol (5 mL). Diluted with and added and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (WACOGEL C-200, 10 g) to elute with chloroform: methanol (50: 1). The eluted fraction was concentrated under reduced pressure and crystallized with diethyl ether to give the title compound (0.49 g, 1.7 mmol, yield 66%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-phenylthioethyl) -4-pyridinecarboximidamide

Melting Point: 114.0 ~ 114.3 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2190, 1590

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (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 = 6.2Hxz).

Elemental Analysis:

Calculated 63.81 5.00 19.84

Found 63.80 4.89 19.71 (%)

(C ₁₅ H ₁₄ N ₄ S)

Example 1-50

Preparation of N-cyano-N '-[2- (4-nitrophenyl) -2-nitoxyethyl] -4-pyridinecarboxyimidamide (additional method)

Isopropyl = N-cyano-4-pyridinecarboxyimidate (0.22 g, 1.2 mmol) was dissolved in methanol (10 mL) and 2- (4-nitrophenyl) -2-nitroethylamine nitrate (0.40 g) , 1.4 mmol) and sodium methoxide (0.14 g, 2.6 mmol) were added and stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (50 mL * 3 times). The chloroform layer was washed with water (100 mL), dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained concentrated residue was provided on silica gel column chromatography (Wakogel C-200, 30 g), and eluted with chloroform: methanol (50: 1). The eluted fractions were concentrated under reduced pressure, and then crystallized with methanol / diethyl ether to obtain the title compound (0.13 g, 0.4 mmol, yield 31%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-[2- (4-nitrophenyl) -2-nitoxyethyl] -4-pyridinecarboxyimidamide

Melting Point: 127.5-129.0 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 1290, 1640, 1590, 1530, 1350

Nuclear Magnetic Resonance Spectrum: (500 MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.78 (2H, d, J = 4.4 Hz), 8.33 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.52 (2H, d, J = 4.4 Hz), 6.31 (1H, dd, J = 3.8, 9.4 Hz), 3.80 (2H, m).

Elemental Analysis:

Calculation 50.57 3.39 23.59

Found 50.46 3.58 23.36 (%)

(C ₁₅ H ₁₂ N ₆ O ₅ )

Preparation Example 1-51

Manufacture

Isopropyl = N-cyano-4-pyridinecarboxyimidate (0.31 g, 1.6 mmol) is dissolved in methanol (15 mL) and 1-methyl-2- (4-nitrophenyl) -2-nitroethylethylamine Nitrate (0.50 g, 1.8 mmol) and sodium methoxide (0.09 g, 1.8 mmol) were added and stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (50 mL * 3 times). The chloroform layer was washed with water (100 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was provided on silica gel column chromatography (Wakogel C-200, 30 g), and eluted with chloroform: methanol (60: 1). The eluted fractions were concentrated under reduced pressure, and then crystallized with methanol / diethyl ether to obtain the title compound (0.03 g, 0.08 mmol, yield 5%) as colorless crystals.

Physicochemical Properties

Melting Point: 153.0 ~ 153.1 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2200, 1650, 1580, 1530, 1350, 1290

Nuclear Magnetic Resonance Spectrum: (500 MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 8.77 (2H, d, J = 5.9 Hz), 8.35 (2H, d, J = 8.9 Hz), 7.69 (2H, d, J = 8.9 Hz), 7.49 (2H, d, J = 5.9 Hz), 6.36 (1H, dd, J = 4.5 Hz), 4.62 (1H, m), 1.32 (3H, d, J = 9.4 Hz).

Elemental Analysis:

Calculation 51.89 3.80 22.69

Found 51.62 3.99 22.57 (%)

(C ₁₆ H ₁₄ N ₆ O ₅ )

Preparation Example 1-52

Preparation of N-cyano-N '-(2-nitoxyethyl) -3- (6-chloropyridine) pyridinecarboximidamide (additional method)

a. 6-Chloro-3-cyanopyridine (3.63 g, 26.2 mmol) was suspended in isopropanol (40 mL), washed with ether to remove the oil component, sodium hydride (0.1 g, 4.2 mmol) was added, and room temperature Stirred for 18 hours. After the reaction, acetic acid (0.27 g, 4.5 mmol) was added to neutralize the reaction solution and concentrated under reduced pressure. The concentrated residue was added with ether (50 mL) to separate the ether insolubles, and the filtrate was concentrated under reduced pressure. Nucleic acid (100 ml) was added to the concentrated residue, and the precipitated unreacted 6-chloro-3-cyanopyridine was separated by filtration. The filtrate was then purified by isopropyl = 3- (6-chloropyridine) carboxamidate (1.88 g) was obtained as a colorless oil. Then, cyanamide (0.80 g, 19.0 mmol), Na 2 HPO 4 (1.34, 9.4 mmol), NaH 2 PO 4 · 2H 2 O (5.90 g, 37.8 mmol) and phosphate buffer (pH 5.4, 37.8 mL) were added to the oil for 24 hours at room temperature. Was stirred. The reaction solution was extracted with dichloromethane (100 mL * 4 times), and the dichloromethane layer was dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 70 g), and eluted with hexane: dichloromethane: methanol (50: 50: 1).

The eluted fractions were concentrated under reduced pressure to obtain isopropyl = N-cyano-3- (6-chloropyridine) carboxyimidate (0.83 g, 3.7 mmol, yield 14%) as a colorless syrup.

Physicochemical Properties of Isopropyl = N-Cyano-3- (6-chloropyridine) carboxyimidate

Infrared absorption spectrum: (cm ^-1 , neat) 2200, 1610, 1580, 1310, 1110

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ -CD ₃ OD) δ (ppm) 9.13 (1H, d, J = 3.0Hz), 8.61 (1H, dd, J = 3.0, 8.6Hz), 7.52 (1H, d, J = 8.6 Hz), 5.43 (1H, m, J = 6.1 Hz), 1.49 (6H, d, J = 6.1 Hz).

b. Isopropyl = N-cyano-3- (6-chloropyridine) carboxyimidate (0.20 g, 0.9 mmol) was dissolved in methanol (8 mL) and 2-nitraethylethylamine nitrate (0.23 g, 1.4 mmol) And sodium methoxide (0.18 g, 1.9 mmol) were added and stirred at room temperature for 5 hours. After the reaction, the residue obtained by concentrating the reaction solution under reduced pressure was extracted with chloroform (50 ml * 3 times). The chloroform worms were washed with water (100 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Wako gel C-200, 25 g) and eluted with chloroform: methanol (50: 1). The elution fraction was concentrated under reduced pressure, and then crystallized with diethyl ether to give the title compound (0.04 g, 0.1 mmol, yield 17%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-nitroethylethyl) -3- (6-chloropyridine) carboxyimidate

Melting Point: 139.0 ~ 140.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1630, 1580, 1280

Nuclear Magnetic Resonance Spectrum: (500MHz, in CD ₃ OD) δ (ppm) 8.62 (1H, d, J = 3.0Hz), 8.08 (1H, dd, j = 3.0, 9.1Hz), 7.65 (1H, d, J = 9.1 Hz), 4.75 (2H, t, J = 7.1 Hz), 3.86 (2H, t, J = 7.1 Hz).

Elemental Analysis:

Calculation 40.09 2.99 25.97

Found 39.95 2.88 25.69 (%)

(C ₉ H ₈ N ₅ Cl)

Preparation Example 1-53

Preparation of N-cyano-N '-(2-phenylethyl) -3- (6-chloropyridine) carboxyimidamide (additional method)

Isopropyl = N-cyano-3- (6-chloropyridine) carboxyimidate (0.30 g, 1.3 mmol) was dissolved in methanol (8 mL) and 2-phenylethylamine (0.18 g, 1.5 mmol) was added. And stirred for 30 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized with diethyl ether to obtain the title compound (0.24 g, 0.8 mmol, yield 63%) as colorless crystals.

Physicochemical Properties of N-cyano-N '-(2-phenylethyl) -3- (6-chloropyridine) carboxyimidamide

Melting Point: 168.8-169.0 ° C

Infrared absorption spectrum: (cm ^-1 , KBr) 2180, 1590,

Nuclear Magnetic Resonance Spectrum: (500MHz, in CD ₃ OD) δ (ppm) 8.47 (1H, d, J = 3.0Hz), 7.96 (1H, dd, J = 3.0, 9.3Hz), 7.61 (1H, d, J = 89.3 Hz), 7.36-7.20 (5H), 3.723 (2H, t, J = 7.2 Hz), 2.99 (2H, t, J = 7.2 Hz).

Elemental Analysis:

Calculated 63.27 4.60 19.68

Found 63.25 4.38 19.37 (%)

(C ₁₅ H ₁₃ N ₄ Cl)

Preparation Example 1-54

Preparation of N-cyano-N'-benzyl-3-pyridinecarboxyimidamide (Me method)

a. N-benzyl nicotinamide (1.0 g, 4.7 mmol) was dissolved in 90 ml of toluene, and a reflux (Lauson) reagent (2.3 g, 5.7 mmol) was added thereto, followed by heating to reflux for 3 hours under an argon stream. After the reaction, the mixture was cooled to room temperature and the reaction solution was concentrated under reduced pressure. The resulting concentrate was extracted with 2N aqueous hydrochloric acid solution (200 mL * 3 times), and the aqueous hydrochloric acid solution layer was washed with chloroform (500 mL). After washing, the aqueous hydrochloric acid layer was neutralized with NaOH and extracted with chloroform (200 mL * 3 times). The chloroform layer was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was crystallized with chloroform / hexane to give N-benzyl nicotinthioamide (0.83 g, 3.6 mmol, yield 77%) as pale yellow acicular crystals.

Physicochemical Properties of N-benzylnicotinthioamide

Melting Point: 136.0 ~ 136.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 3170, 1540, 1420, 1390, 1340, 760, 700

Nuclear Magnetic Resonance Spectrum: (in 100 MHz, CDCl ₃ ) δ (ppm) 8.81 (1H, d, J = 4.1 Hz), 8.57 (1H, d, J = 4.1 Hz), 8.14 (1H, d, J = 2.7, 10.0 Hz), 8.00 (1H, brs), 7.40 (5H, s), 7.35 (1H, m), 5.00 (2H, d, J = 6.2 Hz)

b. N-benzylnicotinamide (0.5 g, 2.2 mmol) was dissolved in acetnitrile (20 mL), phosphorus oxychloride (0.4 g, 2.6 mmol) was added and stirred at room temperature for 9 hours. Cyanamide (0.92 g, 21.9 mmol) and triethylamine (0.27 g, 2.6 mmol) were then added and heated to reflux for 4 hours under an argon stream. After the reaction, the reaction solution was concentrated under reduced pressure, chloroform (50 mL) was added to the concentrated residue, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentrate was provided on silica gel column chromatography (Wakogel C-200, 30 g), and eluted with chloroform: methanol (100: 1) to obtain the title compound. This was further crystallized with methanol / diethyl ether to obtain N-cyano-N'-benzyl-3-pyridinecarboxyimidamide (0.085 g, 0.3 mmol, yield 16%) as colorless needles.

The physicochemical properties of the crystals thus obtained were consistent with those obtained in Examples 1-17 in terms of melting point, infrared absorption spectrum, hex resonance spectrum, and the like.

Example 1-55

(In tablet / 1 tablet)

The ingredients were mixed and pressed to tablets.

Example 1-56

(In / 1 capsule made of capsule)

The above ingredients were mixed and filled into capsules to form capsules.

Example 1-57

The ingredients were mixed, filtered and filled into vials, lyophilized according to conventional methods, then tightly prepared and made into an injection.

2) Compound represented by structural formula (I ')

Reference Example 2-1: Vasorelaxation Effects on Rat Artery Samples

(1) test method

The biological activity of the compound of the present invention was tested by the method using the isolated aorta.

A chest aorta was quickly extracted from a bloody lethal male rat with a weight of 250-350 g, and cut into rounds of 3 mm in width to prepare a specimen.

The samples were suspended in an engine bath filled with 37 ° C. Krebs-Ringer liquid, which was passed a mixture gas of 95% O ₂ -5% CO ₂ .

After 1 g of static tension was loaded to stabilize the tension of the specimen, the inside of the trachea bath was replaced with an isotonic nutrient solution containing 40 mM KCl, and the tension of the specimen was increased.

After the development tension by KCl was constant, test compounds were added cumulatively into the organ bath and the specimens were relaxed.

The tension by KCl was set to 100%, and the relaxation reaction was determined as its inhibition rate, and the IC ₅₀ value (concentration that inhibits the tension by KCl by 50%) was calculated by the probit method in the mean dose-action curve.

(2) results

The I ₅₀ values of the test compounds are shown in the following table.

Reference Example 2-2: Lowering blood pressure (intravenous administration) in spontaneously hypertensive rats

(1) Test method

The hypotensive action of the compound of the present invention was observed in male hypertensive rats (SHR) (Test compound: N-cyano-N '-(2-nitroethylethyl) -2-furancarboxyimidamide ( Compound No. (62)) and N-cyano-N '-(2-nitroethylethyl) -2-thiophenylcarboxyimidamide (Compound No. (66)) Urethane-α-chlorarolob (1 g / The average blood pressure was measured by means of a transducer by inserting a cannula into the carotid artery of the anesthetized rat with kg ~ 25 mg / kg, intraperitoneal administration. The blood pressure before administration was 100%, and the change in blood pressure was obtained as its drop rate, and the ED ₂₀ value (dose with 20% drop in blood pressure) was calculated from the dose-action curve.

(2) results

ED ₂₀ values of the test compounds are shown in the following table.

Ⅰ.Ⅴ. Intravenous administration

Example 2-1

Preparation of N-cyano-N '-(2-nitoxyethyl) -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 and reacted at room temperature for 22 hours. After the reaction, acetic acid (0.07 g, 1.2 mmol) was added to neutralize the reaction solution and concentrated under reduced pressure. Diethyl ether (60 ml) was added to the concentrated residue, and the insolubles were separated by filtration. The filtrate was concentrated under reduced pressure to obtain a methyl = 3-quinolinecarboxyimide crude product. The crude product was then phosphate buffered with cyanamide (0.84 g, 20 mmol) and Na ₂ HPO ₄ (1.42 g, 10 mmol) and NaH ₂ PO ₄ .2H ₂ O (6.24 g, 40 mmol) (pH 5.4, 10 mL). Was added and stirred for 6 hours at room temperature. After the reaction, insoluble matters in the reaction solution were separated by filtration, and the filtrate was dehydrated and concentrated under reduced pressure. The residue was provided on silica gel column chromatography (Wakogel C-200, 25 g) and eluted with dichloromethane: hexane (3: 2). The eluted fractions were concentrated under reduced pressure, and then crystallized with diethyl ether to obtain methyl = N-cyano-3-quinolinecarboxyimidate (1.14 g, 5.4 mmol, 53% yield) as light brown crystals.

Physicochemical Properties of Methyl = N-cyano-3-quinolinecarboxyimidate

Melting Point: 113.5 ~ 113.8 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2190, 1610, 1310

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (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 = 8.0 Hz), 7.90 (1H, dt, J = 1.8, 8.0 Hz), 7.68 (1H, T, J = 8.0 Hz), 4.18 (3H, s).

Elemental Analysis:

Calculation 68.24 4.29 19.89

Found 68.01 4.23 19.67 (%)

(C ₁₂ H ₉ N ₃ O)

b. Methyl = N-cyano-3-quinolinecarboxyimidate (0.32 g, 1.5 mmol) was dissolved in methanol (3 mL), 2-nitoxyethylamine nitrate (0.42 g, 2.5 mmol) and sodium methoxide ( 0.12 g, 2.2 mmol) was added and stirred at room temperature for 18 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 30 g). Dichloromethane: eluted with methanol (50: 1), the eluted fraction was concentrated under reduced pressure, and then crystallized with dichloromethane / diethyl ether to give the title compound (0.23 g, 0.80 mmol, yield 54%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-nitroethylethyl) -3-quinolinecarboxyimidate

Melting Point: 126.5-127.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2190, 1620, 1580, 1560, 1280

Nuclear Magnetic Resonance Spectrum: (500MHz, in CD ₃ OD) δ (ppm) 9.05 (1H, s), 8.71 (1H, s), 8.13 (1H, d, J = 8.0Hz), 8.10 (1H, d, J = 8.0 Hz), 7.93 (1H, t, J = 7.7 Hz), 7.74 (1H, t, J = 7.7 Hz), 4.80 (2H, t, J = 5.7 Hz), 3.92 (2H, t, J = 5.7 Hz).

Elemental Analysis:

Calculated 54.74 2.46 24.55

Found 54.66 2.34 24.29 (%)

(C ₁₃ H ₁₁ N ₅ O ₃ )

Example 2-2

Preparation of N-cyano-N '-(2-finylethyl) -3-quinolinecarboxyimidamide

Methyl = N-3-quinolinecarboxyimidate (0.32 g, 1.5 mmol) was dissolved in methanol (3 mL), 2-phenylethylamine (0.20 g, 1.65 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized with ethyl ether to give the title compound (0.41 g, 1.36 mmol, yield 91%) as pale yellow crystals.

Physicochemical Properties of N-Cyano-N '-(2-phenylethyl) -3-quinolinecarboxyimidamide

Melting Point: 165.0 ~ 167.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2190, 1580, 1560

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 8.84 (1H, s), 8.47 (1H, s), 8.11 (1H, d, J = 8.56Hz), 7.90 (1H, d, J = 8.6 Hz), 7.84 (1H, t, J = 7.3 Hz), 7.65 (1H, t, J = 8.0 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.32-7.25 (3H), 6.05 (1H , brs), 3.87 (2H, doublet of doublets, J = 6.7, 12.8 Hz), 3.06 (2H, t, J = 6.7 Hz).

Elemental Analysis:

Calculated 75.98 5.37 18.65

Found 75.86 5.32 18.42 (%)

(C ₁₉ H ₁₆ N ₄ )

Example 2-3

Preparation of N-cyano-N '-(2-nitoxyethyl) pyrazinecarboxyimidamide

a. Cyanopyrazine (5.26 g, 50 mmol) was dissolved in methanol (40 mL), sodium methoxide (0.27 g, 5.0 mmol) was added and the mixture was allowed to react at room temperature for 45 minutes. After the reaction, acetic acid (0.33 g, 5.5 mmol) was added to neutralize the reaction solution and concentrated under reduced pressure. Diethyl ether (50 ml) and diethylemer (50 ml) were added to the concentrated residue, and the insolubles were separated by filtration. The filtrate was concentrated under reduced pressure to yield a crude product of methyl = pyrazinecarboxyimide (6.87 g). Obtained as a powder. Subsequently, to this powder, a phosphate buffer solution (pH 5.4, 40 ml) of cyanamide (3.15 g, 75 mmol) and Na ₂ HPO ₄ (7.10 g, 50 mmol) and NaH ₂ PO ₄ 2H ₂ O (31.22 g, 200 mmol) Was added and stirred for 48 hours at room temperature. After the reaction, the reaction solution was extracted with dichloromethane (100 mL * 4 times). The dichloromethane layer was washed with saturated brine (300 mL), dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was crystallized with diethyl ether to give methyl = N-cyano-parazinecarboxyimidate (4.53 g, 27.9 mmol, yield 56%) as colorless crystals.

Physicochemical Properties of Methyl = N-cyano-pyrazinecarboxyimidate

Melting Point: 47.5-49.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2190, 1630, 1330

Nuclear magnetic resonance spectra: (500 MHz, in CDCl ₃ ) δ (ppm) 9.33 (1H, s), 8.78 (1H, d, J = 2.2 Hz), 8.74 (1H, brs), 4.07 (3H, s).

Elemental Analysis:

Calculation 51.85 3.73 34.55

Variance 51.71 3.69 34.27 (%)

(C ₇ H ₆ N ₄ O)

b. Methyl = N-cyano-pyrazinecarboximidate (0.49 g, 3.0 mmol) was dissolved in methanol (6 mL), 2-nitoxyethylamine-nitrate (1.01 g, 6.0 mmol) and triethylamine (1.01 g) , 10.0 mmol) was added and stirred at room temperature for 46 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 30 g). Chloromethane: eluted with methanol (300: 1), the eluted fraction was concentrated under reduced pressure, and then crystallized with diethyl ether to give the title compound (0.18 g, 0.78 mmol, yield 26%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-nitroethylethyl) -pyrazinecarboxyimidate

Melting Point: 102.8 ~ 103.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1630, 1620 1290

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ 9.83 (1H, bbrs), 8.88 (1H, s), 8.64 (1H, s), 8.28 (1H, brs), 4.78 (2H, t, J = 4.9 Hz), 4.15 (2H, broad singlet).

Elemental Analysis:

Calculation 40.68 3.41 35.58

Found 40.66 3.27 35.30 (%)

(C ₈ H ₈ N ₆ O ₃ )

Example 2-4

Preparation of N-cyano-N '-(2-nitoxyethyl) -2-furancarboxyimidamide

a. 2-cyanofuran (4.50 g, 48.3 mmol) was dissolved in methanol (25 mL), sodium methoxide (130 mL, 2.4 mmol) was added with cooling and stirred for 2 hours while slowly bringing to room temperature. After the reaction, acetic acid (0.16 g, 2.6 mmol) was added to the reaction solution, neutralized, and concentrated under reduced pressure. Diethyl ether (100 mL) was added to the concentrated residue, and the insolubles were separated by filtration. The filtrate was concentrated under reduced pressure to give methyl = 2-furancarboxyimide crude product (6.0 g) as a pale yellow oil. Subsequently, the oil was phosphate buffered with cyanamide (4.06 g, 96.6 mmol) and Na ₂ HPO ₄ (6.86 g, 48.3 mmol) and NaH ₂ PO ₄ 2H ₂ O (15.08 g, 96.6 mmol) (pH 6.0 30). Ml) was added and stirred for 24 h at room temperature. After the reaction, the reaction solution was extracted with dichloromethane (70 mL * 4 times). The dichloromethane layer was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was crystallized from diisopropyl ether / hexane to give methyl = N-cyano-2-furancarboxyimidate (4.83 g, 32.2 mmol, yield 67%) as colorless crystals.

Physicochemical Properties of Methyl = N-cyano-2-furancarboxyimidate

Melting Point: 58.5 ~ 59.2 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2200, 1600, 1480, 1350

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 7.78 (1H, d, J = 3.8Hz), 7.69 (1H, d, J = 1.8Hz), 6.64 (1H, dd, J = 1.8, 3.8 Hz), 4.05 (3H, s).

Elemental Analysis:

Calculation 56.00 4.03 18.66

Found 55.82 4.04 18.40 (%)

(C ₇ H ₆ N ₂ O ₂ )

b. Methyl = N-cyano-2-furancarboxyimide (0.32 g, 2.09 mmol) was dissolved in methanol (3 mL), 2-nitoxyethylamine nitrate (0.37 g, 2.19 mmol) and triethylamine ( 0.22 g, 2.19 mmol) was added and stirred at room temperature for 16 hours. After the reaction, the reaction solution was eluted, the elution fraction was concentrated under reduced pressure, and then crystallized with dichloromethane to give the title compound (0.20 g, 0.89 mmol, yield 45%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-nitroethylethyl) -2-furancarboxyimidate

Melting Point: 77.0 ~ 77.8 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1630, 1600, 1570

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (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, 3.7 Hz), 4.69 (2H, t, J = 5.5 Hz), 3.87 (2H, dd, J = 5.5, 10.4 Hz).

Elemental Analysis:

Calculation 42.86 3.60 24.99

Found 42.92 3.84 24.72

(C ₈ H ₈ N ₄ O ₄ )

Example 2-5

Preparation of N-cyano-N '-(2-phenylethyl) -2-furancarboxyimidamide

Methyl = N-cyano-2-furancarboxyimide (0.30 g, 2.0 mmol) was dissolved in methanol (2 mL) and 2-phenylethylamine (0.27 g, 2.2 mmol) was added for 1 hour at room temperature. Stirred. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized with diethyl ether / hexane to give the title compound (0.46 g, 1.93 mmol, yield 97%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-phenylethyl) -2-furancarboxyimidate

Melting Point: 88 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1600, 1570

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (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, 3.7 Hz), 6.43 (1H, brs), 3.75 (2H, doublet of doublets, J = 7.3, 13.4 Hz), 2.96 (2H, t, J = 7.3 Hz).

Elemental Analysis:

Calculated 70.28 5.48 17.56

Found 70.12 5.54 17.41 (%)

(C ₁₄ H ₁₃ N ₃ O)

Example 2-6

Preparation of N-cyano-N '-(2-nitoxyethyl) -3-furancarboxyimidamide

a. 3-cyanofuran (3.76 g, 40 mmol) was dissolved in methanol (30 mL), sodium methoxide (0.1 g, 1.9 mmol) was added and stirred at room temperature for 18 hours. After the reaction, acetic acid (0.14 g, 2.3 mmol) was added to the reaction solution to neutralize the reaction solution and concentrated under reduced pressure. After diethyl ether was added to the concentrated residue, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure to obtain a methyl = 3-furancarboxyimide crude product as a pale yellow oil. This oil was then phosphate buffered with cyanamide (3.37 g, 80.2 mmol) and Na ₂ HPO ₄ (5.69 g, 40.1 mmol) and NaH ₂ PO ₄ 2H ₂ O (25.0 g, 160.2 mmol) (pH 5.4, 50 ml) was added and stirred for 18 hours at room temperature. After the reaction, the reaction solution was extracted with dichloroform (100 mL * 3 times). The chloroform layer was dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was provided on silica gel column chromatography (Wakogel C-200, 20 g) and eluted with chloroform. The eluted fraction was concentrated under reduced pressure to obtain methyl = N-cyano-3-furancarboxyimide (1.09 g, 7.3 mmol, yield 18%) as colorless crystals.

Physicochemical Properties of Methyl = N-cyano-3-furancarboxyimidate

Infrared absorption spectrum: (cm ^-1 , neat) 2190, 1610, 1590

Nuclear magnetic resonance spectrum: (100 Hz, in CDCl ₃ ) δ (ppm) 8.59 (1H, d, J = 1.1 Hz), 7.57 (1H, t, J = 2.2 Hz), 7.06 (1H, dd, J = 1.1, 2.2 Hz), 4.00 (3H, s).

b. (0.5 g, 3.3 mmol) of methyl = N-cyano-3-furancarboxyimide was dissolved in methanol (10 mL), 2-nitoxyethylamine nitrate (0.84 g, 5.0 mmol) and sodium methoxide. Side (0.27 g, 5.0 mmol) was added and stirred at room temperature for 26 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with chloroform (60 ml * 3 times). The chloroform layer was washed with water (100 mL), dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrated residue was provided on silica gel column chromatography (Wakogel C-200, 20 g). Chloroform: eluted with methanol (100: 1), the eluted fraction was concentrated under reduced pressure, and then crystallized with methanol / diethyl ether to give the title compound (0.06 g, 0.27 mmol, yield 8%) as colorless crystals.

Physicochemical Properties of N-cyano-N '-(2-nitroethylethyl) -3-furancarboxyimidamide

Melting Point: 107.1 to 107.9 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1640, 1600, 1550

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (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 = 4.9 Hz).

Elemental Analysis:

Calculation 42.86 3.60 24.99

Found 42.61 3.53 24.73 (%)

(C ₈ H ₈ N ₄ O ₄ )

Example 2-7

Preparation of N-cyano-N '-(2-phenylethyl) -3-furancarboxyimidamide

Methyl = N-cyano-3-furancarboxyimide (0.30 g, 2.0 mmol) was dissolved in methanol (10 mL) and 2-phenylethylamine (0.27 g, 2.2 mmol) was added for 2 hours at room temperature. Stirred. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized with diethyl ether to obtain the title compound (0.38 g, 1.59 mmol, yield 79%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-Phenylethyl) -3-furancarboxyimidamide

Melting Point: 132.5 ~ 133.1 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2170, 1610, 1560

Nuclear Magnetic Resonance Spectrum: (100MHz, in CDCl ₃ ) δ (ppm) 8.28 (1H, s), 7.45 (1H, t, J = 1.9Hz), 7.4 ~ 7.1 (5H), 6.69 (1H, s), 6.54 (1H, broad singlet), 3.68 (2H, q, J = 6.6 Hz), 2.95 (2H, t, J = 6.6 Hz).

Elemental Analysis:

Calculated 70.28 5.48 17.56

Found 70.22 5.41 17.37 (%)

(C ₁₄ H ₁₃ N ₃ O)

Example 2-8

Preparation of N-cyano-N '-(2-nitoxyethyl) -2-thiophenecarboximidamide

a. 2-cyanothiophene (5.46 g, 50 mmol) was dissolved in methanol (25 mL), sodium methoxide (0.27 g, 5 mmol) was added and stirred at room temperature for 18 hours. After the reaction, acetic acid (0.33 g, 5.5 mmol) was added to the reaction solution to neutralize the reaction solution, and the resultant was concentrated under reduced pressure. Diethyl ether (40 mL) was added to the concentrated residue, and the insolubles were separated by filtration. The filtrate was concentrated under reduced pressure to give methyl = 2-thiophenecarboxyimidate crude product (6.35 g) as a yellow oil. This oil was then phosphate buffered with cyanamide (2.52 g, 60 mmol) and Na ₂ HPO ₄ (4.26 g, 30 mmol) and NaH ₂ PO ₄ .2H ₂ O (9.36 g, 60 mmol) (pH 6.0, 0.20 mL). Was added and stirred at room temperature for 14 hours. After the reaction, the reaction solution was extracted with dichloroform (50 mL * 4 times). The dichloromethane layer was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrated residue was crystallized from dichloromethane: hexane to give methyl = N-cyano-2-thiophene carboximidate (4.48 g, 27.0 mmol, yield 54%) as colorless crystals.

Physicochemical Properties of Methyl = N-cyano-2-thiophenecarboxyimidate

Melting Point: 66.9 ~ 67.1 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2200, 1580

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 8.64 (1H, d, J = 4.8Hz), 7.77 (1H, d, J = 4.8Hz), 7.27 (1H, t, J = 4.8Hz ), 4.10 (3H, s).

Elemental Analysis:

Calculation 50.59 3.64 16.86

Found 50.46 3.52 16.61 (%)

(C ₇ H ₆ N ₂ OS)

b. Methyl-N-cyano-2-thiophenecarboximidate (0.32 g, 1.9 mmol) was dissolved in methanol (3 mL), 2-nitoxyethylamine-nitrate (0.34 g, 2.0 mmol) and triethylamine (0.20 g, 2.0 mmol) was added and stirred at room temperature for 17 hours. After the reaction, the reaction solution was concentrated under reduced pressure, the obtained residue was subjected to silica gel column chromatography (Wakogel C-200, 25 g), eluted with ethyl acetate, and the elution fraction was concentrated under reduced pressure, and then crystallized with ethyl acetate / hexane. The title compound (0.18 g, 0.77 mmol, yield 40%) was obtained as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-nitroethylethyl) -2-thiophenecarboximidamide

Melting Point: 101.5 ~ 102.0 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2180, 1630, 1570, 1280

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 7.96 (1H, d, J = 3.7Hz), 7.19 (1H, t, J = 3.7Hz), 4.70 (2H, t, J = 4.9Hz ), 3.82 (2H, t, J = 4.9 Hz).

Elemental Analysis:

Calculation 40.00 3.36 23.32

Found 39.88 3.42 23.22 (%)

(C ₈ H ₈ N ₄ O ₃ S)

Example 2-9

Preparation of N-cyano-N '-(2-phenylethyl) -2-thiophenecarboximidamide

Methyl = N-cyano-2-thiophenecarboxyimidate (0.33 g, 2.0 mmol) was dissolved in methanol (2 mL), 2-phenylethylamine (0.27 g, 2.2 mmol) was added, and 1 hour at room temperature. Was stirred. After the reaction, the residue was concentrated under reduced pressure and the residue was crystallized from diethyl ether / hexane to give the title compound (0.50 g, 1.97 mmol, yield 98%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-phenylethyl) -2-thiophenecarboxyimidamide

Melting Point: 106.8 ~ 107.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2200, 1580

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (ppm) 7.89 (1H, s), 7.51 (1H, d, J = 4.9Hz), 7.4 ~ 7.2 (5H), 7.41 (1H, t, J = 4.9 Hz), 5.98 (1H, br s), 3.76 (2H, dd, J = 6.7, 12.8 Hz), 2.97 (2H, t, J = 6.76 Hz).

Elemental Analysis:

Calculated 65.85 5.13 16.46

Found 65.67 5.11 16.36 (%)

(C ₁₄ H ₁₃ N 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 and stirred at room temperature for 28 hours. After the reaction, acetic acid (0.03 g, 0.6 mmol) was added to neutralize the reaction solution and concentrated under reduced pressure. Diethyl ether (50 mL) was added to the residue, and the insolubles were separated by filtration. The blank was concentrated under reduced pressure to obtain a methyl = 3-thiophenecarboxyimidate crude product.

The crude product was then phosphate buffered with cyanamide (0.5 g, 12 mmol) and Na ₂ HPO ₄ (0.86 g, 6 mmol) and NaH ₂ PO ₄ .2H ₂ O (1.89 g, 12 mmol) (pH 6.0, 10 mL). Was added and stirred at room temperature for 74 hours. After the reaction, the reaction solution was extracted with dichloroform (10 mL * 4 times). The dichloromethane layer was washed with water (50 mL), dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrated residue was provided on silica gel column chromatography (Wakogel C-200, 30 g) and eluted with chloroform. The eluted fractions were concentrated under reduced pressure to obtain methyl = N-cyano-3-thiophenecarboxyimidate (0.708 g, 4.2 mmol, yield 70%) as colorless oil.

Physicochemical Properties of Methyl = N-cyano-3-thiophenecarboxyimidate

Infrared absorption spectrum: (cm ^-1 , neat) 2200, 1590, 1300

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (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, 5.6 Hz), 4.03 (3H, s).

b. Methyl = N-cyano-3-thiophenecarboxyimidate (0.33 g, 2.0 mmol) was dissolved in methanol (2 mL), 2-phenylethylamine (0.27 g, 2.2 mmol) was added, and 40 minutes at room temperature. Stirred. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized with diethyl ether to obtain the title compound (0.48 g, 1.89 mmol, yield 95%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-phenylethyl) -3-thiophenecarboxyimidamide

Melting Point: 156.9 ~ 157.7 ℃

Infrared absorption spectrum: (cm ^-1 , KBr) 2170, 1550

Nuclear Magnetic Resonance Spectrum: (500MHz, in CDCl ₃ ) δ (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 = 6.7 Hz).

Elemental Analysis:

Calculated 65.85 5.13 16.46

Found 65.77 5.01 16.29 (%)

(C ₁₄ H ₁₃ N ₃ S)

Example 2-11

Preparation of N-cyano-N '-(2-phenylethyl) -4-cyanobenzenecarboxyimidamide

a. 1, 4-dicyanobenzene (6.41 g, 50 mmol) was suspended in methanol (100 mL), sodium methoxide (0.27 g, 5.0 mmol) was added and stirred at room temperature for 22 hours. After the reaction, acetic acid (0.31 g, 5.1 mmol) was added to the reaction solution, neutralized, and concentrated under reduced pressure. Dichloromethane (50 ml) and dietyl ether (50 ml) were added to the concentrated residue, and the insolubles were separated by filtration. The filtrate was concentrated under reduced pressure to obtain methyl = 4-cyanobenzenecarboxyimide crude product (5.77 g). To a colorless powder. Subsequently, to this powder, a phosphate buffer solution (ph 6.0, 20 mL) of cyanamide (3.05 g, 72 mmol) and Na ₂ HPO ₄ (5.11 g, 36 mmol) and NaH ₂ PO ₄ .2H ₂ O (11.23 g, 72 mmol) was obtained. Was added and stirred at room temperature for 23 hours. After the reaction, the reaction solution was concentrated under reduced pressure, chloroform (200 mL) and methanol (20 mL) were added to the residue, and the insolubles were filtered through celite to concentrate the filtrate. Diethyl ether (100 ml) was added to the concentrated residue, and crystallized precipitated was filtered and washed with diethyl ether. The filtrate and the tax solution were combined and concentrated under reduced pressure to obtain methyl = N-cyano-4-cyanobenzenecarboxyimidate (3.63 g, 19.6 mmol, 39% yield) as a colorless powder.

Physicochemical Properties of Methyl = N-cyano-4-cyanobenzenecarboxyimidate

Melting Point: 94.5-95.0 ° C

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2200, 1600, 1530

Nuclear magnetic resonance spectra: (500 MHz, in CDCl ₃ ) δ (ppm) 8.18 (2H, d, J = 8.6 Hz), 7.83 (2H, d, J = 8.6 Hz), 4.13 (3H, s).

Elemental Analysis:

Calculation 64.86 3.81 22.69

Found 64.81 3.77 22.41 (%)

(C ₁₀ H ₇ N ₃ O)

b. Methyl = N-cyano-4-cyanobenzenecarboxyimidate (0.37 g, 2.0 mmol) was dissolved in methanol (4 mL) and 2-pinylethylamine (0.25 g, 2.1 mmol) was added to give 1 at room temperature. Stir for hours. After the reaction, methanol (6 mL) and diethyl ether (10 mL) were added to the reaction solution, and the precipitated crystals were filtered to obtain the title compound (0.51 g, 1.87 mmol, yield 94%) as colorless crystals.

Physicochemical Properties of N-Cyano-N '-(2-phenylethyl) -4-cyanobenzenecarboxyimidamide

Melting Point: 261.0 ~ 261.8 ℃

Infrared spectrum: (cm ^-1 , KBr) 2170, 1550

Nuclear Magnetic Resonance Spectrum: (500MHz, in CD ₃ OD) δ (ppm) 7.84 (1H, d, J = 8.5Hz), 7.64 (1H, d, J = 8.5Hz), 7.36 ~ 7.22 (5H), 3.72 ( 2H, t, J = 7.3 Hz), 3.00 (2H, t, J = 7.3 Hz)

Elemental Analysis:

Calculated 74.43 5.14 20.42

Found 74.13 5.35 20.21 (%)

(C ₁₇ H ₁₄ N ₄ )

Example 2-12

Preparation of 3-cyano-2-methyl-1- (2-nitroethylethyl) isothiourea

2-Nitoxyethylamine 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) was further added by dissolving in methanol (4 mL) and stirred at room temperature for 24 hours. After the reaction, the residue obtained by concentrating the reaction solution under reduced pressure was crystallized with diethyl ether to obtain a colorless powder. The obtained powder was washed with water and then recrystallized with methanol to give the title compound (0.26 g, 1.3 mmol, yield 43%) as colorless crystals.

Physicochemical Properties of 3-cyano-2-methyl-1- (2-nitroethylethyl) isothiourea

Melting Point: 135 ~ 135.5 ℃

Infrared Absorption Spectrum: (cm ^-1 , KBr) 2170, 1640, 1560, 1280

Nuclear magnetic resonance spectra: (500 MHz, in CD ₃ OD) δ (ppm) 4.63 (2H, s), 3.74 (2H, s), 2.60 (3H, s).

Elemental Analysis:

Calculated 29.41 3.95 27.44

Found 29.33 3.77 27.15 (%)

(C ₅ H ₈ N ₄ O ₃ S)

Claims (26)

The carboxyimidamide derivative represented by the following structural formula (A), or its kidney salt.

In the above formula, B is

(Where X represents a hydrogen atom or a chlorine atom) or

Or H ₃ CS R 'is B

(Where X represents a hydrogen atom or a chlorine atom), -R ¹ or

[Wherein R ¹ is an alkyl group, an alkyl group having a nitroxyl group,

(Wherein R4 represents an alkyl group or an alkoxyl group, b represents an integer of 0 to 1). R ² is selected from the group consisting of alkyl group, aryl group, nitroxyl group, arylalkoxy group, hydroxyl group and hydrogen atom, a represents an integer of 1 to 3 (where a is 2 or more, 2 or more are R <^2> to be may be any 1 type, or multiple types may be sufficient among the above-mentioned group and atom).

R ⁵ represents an alkyl group, an alkoxyl group, an aryl alkoxyl group, a nitro group, an amino group, an alkylamino group, an arylalkylamino group, an alkylthio group, a pafluoroalkyl group, or a halogen atom, and c is an integer of any one of 0 to 5. In addition, when c is 2 or more, any one or more of R 5 which becomes 2 or more of the groups and atoms described above may be used. B

Or H ₃ CS-.

The pyridine carboxyimidamide derivative or acid addition salt thereof according to claim 1, represented by the following structural formula (I).

In the above formula, X represents a hydrogen atom or a chlorine atom.

[Wherein R1 is an alkyl group, an alkyl group having a nitroxyl group,

(Wherein R4 represents an alkyl group or an alkoxyl group, b represents an integer of 0 to 1). R 2 represents an alkyl group, an aryl group, a nitroxyl group, an aryl alkoxyl group, a hydroxyl group, and a hydrogen atom selected from the group consisting of, a represents an integer of 1 to 3 (where a is 2 or more, 2 or more R2 to be used may be any one of the above-described groups and atoms, or may be plural kinds).

R 5 represents an alkyl group, an alkoxyl group, an aryl alkoxyl group, a nitro group, an amino group, an alkylamino group, an arylalkylamino group, an alkylthio group, a pafluoroalkyl group, or a halogen atom, and c represents an integer of 0 to 5. In addition, when c is 2 or more, any one or more of R ⁵ becoming 2 or more may be used among the above-described groups and atoms. The alkyl group of R ¹ of formula (I) has 1 to 10 carbon atoms, an alkyl group having a nitroxyl group has 1 to 5 carbon atoms, an alkyl group of R ² has 1 to 5 carbon atoms, and aryl The alkoxyl of the alkoxyl group has 1 to 3 carbon atoms, the alkyl group of R ⁴ has 1 to 5 carbon atoms, the alkoxy group has 1 to 5 carbon atoms, the alkyl group and the alkoxy group of R ⁵ have 1 to 5 carbon atoms, and the isoalkoxy group Alkoxyl has 1 to 3 carbon atoms, alkyl of alkylamino group has 1 to 5 carbon atoms, alkyl of arylalkylamino group has 1 to 3 carbon atoms, alkyl of alkylthio group has 1 to 5 carbon atoms, Alkyl of a roalkyl group has 1 to 5 carbon atoms, pyridinecarboxyimidamide or an acid addition salt thereof. The alkyl group of R1 of formula (I) has 5 to 8 carbon atoms, the alkyl group having a nitroxyl group has 1 to 3 carbon atoms, the alkyl group of R ² has 1 to 3 carbon atoms, and aryl The alkoxyl of the alkoxyl group has 1 to 3 carbon atoms, the alkyl group of R ⁴ has 1 to 3 carbon atoms, the alkoxy group has 1 to 3 carbon atoms, the alkyl group and the alkoxy group of R ⁵ have 1 to 3 carbon atoms, and the isoalkoxy group Alkoxyl has 1 to 3 carbon atoms, alkyl of alkylamino group has 1 to 3 carbon atoms, alkyl of arylalkylamino group has 1 to 3 carbon atoms, alkyl of alkylthio group has 1 to 3 carbon atoms, Alkyl of a roalkyl group has 1 to 3 carbon atoms, and C has 0 to 2 pyridinecarboximidamide derivative or acid addition salt thereof. The compound represented by formula (I) is N-cyano-N '-(2-nitoxyethyl) -2-pyridinecarboximidamide, N-cyano-N'-(2, 2-dimethylpropyl) -2-pyridinecarboximidamide, N-cyano-N '-(1, 2, 2-trimethylpropyl) -2-pyridinechromoxyimidamide, N-cyano-N'- Phenyl-2-pyridinecarboximidamide, N-cyano-N '-(4-methoxyphenyl) -2-pyridinecarboximidamide, N-cyano-N'-(4-methylbenzyl) -2 -Pyridinecarboximidamide, N-cyano-N '-(4-chlorobenzyl) -2-pyridinecarboximidamide, N-cyano-N'-[4- (trifluoromethyl) benzyl]- 2-pyridinecarboximidamide, N-cyano-N '-[2- (4-methylphenyl) ethyl] -2-pyridinecarboximidamide, N-cyano-N'-[2- (4-chloro Phenyl) ethyl] -2-pyridinecarboximidamide, N-cyano-N '-(-hydroxy-1-methyl-2-phenylethyl) -2-pyridinecarboximidamide, N-cyano-N '-(2-thienylmethyl) -2-pyridineka Boxiimidamide, N-cyano-N '-(2-nitroethylethyl) -3-pyridinecarboxyimidamide, N-cyano-N'-(3-nitropropyl) -3-pyridinecarboxyimide Damide, N-cyano-N '-(3, 3-dimethylbutyl) -3-pyridinecarboximidamide, N-cyano-N'-(4-methylphenyl) -3-pyridinecarboximidamide, N-cyano-N'-benzyl-3-pyridinecarboximidamide, N-cyano-N '-(4-methylbenzyl) -3-pyridinecarboximidamide, N-cyano-N'-( 4-methoxybenzyl) -3-pyridinecarboximidamide, N-cyano-N '-(4-dimethylaminobenzyl) -3-pyridinecarboximidamide, N-cyano-N'-[4- (Trifluoromethyl) benzyl] -3-pyridinecarboximidamide, N-cyano-N '-(4-chlorobenzyl) -3-pyridinecarboximidamide, N-cyano-N'-(4 -Nitrobenzyl) -3-pyridinecarboximidamide, N-cyano-N '-(3,4-dichlorobenzyl) -3-pyridinecarboximidamide, N-cyano-N'-[3, 5 -Bis (trifluorome ) Benzyl] -3-pyridinecarboximidamide, N-cyano-N '-(3-benzyloxybenzyl) -3-pyridinecarboximidamide, N-cyano-N'-(2-phenylethyl) -3-pyridinecarboximidamide, N-cyano-N '-[2- (2-methoxyphenyl) ethyl] -3-pyridinecarboximidamide, N-cyano-N'-[2- ( 2-chlorophenyl) ethyl] -3-pyridinecarboximidamide, N-cyano-N '-[2- (4-chlorophenyl) ethyl] -3-pyridinecarboximidamide, N-cyano-N '-[2- (4-benzylaminophenyl) ethyl] -3-pyridinecarboximidamide, N-cyano-N'-[2- (4-nitrophenyl) -2-nitoxyethyl] -3- Pyridinecarboximidamide, N-cyano-N '-(3-phenylpropyl) -3-pyridinecarboximidamide, N-cyano-N'-dimethylmethyl-3-pyridinecarboximidamide, N- Cyano-N '-(1,2-diphenylethyl) -3-pyridinecarboximidamide, N-cyano-N'-(2,2-diphenylethyl) -3-pyridinecarboximidamide, N-cyano-N '-(3, 3-diphenylpropyl) -3-pyrid Carboxylimidamid, N-cyano-N '-(2-benzyloxy-2-phenylethyl) -3-pyridinecarboximidamide, N-cyano-N'-[2- (3, 4-di Benzyloxyphenyl) ethyl] -3-pyridinecarboximidamide, N-cyano-N'-3- (2, 6-dimethoxypyridine) -3-pyridinecarboximidamide, N-cyano-N ' -(2-nitroethyl) -4-pyridinecarboximidamide, N-cyano-N '-(3-nitropropyl) -4-pyridinecarboximidamide, N-cyano-N'-phenyl 4-pyridinecarboximidamide, N-cyano-N '-(3,4-dichlorobenzyl) -4-pyridinecarboximidamide, N-cyano-N'-(4-methylthiobenzyl)- 4-pyridinecarboximidamide, N-cyano-N '-(3-benzyloxybenzyl) -4-pyridinecarboximidamide, N-cyano-N'-[2- (4-chlorophenyl) ethyl ] -4-pyridinecarboximidamide, N-cyano-N '-[2- (2-methoxyphenyl) ethyl] -4-pyridinecarboximidamide, N-cyano-N'-(phenylthio Ethyl) -4-pyridinecarboxyimidamide, N-cyano-N '-[2- (4-nitrophenyl) -2-nitoxyethyl] -4-pyridinecarboximidamide, N-cyano-N'-(2-nitoxyethyl) -3 Selected from the group consisting of compounds of (6-chloropyridine) -carboxyimidamide, N-cyano-N '-(2-phenylethyl) -3- (6-chloropyridine) -carboxyimidamide Pyridinecarboxyimidamide derivatives or acid addition salts thereof. The compound represented by formula (I) is N-cyano-N '-(2-nitoxyethyl) -2-pyridinecarboximidamide, N-cyano-N'-(2- Nitroethyl) -3-pyridinecarboximidamide, N-cyano-N'-benzyl-3-pyridinecarboximidamide, N-cyano-N '-(2-phenylethyl) -3-pyridinecarboxy Imidamide, N-cyano-N '-[2- (2-chlorophenyl) ethyl] -3-pyridinecarboxyimidamide, N-cyano-N'-(2-nitroethylethyl) -4- A pyridine carboximidamide derivative or acid addition salt thereof selected from the group consisting of pyridine carboximidamides. N-cyano-pyridinecarboxyl represented by the following formula (II) which is an intermediate for producing the pyridinecarboximidamide derivative represented by Structural formula (I) according to any one of claims 2 to 6 or acid salt thereof. Imidate compounds.

In the above formula, X represents a hydrogen atom or a chlorine atom, and R 'represents an alkyl group. A potassium channel activator comprising, as an active ingredient, a pyridinecarboxyimidamide derivative represented by Structural Formula (I) according to any one of claims 2 to 6 or an acid addition salt thereof. 9. An alkyl group according to claim 8, wherein X in formula (I) is a hydrogen atom, and R is an alkyl group having a nitroxyl group, or

A pyridinecarboxyimidamide derivative or its acid addition salt thereof (where d represents an integer of 1 to 3) as an active ingredient. A forcing agent comprising a pyridinecarboxyimidamide derivative represented by Structural Formula (I) according to any one of claims 2 to 6 or an acid addition salt thereof as an active ingredient. The alkyl group according to claim 10, wherein X in formula (I) is a hydrogen atom, and R is an alkyl group having a nitroxyl group, or

A pyridine carboximidamide derivative or an acid addition salt thereof which is (wherein e represents an integer of 1 to 3 and f represents an integer of 0 to 1) as an active ingredient. A therapeutic agent for ischemic heart disease, wherein the pyridinecarboxyimidamide derivative represented by Structural Formula (I) according to any one of claims 2 to 6 or an acid addition salt thereof is used as an active ingredient. The agent for treating ischemic heart disease according to claim 12, wherein X in the formula (I) is a hydrogen atom, and R is an alkyl group having a nitroxyl group, or a pyridinecarboxyimidamide derivative or an acid addition salt thereof as an active ingredient. A therapeutic agent for peripheral circulation insufficiency, wherein the pyridinecarboxyimidamide derivative represented by Structural Formula (I) according to any one of claims 2 to 6 or an acid addition salt thereof as an active ingredient. 15. The therapeutic agent for peripheral circulation insufficiency according to claim 14, wherein X in structural formula (I) is a hydrogen atom, R is an alkyl group having a nitroxyl group, or a pyridinecarboxyimidamide derivative or acid addition salt thereof as an active ingredient. The brain circulation improving agent which uses the pyridine carboxyimidamide derivative represented by structural formula (I) in any one of Claims 2-6, or its acid addition salt as an active ingredient. 17. The brain circulation improving agent according to claim 16, wherein X in the formula (I) is a hydrogen atom, and R is an alkyl group having a nitroxyl group, or a pyridinecarboxyimidamide derivative or an acid addition salt thereof as an active ingredient. A therapeutic drug for a thrombus such as a pyridinecarboxyimidamide derivative represented by the structural formula (I) according to any one of claims 2 to 6 or an acid addition salt thereof as an active ingredient. 19. A thrombosis therapeutic drug according to claim 18, wherein X in breakfast (I) is a hydrogen atom, and R is an alkyl group having a nitroxyl group, or a pyridinecarboxyimidamide derivative or acid addition salt thereof as an active ingredient. A therapeutic agent for asthma, comprising a pyridinecarboxyimidamide derivative represented by the structural formula (I) according to any one of claims 2 to 6 or an acid addition salt thereof as an active ingredient. The asthma therapeutic agent according to claim 14, wherein X in breakfast (I) is a hydrogen atom, and R is an alkyl group having a nitroxyl group, or a pyridinecarboxyimidamide derivative or an acid addition salt thereof as an active ingredient. The carboxyimidamide derivative or acid addition salt thereof according to claim 1, represented by sub structural formula (I ').

Where X is

Or H3C-S-, R '

23. The method of claim 22, wherein N-cyano-N '-(2-nitoxyethyl) -3-quinolinecarboxyimidamide, N-cyano-N'-(2-phenylethyl) -3-quinolinecarboxyimide Damide, N-cyano-N '-(2-nitroethylethyl) -3-pyrazinecarboxyimidamide, N-cyano-N'-(2-nitroethylethyl) -2-furancarboximidamide , N-cyano-N '-(2-phenylethyl) -2-furancarboxyimidamide, N-cyano-N'-(2-nitoxyethyl) -3-furancarboxyimidamide, N- Cyano-N '-(2-phenylethyl) -3-furancarboxyimidamide, N-cyano-N'-(2-nitoxyethyl) -2-thiophenecarboxyimidamide, N-cyano -N '-(2-phenylethyl) -2-thiophenecarboximidamide, N-cyano-N'-(2-phenylethyl) -3-thiophenecarboximidamide, N-cyano-N Carboximides selected from the group of compounds consisting of '-(2-phenylethyl) -4-cyanobenzenecarboxyimidamide and 3-cyano-2-methyl-1- (2-nitoxyethyl) isothiourea Damid Yu Thereof, or acid addition salt thereof. A pressure reducing agent comprising, as an active ingredient, the carboxyimidamide derivative represented by Structural Formula (I ') according to any one of claims 22 to 23 or an acid addition salt thereof. A pharmaceutical agent containing the carboxyimidamide derivative represented by the structural formula (A) according to claim 1 or an acid addition salt thereof as an active ingredient. The compound represented by the following structural formula (III) is reacted with alcohol, sodium hydride or sodium alkoxide to obtain the compound represented by the following structural formula (IV), and then cyanamide is reacted in a buffer of pH 5.0 to 6.0. An N-cyano-pyridinecarboximidate compound represented by (II) according to claim 7 is produced, and then NH ₂ -R, wherein R is the same as R in structural formula (I) of claim ₂ A method for producing a pyridinecarboximidamide derivative represented by Structural Formula (I) according to any one of claims 1 to 6, characterized by reacting an amine compound represented by the formula (I).

In the above formula, X represents a hydrogen atom or a chlorine atom, and R 'represents an alkyl group.

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