JP2846070B2 - Carboximidamide derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel carboximidamide derivative having a vasodilatory effect and a hypotensive effect.

<Prior Art> Conventionally known carboximidamide compounds related to the present invention include N-cyano-3-pyridinecarboximidamide, N-cyano-2-thiophenecarboxyimidamide, N-cyano-3-thiophenecarboxy. Imidamide (all three, Journal of Medicinal Chemistry, 23rd
Vol. 690-692, 1980), N-cyano-4- (2-ethylpyridine) carboximidamide (Leprosy Review, 23-30, 1983), N-
Cyano-4-pyridinecarboximidamide (Bulletin des Societes Kimix Berges)
des Societes Chimiques Belges), Vol. 78, 41-46
P. 1969), N-cyano-5-nitro-2-furamidine (JP-B-43-20543 and British Patent No. 1133950) and N- (N-cyanoimidoyl) -sulfoxyimides (Chemich Berichte). (Chemische Bericht
e), Vol. 121, pp. 383-386, 1988).
However, these compounds have been reported as antimicrobial agents, intermediates for the production of diuretics and intermediates for the production of thiatriazines, respectively, and have no reports on vasodilatory and hypotensive effects. Further, among carboximidamide compounds related to the present invention, those having an alkyl substituent at the N'-position have not been known at all.

[Summary of the Invention]

<Summary> The present invention has been made for the purpose of providing a novel compound having a vasodilatory effect, and is one of N-cyano-N'-substituted-carboximidamide derivatives.
By finding that the novel compound substituted at the position with an alkyl substituent has vasodilatory and antihypertensive effects,
It has been completed.

That is, the carboximidamide derivative according to the present invention is represented by the following formula (I).

[In the formula, the substituent is defined by any of the following (1) to (5).

(1) X is Or its acid adduct, Or its acid adduct, Or its acid adduct, (Where R ₁ represents a hydrogen atom or a cyano group), a methyl group or CH ₃ —S—, and Y is And Z is (Where R ₂ represents a hydrogen atom or a chlorine atom).

(2) X is Or Y represents an acid adduct thereof. The expressed, Z is _{- (CH 2) m -R 3} [ wherein m represents an integer of 1 to 3, when m is 1, R ₃ is And when m is 2, R ₃ is Dimethylamino group, acetamido group, −SO ₃ ^- Na ⁺ , Azide group or -OR ₅ (where R ₅ is a methyl group, -SO ₃ ^- N
a ⁺ , benzyl, phenyl, hydrogen, benzoyl, acetyl, -P (O) (OCH ₂ CH ₃ ) ₂ , ethoxycarbonyl, or And when m is 3, R ₃ is —COOCH ₂ CH
₃ , -COOH or a nitro group].

(3) X is Or Y represents an acid adduct thereof. Wherein R ₄ represents a methyl group or a benzyl group, and Z is Represents

(4) X is Or Y represents an acid adduct thereof. (Where Q represents a nitrogen atom or a carbon atom), and Z is bonded to Q, and when Q is a nitrogen atom, (Where R ₆ represents an acetyl group, a nitro group, a chlorine atom or a methoxy group), And when Q is a carbon atom, Represents a benzyl group, a hydroxyl group, or a nitroxyl group.

(5) X is Or Y represents an acid adduct thereof. And Z is Represents <Effect of the Invention> The carboximidamide derivative according to the present invention, that is, the N-cyano-N′-substituted-carboximidamide derivative, has an excellent vasodilatory action and also has a strong antihypertensive action. . It can be said that the property that the carboximidamide derivative according to the present invention has a strong antihypertensive effect in addition to an excellent vasodilator effect in this way was unexpected.

[Specific description of the invention]

[I] N-cyano-N'-substituted-carboximidamide derivative The carboximidamide derivative according to the present invention is represented by the following formula (I) as described above, and N-cyano-N ' -Substituted-carboximidamide derivatives.

[In the formula, the substituent is defined by any of the following (1) to (5).

(1) X is Or its acid adduct, Or its acid adduct, Or its acid adduct, (Where R ₁ represents a hydrogen atom or a cyano group), a methyl group or CH ₃ —S—, and Y is And Z is (Where R ₂ represents a hydrogen atom or a chlorine atom).

(2) X is Or Y represents an acid adduct thereof. The expressed, Z is _{- (CH 2) m -R 3} [ wherein m represents an integer of 1 to 3, when m is 1, R ₃ is And when m is 2, R ₃ is Dimethylamino group, acetamido group, −SO ₃ ^- Na ⁺ , Azide group or -OR ₅ (where R ₅ is a methyl group, -SO ₃ ^- N
a ⁺ , benzyl, phenyl, hydrogen, benzoyl, acetyl, -P (O) (OCH ₂ CH ₃ ) ₂ , ethoxycarbonyl, or And when m is 3, R ₃ is —COOCH ₂ CH
₃ , -COOH or a nitro group].

(3) X is Or Y represents an acid adduct thereof. Wherein R ₄ represents a methyl group or a benzyl group, and Z is Represents

(4) X is Or Y represents an acid adduct thereof. (Where Q represents a nitrogen atom or a carbon atom), and Z is bonded to Q, and when Q is a nitrogen atom, (Where R ₆ represents an acetyl group, a nitro group, a chlorine atom or a methoxy group), And when Q is a carbon atom, Represents a benzyl group, a hydroxyl group, or a nitroxyl group.

(5) X is Or Y represents an acid adduct thereof. And Z is Represents Where X is Acid adduct of Acid adduct of Acid adduct of When the compound is an acid adduct of the formula (I), the compound of the formula (I) may form an acid addition salt.

That is, in the carboximidamide derivative according to the present invention, the group represented by X in the above formula (I) has a basic nitrogen atom. Where the acid addition salt is present. Acids to form acid addition salts include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, propionic acid, maleic acid, oleic acid, palmitic acid, citric acid, succinic acid,
Organic acids such as tartaric acid, fumaric acid, glutamic acid, pantothenic acid, laurylsulfonic acid, methanesulfonic acid, and toluenesulfonic acid can be given. When an acid addition salt is used as a medicine, it goes without saying that the acid must be pharmaceutically acceptable.

The N-cyano-N'- of the formula (I) according to the invention
Representative examples of the substituted-carboximidamide derivatives include the following.

The structures of these compounds are shown below.

[II] Production of N-cyano-N'-substituted-carboximidamide derivative The N-cyano-N'-substituted-carboximidamide derivative according to the present invention can be produced by any suitable method. For example, the method (A) described below,
Method (B), method (C), method (D), method (E) and (F)
It can be manufactured by six manufacturing methods. However, the methods (B), (C) and (F) are methods for chemically converting the compound obtained by the method (A).

1) Among the carboximidamide derivative in A method present invention, when X is methyl, phenyl or CH ₃ -S-, or a compound Y is except in the case of N-COCH ₃ is
As shown in the reaction formula (A), the nitrile represented by the formula (II) can be converted to a cyanoimidate of the formula (IV) and reacted with an amine compound.

[In the formula, R ′ and R ″ represent a linear or cyclic alkyl group having 1 to 8 carbon atoms. R ′ and R ″ may be the same or different. Hereinafter, this production method will be described in more detail according to the reaction formula (A).

(A) Compound (II) → Compound (III) The nitrile represented by the formula (II) is prepared by reacting R ″ ONa, that is, sodium alkoxide, sodium hydroxide or potassium hydroxide in R′OH, that is, in alcohol. The amount of R ″ OH, sodium hydroxide or potassium hydroxide used in this reaction is a catalytic amount, which is usually based on 1 mol of the nitrile represented by the formula (II). On the other hand, it is good to carry out in the range of 0.01 mol to 0.5 mol, more preferably 0.02 mol to 0.2 mol.

The alcohol (R'OH) that can be used in this reaction may be either a linear or cyclic alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Butanol, cyclopentanol, cyclohexanol, n-octanol and the like. These alcohols can be used as a reaction solvent, or can be used only as a reaction reagent in the presence of another solvent. Generally, when used as a reaction solvent, 1 mole of nitrile
Usually, it is used in the range of 10 to 50 mol, and when it is used in the presence of another solvent, it is preferably in the range of 1 to 5 mol per mol of nitrile. As a solvent that can be used in this reaction, for example, an aprotic solvent such as hexane, benzene, toluene, diethyl ether, petroleum ether, and tetrahydrofuran are preferable. The reaction temperature is in the range of 0 ° C to 50 ° C, particularly preferably 0 ° C to room temperature.

Under the above reaction conditions, this reaction can be completed usually in 0.5 to 28 hours.

The obtained imidate compound represented by the formula (III) can be subjected to the next reaction without isolation and purification. In the case of isolation and purification, the method includes a distillation method and a column chromatography using silica gel as a carrier. A purification method known in the field of organic synthetic chemistry, such as chromatography, can be used.

(B) Compound (III) → Compound (IV) An imidate compound represented by the formula (III) is prepared by treating cyanamide (NH ₂ C
By the action of N), it is converted to a cyanomimidate compound represented by formula (IV).

The amount of cyanamide used is preferably at least 1 mol or more, particularly preferably 2 to 3 mol, per 1 mol of the imidate compound. This reaction is carried out in a buffer solution (preferably a phosphate buffer solution) as described above. However, when the solvent of the raw material is low, an organic solvent such as acetonitrile can be added. The pH range is advantageously in the range 5.0 to 6.5, more preferably in the range 5.2 to 6.2, and the buffer concentration is in the range 0.5 to 4M, especially 1 to 3M. In order to maintain sufficient buffering capacity, in the case of a buffer component, that is, in the case of a phosphate buffer, for example, Na ₂ HPO ₄ and NaH ₂ PO ₄ are at least 1 component per mole of imidate compound. It is desirable to use more than moles. The reaction temperature is preferably in the range of 0 to 50 ° C, and particularly preferably around room temperature.

Under such reaction conditions, the imidate compound represented by the formula (III) is completely converted into the cyanoimidate compound represented by the formula (IV) usually in 2 to 75 hours.

As a method for isolating and purifying the thus obtained cyanoimidate compound represented by the formula (IV), a crystallization method,
A purification method known in the field of organic synthetic chemistry, such as a distillation method and column chromatography using silica gel as a carrier, can be used.

(C) Compound (IV) → Compound (I) The cyanoimidate compound represented by the formula (IV) is reacted with various amine compounds to form an N-cyano-N′-substituted compound represented by the formula (I). Carboximidamide derivatives can be produced.

The amount of the amine compound to be used is suitably at least 1 mol or more, more preferably 1 to 2 mol, per 1 mol of the cyanoimidate compound represented by the formula (IV). This reaction is usually carried out in a solvent. Examples of usable solvents include methanol, ethanol, dichloromethane, chloroform, carbon tetrachloride, and the like.
Organic solvents such as dioxane and tetrahydrofuran, or water. The reaction temperature is in the range of 0 ° to the boiling point of the solvent, and particularly preferably around room temperature.

Under the above reaction conditions, this reaction is usually performed for 5 minutes to
It can be finished in 50 hours.

The method for isolating and purifying the compound represented by the formula (I) from the reaction mixture obtained by the above reaction is the same as that described in the section of the isolation and purification of the cyanoimidate compound represented by the formula (IV). .

2) Method B As described above, the method (B) is a method of chemically converting the compound obtained by the method (A). Among the carboximidamide derivatives in the compound of the present invention, Z is Or Is a compound (VI) wherein Z which can be obtained by the method (A) is Can be obtained by using a compound (V) as a raw material by a process as shown in a reaction formula (B).

Hereinafter, this production method will be described in more detail according to the reaction formula (B).

The compound represented by the formula (VI) can be produced by esterifying a hydroxyl group of the compound (V) with an esterification reagent. Examples of the esterification reagent include acid halides, acid anhydrides, active esters, and the like. The reaction conditions are as follows. In an organic solvent inert to the esterification reaction, such as pyridine, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, or acetonitrile, the esterification reagent is preferably used in an amount of 1.5 mol per mol of the raw material (V).
The reaction is carried out using 2.52.5 mol. The reaction is preferably performed in the presence of a base such as an organic base such as triethylamine and pyridine and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. The reaction temperature is preferably from 0 ° C. to room temperature.

After post-treatment of the reaction mixture obtained by the above reaction according to a conventional method, the compound of formula (VI) is obtained by a method known in the field of organic synthetic chemistry, such as a crystallization method or column chromatography using silica gel as a carrier. Can be isolated and purified.

3) Method C As described above, the method (C) is a method of chemically converting the compound obtained by the method (A).

Among the carboximidamide derivatives in the compound of the present invention, N-cyano-N '-(3-carboxypropyl)
-3-pyridinecarboximidamide (formula (VIII))
Is N-cyano- which can be obtained by the method (A).
Using N '-(3-ethoxycarbonylpropyl) -3-pyridinecarboximidamide (formula (VII)) as a raw material, it can be obtained by a process as shown in reaction formula (C).

Hereinafter, this production method will be described in more detail according to the reaction formula (C).

The compound represented by the formula (VIII) can be produced by hydrolyzing the carboxylic acid ester of the compound (VII).

The reaction is carried out in a polar organic solvent such as methanol, ethanol, N, N-dimethylformamide or acetonitrile or in an aqueous solution by adding an excess molar amount of potassium hydroxide or sodium hydroxide to the raw material (VII).
In the reaction in an organic solvent, it may be advantageous to carry out the reaction in the presence of water. The reaction temperature is preferably from 0 ° C. to room temperature. By removing potassium ions or sodium ions from the reaction mixture obtained by the above reaction according to a conventional method, the target compound represented by the formula (VIII) can be obtained.

4) Method D Among the carboximidamide derivatives in the compound of the present invention, a compound wherein X is a methyl group or a phenyl group is
As shown in the reaction formula (D), the orthoester represented by the formula (IX) is led to a cyanoimidate compound of the formula (X),
It can be obtained by reacting this with 2-phenylethylamine.

Hereinafter, this production method will be described in more detail according to the reaction formula (D).

(A) Compound (IX) → Compound (X) The orthoester represented by the formula (IX) is
By reacting with cyanamide (NH ₂ CN), it is converted into a cyanoimidate compound represented by the formula (X). The reaction conditions are preferably 1 to 1 mol of the raw material (IX).
It is preferred to carry out at room temperature using ~ 2 mol of cyanamide and 2-4 mol of acetic anhydride. After post-treatment of the reaction mixture obtained by the above-mentioned reaction according to a conventional method, a cyanoimide represented by the formula (X) is obtained by a method known in the field of organic chemistry, such as a crystallization method or column chromatography using silica gel as a carrier. The date compound can be isolated and purified.

(B) Compound (X) → Compound (XI) The carboximidamide derivative represented by the formula (XI) is
It can be obtained by the same reaction as in method (A) (A).

5) Method E Among the compounds of the present invention, 3-cyano-2-methyl-1-
(2-Nitroxyethyl) isothiourea is produced by reacting 2-nitroxylethylamine with dimethyl-N-cyanodithioiminocarbonate represented by the formula (XII) as shown in the following reaction formula (E). can do.

The amount of 2-nitroxyethylamine used in this reaction is preferably at least 1 mol, more preferably 1 to 2 mol, per 1 mol of dimethyl-N-cyanodithioiminocarbonate represented by the formula (XII). This reaction is generally carried out in a solvent, and suitable solvents that can be used include alcohols such as methanol, ethanol and isopropanol, and solvents such as chloroform, dichloromethane, tetrahydrofuran, benzene and toluene. The reaction temperature is preferably in the range from the freezing point of the solvent to 50 ° C., and particularly preferably around room temperature. Under the above reaction conditions, this reaction can be completed in 1 to 30 hours.

From the reaction mixture obtained in the above reaction, 3-cyano-2
As a method for isolating and purifying -methyl-1- (2-nitroxyethyl) isothiourea, a purification method known in the field of organic synthetic chemistry such as a crystallization method, a distillation method, and chromatography using silica gel as a carrier is used. be able to.

6) Method F Among the compounds of the present invention, N-cyano-N'-acetyl-
[2- (2-Chlorophenyl) ethyl] -3-pyridinecarboximidamide can be obtained by reacting N-cyano-N '-[2-
(2-chlorophenyl) ethyl] -3-pyridinecarboximidamide can be produced by reacting with acetic anhydride.

The amount of acetic anhydride used in this reaction is at least 1 mol per 1 mol of N-cyano-N '-[2- (2-chlorophenyl) ethyl] -3-pyridinecarboximidamide represented by the formula (XIII). As described above, the amount is particularly preferably 1 to 2 mol. This reaction is usually carried out in a solvent, and suitable solvents that can be used include pyridine, tetrahydrofuran, dichloromethane, chloroform and other solvents inert to the reaction. The reaction is preferably performed in the presence of an organic base such as triethylamine and pyridine.
The reaction temperature is preferably from 0 ° C. to room temperature.

From the reaction mixture obtained by the above reaction, N-
Cyano-N'-acetyl-N '-[2- (2-chlorophenyl) ethyl] -3-pyridinecarboximidamide can be isolated and purified.

Among the compounds represented by the formula (I) according to the present invention, those having a basic nitrogen can be converted into acid addition salts thereof according to a method known per se. Acids that can be added salts are as described above.

[III] Use of Compound As described above, the compound according to the present invention has vasodilatory and hypotensive effects. Therefore, the compounds of the present invention are useful as vasodilators or antihypertensives.

When the compounds according to the invention are administered as vasodilators or antihypertensives, they are administered orally or parenterally (intramuscularly,
(Subcutaneous, intravenous, transdermal absorption) or sublingual tablets, suppositories and the like.

It goes without saying that the dose and the method of administration of the compound of the present invention will vary depending on the condition of the patient, for example, body weight, sex, sensitivity, administration time, the concomitant drug, the patient or the degree of the disease, and under certain conditions. The appropriate amount and the number of administrations in the above should be determined by an appropriate amount determination test by a specialist on the basis of the above guidelines, and usually, the daily dose for an adult is about 0.1 to 200 mg, preferably about 0.5 to 100 mg.

When the compound of the present invention is orally administered as a medicine, it is administered as a tablet, granule, powder, or capsule, and when administered parenterally, it is administered as an injection or suspension.
To produce these preparations, excipients, binders, disintegrants, lubricants, stabilizers and the like can be added.

As an excipient, for example, lactose, starch, crystalline cellulose, mannitol, maltose, calcium hydrogen phosphate, light anhydrous silicic acid, calcium carbonate, etc., as a binder, for example, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, ethyl cellulose, carboxymethyl cellulose , Gum arabic, etc., as disintegrants
For example, starch, carboxymethylcellulose calcium and the like, as a lubricant, for example, magnesium stearate, talc, hydrogenated oil and the like, as a stabilizer, for example, lactose,
Mannitol, maltose, polysorbates, macrogol, polyoxyethylene hydrogenated castor oil and the like.

These components can be used to produce tablets, granules, capsules, injections and the like.

EXPERIMENTAL EXAMPLES The following Reference Examples and Examples serve to explain the present invention in more detail, but are not intended to limit the present invention.

Reference Example 1 Vasodilatory action on rat aorta specimen (1) Test method The physiological activity of the compound of the present invention was tested by a method using the aorta of an isolated rat.

The thoracic aorta was immediately excised from a male Wistar rat weighing 250 to 350 g, which had been killed by exsanguination, and a 3 mm-wide slice was prepared. Specimens were Krebs-Ringer at 37 ° C. aerated with a gas mixture of 95% O ₂ -5% CO _2.
It was suspended in an organ bath filled with liquid.

After applying a static tension of 1 g and the tension of the specimen is stabilized, the organ bath is replaced with an isotonic nutrient solution containing 40 mM KCl,
The specimen tension was increased.

After the tension generated by KCl became constant, the test compound was cumulatively added to the organ bath to relax the specimen.

The relaxation reaction was determined as the inhibition rate, with the tension due to KCl being 100%, and the IC ₅₀ value (concentration at which the tension due to KCl was inhibited by 50%) was calculated from the average dose-effect curve by the probit method.

(2) Results Among the compounds of the present invention, a representative compound (Compound No. 1
1, 22, 31, 48, 49, 50, 51, 52, 53, 54, 55, 56, 5
The IC ₅₀ values of 8, 59, 60, and 62) are shown in Table 1.

Reference Example 2 Blood pressure lowering effect on spontaneously hypertensive rats (intravenous administration) (1) Test method The blood pressure lowering effect of the compound of the present invention was observed in male spontaneously hypertensive rats (SHR) (Test Compounds (4) and (8)). )).

The carotid artery of a rat anesthetized with urethane-α-chloralose (1 g / kg-25 mg / kg, intraperitoneal injection) was cannulated, and the mean blood pressure was measured via a pressure transducer. Compounds were cumulatively administered every 30 minutes from a cannula inserted into the jugular vein. The blood pressure before the administration is 100%, determine the change in blood pressure as a descent rate, dose - were calculated from the working curve ED ₂₀ value (dose that blood pressure drops 20%).

(2) Results Among the compounds of the present invention, representative compounds (compound No. 51,
Table 2 shows the ED ₂₀ value of 55).

Example 1 N-cyano-N '-[2- (1-piperidino) ethyl]
Preparation of -3-pyridinecarboximidamide a) 3-cyanopyridine (10 g, 0.10 mol) and sodium hydroxide (0.20 g, 5.0 mmol) were added to n-propanol (60 m
l) and reacted at 0 ° C. overnight. After the reaction, acetic acid (0.32 g, 5.3 mmol) was added to neutralize the reaction solution, and concentrated under reduced pressure. The obtained residue was distilled under reduced pressure at 4 mmHg under reduced pressure to obtain 100.
N-Propyl-3-pyridinecarboximidate was distilled at ~ 110 ° C to give an oil (11.4 g, 0.07 mol, yield 70
%).

Then add 11.4g of this oil to cyanamide (4.5g, 0.11mo
l) and Na ₂ HPO ₄ (9.8 g, 0.07 mol) and NaH ₂ PO ₄ .2H ₂ O (4
(3.4 g, 0.28 mol) of a phosphate buffer (pH 5.4, 60 ml) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction, extraction was performed with dichloromethane (50 ml × 3 times). The dichloromethane layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g), and eluted with hexane: diethyl ether (1: 2). Cyano-3-pyridinecarboximidate (12.1 g, 0.06 mol, 86% yield) was obtained as a syrup.

Physicochemical properties of n-propyl = N-cyano-3-pyridinecarboximidate Infrared absorption spectrum (cm ⁻¹ , neat): 2200, 1610, 132
0,720 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 9.21 (1H, brs), 8.83 (1H, d, J = 4.9Hz), 8.47 (1H, br
d, J = 7.9 Hz), 7.53 (1H, dd, J = 4.9, 7.9 Hz), 5.36 (1
H, brs), 4.45 (2H, t, J = 6.4Hz), 1.90 (2H, m), 1.07
(3H, t, J = 7.3 Hz) b) n-propyl = N-cyano-3-pyridinecarboximidate (0.70 g, 3.7 mmol) was added to methanol (10 m
l), N- (2-aminoethyl) piperidine (0.56 g, 4.4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.1%).
76 g, 3.0 mmol, 84% yield) were obtained as crystals.

N-cyano-N '-[2- (1-piperidino) ethyl]
Physicochemical properties of -3-pyridinecarboximidamide Melting point: 130.5 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2190, 1590, 156
0,710 Nuclear magnetic resonance spectrum (100 MHz, in CDCl ₃ ): δ (pp
m) 8.84 to 8.76 (2H, m), 8.11 (1H, dt, J = 2.1,7.9Hz), 7.
48 (1H, dd, J = 0.6,7.9Hz), 3.58 (2H, t, J = 6.0Hz),
2.58 (2H, t, J = 5.8Hz), 2.51 ~ 2.34 (4H, m), 1.70 ~
1.40 (6H, m) mass spec: m / e 257 M ⁺ Example 2 N-cyano-N '-[2- (2-pyridyl) ethyl]-
Preparation of 3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.70 g, 3.7 mmol) was dissolved in methanol (20 ml), and 2- (2-aminoethyl) pyridine (0.54 g) was dissolved. ,
4.4 mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.49 g, 2.0
mmol, yield 54%) as crystals.

N-cyano-N '-[2- (2-pyridyl) ethyl]-
Physicochemical properties of 3-pyridinecarboximidamide Melting point: 143.5-144 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2170, 1590, 155
0,710 Nuclear magnetic resonance spectrum (100 MHz, in CDCl ₃ ): δ (pp
m) 8.83-8.74 (2H, m), 8.49-8.44 (1H, m), 8.19-8.05
(1H, m), 7.79 to 7.38 (2H, m), 7.33 to 7.16 (2H, m),
4.06 to 3.83 (2H, m), 3.25 to 3.06 (2H, m) Mass spec: m / e 251 M ⁺ Example 3 N-cyano-N '-{2- [2- (1-methylpyrrolyl) ethyl]} Preparation of -3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.70 g, 3.7 mmol) is dissolved in methanol (20 ml) and 2- (2-aminoethyl) -1- Methyl-pyrrole (0.55 g, 4.4 mmol) was added and stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.61 g, 2.4 mmol, yield 65%) as crystals.

Physicochemical properties of N-cyano-N '-{2- [2- (1-methylpyrrolyl) ethyl]}-3-pyridinecarboximidamide Melting point: 168-168.5 ° C Infrared absorption spectrum (cm ^-1 , KBr) : 2160, 1580, 710 Nuclear magnetic resonance spectrum (100 MHz, in CDCl ₃ ): δ (pp
m) 8.77 to 8.64 (2H, m), 7.99 (1H, dt, J = 1.9,7.9Hz), 7.
42 (1H, dd, J = 0.6,7.9Hz), 6.61 (1H, t, J = 2.0Hz),
6.10-5.91 (2H, m), 3.86-3.66 (2H, m), 3.59 (3H, m
s), 2.97 (2H, t, J = 6.6 Hz) Mass spec: m / e 253 M ⁺ Example 4 N-cyano-N '-{2- [2- (1-methylpyrrolidinyl) ethyl]} Preparation of -3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.70 g, 3.7 mmol) was dissolved in methanol (20 ml), and 2- (2-aminoethyl) -1- Methylpyrrolidine (0.48 g, 3.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wacoal Gel C-200, 1
00g). The compound was eluted with chloroform: methanol (5: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (0.62 g, 2.4 mmol, yield 65%) as crystals.

Physicochemical properties of N-cyano-N '-{2- [2- (1-methylpyrrolidinyl) ethyl]}-3-pyridinecarboximidamide Melting point: 91-92 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1590, 156
0,720 Nuclear magnetic resonance spectrum (100 MHz, in CDCl _3): δ (pp
m) 8.79-8.72 (2H, m), 8.12 (1H, dt, J = 2.1,7.9Hz), 7.
53-7.37 (1H, m), 3.99-3.38 (2H, m), 3.11-2.86
(1H, m), 2.72-2.52 (1H, m), 2.33 (3H, s), 2.29-
1.63 (7H, m) mass spec: m / e 257 M ⁺ Example 5 Preparation of N-cyano-N '-[2- (1-morpholino) ethyl]}-3-pyridinecarboximidamide n-propyl = N -Cyano-3-pyridinecarboximidate (0.70 g, 3.7 mmol) was dissolved in methanol (20 ml) and N- (2-aminoethyl) morpholine (0.48
g, 3.7 mmol) and stirred at room temperature for 2 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.68 g,
2.6 mmol, yield 70%) as crystals.

N-cyano-N '-[2- (1-morpholino) ethyl]
Physicochemical properties of -3-pyridinecarboximidamide Melting point: 137.5 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2190, 1590, 158
0, 1560, 1120, 710 Nuclear magnetic resonance spectrum (100 MHz, in CDCl ₃ ): δ (pp
m) 8.86-8.76 (2H, m), 8.21-8.03 (1H, m), 7.58-7.42
(1H, m), 3.75 to 3.65 (6H, m), 2.85 to 2.40 (6H, m) Mass spec: m / e 259 M ⁺ Example 6 N-cyano-N '-[2- (dimethylamino) ethyl ]
Preparation of -3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml) and N, N-dimethylethylenediamine (0.26 g, 3.0 m
mol) and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wacoal gel C-200, 100 g). The mixture was eluted with chloroform: methanol (20: 1). The eluted fraction was concentrated under reduced pressure and then crystallized from diethyl ether to give the title compound (0.07 g, 0.3 mmol, yield 12%) as crystals.

N-cyano-N '-[2- (dimethylamino) ethyl]
Physicochemical properties of -3-pyridinecarboximidamide Melting point: 86 to 87 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1600, 156
0,720 Nuclear magnetic resonance spectrum (100 MHz, in CDCl _3): δ (pp
m) 7.9-7.4 (2H), 7.08 (1H, ddd, J = 2.0,2.0,7.9Hz),
6.46 (1H, dd, J = 5.0,7.8Hz), 3.57 (2H, t, J = 5.0H
z), 2.57 (2H, t, J = 5.0 Hz), 2.26 (6H, s) Mass spec: m / e 218 [M + H] ⁺ Example 7 N-cyano-N '-(2-acetamidoethyl) -3- Preparation of pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and N-acetylethylenediamine (0.30 g, 2.9 mm) was dissolved.
ol) and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was crystallized from methanol / diethyl ether to give the title compound (0.47 g, 2.0 mmol,
(Yield 77%) as crystals.

Physicochemical properties of N-cyano-N '-(2-acetamidoethyl) -3-pyridinecarboximidamide Melting point: 183 to 185 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1660, 160
0,1550,720 Nuclear magnetic resonance spectrum (100 MHz, in CDCl _3): δ (pp
m) 8.85-8.70 (2H, m), 8.08 (1H, ddd, J = 1.9,2.0,7.9H
z), 7.55 (1H, dd, J = 4.9,7.9Hz), 3.70-3.30 (4H,
m), 1.99 (3H, s) mass spec: m / e 232 [M + H] ⁺ Example 8 N-cyano-N '-[2- (2-indolyl) ethyl]
Preparation of -3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2- (2-aminoethyl) indole / hydrochloric acid was dissolved. Salt (0.46 g, 2.9 mmol) and sodium methoxide (0.16
g, 2.9 mmol) and stirred at room temperature for 1.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was 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 crystallized from methanol / diethyl ether to give the title compound (0.43 g, 1.5 mmol, yield 56%) as crystals.

N-cyano-N '-[2- (2-indolyl) ethyl]
Physicochemical properties of -3-pyridinecarboximidamide Melting point: 121 to 122 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1730, 147
0,1210,830,630 Nuclear magnetic resonance spectrum (100 MHz, in CDCl _3): δ (pp
m) 8.64 (1H, dd, J = 1.9,4.9Hz), 8.53 (1H, d, J = 2.0H)
z), 7.96 (1H, ddd, J = 1.9,2.0,7.9HZ), 7.70-7.05
(6H, m), 3.80 (2H, t, J = 5.5HZ), 3.11 (2H, t, J = 5.5
HZ) mass spec: m / e 290 [M + H] ⁺ Example 9 Preparation of N-cyano-N '-[2- (1-pyrrolidinyl) ethyl] -3-pyridinecarboximidamide n-propyl = N-cyano- 3-Pyridine carboximidate (0.70 g, 3.7 mmol) was dissolved in methanol (20 ml), and 1- (2-aminoethyl) pyrrolidine (0.42
g, 3.7 mmol) and stirred at room temperature for 2.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate / hexane to give the title compound (0.74 g, 3.0 mm
ol, yield 81%) as crystals.

Physicochemical properties of N-cyano-N '-[2- (1-pyrrolidinyl) ethyl] -3-pyridinecarboximidamide Melting point: 114 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1590, 156
0,710 Nuclear magnetic resonance spectrum (100 MHz, in CDCl ₃ ): δ (pp
m) 8.78 to 8.76 (2H, m), 8.09 (1H, dt, J = 2.0,8.2Hz), 7.
45 (1H, ddd, J = 0.6,4.9,7.9Hz), 3.59 (2H, t, J = 5.6H
z), 2.75 (2H, t, J = 5.6Hz), 2.60-2.40 (4H, m), 1.
80-1.70 (4H, m) mass spec: m / e 243 M ⁺ Example 10 N-cyano-N '-{2- [2- (5-nitropyridyl) amino] ethyl} -3-pyridinecarboximidamide Preparation of n-propyl = N-cyano-3-pyridinecarboximidate (0.70 g, 3.7 mmol) was dissolved in methanol (20 ml), and 2- (2-aminoethylamino) -5-nitropyridine (0.68 g, 3.7 mmol) and stirred at room temperature for 2.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (1.04 g, 3.3 mmol, yield 89%) as crystals.

Physicochemical properties of N-cyano-N '-{2- [2- (5-nitropyridyl) amino] ethyl} -3-pyridinecarboximidamide Melting point: 192 ° C Infrared absorption spectrum (cm ^-1 , KBr) : 2220,1600,156
0, 1330, 1300, 1120, 830, 720 Nuclear magnetic resonance spectrum (100 MHz, in CD ₃ OD): δ (pp
m) 8.95-8.90 (1H, m), 8.80-8.71 (2H, m), 8.26-7.95
(2H, m), 7.70-7.45 (1H, m), 6.55 (1H, d, J = 9.0H
z), 3.80-3.70 (4H, m) Mass spec: m / e 311 M ⁺ Example 11 Preparation of 1- (4-diphenylmethylpiperazinyl) N-cyano-3-pyridinecarboximidamide and its hydrochloride n-Propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 1- (diphenylmethyl) piperazine (0.73 g) was dissolved.
g, 2.9 mmol) and stirred at room temperature for 2 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g).
Elution was performed with chloroform: methanol (100: 1), and the eluted fraction was concentrated under reduced pressure to obtain the title compound (0.80 g, 2.1 mmol, yield 81%) as a syrup. 5% more for syrup
The mixture was dissolved by adding a methanol solution of hydrogen chloride (3 ml) and concentrated under reduced pressure. The concentrated residue was crystallized from methanol / diethyl ether to give the title hydrochloride (0.91 g, 2.0 mmol, yield 77%) as crystals.

Physicochemical properties of 1- (4-diphenylmethylpiperazinyl) N-cyano-3-pyridinecarboximidamide hydrochloride Melting point: 131-132 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1580 , 720 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m), 9.1-8.8 (2H), 8.0-7.3 (12H) 5.4 (1H, brs), 4.8
-4.3 (2H), 3.5-3.2 (2H), 2.9-2.6 (4H) Mass spectrometry: m / e 381 [M-HCl] ⁺ Example 12 1- (4-benzylpiperazinyl) N-cyano-3 −
Preparation of pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and N-benzylpiperazine (0.51 g, 2.9 mmol) was added. Stir at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.48 g, 1.6 mmol, yield 62).
%) As crystals.

1- (4-benzylpiperazinyl) N-cyano-3-
Physicochemical properties of pyridinecarboximidamide Melting point: 134-136 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1580, 145
0,1310,1010,740 nuclear magnetic resonance spectrum (500 MHz, in CDCl _3): δ (pp
m) 8.77 (1H, d, J = 4.9Hz), 8.58 (1H, brs), 7.74 (1H, br
d, J = 7.9Hz), 7.48 (1H, dd, J = 4.9,7.9Hz), 7.35-7.
20 (5H, m), 4.00 to 3.98 (2H, m), 3.55 (2H, s), 3.40
~ 3.25 (2H, m), 3.65 ~ 3.55 (2H, m), 3.45 ~ 3.35 (2
H, m) mass spec: m / e 305 M ⁺ Example 13 1- [4- (4-acetylphenyl) piperazinyl]
Preparation of N-cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml) and 4-piperazino-acetophenone (0.59 g) , 2.9
mmol) and stirred at room temperature for 1.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.71 g, 2.1 mm
ol, yield 81%) as crystals.

1- [4- (4-acetylphenyl) piperazinyl]
Physicochemical properties of N-cyano-3-pyridinecarboximidamide Melting point: 175-176 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1660, 160
0, 1540, 1240, 720 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.82 (1H, d, J = 4.9 Hz), 8.64 (1H, brs), 7.9 (2H, d, J
= 9.1Hz), 7.80 (1H, brd, J = 7.9Hz), 7.53 (1H, dd, J
= 4.9,7.9Hz), 7.87 (2H, d, J = 9.1Hz), 4.20 ~ 4.05
(2H, m), 3.55-3.50 (4H, m), 3.40-3.30 (2H, m),
2.54 (3H, s) mass spec: m / e 333 M ⁺ Example 14 1- [4- (4-nitrophenyl) piperazinyl] N
Preparation of -cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml) and 1- (4-nitrophenyl) piperazine was used. (0.60
g, 2.9 mmol) and stirred at room temperature for 6 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g).
Elution was performed with chloroform: methanol (100: 1), and the elution fraction was concentrated under reduced pressure. The concentrated compound was crystallized from methanol / diethyl ether to give the title compound (0.56 g, 1.7 mm
ol, yield 65%) as crystals.

1- [4- (4-nitrophenyl) piperazinyl] N
Physicochemical properties of -cyano-3-pyridinecarboximidamide Melting point: 239 to 240 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2180, 1600, 154
0, 1320, 1240, 1110 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.82 (1H, d, J = 4.9Hz), 8.64 (1H, brs), 8.18 (2H, d,
J = 9.1Hz), 7.84 (1H, brd, J = 7.9Hz), 7.58 (1H, dd, J
= 4.9,7.9Hz), 6.87 (2H, d, J = 9.1Hz), 4.15-4.08
(2H, m), 3.66 to 3.54 (4H, m), 3.48 to 3.42 (2H, m) Mass spec: m / e 336 M ⁺ Example 15 1- [4- (3-Chlorophenyl) piperazinyl] N
Preparation of -cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 1- (3-chlorophenyl) piperazine. Hydrochloride (0.68 g, 2.9 mmol) and sodium methoxide (0.16
g, 2.9 mmol) and stirred at room temperature for 6 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, and the residue was 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 subjected to silica gel column chromatography (Wacoal gel C-200, 50 g). The mixture was eluted with chloroform: methanol (100: 1). The eluted fraction was concentrated under reduced pressure, and crystallized from methanol / diethyl ether to obtain the title compound (0.14 g, 0.4 mmol, yield 15%).

1- [4- (3-chlorophenyl) piperazinyl] N
Physicochemical properties of -cyano-3-pyridinecarboximidamide Melting point: 152-153 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1600, 156
0, 1240 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.82 (1H, d, J = 4.9Hz), 8.63 (1H, brs), 7.79 (1H, br
d, J = 7.9Hz), 7.52 (1H, dd, J = 4.9,7.9Hz), 7.21 (1
H, t, J = 8.0Hz), 6.91 (1H, d, J = 8.0Hz), 6.88 (1H, br
s), 6.79 (1H, d, J = 8.0 Hz), 4.13 to 4.04 (2H, m), 3.
55 ~ 3.44 (2H, m), 3.38 ~ 3.32 (2H, m), 3.19 ~ 3.14
(2H, m) mass spectrometry: m / e 325 M ⁺ Example 16 1- [4- (4-chlorophenyl) piperazinyl] N
Preparation of -cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 1- (4-chlorophenyl) piperazine ( 0.57
g, 2.9 mmol) and stirred at room temperature for 6 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.63 g,
1.9 mmol, yield 73%) as crystals.

1- [4- (4-chlorophenyl) piperazinyl] N
Physicochemical properties of -cyano-3-pyridinecarboximidamide Melting point: 186-187 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1590, 150
0, 1240 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.82 (1H, d, J = 4.9Hz), 8.63 (1H, brs), 7.80 (1H, br
d, J = 7.9Hz), 7.53 (1H, dd, J = 4.9,7.9Hz), 7.25 (2
H, d, J = 9.1Hz), 6.84 (2H, d, J = 9.1Hz), 4.14 to 4.05
(2H, m), 3.56-3.45 (2H, m), 3.33-3.26 (2H, m),
3.17-3.10 (2H, m) mass spec: m / e 325 M ⁺ Example 17 1- [4- (α, α-diphenyl-hydroxymethyl)
Piperidino] Production of N-cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (15 ml), and α, α-diphenyl- 4-Piperidinomethanol hydrochloride (0.78 g, 2.9 mmol) and sodium methoxide (0.16 g, 2.9 mmol) were added, and the mixture was stirred at room temperature for 6 hours.
After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was chloroform (50
ml × 3). Chloroform layer is water (100ml)
, Dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (Wacoal gel C-200, 50 g). The mixture was eluted with chloroform: methanol (100: 1). The eluted fraction was concentrated under reduced pressure, and then crystallized from methanol / diethyl ether to give the title compound (0.77 g, 1.9 mmol, yield 73%) as crystals.

1- [4- (α, α-diphenyl-hydroxymethyl)
Piperidino] Physicochemical properties of N-cyano-3-pyridinecarboximidamide Melting point: 208-209 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1580, 145
0,710 nuclear magnetic resonance spectrum (500 MHz, in CDCl _3): δ (pp
m) 8.73 (1H, d, J = 4.9Hz), 8.55 (1H, brs), 7.72 (1H, br
d, J = 7.9Hz), 7.50-7.15 (11H, m), 4.88 (1H, br
d), 3.53-3.47 (1H, m), 3.28-2.90 (1H, m), 2.76
~ 2.67 (1H, m), 2.36 ~ 2.32 (1H, m), 1.80 ~ 1.72 (1
H, m), 1.65 to 1.42 (3H, m) mass spec: m / e 396 M ⁺ Example 18 1- [4- (4-methoxyphenyl) piperazinyl]
Preparation of N-cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (15 ml) and 1- (4-methoxyphenyl) Piperazine dihydrochloride (0.77 g, 2.9 mmol) and sodium methoxide (0.31 g, 5.7 mmol) were added, and the mixture was stirred at room temperature for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was chloroform (50 ml).
× 3 times). Chloroform layer is water (100ml)
, Dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was crystallized from methanol / diethyl ether to give the title compound (0.60 g, 1.9 mmol, yield 71).
%) As crystals.

1- [4- (4-methoxyphenyl) piperazinyl]
Physicochemical properties of N-cyano-3-pyridinecarboximidamide Melting point: 191 to 192 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1580, 151
0, 1250 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.80 (1H, d, J = 4.9Hz), 8.63 (1H, brs), 7.79 (1H, br
d, J = 7.9Hz), 7.52 (1H, dd, J = 4.9,7.9Hz), 6.89 (2
H, d, J = 9.1Hz), 6.86 (2H, d, J = 9.1Hz), 4.15 to 4.05
(2H, m), 3.78 (3H, s), 3.56-3.44 (2H, m), 3.23-
3.16 (2H, m), 3.07 to 3.00 (2H, m) Mass spec: m / e 321 M ⁺ Example 19 1- [4- (2-methoxyphenyl) piperazinyl]
Preparation of N-cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml) and 1- (2-methoxyphenyl) Piperazine (0.
56 g, 2.9 mmol) and stirred at room temperature for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.67
g, 2.1 mmol, 81% yield) as crystals.

1- [4- (2-methoxyphenyl) piperazinyl]
Physicochemical properties of N-cyano-3-pyridinecarboximidamide Melting point: 192 ° C Infrared absorption spectrum (cm ⁻¹ , KBr): 2200, 1580, 151
0, 1250, 1020 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.79 (1H, d, J = 4.9Hz), 8.64 (1H, brs), 7.80 (1H, br
d, J = 7.9Hz), 7.52 (1H, dd, J = 4.9,7.9Hz), 7.07 (1
H, ddd, J = 2.6,7.7,7.7Hz), 6.97-6.87 (3H, m), 4.20
~ 4.05 (2H, m), 3.87 (3H, s), 3.59 ~ 3.45 (2H, m),
3.25 to 3.17 (2H, m), 3.08 to 3.00 (2H, m) Mass spec: m / e 321 M ⁺ Example 20 1- [4- (2,3-dimethylphenyl) piperazinyl]
Preparation of N-cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml) and N- (2,3-dimethyl (Phenyl) piperazine (0.55 g, 2.9 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.1%).
66 g, 2.1 mmol, yield 81%) were obtained as crystals.

1- [4- (2,3-dimethylphenyl) piperazinyl]
Physicochemical properties of N-cyano-3-pyridinecarboximidamide Melting point: 130 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1580, 145
0,1300,870 nuclear magnetic resonance spectrum (500 MHz, in CDCl _3): δ (pp
m) 8.80 (1H, d, J = 4.9Hz), 8.64 (1H, brs), 7.80 (1H, br
d, J = 7.9Hz), 7.52 (1H, dd, J = 4.9,7.9Hz), 7.10 (1
H, t, J = 7.7Hz), 6.97 (1H, d, J = 7.7Hz), 6.88 (1H, d,
J = 7.7Hz), 4.26-3.92 (2H, m), 3.58-3.40 (2H,
m), 3.10-2.80 (4H, m), 2.28 (3H, s), 2.24 (3H,
s) Mass spec: m / e 319 M ⁺ Example 21 1- [4- (2,6-dimethylphenyl) piperazinyl].
Preparation of N-cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml) and N- (2,6-dimethyl (Phenyl) piperazine (0.55 g, 2.9 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.1%).
56 g, 1.8 mmol, 70% yield) were obtained as crystals.

1- [4- (2,6-dimethylphenyl) piperazinyl]
Physicochemical properties of N-cyano-3-pyridinecarboximidamide Melting point: 216-218 ° C. Infrared absorption spectrum (cm ⁻¹ , KBr): 2200, 1580, 1300 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.80 (1H, d, J = 4.9Hz), 8.65 (1H, brs), 7.80 (1H, br
d, J = 7.9Hz), 7.52 (1H, dd, J = 4.9,7.9Hz), 7.02 (3
H, brs), 4.10-4.00 (2H, m), 3.50-3.40 (2H, m),
3.30-3.28 (2H, m), 3.15-3.00 (2H, m), 2.31 (6H,
s) Mass spec: m / e 319 M ⁺ Example 22 Preparation of 1- (4-benzylpiperidino) N-cyano-3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), N-benzylpiperidine (0.51 g, 2.9 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.32 g, 1.1 mmol, yield 42).
%) As crystals.

Physicochemical properties of 1- (4-benzylpiperidino) N-cyano-3-pyridinecarboximidamide Melting point: 128-129 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1580, 146
0,710 nuclear magnetic resonance spectrum (500 MHz, in CDCl _3): δ (pp
m) 8.77 (1H, d, J = 5.0Hz), 8.58 (1H, brs), 7.73 (1H, br
s), 7.48 (1H, dd, J = 5.0,7.9Hz), 7.29 (2H, t, J = 7.4
Hz), 7.22 (1H, t, J = 7.4Hz), 7.13 (2H, d, J = 7.4H)
z), 4.84 (1H, brd), 3.50 (1H, brd), 3.13-2.50 (3
H, m), 1.95 to 1.05 (6H, m) mass spec: m / e 304 M ⁺ Example 23 1- (4-hydroxypiperidino) N-cyano-3-
Preparation of pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml) and 4-hydroxypiperidine (0.29 g, 2.9 mmol)
Was added and stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wacoal gel C-200, 50 g). Elution was performed with chloroform: methanol (50: 1), and the elution fraction was concentrated under reduced pressure. The concentrated compound was crystallized from methanol / diethyl ether to give the title compound (0.38 g, 1.7 mmol, yield 65).
%) As crystals.

1- (4-hydroxypiperidino) N-cyano-3-
Physicochemical properties of pyridinecarboximidamide Melting point: 129-130 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1580, 146
0, 1070 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.78 (1H, dd, J = 1.2,4.9Hz), 8.59 (1H, brs), 7.75
(1H, brd, J = 7.9Hz), 7.50 (1H, dd, J = 4.9,7.9Hz),
4.20 to 4.00 (2H, m), 3.90 to 3.80 (1H, m), 3.60 to 3.50
(1H, m), 3.25-3.15 (1H, m), 2.05-1.95 (2H, m),
1.90-1.70 (3H, m) Mass Spec: m / e 230 M ⁺ Example 24 Preparation of N-cyano-N'-methyl-N '-(2-phenylethyl) -3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (1.00 g, 5.3 mmol) was dissolved in methanol (20 ml) and N-methylphenethylamine (0.72 g, 5.3 mmol) was dissolved.
l) was added and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wacoal gel C-200, 100 g). The mixture was eluted with chloroform: methanol (50: 1), and the eluted fraction was concentrated under reduced pressure and then crystallized from diethyl ether to give the title compound (1.30 g, 4.9 mmol, yield 92%) as crystals.

Physicochemical properties of N-cyano-N'-methyl-N '-(2-phenylethyl) -3-pyridinecarboximidamide Melting point: 68 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1590, 142
0,760,710 magnetic resonance spectrum (500 MHz, in _{CDCl 3); δ (ppm)} 8.72 (1H, d, J = 4.9Hz), 8.31 (1H, brs), 7.64 (1H, br
d, J = 7.9Hz), 7.41 (1H, dd, J = 4.9,7.9Hz), 7.30-7.
20 (5H), 3.81 (2H, m), 3.06 (3H, S), 3.01 (2H, t, J
= 6.6 Hz) Mass Spectrometry: m / e 264 M ⁺ Example 25 Preparation of N-cyano-N'-benzyl-N '-(2-phenylethyl) -3-pyridinecarboximidamide n-propyl = N-cyano -3-Pyridinecarboximidate (1.00 g, 5.3 mmol) was dissolved in methanol (5 ml) and N-benzyl-2-phenylenylamine (1.
12 g, 5.3 mmol) and stirred at room temperature for 48 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 100 g). Elution was performed with hexane: ethyl acetate (1: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (1.13).
g, 3.3 mmol, yield 62%) as crystals.

Physicochemical properties of N-cyano-N'-benzyl-N '-(2-phenylethyl) -3-pyridinecarboximidamide Melting point: 100 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1580; 156
0,1440,760,710 magnetic resonance spectrum (500 MHz, in _{CDCl 3); δ (ppm)} 8.75 (1H, d, J = 4.9Hz), 8.41 (1H, brs), 7.64 (1H, br
d, J = 7.9Hz), 7.50-7.10 (11H), 4.98 (2H, brs),
3.91 (2H, m), 3.24 (2H, t, J = 5.9 Hz) Mass spec: m / e 340 M ⁺ Example 26 N-cyano-N '-(2-methoxyethyl) -3-pyridinecarboximidamide And preparation of the methanesulfonate n-propyl = N-cyano-3-pyridinecarboximidate (2.00 g, 10.6 mmol) in methanol (20 ml)
And dissolved in 2-methoxyethylamine (0.95 g, 12.6 mmo
l) was added and stirred at room temperature for 1.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 100 g). The mixture was eluted with chloroform: methanol (50: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (2.07 g, 10.1 mmol).
l, 95% yield) as a syrup.

Further, the syrup was dissolved in methanol (10 ml), methanesulfonic acid (1.0 g) was added, and the mixture was concentrated under reduced pressure. The concentrated residue was crystallized from methanol / diethyl ether to give the title methanesulfonate (2.80 g, 9.3 mmol, yield 88).
%) As a hygroscopic powder.

N- cyano -N '- (2-methoxyethyl) -3-pyridine carboximidamide physicochemical properties NMR spectrum bromide (500 MHz, in CDCl _3): δ (pp
m) 8.77 (1H, brs), 8.76 (1H, d, J = 4.9Hz), 8.04 (1H, brs)
brd, J = 7.9Hz), 7.46 (1H, dd, J = 4.9,7.9Hz), 6.79
(1H, brs), 3.71 (2H, m), 3.61 (2H, t, J = 5.5Hz),
3.39 (3H, s) Physicochemical properties of N-cyano-N '-(2-methoxyethyl) -3-pyridinecarboxyimidamide methanesulfonate Infrared absorption spectrum (cm ^-1 , KBr): 2200 1600, 121
0,1060 Mass spectrometry: m / e 205 [M-CH ₃ SO _3] ⁺ Example 27 N-cyano--N '- (3- ethoxycarbonylpropyl) -3-pyridine-carboximidamide manufacturing n- propyl = N -Cyano-3-pyridinecarboximidate (3.00 g, 15.9 mmol) in ethanol (50 ml)
And dissolved in 4-aminobutyric acid ethyl ester hydrochloride (5.
30 g, 31.6 mmol) and triethylamine (4.80 g, 47.4 mm)
ol) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 100 g). Elution was performed with chloroform: methanol (50: 1). The title compound (3.18 g, 12.2 m
mol, yield 77%) as a powder.

Physicochemical properties of N-cyano-N '-(3-ethoxycarbonylpropyl) -3-pyridinecarboximidamide Melting point: 57 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1740, 159
0, 1550, 1190, 710 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.78 (1H, brs), 8.75 (1H, d, J = 4.9Hz), 8.04 (1H, brs)
brd, J = 7.9Hz), 7.59 (1H, brs), 7.45 (1H, dd, J = 4.
9,7.9Hz), 4.14 (2H, q, J = 7.3Hz), 3.56 (2H, m), 2.
49 (2H, t, J = 6.7Hz), 2.00 (2H, m), 1.26 (3H, t, J =
7.3 Hz) mass spec: m / e 260 M ⁺ Example 28 N-cyano-N '-(3-carboxypropyl) -3-
Preparation of pyridinecarboximidamide N-cyano-N '-(3-ethoxycarbonylpropyl) -3-pyridinecarboximidamide (1.63 g, 6.3
was dissolved in methanol (60 ml), a solution of sodium hydroxide (0.43 g, 10.7 mmol) in water (50 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction, Dowex 50-X2 (H ⁺ type)
(2.5 g dry weight, 11.3 equivalents) was added, and the mixture was stirred for 30 minutes. The reaction solution was washed with 30 ml of ethyl acetate and freeze-dried in vacuo to give the title compound (1.37 g, 5.9 mmol, yield 94%) as a hygroscopic powder.

N-cyano-N '-(3-carboxypropyl) -3-
Physicochemical properties of pyridinecarboximidamide Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1600, 157
0, 1410, 720 Nuclear magnetic resonance spectrum (500 MHz, in CD ₃ OD): δ (pp
m) 8.67 (1H, brs), 8.63 (1H, d, J = 5.5Hz), 8.03 (1H, br
d, J = 8.5Hz), 7.54 (1H, dd, J = 5.5,8.5Hz), 3.40 (2
H, t, J = 7.3Hz), 2.19 (2H, t, J = 7.9Hz), 1.83 (2H,
m) Example 29 Preparation of N-cyano-N '-(2-sulfoethyl) -3-pyridinecarboximidamide sodium salt Taurine (2.71 g, 21.6 mmol) and sodium hydroxide (8
65 mg, 21.6 mmol) in 10 ml of water, and n-propyl = N
-Cyano-3-pyridinecarboximidate (4.50
g, 23.81 mmol) and stirred at room temperature for 30 minutes. After the reaction, the reaction solution was added to acetone (200 ml). The precipitate formed was filtered and washed with acetone to give the title compound (5.59 g, 20.2 mmol, yield 85%) as a powder.

Physicochemical properties of N-cyano-N '-(2-sulfoethyl) -3-pyridinecarboximidamide sodium salt Infrared absorption spectrum (cm- ¹ , KBr): 2200, 1600, 156
0, 1230, 1070, 720 Nuclear magnetic resonance spectrum (500 MHz, in CD ₃ OD): δ (pp
m) 8.72 (1H, brs), 8.67 (1H, d, J = 4.9Hz), 8.07 (1H, br
d, J = 7.9Hz), 7.57 (1H, dd, J = 4.9,7.9Hz), 3.82 (2
(H, t, J = 6.7 Hz), 3.22 (2H, t, J = 6.7 Hz) Example 30 Production of sodium salt of N-cyano-N '-(2-sulfoxyethyl) -3-pyridinecarboxyimidamide 2-aminoethyl hydrogen sulfate (2.95 g, 2
0.9 mmol) and sodium hydroxide (0.84 g, 20.9 mmol) in water
Dissolve in 10 ml, add n-propyl = N-cyano-3-pyridinecarboximidate (4.37 g, 23.1 mmol),
Stirred at room temperature for 30 minutes. After the reaction, the reaction solution was washed with acetone (20
0 ml). The precipitate formed was filtered and washed with acetone to give the title compound (0.13 g, 0.4 mmol, yield 1.
7%) as a gum.

Physicochemical properties of N-cyano-N '-(2-sulfoxyethyl) -3-pyridinecarboxyimidamide sodium salt Infrared absorption spectrum (cm ^-1 , KBr): 2190, 1600, 1250 Nuclear magnetic resonance spectrum (500MHz, CD ₃ OD): δ (pp
m) 8.75 (1H), 8.70 (1H), 8.10 (1H), 7.57 (1H), 4.
25 (2H), 3.77 (2H) Example 31 1- (4-Nitroxypiperidino) N-cyano-3-
Production of pyridinecarboximidamide 4-nitroxypiperidine / nitrate (5.00 g, 23.9 mmo
l) was suspended in water (7 ml), and an aqueous sodium hydroxide solution (0.80 g, 20.0 mmol / water 5 ml) was added. n-propyl =
N-cyano-3-pyridinecarboximidate (3.60
g, 19.1 mmol), and the mixture was stirred at room temperature for 15 minutes, and then left to stand to crystallize the target compound.

After standing at 0 ° C. for 6 hours, the crystals were collected and washed with water to give the title compound (3.85 g, 14.0 mmol, yield 73).
%) As crystals.

1- (4-nitroxypiperidino) N-cyano-3-
Physicochemical properties of pyridinecarboximidamide Melting point: 170 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1630, 158
0, 1280, 880 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.80 (1H, d, J = 4.9Hz), 8.60 (1H, brs), 7.77 (1H, br
d, J = 7.3 Hz), 7.52 (1H, dd, J = 4.9, 7.9 Hz), 5.26 (1
H, m), 4.15-3.90 (2H, m), 3.60-3.25 (2H, m), 2.3
0-2.10 (1H, m), 2.10-1.90 (2H, m), 1.90-1.75 (1
H, m) mass spec: m / e 275 M ⁺ Example 32 N-cyano-N '-[2- (3-thienyl) ethyl]-
Preparation of 3-pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3- (2-aminoethyl) thiophene (0.37 g) was dissolved.
g, 2.9 mmol) and stirred at room temperature for 6 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.47 g,
1.8 mmol, yield 69%) as crystals.

N-cyano-N '-[2- (3-thienyl) ethyl]-
Physicochemical properties of 3-pyridinecarboximidamide Melting point: 134.5 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1590, 155
0, 1380, 710 Nuclear magnetic resonance spectrum (100 MHz, in CDCl ₃ ): δ (pp
m) 8.81 (1H, d, J = 5.1Hz), 8.70 (1H, brs), 7.97 (1H, br
d, J = 7.5Hz), 7.52 to 7.23 (2H, m), 7.12 to 6.94 (2H,
m), 3.81 (2H, m), 3.04 (2H, t, J = 7.0 Hz) Mass spec: m / e 256 M ⁺ Example 33 N-cyano-N '-(3-nitropropyl) -3-pyridine Preparation of carboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml) and 3-nitropropylamine (0.27 g, 2.6 mmol)
Was added and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.47 g, 2.0 mmol, yield)
77%) as a powder.

Physicochemical properties of N-cyano-N '-(3-nitropropyl) -3-pyridinecarboximidamide Melting point: 90 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2160, 1590, 157
0,710 Nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ -CD ₃ OD):
δ (ppm) 7.55-7.40 (2H), 6.86-6.73 (1H), 6.36-6.20 (1
H), 3.37-3.25 (2H), 2.42-2.26 (2H), 1.21-1.0
5 (2H) mass spec: m / e 233 M ⁺ Example 34 Production of N-cyano-N'-methyl-N '-(2-nitroxyethyl) -3-pyridinecarboximidamide and its hydrochloride n- Propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and N-methyl-2-nitroxyethylamine hydrochloride (0.45 g, 2.9 mmol) and sodium methoxy were used. (0.
16g, 2.9mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was treated with ethyl acetate (50 ml ×
Extracted in 3). The ethyl acetate layer was washed with water (100 ml), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure.
The concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g). The compound was eluted with chloroform: methanol (100: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (0.45 g, 1.8 mmol, yield 69%).
Was obtained as a syrup. Further, a 5% methanol solution of hydrogen chloride (3 ml) was added to the syrup for dissolution, followed by concentration under reduced pressure. The concentrated residue was crystallized from methanol / diethyl ether to give the title hydrochloride (0.41 g, 1.4 mmol, 54% yield)
Was obtained as a gum.

N- cyano -N'- methyl -N '- (2-nitro-carboxyethyl) -3-pyridine carboximidamide physicochemical properties NMR spectrum bromide (500 MHz, in CDCl _3): δ (pp
m) 8.81 (1H, d, J = 4.9Hz), 8.62 (1H, brs), 7.76 (1H, br
d, J = 7.9Hz), 7.52 (1H, dd, J = 4.9,7.9Hz), 4.85 (2
H, t, J = 4.9Hz), 4.02 (2H, m), 3.06 (3H, s) N-cyano-N'-methyl-N '-(2-nitroxyethyl) -3-pyridinecarboximidamide. Physicochemical properties of hydrochloride Infrared absorption spectrum (cm ^-1 , neat): 2250, 2200, 164
0, 1580, 720 Mass spectrometry: m / e 249 [M-HCl] ⁺ Example 35 N-cyano-N '-(2,2-dimethoxyethyl) -3-
Preparation of pyridinecarboximidamide n-propyl = N-cyano- (3-pyridinecarboximidate (0.50 g, 2.6 mmol) in methanol (10 ml)
And aminoacetaldehyde dimethyl acetal (0.30 g, 2.9 mmol) was added thereto, followed by stirring at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g). Elution with chloroform: methanol (50: 1)
The title compound (0.
39 g, 1.7 mmol, 63% yield) were obtained as crystals.

N-cyano-N '-(2,2-dimethoxyethyl) -3-
Physicochemical properties of pyridinecarboximidamide Melting point: 69 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1590, 155
0, 1130, 1070, 710 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.77 to 8.76 (2H, m), 8.04 (1H, d, J = 7.9Hz), 7.46 (1
H, dd, J = 4.9,7.9Hz), 4.57 (1H, t, J = 4.9Hz), 3.66
(2H, d, J = 4.9 Hz), 3.44 (6H, s) Mass spectrometry: m / e 235 [M + H] ⁺ , 159 [M-CH
(OCH _{3) 2]} ⁺ Example 36 N-cyano--N '- (2-benzyloxy-ethyl) -3
-Preparation of pyridinecarboximidamide n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-benzyloxyethylamine (0.44 g, 2.9
mmol) and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g). Elution was performed with chloroform: methanol (100: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (0.55 g, 2.0 mm
ol, yield 71%) as crystals.

N-cyano-N '-(2-benzyloxyethyl) -3
Physicochemical properties of pyridinecarboximidamide Melting point: 69-70 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1600, 156
0,1410,720 nuclear magnetic resonance spectrum (500 MHz, in CDCl _3): δ (pp
m) 8.78 (1H, d, J = 4.9Hz), 8.73 (1H, brs), 8.01 (1H, br
d, J = 7.9Hz), 7.45 (1H, dd, J = 4.9,7.9Hz), 6.42 (1
H, brs), 4.55 (2H, s), 3.74-3.70 (4H, m) Mass spec: m / e 280 M ⁺ Example 37 N-cyano-N '-(2-phenyloxyethyl) -3.
Preparation of -Pyridinecarboximidamide and its methanesulfonate n-propyl = N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-phenyloxyethylamine (0.40 g) was dissolved. g, 2.9
mmol) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g). The mixture was eluted with chloroform: methanol (50: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (0.46 g, 1.7 mmol,
(65% yield) as a syrup.

Further, the syrup was dissolved in methanol (5 ml), methanesulfonic acid (0.17 g) was added, and the mixture was concentrated under reduced pressure. The concentrated residue was crystallized from methanol / diethyl ether to give the title methanesulfonate (0.50 g, 1.4 mmol, yield 54).
%) As crystals.

N-cyano-N '-(2-phenyloxyethyl) -3
- pyridine carboximidamide physicochemical properties NMR spectrum bromide (500 MHz, in CDCl _3): δ (pp
m) 8.63 (1H, brs), 8.56 (1H, d, J = 4.9Hz), 8.21 (1H, t,
J = 5.5Hz), 7.88 (1H, brd, J = 7.9Hz), 7.30 (1H, dd, J
= 4.9,7.9Hz), 7.25 (1H, m), 6.95 (1H, t, J = 7.3H)
z), 6.85 (2H, brd, J = 7.9Hz), 4.13 (2H, t, J = 5.5H)
z), 3.82 (2H, m) N-cyano-N '-(2-phenyloxyethyl) -3
-Physicochemical properties of pyridinecarboximidamide methanesulfonate Melting point: 163 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1600, 122
0,1050,760 Mass spectrometry: m / e 266 [M-CH ₃ SO ₃ H] ⁺ Example 38 N-cyano--N '- (2-azidoethyl) -3-pyridine-carboximidamide manufacturing n- propyl = N-Cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), 2-azidoethylamine (0.25 g, 2.9 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g). Chloroform:
Elution was performed with methanol (50: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (0.41 g, 1.9 mmol, yield 72%).
%) As crystals.

Physicochemical properties of N-cyano-N '-(2-azidoethyl) -3-pyridinecarboximidamide Melting point: 75-76 ° C Infrared absorption spectrum (cm- ¹ , KBr): 2200, 2130, 160
0, 1550, 710 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.78-8.75 (2H, m), 8.03 (1H, d, J = 7.9Hz), 7.47 (1
H, dd, J = 4.9,7.9 Hz), 3.69-3.64 (4H, m) mass spec: m / e 215 M ⁺ Example 39 N-cyano-N '-(2-hydroxyethyl) -3-pyridinecarboxy. Production of imidamide Ethanolamine (20 g, 0.33 mol) was dissolved in water (30 ml), n-propyl = N-cyano-3-pyridinecarboximidate (60 g, 0.32 mol) was added, and the mixture was stirred at room temperature for 30 minutes. . When left at 0 ° C. overnight, the target compound crystallized. The crystals were collected and washed with water to give the title compound (34 g, 0.18 mol, yield 56%) as crystals.

Physicochemical properties of N-cyano-N '-(2-hydroxyethyl) -3-pyridinecarboximidamide Melting point: 132 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1610, 158
0, 1550, 1070, 710 Nuclear magnetic resonance spectrum (500 MHz, in CD ₃ OD): δ (pp
m) 8.81 (1H), 8.74 (1H), 8.12 (1H), 7.61 (1H), 3.
77 (2H), 3.61 (2H) Mass spec: m / e 190 M ⁺ Example 40 N-cyano-N '-(2-benzoyloxyethyl)-
Production of 3-pyridinecarboximidamide N-cyano-N '-(2-hydroxyethyl) -3-
Pyridinecarboximidamide (2.00 g, 10.5 mmol) and pyridine (2.5 ml) are combined with N, N-dimethylformamide (10 m
l) and benzoyl chloride (1.80 g, 12.8 g) under ice-water cooling.
mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml × 2). The ethyl acetate layer was washed with a saturated aqueous solution of NaCl (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The concentrated residue was crystallized from methanol / diethyl ether to give the title compound (2.41 g, 8.2 mmol, yield 78%) as crystals.

N-cyano-N '-(2-benzoyloxyethyl)-
Physicochemical properties of 3-pyridinecarboximidamide Melting point: 134 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1700, 161
0,1290,720 nuclear magnetic resonance spectrum (500 MHz, in CDCl _3): δ (pp
m) 8.75 (1H, brs), 8.71 (1H, d, J = 4.9Hz), 7.95 to 8.03
(3H, m), 7.59 (1H, t, J = 7.3Hz), 7.46-7.42 (2H,
m), 7.41 (1H, dd, J = 4.9,7.9Hz), 7.38 (1H, brs),
4.59 (2H, t, J = 4.9 Hz), 3.89 (2H, m) Mass spec: m / e 294 M ⁺ Example 41 N-cyano-N '-(2-acetyloxyethyl) -3
-Production of pyridinecarboximidamide and its methanesulfonate N-cyano-N '-(2-hydroxyethyl) -3-
Pyridinecarboximidamide (2.00 g, 10.5 mmol) and pyridine (2.5 ml) are combined with N, N-dimethylformamide (10 m
l) and acetic anhydride (1.30 g, 12.7 mmol) under ice-water cooling
Was added and stirred at room temperature for 3 hours. After the reaction, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml × 2). The ethyl acetate layer was washed with a saturated aqueous solution of NaCl (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 100 g). The mixture was eluted with chloroform: methanol (50: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (1.96 g, 8.4 mmol, yield 80%) as a syrup.

Further, the syrup was dissolved in methanol (10 ml), methanesulfonic acid (0.9 g) was added, and the mixture was concentrated under reduced pressure. Diethyl ether was added to the concentrated residue, and the mixture was allowed to stand overnight, whereby the title methanesulfonate (2.40 g, 7.3 mmol, yield 70
%) As a gum.

N-cyano-N '-(2-acetyloxyethyl) -3
- pyridine carboximidamide physicochemical properties NMR spectrum bromide (500 MHz, in CDCl _3): δ (pp
m) 8.76 (1H, brs), 8.75 (1H, d, J = 4.9Hz), 8.01 (1H, br
d, J = 7.9Hz), 7.45 (1H, dd, J = 4.9,7.9Hz), 7.37 (1
H, brs), 4.33 (2H, t, J = 5.2Hz), 3.76 (2H, m), 2.08
(3H, s) N-cyano-N '-(2-acetyloxyethyl) -3
Physicochemical properties of pyridinecarboxyimidamide methanesulfonate Infrared absorption spectrum (cm ⁻¹ , neat): 2200, 1740, 159
0, 1200, 1060 Mass spectrometry: m / e 232 [M-CH ₃ SO ₃ H] ⁺ Example 42 Production of N-cyano-N ′-(2-diethylphosphonooxyethyl) -3-pyridinecarboximidamide N-cyano-N '-(2-hydroxyethyl) -3-
Pyridinecarboximidamide (2.00 g, 10.5 mmol) and pyridine (2.5 ml) are combined with N, N-dimethylformamide (10 m
l), diethyl chlorophosphate (3.82 g, 22.1 mmol) was added under ice-water cooling, and the mixture was stirred at room temperature for 5 hours.
After the reaction, the reaction solution was poured into water (50 ml), and ethyl acetate (50 ml) was added.
× 2). The ethyl acetate layer was washed with a saturated NaCl aqueous solution (50 ml), dehydrated with anhydrous sodium sulfate,
It was concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 100 g). Elution was performed with chloroform: methanol (50: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (0.74 g, 2.3 mmo).
l, yield 22%) as a syrup.

N- cyano -N '- (2-diethyl phosphonooxy oxyethyl) -3-pyridine carboximidamide physicochemical properties NMR spectrum bromide (500 MHz, in CDCl _3): δ (pp
m) 8.87 (1H, brs), 8.70 (1H, d, J = 4.9Hz), 8.11 (1H, br
d, J = 7.9Hz), 7.45 (1H, dd, J = 4.9,7.9Hz), 4.26 (2
H, t, J = 5.1Hz), 4.06 (4H, q, J = 7.1Hz), 3.79 (2H,
m), 1.31 (6H, t, J = 7.1 Hz) Mass spec: m / e 327 [M + H] ⁺ Example 43 N-cyano-N '-(2-ethoxycarbonyloxyethyl) -3-pyridinecarboximidamide And production of methanesulfonate thereof N-cyano-N '-(2-hydroxyethyl) -3-
Pyridinecarboximidamide (2.00 g, 10.5 mmol) and pyridine (2.5 ml) are combined with N, N-dimethylformamide (10 m
l) and ethyl chloroformate (1.70 g, 1
5.7 mmol) and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml × 2). The ethyl acetate layer was washed with a saturated aqueous solution of NaCl (50 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-200, 100 g). The compound was eluted with chloroform: methanol (50: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (2.59 g, 9.9 mmol, yield 94%).
Was obtained as a syrup. Further, the syrup was dissolved in methanol (20 ml), methanesulfonic acid (1 g) was added, and the mixture was concentrated under reduced pressure. The concentrated residue was crystallized from methanol / diethyl ether to give the title methanesulfonate (2.
89 g, 8.1 mmol, yield 77%) as a hygroscopic powder.

N- cyano -N '- (2-ethoxycarbonyloxy-ethyl) -3-pyridine carboximidamide physicochemical properties NMR spectrum bromide (500 MHz, in CDCl _3): δ (pp
m) 8.79 (1H, brs), 8.78 (1H, d, J = 4.9Hz), 8.07 (1H, br
d, J = 7.9Hz), 7.47 (1H, dd, J = 4.9,7.9Hz), 6.95 (1
H, brs), 4.40 (2H, t, J = 4.9Hz), 4.22 (2H, q, J = 7.3H)
z), 3.83 (2H, m), 1.32 (3H, t, J = 7.3Hz) Physics of N-cyano-N '-(2-ethoxycarbonyloxyethyl) -3-pyridinecarboximidamide methanesulfonate Chemical properties Infrared absorption spectrum (cm ^-1 , KBr): 2170, 1740, 158
0,1260,1200,780,560 Mass spectrometry: m / e 263 [M-CH ₃ SO _3] ⁺ Example 44 N-cyano--N '- (2-cyclopentylcarbonyloxy-ethyl) -3-pyridine-carboximidamide Production of N-cyano-N '-(2-hydroxyethyl) -3-
Pyridinecarboximidamide (2.00 g, 10.5 mmol) and pyridine (2.5 ml) are combined with N, N-dimethylformamide (10 m
l), cyclopentylcarbonyl chloride (1.70 g, 12.8 mmol) was added under ice-water cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml × 2). The ethyl acetate layer was washed with saturated saline (50 ml), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wacoal gel C-200, 100 g). Elute with chloroform: methanol (50: 1) and concentrate the eluted fraction under reduced pressure to give the title compound (2.25 g, 7.9 mm
ol, yield 75%) as a syrup.

Physicochemical properties of N-cyano-N '-(2-cyclopentylcarbonyloxyethyl) -3-pyridinecarboximidamide Infrared absorption spectrum (cm ^-1 , neat): 2170, 1720, 158
0, 1180, 750 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.80-8.70 (2H, m), 8.03 (1H, brd, J = 6.7Hz), 7.37
(1H, dd, J = 4.5,6.7Hz), 7.24 (1H, brs), 4.35 (2H,
t, J = 4.6Hz), 3.77 (2H, m), 2.75 (1H, m), 1.90-1.
55 (8H, m) mass spec: m / e 286 M ⁺ Example 45 N-cyano-N '-(2-nitroxyethyl) -3-
Preparation of (6-methylpyridine) carboximidamide a) 3-cyano-6-methylpyridine (3.00 g, 25.4 m
mol) was dissolved in n-propanol (30 ml), sodium methoxide (0.07 g, 1.3 mmol) was added, and the mixture was reacted at room temperature for 6 hours. After the reaction, acetic acid (0.08 g, 1.3 mmol) was added to neutralize the reaction solution, and concentrated under reduced pressure. Diethyl ether (50 ml) was added to the concentrated residue, and after separating insolubles, the solution was concentrated under reduced pressure to obtain n-propyl = 3- (6-methylpyridine).
A crude carboximidate was obtained.

Subsequently, cyanamide (2.14 g, 50.9 mmo) was added to the crude product.
l) and Ha ₂ HPO ₄ (3.61 g, 25.4 mmol) and NaH ₂ PO ₄ .2H ₂ O
(15.9 g, 102 mmol) of a phosphate buffer (pH 5.4, 40 ml) and acetonitrile (10 ml) were added, and the mixture was stirred at room temperature for 6 hours. After the reaction, the reaction solution was extracted with chloroform (70 ml × 3 times). The chloroform layer was washed with a saturated aqueous solution of NaCl,
After dehydration with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wacoal Gel C-
200, 50 g) and hexane: diethyl ether (1:
Eluted in 1). The eluted fraction was concentrated under reduced pressure to give n-propyl = N-cyano-3- (6-methylpyridine) carboximidate (2.16 g, 10.6 mmol, yield 42).
%) As a syrup.

b) n-Propyl-N-cyano-3- (6-methylpyridine) carboximidate (0.30 g, 1.5 mmol) was dissolved in methanol (5 ml), and 2-nitroxyethylamine methanesulfonate (0.33 g) was dissolved. , 1.6 mmol) and sodium methoxide (0.09 g, 1.6 mmol).
Stirred for hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (30 ml × 3 times). The chloroform layer was washed with water (50 ml), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was crystallized from methanol / diethyl ether to give the title compound (0.12 g,
0.5 mmol, yield 33%) as crystals.

N-cyano-N '-(2-nitroxyethyl) -3-
Physicochemical properties of (6-methylpyridine) carboximidamide Melting point: 124-125 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2170, 1630, 157
0, 1280, 860 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.68 (1H, d, J = 1.8Hz), 7.98 (1H, dd, J = 2.4,7.9H)
z), 7.33 (1H, d, J = 7.9 Hz), 6.31 (1H, brs), 4.73
(2H, t, J = 4.9 Hz), 3.90 (2H, m), 2.64 (3H, s) Mass spec: m / e 249 M ⁺ Example 46 N-cyano-N '-(2-phenylethyl)- 3- (6
Preparation of -methylpyridine) carboximidamide n-propyl = N-cyano-3- (6-methylpyridine) carboximidate (0.30 g, 1.5 mmol) was dissolved in methanol (5 ml), and 2-phenylethylamine (0.2
0 g, 1.7 mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.29
g, 1.1 mmol, yield 74%) as crystals.

N-cyano-N '-(2-phenylethyl) -3- (6
Physicochemical properties of (-methylpyridine) carboximidamide Melting point: 142-144 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2170, 1570, 154
0, 1380 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.48 (1H, d, J = 1.8Hz), 7.90 (1H, dd, J = 2.4,7.9H)
z), 7.35 (1H, t, J = 7.3Hz), 7.30-7.20 (5H, m), 5.
87 (1H, brs), 3.81 (2H, m), 3.01 (2H, t, J = 6.7H
z), 2.60 (3H, s) mass spec: m / e 264 M ⁺ Example 47 N-cyano-N '-[2- (2-chlorophenyl) ethyl] -3- (6-methylpyridine) carboximidamide Preparation of n-propyl = N-cyano-3- (6-methylpyridine) carboximidate (0.30 g, 1.5 mmol) was dissolved in methanol (5 ml), and 2- (2-chlorophenyl) ethylamine (0.25 g, 1.6 mmol) and stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.31 g, 1.0 mmol, yield 70%) as crystals.

Physicochemical properties of N-cyano-N '-[2- (2-chlorophenyl) ethyl] -3- (6-methylpyridine) carboximidamide Melting point: 183-184 ° C Infrared absorption spectrum (cm ^-1 , KBr ): 2170, 1570, 740 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.52 (1H, d, J = 1.8Hz), 7.92 (1H, dd, J = 2.4,7.9H)
z), 7.40 (1H, brd), 7.35-7.20 (4H, m), 5.96 (1H,
brs), 3.83 (2H, m), 3.16 (2H, t, J = 6.7Hz), 2.61
(3H, s) mass spectrometry: m / e 299 M ⁺ Example 48 Preparation of N-cyano-N '-(2-nitroxyethyl) -3-quinolinecarboximidamide a) 3-cyanoquinoline (1.58 g, 10.2 mmol) was dissolved in methanol (20 ml), and sodium methoxide (0.06
g, 1.1 mmol) and reacted at room temperature for 22 hours. After the reaction, acetic acid (0.07 g, 1.1 mmol) was added to neutralize the reaction solution, and concentrated under reduced pressure. The concentrated residue contains diethyl ether (60
ml) was added, and the insolubles were separated. The solution was concentrated under reduced pressure to obtain a crude product of methyl 3-quinolinecarboximidate.

Subsequently, cyanamide (0.84 g, 20 mmol) was added to the crude product.
And Na ₂ HPO ₄ (1.42 g, 10 mmol) and NaH ₂ PO ₄ .2H ₂ O (6.24
g, 40 mmol) of a phosphate buffer (pH 5.4, 10 ml) and stirred at room temperature for 6 hours. After the reaction, insoluble materials in the reaction solution were separated, and the solution was extracted with dichloromethane (50 ml × 3). The dichloromethane layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-200, 2
5g) and eluted with dichloromethane: hexane (3: 2). The eluted fraction was concentrated under reduced pressure and crystallized from diethyl ether to obtain methyl = N-cyano-3-quinolinecarboximidate (1.14 g, 5.4 mmol, yield 53%) as pale brown crystals.

Physicochemical properties of methyl = N-cyano-3-quinolinecarboximidate Melting point: 113.5 to 113.8 ° C. Infrared absorption spectrum (cm ⁻¹ , KBr): 2190, 1610, 1310 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃₎ ): Δ (pp
m) 9.35 (1H, d, J = 2.6Hz), 9.17 (1H, d, J = 2.6Hz), 8.17
(1H, d, J = 8.0Hz), 8.00 (1H, d, J = 8.0Hz), 7.90 (1
H, dt, J = 1.8,8.0Hz), 7.68 (1H, t, J = 8.0Hz), 4.18
(3H, s) Elementary analysis: C H N Calculated 68.24 4.29 19.89 Analytical values 68.01 4.23 19.67 (%) (C 12 H 9 N 3 O) b) Methyl = N- cyano-3-quinolinecarboxylate imidate (0.32 g , 1.5 mmol) was dissolved in methanol (3 ml), and 2-nitroxyethylamine / nitrate (0.42 g,
2.5 mmol) and sodium methoxide (0.12 g, 2.2 mmo
l) was added and the mixture was 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). The mixture was eluted with dichloromethane: methanol (50: 1). The eluted fraction was concentrated under reduced pressure and crystallized from dichloromethane / diethyl ether to give the title compound (0.23 g, 0.80 mmol, yield 54).
%) As colorless crystals.

Physicochemical properties of N-cyano-N '-(2-nitroxyethyl) -3-quinolinecarboximidamide Melting point: 126.5 to 127.0 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2190, 1620, 158
0, 1560, 1280 Nuclear magnetic resonance spectrum (500 MHz, in CD ₃ OD): δ (pp
m) 9.05 (1H, s), 8.71 (1H, s), 8.13 (1H, d, J = 8.0H
z), 8.10 (1H, d, J = 8.0Hz), 7.93 (1H, t, J = 7.7H)
z), 7.74 (1H, t, J = 7.7Hz), 4.80 (2H, t, J = 5.7H)
z), 3.92 (2H, t , J = 5.7Hz) Elemental analysis: C H N Calculated 54.74 2.46 24.55 Analytical values 54.66 2.34 24.29 (%) (C 13 H 11 N 5 O 3) Example 49 N-Cyano - Preparation of N '-(2-phenylethyl) -3-quinolinecarboximidamide Methyl N-cyano-3-quinolinecarboximidate (0.32 g, 1.5 mmol) was dissolved in methanol (3 ml), and 2-phenylethylamine was dissolved. (0.20 g, 1.65 mmol) and stirred at room temperature for 30 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from diethyl 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-quinolinecarboximidamide Melting point: 165.0-167.0 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2190, 1580, 156
0, nuclear magnetic resonance spectrum (500 MHz, in CDCl _3): δ (pp
m) 8.84 (1H, s), 8.47 (1H, s), 8.11 (1H, d, J = 8.5H)
z), 7.90 (1H, d, J = 8.6Hz), 7.84 (1H, t, J = 7.3H)
z), 7.65 (1H, t, J = 8.0Hz), 7.37 (2H, t, J = 7.3H)
z), 7.32-7.25 (3H), 6.05 (1H, brs), 3.87 (2H, d
d, J = 6.7,12.8Hz), 3.06 (2H, t, J = 6.7Hz) Elemental analysis: C H N Calculated 75.98 5.37 18.65 Analytical values 75.86 5.32 18.42 (%) (C 19 H 16 N 4) Example Preparation of 50 N-cyano-N '-(2-nitroxyethyl) pyrazinecarboximidamide a) Cyanopyrazine (5.26 g, 50 mmol) was dissolved in methanol (40 ml) and sodium methoxide (0.27 g, 5.0
mmol) and stirred 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. Dichloromethane (50 ml) and diethyl ether (50 ml) were added to the concentrated residue, the insolubles were separated, and the solution was concentrated under reduced pressure to obtain a crude product of methyl pyrazinecarboximidate (6.87 g) as a colorless powder. .

Next, 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 m
mol) and a phosphate buffer (pH 5.4, 40 ml) at room temperature.
Stirred for 48 hours. After the reaction, the reaction solution was diluted with dichloromethane (10
(0 ml × 4 times). The dichloromethane layer is saturated NaC
After washing with an aqueous solution (300 ml), the solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give methyl = N-cyanopyrazinecarboximidate (4.53 g, 27.9 mmol, yield 56%) as colorless crystals.

Physicochemical properties of methyl = N-cyanopyrazinecarboximidate Melting point: 47.5-49.0 ° C. Infrared absorption spectrum (cm ⁻¹ , KBr): 2190, 1630, 1330 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (Ppm) 9.33 (1H, s), 8.78 (1H, d, J = 2.2Hz), 8.74 (1H, br
s), 4.07 (3H, s ) Elementary analysis: C H N Calculated 51.85 3.73 34.55 Analytical values 51.71 3.69 34.29 (%) (C 7 H 6 N 4 O) b) Methyl = N- cyano pyrazinecarboxylate imidate (0.49 g, 3.0 mmol) in methanol (6 ml),
2-nitroxyethylamine / nitrate (1.01g, 6.0mmo
l) and triethylamine (1.01 g, 10.0 mmol) were added,
Stirred at room temperature for 46 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, 300 g). Elution was performed with chloroform: methanol (300: 1), and the eluted fraction was concentrated under reduced pressure, and further crystallized from diethyl ether to obtain the title compound (0.18 g, 0.78 mmol, yield 26%) as colorless crystals.

Physicochemical properties of N-cyano-N '-(2-nitroxyethyl) pyrazinecarboximidamide Melting point: 102.8-103.0 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2180, 1630, 162
0, 1290 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 9.83 (1H, brs), 8.88 (1H, s), 8.64 (1H, s), 8.28
(1H, brs), 4.78 ( 2H, t, J = 4.9Hz), 4.15 (2H, brs) Elemental analysis: C H N Calculated 40.68 3.41 35.58 Analytical values 40.66 3.27 35.30 (%) (C 8 H 8 N 6 O ₃ ) Example 51 Preparation of N-cyano-N ′-(2-nitroxyethyl) -2-furancarboximidamide a) 2-Cyanofuran (4.50 g, 48.3 mmol) was dissolved in methanol (25 ml). Sodium methoxide (130 mg, 2.4 mmol) was added while cooling with ice, and the mixture was stirred for 2 hours while gradually returning to room temperature. After the reaction, acetic acid (0.16
g, 2.6 mmol) and neutralized, and concentrated under reduced pressure. Diethyl ether (100 ml) was added to the concentrated residue, the insolubles were separated, and the solution was concentrated under reduced pressure to obtain a crude product of methyl 2-furancarboximidate (6.0 g) as a pale yellow oil.

Then add cyanamide (4.06 g, 96.6 mmol) to this oil
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) and a phosphate buffer (pH 6.0, 30 ml) were added, and the mixture was stirred at room temperature for 24 hours. After the reaction, the reaction solution was extracted with dichloromethane (70 ml × 4 times), and the dichloromethane layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The residue is
Crystallized from diisopropyl ether / hexane to give methyl = N-cyano-2-furancarboximidate (4.
83g, 32.2mmol, 67% yield) as colorless crystals.

Physicochemical properties of methyl = N-cyano-2-furancarboximidate Melting point: 58.5-59.2 ° C. Infrared absorption spectrum (cm ⁻¹ , KBr): 2200, 1600, 148
0, 1350 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 7.78 (1H, d, J = 3.8Hz), 7.69 (1H, d, J = 1.8Hz), 6.64
(1H, dd, J = 1.8,3.8Hz ), 4.05 (3H, s) Elementary analysis: C H N Calculated 56.00 4.03 18.66 Analytical values 55.82 4.04 18.40 (%) (C 7 H 6 N 2 O 2) b) Methyl N-cyano-2-furancarboximidate (0.32 g, 2.09 mmol) was dissolved in methanol (3 ml), and 2-nitroxyethylamine / nitrate (0.37 g, 2.1
9 mmol) and triethylamine (0.22 g, 2.19 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-200, 25 g), and eluted with dichloromethane. The eluted fraction was concentrated and then crystallized from dichloromethane to give the title compound (0.20 g, 0.89 mmol, yield 45%) as colorless crystals.

Physicochemical properties of N-cyano-N '-(2-nitroxyethyl) -2-furancarboximidamide Melting point: 77.0 to 77.8 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2180, 1630, 160
0,1570 nuclear magnetic resonance spectrum (500 MHz, in CDCl _3): δ (pp
m) 8.04 (1H, d, J = 3.7Hz), 7.57 (1H, d, J = 1.2Hz), 6.79
(1H, brs), 6.66 (1H, dd, J = 1.2,3.7Hz), 4.69 (2H,
t, J = 5.5Hz), 3.87 (2H, dd, J = 5.5Hz, 10.4Hz) Elemental analysis: C H N Calculated 42.86 3.60 24.99 Analytical values 42.92 3.48 24.72 (%) (C 8 H 8 N 4 O 4 Example 52 Preparation of N-cyano-N '-(2-phenylethyl) -2-furancarboximidamide Methyl N-cyano-2-furancarboximidate (0.30 g, 2.0 mmol) in methanol (2 ml) Dissolved in
2-phenylethylamine (0.27 g, 2.2 mmol) was added,
Stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from diethyl ether / hexane to give the title compound (0.46 g, 1.93 mmol, yield 97%)
Was obtained as colorless crystals.

Physicochemical properties of N-cyano-N '-(2-phenylethyl) -2-furancarboximidamide Melting point: 88 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2180, 1600, 1570 Nuclear magnetic resonance spectrum (500MHz, in CDCl ₃ ): δ (pp
m) 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 (1
H, brs), 3.75 (2H, dd, J = 7.3,13.4Hz), 2.96 (2H, t, J
= 7.3 Hz) Elemental analysis: C H N Calculated 70.28 5.48 17.56 Analytical values 70.12 5.54 17.41 (%) (C 14 H 13 N 3 O) Example 53 N-cyano--N '- (2-nitro-carboxyethyl) - Preparation of 3-furancarboximidamide a) 3-Cyanofuran (3.76 g, 40.1 mmol) was dissolved in methanol (30 ml), and sodium methoxide (0.1 g,
1.9 mmol) and stirred at room temperature for 18 hours. After the reaction, the reaction solution was neutralized by adding acetic acid (0.14 g, 2.3 mmol) and concentrated under reduced pressure. Diethyl ether was added to the residue to separate insolubles, and the solution was concentrated under reduced pressure to obtain a crude product of methyl 3-furancarboximidate as a pale yellow oil.

Then add cyanamide (3.37g, 80.2mmol) to this oil
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) and a phosphate buffer (pH 5.4, 50 ml) were added, and the mixture was stirred at room temperature for 18 hours. After the reaction, the reaction solution was extracted with chloroform (100 ml × 3 times), and the chloroform layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The residue is
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-furancarboximidate (1.09 g, 7.3 mmol, yield 18%) as a colorless oil.

Physicochemical properties of methyl = N-cyano-3-furancarboximidate Infrared absorption spectrum (cm ⁻¹ , neat): 2190, 1610, 159
0 Nuclear magnetic resonance spectrum (100 MHz, in CDCl ₃ ): δ (pp
m) 8.59 (1H, t, J = 1.1Hz), 7.57 (1H, t, J = 2.2Hz), 7.06
(1H, dd, J = 1.1,2.2Hz), 4.00 (3H, s) b) Methyl = N-cyano-3-furancarboximidate (0.5 g, 3.3 mmol) was dissolved in methanol (10 ml), -Nitroxyethylamine / nitrate (0.84 g, 5.0
mmol) and sodium methoxide (0.27 g, 5.0 mmol), and the mixture was 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). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (Wakogel C-
200,20g), chloroform: methanol (100: 1)
Was eluted. The eluted fraction was concentrated under reduced pressure and crystallized from methanol / diethyl ether to give the title compound (0.06
g, 0.27 mmol, yield 8%) as colorless crystals.

Physicochemical properties of N-cyano-N '-(2-nitroxyethyl) -3-furancarboximidamide Melting point: 107.1 to 107.9 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2180, 1640, 160
0, 1550 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.44 (1H, s), 7.53 (1H, s), 6.83 (1H, s), 4.68 (2
H, t, J = 4.9Hz) , 3.80 (2H, t, J = 4.9Hz) Elemental analysis: C H N Calculated 42.86 3.60 24.99 Analytical values 42.61 3.53 24.73 (%) (C 8 H 8 N 4 O 4) Example 54 Preparation of N-cyano-N '-(2-phenylethyl) -3-furancarboximidamide Methyl N-cyano-3-furancarboximidate (0.30 g, 2.0 mmol) in methanol (10 ml) Dissolve,
2-phenylethylamine (0.27 g, 2.2 mmol) was added,
Stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure,
The residue was crystallized from diethyl ether to give the title compound (0.38 g, 1.59 mmol, yield 79%) as colorless crystals.

Physicochemical properties of N-cyano-N '-(2-phenylethyl) -3-furancarboximidamide Melting point: 132.5 to 133.1 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2170, 1610, 1560 Nuclear magnetism resonance spectrum (100 MHz, in CDCl _3): δ (pp
m) 8.28 (1H, s), 7.45 (1H, t, J = 1.9Hz), 7.4-7.1 (5
H), 6.69 (1H, s), 6.54 (1H, brs), 3.68 (2H, q, J =
6.6Hz), 2.95 (2H, t , 6.6Hz) Elemental analysis: C H N Calculated 70.28 5.48 17.56 Analytical values 70.22 5.41 17.37 (%) (C 14 H 13 N 3 O) Example 55 N-cyano--N ' Preparation of-(2-nitroxyethyl) -2-thiophenecarboximidamide a) 2-Cyanothiophene (5.46 g, 50 mmol) was dissolved in methanol (25 ml) and sodium methoxide (0.27
g, 5 mmol) and stirred at room temperature for 18 hours. 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 (40 ml) was added to the residue,
After separating the insoluble matter, the liquid was concentrated under reduced pressure to obtain a crude product of methyl 2-thiophenecarboximidate (6.35 g) as a yellow oil.

Next, cyanamide (2.52 g, 60 mmol) and N
a ₂ HPO ₄ (4.26 g, 30 mmol) and NaH ₂ PO ₄ .2H ₂ O (9.36 g, 60 m
mol) and phosphate buffer (pH 6.0, 20 ml)
Stir for 14 hours. After the reaction, the reaction solution was diluted with dichloromethane (50
ml × 4), the dichloromethane layer was dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was crystallized from dichloromethane / hexane to give methyl = N-cyano-2-thiophenecarboximidate (4.48 g, 27.0 m
mol, yield 54%) as colorless crystals.

Physicochemical properties of methyl = N-cyano-2-thiophenecarboximidate Melting point: 66.9-67.1 ° C. Infrared absorption spectrum (cm ⁻¹ , KBr): 2200, 1580 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 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) Elementary analysis: C H N Calculated 50.59 3.64 16.86 Analytical values 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), and 2-nitroxyethylamine / nitrate (0.34 g) was dissolved.
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, and the residue was subjected to silica gel column chromatography (Wakogel C-200, 25 g), and eluted with ethyl acetate. The eluted fraction was concentrated under reduced pressure and then crystallized from ethyl acetate / hexane to give the title compound (0.18 g, 0.77 mmol, yield 40%) as colorless crystals.

Physicochemical properties of N-cyano-N '-(2-nitroxyethyl) -2-thiophenecarboximidamide Melting point: 101.5-102.0 ° C Infrared absorption spectrum (cm- ¹ , KBr): 2180, 1630, 157
0,1280 nuclear magnetic resonance spectrum (500 MHz, in CDCl _3): δ (pp
m) 7.96 (1H, d, J = 3.7Hz), 7.61 (1H, d, J = 3.7Hz), 7.19
(1H, t, J = 3.7Hz), 4.70 (2H, t, J = 4.9Hz), 3.82 (2
H, t, J = 4.9Hz) Elemental analysis: C H N Calculated 40.00 3.36 23.32 Analytical values 39.88 3.42 23.22 (%) (C 8 H 8 N 4 O 3 S) Example 56 N-cyano--N '- ( Preparation of 2-phenylethyl) -2-thiophenecarboximidamide Methyl N-cyano-2-thiophenecarboximidate (0.33 g, 2.0 mmol) was dissolved in methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) and stirred at room temperature for 1 hour. After the reaction, the reaction solution 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-thiophenecarboximidamide Melting point: 106.8-107.5 ° C. Infrared absorption spectrum (cm ⁻¹ , KBr): 2200, 1580 Nuclear magnetic resonance spectrum (500MHz, in CDCl ₃ ): δ (pp
m) 7.89 (1H, s), 7.51 (1H, d, J = 4.9Hz), 7.4-7.2 (5
H), 7.14 (1H, t, J = 4.9Hz), 5.98 (1H, brs), 3.76
(2H, dd, J = 6.7,12.8Hz ), 2.97 (2H, t, J = 6.7Hz) Elemental analysis: C H N Calculated 65.85 5.13 16.46 Analytical values 65.67 5.11 16.36 (%) (C 14 H 13 N 3 S) Example 57 Preparation of N-cyano-N '-[2- (2-chlorophenyl) ethyl) -2-thiophenecarboximidamide Methyl N-cyano-2-thiophenecarboximidate (0.33 g, 2.0 mmol) Was dissolved in methanol (2 ml), and 2- (2-chlorophenyl) ethylamine (0.34
g, 2.2 mmol) and stirred at room temperature for 1 hour. After the reaction,
The reaction solution was concentrated under reduced pressure, and the residue was crystallized from diethyl ether / hexane to give the title compound (0.54 g, 1.87 mmol, yield 94%) as crystals.

Physicochemical properties of N-cyano-N '-[2- (2-chlorophenyl) ethyl) -2-thiophenecarboximidamide Melting point: 134-135 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1560 , 143
0,720 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 7.92 (1H, brs), 7.53 (1H, d, J = 4.3Hz), 7.39 (1H, br
s), 7.30-7.20 (3H, m), 7.16 (1H, t, J = 4.9Hz), 5.
93 (1H, brs), 3.79 (2H, m), 3.14 (2H, t, J = 6.7Hz) Mass spec: m / e 289 M ⁺ Example 58 N-cyano-N '-(2-phenylethyl) Preparation of -3-thiophenecarboximidamide a) 3-Cyanothiophene (0.66 g, 6.0 mmol) was dissolved in methanol (6 ml), and sodium methoxide (0.03 g) was dissolved.
g, 0.6 mmol) and stirred at room temperature for 28 hours. After the reaction,
Acetic acid (0.03 g, 0.6 mmol) was added to the reaction solution to neutralize, and concentrated under reduced pressure. Diethyl ether (50 ml) was added to the residue,
After separating the insoluble matter, the liquid was concentrated under reduced pressure to obtain a crude product of methyl 3-thiophenecarboximidate.

Subsequently, to this crude product, cyanamide (0.5 g, 12 mmol), Na ₂ HPO ₄ (0.86 g, 6 mmol) and NaH ₂ PO ₄ .2H ₂ O (1.89 g, 1
2 mmol) and a phosphate buffer (pH 6.0, 10 ml) were added, and the mixture was stirred at room temperature for 74 hours. After the reaction, the reaction solution was extracted with dichloromethane (10 m × 4 times).
The mixture was washed in l), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 30 g), and eluted with chloroform. The eluted fraction was concentrated under reduced pressure, and methyl = N-
Cyano-3-thiophene carboximidate (0.70
g, 4.2 mmol, 70% yield) as a colorless oil.

Physicochemical properties of methyl = N-cyano-3-thiophenecarboximidate Infrared absorption spectrum (cm ⁻¹ , neat): 2200, 1590, 130
0 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.69 (1H, dd, J = 2.0,3.4Hz), 7.82 (1H, dd, J = 2.0,5.6)
Hz), 7.41 (1H, dd, J = 3.4, 5.6 Hz), 4.03 (3H, s) b) Methyl N-cyano-3-thiophenecarboximidate (0.33 g, 2.0 mmol) in methanol (2 ml) Dissolve, 2-phenylethylamine (0.27 g, 2.2 mmol)
Was added and stirred at room temperature for 40 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was crystallized from diethyl ether to give the title compound (0.48 g, 1.89 mmol, yield 95%) as colorless crystals.

Physicochemical properties of N-cyano-N '-(2-phenylethyl) -3-thiophenecarboximidamide Melting point: 156.9 to 157.7 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2170, 1550 Nuclear magnetic resonance spectrum (500MHz, in CDCl ₃ ): δ (pp
m) 7.96 (1H, s), 7.45-7.20 (7H), 6.20 (1H, brs), 3.
73 (2H, dd, J = 6.7,13.4Hz), 2.97 (2H, t, J = 6.7Hz) Elemental analysis: C H N Calculated 65.85 5.13 16.46 Analytical values 65.77 5.01 16.29 (%) (C 14 H 13 N suspension (2-phenylethyl) -4-cyano-benzene carboximidamide manufacturing a diopter) 1,4-dicyanobenzene (6.41 g, 50 mmol) in methanol (100 ml) - ₃ S) example 59 N-cyano--N ' Cloudy, sodium methoxide (0.2
7 g, 5.0 mmol) and stirred for 22 hours. After the reaction, the reaction solution was neutralized by adding acetic acid (0.31 g, 5.1 mmol) and concentrated under reduced pressure. Dichloromethane (50 ml) and diethyl ether (50 ml) were added to the residue, the insolubles were separated, and the solution was concentrated under reduced pressure to give a crude product of methyl 4-cyanobenzenecarboximidate (5.77 g) as a colorless powder. As obtained.

Subsequently, cyanamide (3.03 g, 72 mmol) and N
a ₂ HPO ₄ (5.11 g, 36 mmol) and NaH ₂ PO ₄ .2H ₂ O (11.23 g, 72
mmol) (pH 6.0, 20 ml) and stirred at room temperature for 23 hours. After the reaction, the reaction solution was concentrated under reduced pressure, chloroform (200 ml) and methanol (200 ml) were added to the residue, the insoluble matter was filtered through celite, and the solution was concentrated. The concentrated residue was crystallized by adding diethyl ether (100 ml),
The precipitated crystals were collected and washed with diethyl ether. The solution and the washing solution are combined and concentrated under reduced pressure, and methyl = N
-Cyano-4-cyanobenzenecarboximidate (3.63 g, 19.6 mmol, yield 39%) was obtained as a colorless powder.

Physicochemical properties of methyl = N-cyano-4-cyanobenzenecarboximidate Melting point: 94.5-95.0 ° C. Infrared absorption spectrum (cm ⁻¹ , KBr): 2200, 1600, 1350 Nuclear magnetic resonance spectrum (500 MHz, CDCl ₃₎ Medium): δ (pp
m) 8.18 (2H, d, J = 8.6Hz), 7.83 (2H, d, J = 8.6Hz), 4.13
(3H, s) Elementary analysis: C H N Calculated 64.86 3.81 22.69 Analytical values 64.81 3.77 22.41 (%) (C 10 H 7 N 3 O) b) Methyl = N- cyano-4-cyano benzenecarboximidoyl imidate (0.37 g, 2.0 mmol) in methanol (4 m
l) and suspended in 2-phenylethylamine (0.25 g, 2.1 m
mol) and stirred at room temperature for 1 hour. After the reaction, methanol (6 ml) and diethyl ether (10 ml) were added to the reaction solution, and the precipitated crystals were filtered to remove the title compound (0.51 ml).
g, 1.87 mmol, 94% yield) as colorless crystals.

Physicochemical properties of N-cyano-N '-(2-phenylethyl) -4-cyanobenzenecarboximidamide Melting point: 261.0-261.8 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2170, 1550 Nuclear magnetic resonance Spectrum (500MHz, in CD ₃ OD): δ (pp
m) 7.84 (2H, d, J = 8.5Hz), 7.64 (2H, d, J = 8.5Hz), 7.36
-7.22 (5H), 3.73 (2H, t, J = 7.3Hz), 3.00 (2H, t, J
= 7.3 Hz) Elemental analysis: C H N Calculated 74.43 5.14 20.42 Analytical values 74.13 5.35 20.21 (%) (C 17 H 14 N 4) Example 60 N-cyano--N '- (2-phenylethyl) benzene carboxymethyl Imi Production of Damide a) Trimethyl orthobenzoate (1.00 g, 5.5 mmo
l), cyanamide (0.23 g, 5.5 mmol) and acetic anhydride (1.12
g, 11.0 mmol) was heated to 130-140 ° C. with stirring and reacted overnight. After the reaction, the reaction solution was extracted with chloroform (30 ml × 3 times). The chloroform layer is water (50
ml), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-200, 50 g). The mixture was eluted with hexane: diethyl ether (1: 1), and the eluted fraction was concentrated under reduced pressure to obtain methyl = N-cyano-benzenecarboximidate (0.52 g, 3.2 mmol, yield 59%) as a syrup.

Physicochemical properties of methyl = N-cyano-benzenecarboximidate Infrared absorption spectrum (cm ⁻¹ , neat): 2200, 1600, 144
0,700 Nuclear magnetic resonance spectrum (100 MHz, in CDCl _3): δ (pp
m) 8.2-8.0 (2H, m), 7.7-7.4 (3H, m), 4.08 (3H, s) b) Methyl N-cyano-benzenecarboximidate (0.50 g, 3.1 mmol) in methanol (10 ml) And 2-phenylethylamine (0.42 g, 3.5 mmol) was added thereto, followed by stirring at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / ether to give the title compound (0.43 g, 1.7 mmol, yield 55%) as crystals.

Physicochemical properties of N-cyano-N '-(2-phenylethyl) -benzenecarboximidamide Melting point: 166 to 168 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2200, 1590, 155
0,700 Nuclear magnetic resonance spectrum (100 MHz, in CDCl _3): δ (pp
m) 7.65-7.13 (10H, m), 3.77 (2H, m), 2.97 (2H, t, J =
5.1 Hz) mass spec: m / e 249 M ⁺ Example 61 Preparation of N-cyano-N '-(2-phenylethyl) acetimidamide trimethyl orthoacetate (1.00 g, 8.3 mmol), cyanamide (0.35 g, 8.3 mmol) And acetic anhydride (1.70 g, 16.7 m
mol) is heated to 130-140 ° C. with stirring,
Allowed to react for hours. After the reaction, the reaction mixture was reduced to 20 mmHg under reduced pressure.
Distillation under reduced pressure at 100 ° C. gives methyl = N-cyano-
A crude product of acetimidate (1.04 g) was obtained. Subsequently, the crude product was dissolved in methanol (10 ml), and 2-phenylethylamine (1.41 g, 11.6 mmol) was added.
Stir for 3.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from methanol / diethyl ether to give the title compound (0.88 g, 4.7 mmol, yield 57%) as crystals.

Physicochemical properties of N-cyano-N '-(2-phenylethyl) acetimidamide Melting point: 138 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2180, 1600, 156
0, 1360, 700 Nuclear magnetic resonance spectrum (100 MHz, in CDCl ₃ ): δ (pp
m) 7.39 to 7.11 (5H, m), 3.60 (2H, m), 2.88 (2H, t, J = 5.
5 Hz), 2.28 (3H, s) Mass spec: m / e 187 M ⁺ Example 62 Production of 3-cyano-2-methyl-1- (2-nitroxyethyl) isothiourea 2-nitroxyethylamine nitrate ( 0.56g, 3.3mmo
l) was dissolved in methanol (2 ml) and sodium methoxide (0.18 g, 3.3 mmol) was added. Furthermore, dimethyl-N-
Cyanodithioiminocarbonate (0.44 g, 3.0 mmol) dissolved in methanol (4 ml) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from diethyl ether to obtain a colorless powder. The obtained powder was washed with water and recrystallized from 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-nitroxyethyl) isothiourea Melting point: 135-135.5 ° C. Infrared absorption spectrum (cm ⁻¹ , KBr): 2170, 1640, 156
0,1280 Nuclear magnetic resonance spectrum (500 MHz, in CD ₃ OD): δ (pp
m) 4.63 (2H, s) , 3.74 (2H, s), 2.60 (3H, s) Elementary analysis: C H N Calculated 29.41 3.95 27.44 Analytical values 29.33 3.77 27.15 (%) (C 5 H 8 N 4 O 3 S) Example 63 Preparation of N-cyano-N'-acetyl-N '-[2- (2-chlorophenyl) ethyl] -3-pyridinecarboximidamide N-cyano-N'-[2- (2-chlorophenyl ) Ethyl] -3-pyridinecarboximidamide (1.50 g,
5.3 mmol) was dissolved in dichloromethane (10 ml), and triethylamine (2.20 g, 21.7 mmol) and acetic anhydride (1.00 g, 9.
8 mmol) and stirred at room temperature for 6 hours. After the reaction, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml × 2). The ethyl acetate layer was washed with a saturated aqueous solution of NaCl (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (Wakogel C-200, 100 g). Ethyl acetate:
The mixture was eluted with hexane (1: 1), and the eluted fraction was concentrated under reduced pressure to give the title compound (1.35 g, 4.1 mmol), yield 77.
%) As crystals.

Physicochemical properties of N-cyano-N'-acetyl-N '-[2- (2-chlorophenyl) ethyl] -3-pyridinecarboximidamide Melting point: 112 ° C Infrared absorption spectrum (cm ^-1 , KBr): 2190, 1700, 158
0, 1350, 1160, 750 Nuclear magnetic resonance spectrum (500 MHz, in CDCl ₃ ): δ (pp
m) 8.78 (1H, brs), 8.47 (1H, brs), 7.69 (1H, brd, J = 7.
3Hz), 7.45 (1H, dd, J = 4.9,7.9Hz), 7.34 (1H, br
s), 7.27 to 7.23 (3H), 4.11 (2H, t, J = 6.7Hz), 3.15
(2H, t, J = 6.7Hz), 2.19 (3H, s)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/495 A61K 31/495 C07D 213/58 C07D 213/58 213/74 213/74 215/54 215/54 307/56 307 / 56 333/38 333/38 401/12 401/12 413/12 413/12 (72) Inventor Yuji Soezuka 1-2-2 Soja-cho, Maebashi-shi, Gunma Pref. 72) Inventor Tatsuo Nakajima 1-2-2 Soja-cho, Maebashi-shi, Gunma Pref. Kirin Brewery Co., Ltd. Pharmaceutical Development Laboratory (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 261/04 C07D 213 / 58,213 / 74,215 / 54 C07D 307 / 56,333 / 38,401 / 12,413 / 12 A61K 31 / 44,31 / 47,31 / 495,31 / 34,31 / 38 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A carboximidamide derivative represented by the following formula (I). [In the formula, the substituent is defined by any of the following (1) to (5). (1) X is Or its acid adduct, Or its acid adduct, Or its acid adduct, (Where R ₁ represents a hydrogen atom or a cyano group), a methyl group or CH ₃ —S—, and Y is And Z is (Where R ₂ represents a hydrogen atom or a chlorine atom). (2) X is Or Y represents an acid adduct thereof, And Z is-(CH ₂ ) _m -R ₃ [where m represents an integer of any of 1 to 3, and when m is 1, R ₃ is And when m is 2, R ₃ is Dimethylamino group, acetamido group, −SO ₃ ^- Na ⁺ , Azide group or -OR ₅ (where R ₅ is a methyl group, -SO ₃ ^- N
a ⁺ , benzyl group, phenyl group, hydrogen atom, benzoyl group, acetyl group, -P (O) (OCH ₂ CH ₃ ) ₂ , ethoxycarbonyl group or And when m is 3, R ₃ is —COOCH ₂ CH ₃ , —COOH
Or a nitro group]. (3) X is Or Y represents an acid adduct thereof, (Where R ₄ represents a methyl group or a benzyl group), and Z is Represents (4) X is Or Y represents an acid adduct thereof, (Where Q represents a nitrogen atom or a carbon atom), and Z is bonded to Q, and when Q is a nitrogen atom, Benzyl group, (Where R ₆ represents an acetyl group, a nitro group, a chlorine atom or a methoxy group), And when Q is a carbon atom, Represents a benzyl group, a hydroxyl group, or a nitroxyl group. (5) X is Or Y represents an acid adduct thereof, And Z is Represents ] 2. A vasodilator comprising the carboximidamide derivative represented by the formula (I) according to claim 1 as an active ingredient. 3. An antihypertensive comprising a carboximidide derivative represented by the formula (I) according to claim 1 as an active ingredient.