JP2974791B2 - Carboximidamide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[Background of the Invention]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel carboximidamide derivative having a vasodilator action.

[0002]

BACKGROUND OF THE INVENTION Carboximidamide compounds related to the present invention include N, which has a vasodilating action, a hypotensive action and the like.
-Cyano-N'-substituted carboximidamide compounds (see EP 0 388 528 A) are known.

[Summary of the Invention]

However, patients,
Considering the variety of disease states, there is a constant need for new vasodilators and antihypertensive agents.

An object of the present invention is to provide a novel compound having a vasodilatory effect.

[0005]

SUMMARY OF THE INVENTION The present invention provides an N-cyano-
The object was achieved by finding that N'-carboximidamide derivatives have a vasodilatory effect. That is, the carboximidamide derivative according to the present invention is represented by the following formula (I).

Embedded image [Wherein, the substituents are defined as follows.
X is

Embedded image

Embedded image Or its acid adduct,

Embedded image Or

Embedded image Or Y represents an acid adduct thereof,

Embedded image (Where R represents a chlorine atom or a hydrogen atom) or — (CH ₂ ) ₂ ONO ₂ . ]

DETAILED DESCRIPTION OF THE INVENTION [I] N-Cyano-N'-carboximidamide derivative The carboximidamide derivative according to the present invention has the formula (I)
Is as described above, and is structurally an N-cyano-N'-carboximidamide derivative. In the formula (I), X is

Embedded image Or

Embedded image In the case where is, the compound represented by 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.

Embedded image Or

Embedded image In the case where is, the acid addition salt is present. Examples of the acid to form an acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and acetic acid, propionic acid, maleic acid, oleic acid, palmitic acid, citric acid, succinic acid, and the like.
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.

According to the present invention, there is provided an N-shear of the formula (I)
Representative examples of no-N'-carboximidamide derivatives
Are listed below.Compound No. Compound name  (1) N-cyano-N '-[2- (2-chlorophenyl) ethyl] -2- (3-methylthiophene) carboximidamide (2) N-cyano-N'-(2-phenylethyl) -2 -(3-methylthiophene) carboximidamide (3) N-cyano-N '-(2-nitroxyethyl) -2- (3-methylthiophene) carboximidamide (4) N-cyano-N'-[ 2- (2-chlorophenyl) ethyl] -2- (5-methylthiophene) carboximidamide (5) N-cyano-N '-(2-phenylethyl) -2- (5-methylthiophene) carboximidamide ( 6) N-cyano-N '-(2-nitroxyethyl) -2- (5-methylthiophene) carboximidamide (7) N-cyano-N'-[2- (2-chlorophene Nyl) ethyl] -3- (6-chloro-2H-1-benzopyran) carboximidamide (8) N-cyano-N '-[2- (2-chlorophenyl) ethyl] -3- (5-methoxy-1 -Methylindole) carboximidamide (9) N-cyano-N '-(2-phenylethyl) -3- (5-methoxy-1-methylindole) carboximidamide (10) N- [2- (2- Chlorophenyl) ethyl] -N'-cyano-3- (2-thienyl) propenylamidine (11) N- (2-phenylethyl) -N'-cyano-3- (2-thienyl) propenylamidine (12) N- (2-Nitrooxyethyl) -N'-cyano-3- (2-thienyl) propenylamidine (13) N-cyano-N '-(2-nitroxyethyl) -2-benzothiophene Carboximidamide (14) N-cyano-N '-[2- (2-chlorophenyl) ethyl] -3-pyridyl-2-benzyloxyiminoacetamidine (15) N-cyano-N'-(2-nitroxy Ethyl) -3-pyridyl-2-benzyloxyiminoacetamidine The structures of these compounds are shown in Table 1 below.

[Table 1]

[Table 2]

[Table 3]

[II] N-cyano-N'-carboxyi
Preparation of midamide derivatives N-cyano-N'-carboximidamide according to the invention
Derivatives may be manufactured by any suitable method
Can be manufactured, for example, by the method described below.
be able to.Method  The compound of the present invention has the formula (I) as shown in the reaction formula A described below.
A nitrile represented by I) or an amide represented by formula (III)
Lead to the cyano imidate of formula (V),
By reacting the compound. Up
The nitrile or amide is an alkyl, halogenated
Any suitable purpose such as alkyl, aldehyde, carboxylic acid, etc.
It is manufactured from raw materials by methods known in the field of synthetic organic chemistry.
(Reference "Organic funksi
Organic Group Preparations (Organic Func
National Group Preparations) ", 1, S.R.Sandler and W.
Karo, Academic Press, 1968). Reaction formula A:

Embedded image [Wherein, 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. X and Y are as described above. ]
Hereinafter, this production method will be described in more detail according to a reaction formula. (A) Compound (II) → Compound (IV) The nitrile represented by the formula (II) is R′OH (alcohol)
By reacting with hydrogen chloride gas or R ″ ONa (sodium alkoxide), an imidate represented by the formula (IV) is obtained. In the case of reacting with hydrogen chloride gas, alcohols (R′OH) that can be used include: And any of linear and cyclic alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, cyclopentanol, cyclohexanol, and n-octanol. Is used in an amount of at least 3 based on 1 mole of the nitrile represented by the formula (II).
0 mol or more, especially 30 to 300 mol is preferable. The amount of hydrogen chloride gas should be at least 2 per mole of nitrile.
0 mol or more, especially 20 to 200 mol is preferable. The reaction temperature is preferably from -10 to 10C, more preferably from -5 to 5C. Under the above reaction conditions, this reaction is usually 15 to
It can finish in 95 hours. The obtained imidate is a hydrochloride and can be converted into a free form by treating with an alkali. On the other hand, when R "ONa is allowed to act, the type of alcohol that can be used is the same as when hydrogen chloride gas is actuated, and the amount used is preferably 5 to 500 mol, more preferably 1 mol to 1 mol of nitrile. The amount of R ″ ONa is preferably a catalytic amount, and is preferably 0.1 to 1 mol per mol of nitrile.
Within the range of 01 to 0.5 mol, more preferably 0.02 to
0.2 mol. The reaction temperature is preferably in the range of 0 to 50 ° C, more preferably 0 ° C to room temperature. Under the above reaction conditions, this reaction can be completed usually in 1 to 24 hours. The obtained imidate represented by the formula (IV) can be subjected to the next reaction without isolation and purification,
As a method for isolation and purification, 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. (B) Compound (III) → Compound (IV) The amide represented by the formula (III) is converted into an imidate represented by the formula (IV) by the action of dimethyl sulfate. The amount of dimethyl sulfate used in this reaction is determined by the formula (II
It is preferably at least 3 mol or more, particularly preferably 3 to 6 mol, per 1 mol of the amide shown in I). Reaction temperature is 50-15
0 ° C is preferred, and 100 to 105 ° C is more preferred. Under the above reaction conditions, this reaction can be completed usually in 2 to 3 hours. The method for isolating and purifying the obtained imidate is the same as that described in (A). (C) Compound (IV) → Compound (V) The imidate represented by the formula (IV) is reacted with cyanamide (NH ₂ CN) in a buffer, preferably in a phosphate buffer, to give the compound of the formula (V) Is converted to cyanoimidate. The amount of cyanamide used is imidate 1
It is preferably at least 1 mol or more, more preferably 2 to 3 mol, per mol. This reaction is carried out in a buffer (preferably a phosphate buffer) as described above, but can be carried out in the presence of a solvent. Solvents that can be used include, for example, acetonitrile, dichloromethane, chloroform,
Organic solvents such as dioxane. The pH range is preferably within the range of 5.0 to 6.5, more preferably 5.0.
Advantageously, it is in the range of 2 to 6.2, and the concentration of the buffer is preferably in the range of 0.1 to 4M, especially 0.2 to 3M. In addition, in the case of a phosphate buffer, for example, Na ₂ HPO ₄ and NaH ₂ PO ₄ are at least 1 mole per 1 mole of imidate in order to maintain sufficient buffer capacity. As described above, it is desirable to use 1 to 4 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 represented by the formula (IV) is usually converted to the cyanoimidate represented by the formula (V) in 6 to 70 hours. The method for isolating and purifying the thus obtained cyanoimidate represented by the formula (V) as necessary includes crystallization, distillation, and column chromatography using silica gel as a carrier. Purification methods known in the field of chemistry can be used. (D) Compound (V) → Compound (I) The cyanoimidate represented by the formula (V) is reacted with an amine compound to form an N-cyano-compound represented by the formula (I).
N'-carboximidamide derivatives can be produced. The amount of the amine compound used is at least 1 mol or more per 1 mol of the cyanoimidate represented by the formula (V),
More preferably, the range is from 1 to 2.5 mol.
This reaction is generally carried out in a solvent, and examples of usable solvents include alcohols such as methanol and ethanol, organic solvents such as dichloromethane, chloroform, carbon tetrachloride, dioxane and tetrahydrofuran, and water. Can be The reaction temperature is in the range of 0 ° C. to the boiling point of the solvent, and particularly preferably around room temperature. Under the above reaction conditions, this reaction can be completed usually in 5 minutes to 6 days. 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 represented by the formula (V). 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 The compound according to the present invention has a vasodilatory effect as shown in the experimental examples described later, and is useful as a vasodilator. When the compound according to the present invention is administered as a vasodilator, it can be administered orally or parenterally (intramuscularly, subcutaneously, intravenously, transdermally) or as a sublingual tablet, suppository or 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 times of administration must be determined by an appropriate amount determination test of a specialist based on the above guidelines, but usually, the daily dose per adult is about 0.1 to 200 mg, preferably 0.5 to 100 mg. It is about. When the compound of the present invention is orally administered as a pharmaceutical, it is administered in the form of tablets, granules, powders, capsules and the like, and when administered parenterally, it is administered in the form of injections, suspensions and the like. To produce these formulations, excipients, binders, disintegrants, lubricants,
Additives such as stabilizers 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, hydroxypropylcellulose, ethylcellulose, Carboxymethyl cellulose, gum arabic and the like, as disintegrants, for example, starch, carboxymethyl cellulose calcium and the like,
As the lubricant, for example, magnesium stearate, talc, hydrogenated oil, etc., as the stabilizer, for example, lactose, mannitol, maltose, polysorbates, macrogol, polyoxyethylene hydrogenated castor oil, etc. The ones usually used are listed. These components can be used to produce tablets, granules, capsules, injections and the like in a usual manner.

[0009]

The carboximidamide derivative according to the present invention, that is, the N-cyano-N'-carboximidamide derivative has an excellent vasodilator effect. It can be said that the property that the carboximidamide derivative according to the present invention has such excellent vasodilatory action was unexpected to those skilled in the art.

[Experimental example]

The following experimental examples are provided to explain the present invention in more detail, and the present invention is not limited thereto. <Pharmacological Test> Test Example : 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. Bleeding dead weight 25
The thoracic aorta was immediately excised from 0 to 350 g of male Wistar rats, and a 3 mm-wide slice was prepared. The specimen was aerated with a gas mixture of 95% O ₂ -5% CO ₂ 37
Suspended in an organ bath filled with Krebs-Ringer solution at ℃. Apply a static tension of 1 g,
After the tension of the specimen is stabilized, 40 mM K
The specimen was replaced with an isotonic nutrient solution containing Cl to increase the tension of the specimen. After the tension generated by KCl became constant, the test compound was cumulatively added to the organ bath to relax the specimen. The tension due to KCl was taken as 100%, and the relaxation reaction was determined as its inhibition rate. The IC ₅₀ value (the tension due to KCl was 5%)
0% inhibitory concentration) was calculated from the average dose-effect curve by the probit method. (2) Results Table 2 shows the IC ₅₀ value of the compound of the present invention.

[Table 4] Example 1  N-cyano-N '-[2- (2-chlorophenyl) e
Tyl] -2- (3-methylthiophene) carboximi
Damide production  a) 3-Methyl-2-thiophenecarboxylic acid (20
g, 0.14 mol) in tetrahydrofuran (200 ml)
Dissolved and triethylamine (18.38g, 0.18mo
l) was added. Further, under ice-water cooling, ethyl chlorocarbonate (1
8.23 g (0.17 mol) in tetrahydrofuran (80
The resulting solution was stirred at room temperature for 3 hours. Then ice water
Under cooling, 28% aqueous ammonia (40 ml, 0.66 mol) was added.
Then, the mixture was stirred at room temperature for 45 minutes. After the reaction, the reaction solution is concentrated under reduced pressure.
And the residue is subjected to silica gel column chromatography (Wako
-Gel C-200, 1200 g).
Eluted with methanol: methanol (50: 1). Elution category is
By concentrating under reduced pressure, 3-methyl-2-thiophene
The crude product of carboxamide (10.22 g) was pale yellow
Obtained as crystals. Subsequently, titanium tetrachloride (27.3 g,
0.14 mol) in carbon tetrachloride (50 ml).
At 0 ° C. it was added to tetrahydrofuran (100 ml). Further
Dissolve the above crystals in tetrahydrofuran (130ml)
And added at 0-10 ° C. Next, triethylamine (2
9.09 g, 0.29 mol) in tetrahydrofuran (50
dissolve in the mixture at 0-10 ° C and stir at room temperature for 65 hours
did. After the reaction, water (100 ml) was added to the reaction mixture under ice-water cooling.
And concentrated under reduced pressure, and the aqueous layer was extracted with ethyl acetate (100 ml x 3 times).
Extracted. Ethyl acetate layer is saturated sodium bicarbonate
Wash with aqueous solution, dehydrate with anhydrous sodium sulfate, and concentrate under reduced pressure.
3-Methyl-2-cyanothiophene
(5.25 g) was obtained as a yellow syrup.
Subsequently, hydrogen chloride gas (26.
89 g, 0.74 mol) in methanol (50 ml).
And stirred at 0 ° C. for 17 hours. After the reaction,
After concentration under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added,
The mixture was extracted with ethyl ether (100 ml × 3 times). Jie
The tyl ether layer is dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure.
By condensation, methyl = 2- (3-methylthiophene
G) the crude product of carboximidate (4.94 g)
Obtained as a yellow syrup. Then this syrup is Ciana
Mid (2.67 g, 63.7 mmol) and Na₂HPO₄
(4.52 g, 31.8 mmol) and NaH₂PO₄・ 2H
₂Phosphate buffer with O (19.87 g, 127 mmol)
(PH 5.4, 210 ml) and stirred at room temperature for 18 hours.
Was. After the reaction, the reaction solution was diluted with dichloromethane (100 ml × 3).
Times), and the dichloromethane layer is dried over anhydrous sodium sulfate.
After dehydration with a solvent, the mixture was concentrated under reduced pressure. Silica gel column residue
Chromatography (Wakogel C-200, 125g)
And eluted with hexane: ethyl acetate (4: 1)
Was. The eluted fraction was concentrated under reduced pressure to give methyl = N-
Cyano-2- (3-methylthiophene) carboximi
Date (1.55 g, 8.61 mmol, 6% yield) colorless
Obtained as crystals. b) 2- (2-chlorophenyl) d
Methylamine (0.26 g, 1.67 mmol) in methanol
(50 ml), and methyl = N-cyano-2- (3-
Methylthiophene) carboximidate (0.3 g,
(1.67 mmol) and stirred at room temperature for 64 hours. reaction
Thereafter, the reaction solution was concentrated under reduced pressure, and the residue was treated with methanol / diethyl.
The title compound was crystallized from ether (0.38 g,
1.25 mmol, yield 75%) as colorless crystals.N-cyano-N '-[2- (2-chlorophenyl) ethyl
Ru] -2- (3-Methylthiophene) carboximida
Physicochemical properties of mid  Melting point: 134.5 to 135 ° C Infrared absorption spectrum (cm^-1, KBr): 2200, 15
80, 1560, 1430, 740. Nuclear magnetic resonance spec
Torr (100MHz, CDCl₃During):δ (ppm)7.5-
7.0 (5H), 6.89 (1H, d, J = 5.3H
z), 6.13 (1H, brs), 3.75 (2H,
m), 3.10 (2H, t, J = 6.7 Hz), 2.34
(3H, s). Mass spectrometry: m / z 303 (M⁺)Example 2  N-cyano-N '-(2-phenylethyl) -2-
Production of (3-methylthiophene) carboximidamide  2-phenylethylamine (0.2 g, 1.67 mmol
l) was dissolved in methanol (50 ml) and methyl
Ano-2- (3-methylthiophene) carboximide
(0.3 g, 1.67 mmol) at room temperature.
Stir for 5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was removed.
Crystallization from diethyl ether gave the title compound (0.3
7 g, 1.38 mmol, yield 82%) as colorless crystals.
Was.N-cyano-N '-(2-phenylethyl) -2- (3
Physical Chemistry of (-Methylthiophene) carboximidamide
Characteristic  Melting point: 129.5 to 130 ° C Infrared absorption spectrum (cm^-1, KBr): 2180, 15
60, 1470, 735. Nuclear magnetic resonance spectrum (10
0MHz, CDCl₃During):δ (ppm)7.5-7.0 (6
H), 6.88 (1H, d, J = 5.3 Hz), 6.06
(1H, brs), 3.73 (2H, m), 2.95
(2H, t, J = 6.7 Hz), 2.30 (3H, s). Mass spec: m / z 269 (M⁺)

[0011]Example 3  N-cyano-N '-(2-nitroxyethyl) -2-
Production of (3-methylthiophene) carboximidamide  2-Nitroxyethylamine / P-toluene sulfone
The acid salt (0.92 g, 3.34 mmol) was added to methanol (30
sodium methoxide (0.18 g,
(3.34 mmol) were added. Further methyl = N-cyano-
2- (3-methylthiophene) carboximidate
(0.3 g, 1.67 mmol) and stirred at room temperature for 5 hours
did. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was
(40 ml × 3 times). No chloroform layer
After dehydration with sodium hydrogen sulfate, the mixture was concentrated under reduced pressure. Residue
Kagel column chromatography (Wakogel C-20)
0, 14 g) and hexane: ethyl acetate (3: 2)
Was eluted. The elution fraction is concentrated under reduced pressure
To give the title compound (0.23 g, 0.91 g).
mmol, yield 54%) as colorless crystals.N-cyano-N '-(2-nitroxyethyl) -2-
Physics of (3-methylthiophene) carboximidamide
chemical property  Melting point: 114.5 to 115 ° C Infrared absorption spectrum (cm^-1, KBr): 2180, 16
30, 1570, 1550, 1280. Nuclear magnetic resonance spectroscopy
Cuttle (100MHz, CDCl₃During):δ (ppm)7.4
0 (1H, d, J = 5.0 Hz), 6.93 (1H, d,
J = 5.0 Hz), 6.72 (1H, brs), 4.67
(2H, t, J = 5.3 Hz), 3.80 (2H, m),
2.37 (3H, s). Mass spec: m / z 255
([M + H]⁺)

[0012]Example 4  N-cyano-N '-[2- (2-chlorophenyl) e
Tyl] -2- (5-methylthiophene) carboxyimi
Damide production  a) 5-methyl-2-thiophenecarboxylic acid (5 g,
35.2 mmol) in tetrahydrofuran (50 ml)
And triethylamine (4.65 g, 46 mmol) was added.
Was. Ethyl chlorocarbonate (4.56 g,
42 mmol) in tetrahydrofuran (20 ml)
The mixture was stirred at room temperature for 4 hours. Then, under ice water cooling, ammonia
Agus was blown for one hour. After the reaction, the reaction solution is concentrated under reduced pressure.
And the residue is subjected to silica gel column chromatography (Wako
-Gel C-200, 370 g) and chloroform:
Elution was carried out with methanol (50: 1). Elution category reduced pressure
By concentrating, 5-methyl-2-thiophenecar
A crude product of boxyamide (2 g) was obtained as pale yellow crystals.
Was. Subsequently, dimethyl sulfate (5.36 g, 4
2.5 mmol) and stirred at 100-105 ° C. for 2 hours.
Was. After the reaction, the reaction solution was diluted with diethyl ether (100 ml).
After washing, 30% aqueous sodium carbonate solution was added,
Extracted with ether (40 ml × 3 times). Diethyl ether
The tellurium layer is dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure.
According to, methyl = 2- (5-methylthiophene) cal
The crude product of boxiimidate (2.24 g) was
Obtained as wrap. Then this syrup is cyanamide
(1.21 g, 28.8 mmol) and Na₂HPO
₄(2.04 g, 14.4 mmol) and NaH₂PO₄・ 2
H₂Phosphate buffer with O (8.99 g, 57.6 mmol)
(PH 5.4, 100 ml) and stirred at room temperature for 40 hours.
Was. After the reaction, the reaction solution was diluted with dichloromethane (50 ml × 3 times)
And the dichloromethane layer is extracted with anhydrous sodium sulfate.
After dehydration, the mixture was concentrated under reduced pressure. The residue is purified by silica gel column chromatography.
For wrist chromatography (Wakogel C-200, 60 g).
And eluted with hexane: ethyl acetate (4: 1). Dissolution
The eluate is concentrated under reduced pressure to obtain methyl N-cyano.
-2- (5-Methylthiophene) carboximidate
(1.05 g, 5.83 mmol, 17% yield) as colorless crystals
As obtained. b) 2- (2-chlorophenyl) ethyl
The amine (0.26 g, 1.67 mmol) was added to methanol (5
0 ml), and methyl = N-cyano-2- (5-methyl
Luthiophene) carboximidate (0.3 g, 1.
67 mmol) and stirred at room temperature for 18 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, and the residue was crystallized from diethyl ether.
To give the title compound (0.4 g, 1.32 mmol, yield 7).
9%) as colorless crystals.N-cyano-N '-[2- (2-chlorophenyl) ethyl
Ru] -2- (5-Methylthiophene) carboximida
Physicochemical properties of mid  Melting point: 127 to 127.5 ° C Infrared absorption spectrum (cm^-1, KBr): 2180, 15
70, 1560. Nuclear magnetic resonance spectrum (100MHz,
CDCl₃During):δ (ppm)7.71 (1H, d, J =
3.8 Hz), 7.5-7.0 (4H), 6.78 (1
H, d, J = 3.8 Hz), 6.37 (1H, brs),
3.73 (2H, m), 3.10 (2H, t, J = 6.
7 Hz), 2.51 (3H, s). Mass spectrometry: m / z 303 (M⁺)

[0013]Example 5  N-cyano-N '-(2-phenylethyl) -2-
Production of (5-methylthiophene) carboximidamide  2-phenylethylamine (0.2 g, 1.67 mmol
l) was dissolved in methanol (20 ml) and methyl
Ano-2- (5-methylthiophene) carboximide
(0.3 g, 1.67 mmol) at room temperature for 66 hours.
While stirring. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was
The title compound (0.35) was crystallized from tyl ether.
g, 1.3 mmol, 78% yield) as colorless crystals.N-cyano-N '-(2-phenylethyl) -2- (5
Physical Chemistry of (-Methylthiophene) carboximidamide
Characteristic  Melting point: 97-97.5 ° C Infrared absorption spectrum (cm^-1, KBr): 2180, 15
80, 1550, 1470. Nuclear magnetic resonance spectrum (1
00MHz, CDCl₃During):δ (ppm)7.69 (1H,
d, J = 3.8 Hz), 7.5-7.0 (5H), 6.7
7 (1H, d, J = 3.8 Hz), 6.24 (1H, br
s), 3.71 (2H, m), 2.94 (2H, t, J
= 6.7 Hz), 2.50 (3H, s). Mass spectrometry: m /
z 269 (M⁺)

[0014]Example 6  N-cyano-N '-(2-nitroxyethyl) -2-
Production of (5-methylthiophene) carboximidamide  2-Nitroxyethylamine / P-toluene sulfone
Acid salt (1.39 g, 5 mmol) in methanol (50 ml)
Dissolve, sodium methoxide (0.27 g, 5 mmol)
Was added. Furthermore, methyl = N-cyano-2- (5-methyl
Luthiophene) carboximidate (0.45 g,
2.5 mmol) and stirred at room temperature for 65 hours. reaction
Thereafter, the reaction solution was concentrated under reduced pressure, and the residue was chloroform (40 ml).
× 3 times). Chloroform layer is anhydrous sodium sulfate
After dehydration with lithium, the mixture was concentrated under reduced pressure. Silica gel residue
Chromatography (Wakogel C-200, 23
g) and elute with hexane: ethyl acetate (3: 2)
did. The elution fraction is concentrated from vacuum
After crystallization, the title compound (0.27 g, 1.06 mmol, yield
(43%) as colorless crystals.N-cyano-N '-(2-nitroxyethyl) -2-
Physics of (5-methylthiophene) carboximidamide
chemical property  Melting point: 91.5-92 ° C Infrared absorption spectrum (cm^-1, KBr): 2170, 16
20, 1565, 1280. Nuclear magnetic resonance spectrum (1
00MHz, CDCl₃During):δ (ppm)7.78 (1H,
d, J = 3.8 Hz), 7.11 (1H, brs), 6.
81 (1H, d, J = 3.8 Hz), 4.68 (2H,
t, J = 5.2 Hz), 3.81 (2H, m), 2.53
(3H, s). Mass spec: m / z 254 (M⁺)

[0015]Example 7  N-cyano-N '-[2- (2-chlorophenyl) e
Tyl] -3- (6-chloro-2H-1-benzopyran)
Production of carboximidamide  a) 6-chloro-3-cyano-2H-1-benzopyra
(0.5 g, 2.61 mmol) under ice-cooling with hydrogen chloride gas.
Was added to methanol (35 ml) at 0 ° C.
Stir for 7.5 hours. After the reaction, add saturated sodium bicarbonate to the reaction mixture.
An aqueous thorium solution is added, and chloroform (150 ml × 3
Times). Chloroform layer is saturated NaCl aqueous solution
Wash with liquid, dehydrate with anhydrous magnesium sulfate, and concentrate under reduced pressure
By doing so, methyl = 3- (6-chloro-2H-1
-Benzopyran) carboximidate (0.5 g,
2.24 mmol, 86% yield) as yellow crystals. Continued
The crystals were dissolved in acetonitrile (25 ml).
Anamide (0.18 g, 4.4 mmol) and Na₂HPO
₄(0.31 g, 2.2 mmol) and NaH₂PO₄・ 2H
₂O (1.37 g, 8.8 mmol) in phosphate buffer (pH
5.4, 10 ml) and stirred at room temperature for 21.5 hours.
Was. After the reaction, the reaction solution was poured into ice water (200 ml), and chloro
Extracted with form (150 ml × 3 times). Chloroform
The layer is washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate.
After dehydration with a solvent, the mixture is concentrated under reduced pressure to give methyl
Ano-3- (6-chloro-2H-1-benzopyran) ca
Ruboximidate (0.52 g, 2.09 mmol, yield
93%) as yellow crystals. b) Methyl = N-si
Ano-3- (6-chloro-2H-1-benzopyran) ca
Ruboximidate (0.52 g, 2.09 mmol)
Dissolve in ethanol (40 ml) and add 2- (2-chlorophenyl)
L) ethylamine (0.72 g, 4.6 mmol) was added,
Stirred at room temperature for 10 minutes. After the reaction, the reaction solution was concentrated under reduced pressure,
The residue was crystallized from diethyl ether / hexane to give the title
(0.47 g, 1.26 mmol, 60% yield)
Obtained as pale yellow crystals.N-cyano-N '-[2- (2-chlorophenyl) ethyl
Ru] -3- (6-Chloro-2H-1-benzopyran) ca
Physicochemical properties of ruboximidamide  Melting point: 173-174 ° C Infrared absorption spectrum (cm^-1, KBr): 2170, 15
80, 1550. Nuclear magnetic resonance spectrum (100MHz,
(CD₃)₂During SO):δ (ppm)9.20 (1H, br
s), 7.5-7.2 (6H), 7.06 (1H,
s), 6.93 (1H, d, J = 7.7 Hz), 4.93
(2H, s), 3.56 (2H, m), 2.99 (2
H, t, J = 6.7 Hz). Mass spec: m / z 372 (M⁺)

[0016]Example 8  N-cyano-N '-[2- (2-chlorophenyl) e
Tyl] -3- (5-methoxy-1-methylindole)
Production of carboximidamide  a) 3-cyano-5-methoxyindole (2.77
g, 16.1 mmol) in tetrahydrofuran (50 ml).
Dissolve and add 60% sodium hydride (0.7
7 g, 19.3 mmol) and methyl iodide (2.74 g,
19.3 mmol) and stirred at room temperature for 30 minutes. reaction
Thereafter, methanol (8 ml) and water (8 ml) were added to the reaction solution.
And concentrated under reduced pressure, and the residue was chloroform (160 ml x 3 times).
Extracted. The chloroform layer is washed with water and
After dehydration with sodium, the mixture was concentrated under reduced pressure. Residue in diethyl
Crystallized from ether / hexane to give 3-cyano-5-methoate
Xy-1-methylindole (2.78 g, 15 mmol,
(93% yield) as colorless crystals. Then on this crystal
Saturate hydrogen chloride gas with methanol (50 ml) under ice-water cooling
And stirred at 0 ° C. for 95 hours. After the reaction, the reaction solution
Was concentrated under reduced pressure, and the residue was subjected to chloroform (150 ml × 3 times).
Extracted. Chloroform layer is saturated sodium bicarbonate
Wash with aqueous solution (200 ml) and dry with anhydrous sodium sulfate.
After dehydration and concentration under reduced pressure, methyl = 3- (5-
(Methoxy-1-methylindole) carboximidate
The crude product was obtained as pale yellow crystals. Then this crystal
Was dissolved in acetonitrile (30 ml) and cyanamide
(1.25 g, 30 mmol) and Na₂HPO₄(2.2
g, 15 mmol) and NaH₂PO₄・ 2H₂O (9.3
g, 60 mmol) in phosphate buffer (pH 5.4, 100 m
l) was added and the mixture was stirred at room temperature for 70 hours. After the reaction, the reaction solution
Was extracted with chloroform (150 ml × 3 times).
The form layer is dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure.
Was. The residue was subjected to silica gel column chromatography (Wako
-Gel C-200, 70 g) and hexane: diethyl
Eluted with 1: 1 ether. Elution category is reduced pressure
By contraction, methyl = N-cyano-3- (5-me
Toxi-1-methylindole) carboximidate
(2.19 g) was obtained as pale yellow crystals. b) Methyl = N-cyano-3- (5-methoxy-1-
Methylindole) crude product of carboximidate
(0.5 g) in methanol (10 ml) and chloroform
(5 ml) and dissolved in 2- (2-chlorophenyl) ethyl
Add amine (0.32 g, 2.05 mmol) and add 7
Stir for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was removed.
Silica gel column chromatography (Wakogel C-
200, 15 g) and eluted with chloroform.
The eluted fraction is concentrated under reduced pressure to give the title compound.
(0.05 g, 0.14 mmol, 4% yield) as colorless crystals
I got it.N-cyano-N '-[2- (2-chlorophenyl) ethyl
Ru] -3- (5-Methoxy-1-methylindole)
Physicochemical properties of ruboximidamide  Melting point: 171-172 ° C Infrared absorption spectrum (cm^-1, KBr): 2160, 15
40. Nuclear magnetic resonance spectrum (100 MHz, CDCl₃
During):δ (ppm)8.13 (1H, s), 7.4-7.1
(5H), 6.98 (1H, d, J = 2.8 Hz), 6.
77 (1H, d, J = 2.8 Hz), 3.90 (2H,
t, J = 6.6 Hz), 3.81 (3H, s), 3.70
(3H, s), 3.02 (2H, t, J = 6.6 Hz). Mass spec: m / z 367 ([M + H]⁺)Example 9  N-cyano-N '-(2-phenylethyl) -3-
(5-methoxy-1-methylindole) carboxyl
Production of midamide  Methyl = N-cyano-3- (5-methoxy-1-methyl
Ruindole) carboximidate crude product (0.
5 g) in methanol (10 ml) and chloroform (5 m
l) and dissolved in 2-phenylethylamine (0.25
g, 2.07 mmol) and stirred at room temperature for 72 hours.
After the reaction, the reaction solution is concentrated under reduced pressure, and the residue is
Chromatography (Wakogel C-200, 15g)
And eluted with chloroform. Elution category is reduced pressure
The title compound (0.04 g, 0.1
(2 mmol, 4% yield) as colorless crystals.N-cyano-N '-(2-phenylethyl) -3- (5
-Methoxy-1-methylindole) carboximida
Physicochemical properties of mid  Melting point: 173-174 ° C Infrared absorption spectrum (cm^-1, KBr): 2170, 15
40. Nuclear magnetic resonance spectrum (100 MHz, CDCl₃
During):δ (ppm)8.15 (1H, s), 7.4-7.1
(6H), 7.0-6.7 (2H), 3.90 (2H,
t, J = 6.7 Hz), 3.82 (3H, s), 3.70
(3H, s) 3.05 (2H, t, J = 6.7 Hz). Mass spec: m / z 333 ([M + H]⁺)

[0017]Example 10  N- [2- (2-chlorophenyl) ethyl] -N'-
Preparation of cyano-3- (2-thienyl) propenylamidine
Construction  a) 2-thiopheneacrylic acid (5 g, 32.4 mmol)
l) with thionyl chloride (11.46 g, 96.3 mmol)
The mixture was stirred at room temperature for 1.5 hours. Further under ice-water cooling, 2
8% aqueous ammonia (10 ml, 0.16 mol) was added and room temperature was added.
For 4 hours. After the reaction, add saturated potassium carbonate
Add aqueous solution and extract with chloroform (100 ml x 3 times)
Issued. Chloroform layer is dehydrated with anhydrous sodium sulfate
Then, it is concentrated under reduced pressure to give 2-thiophene acrylic.
The amide (3.03 g, 19.8 mmol, 61% yield) was eluted.
Obtained as yellow crystals. Subsequently, sulfuric acid was added to the crystals (1.5 g).
Dimethyl acid (7.71 g, 61.2 mmol) was added and 10
The mixture was stirred at 0 to 105 ° C for 3 hours. After the reaction, 30
% Sodium carbonate aqueous solution, and chloroform (50 ml
× 2). Chloroform layer is anhydrous magnesium sulfate
After dehydration with nesium, concentration under reduced pressure gives methyl =
Crude 3- (2-thienyl) propenylimidate
(2.2 g) was obtained as a brown syrup. Then this
Dissolve the wrap in dichloromethane (10 ml),
Mid (1.66 g, 39.6 mmol) and Na₂HPO₄
(1.87 g, 13.2 mmol) and NaH₂PO₄・ 2H
₂Phosphate buffer with O (4.12 g, 26.4 mmol)
(PH 6.0, 20 ml) and stirred at room temperature overnight. Anti
After the reaction, the reaction solution was extracted with chloroform (50 ml x 2).
did. The chloroform layer is washed with a saturated aqueous solution of NaCl,
After dehydration with anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue
Silica gel column chromatography (Wakogel C-
200, 150 g) and hexane: acetone (1
0: 1). The elution category should be concentrated under reduced pressure.
From methyl = N-cyano-3- (2-thienyl) pro
Penilimidate (1.1 g, 5.73 mmol, yield 58)
%) As pale yellow crystals. b) Methyl = N-sia
No-3- (2-thienyl) propenylimidate (0.
2g, 1.04mmol) in methanol (10ml)
And 2- (2-chlorophenyl) ethylamine (0.1
6 g, 1.04 mmol) and stirred at room temperature for 1.5 hours.
Was. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was diethyl ether
The title compound (0.28 g, 0.8
9 mmol, yield 86%) as colorless crystals.N- [2- (2-chlorophenyl) ethyl] -N'-si
Physics of ano-3- (2-thienyl) propenylamidine
chemical property  Melting point: 159-162 ° C Infrared absorption spectrum (cm^-1, KBr): 2170, 16
30, 1580. Nuclear magnetic resonance spectrum (100MHz,
CDCl₃During):δ (ppm)7.6-7.0 (8H),
6.63 (1H, d, J = 16.1 Hz), 6.15 (1
H, brs), 3.70 (2H, q, J = 6.7 Hz),
3.09 (2H, t, J = 6.7 Hz). Mass spectrometry: m / z 315 (M⁺)

[0018]Example 11  N- (2-phenylethyl) -N'-cyano-3-
Production of (2-thienyl) propenylamidine  Methyl N-cyano-3- (2-thienyl) propeni
Luimidate (0.2 g, 1.04 mmol) in methanol
(10 ml) and dissolved in 2-phenylethylamine (0.
13g, 1.04mmol) and stirred at room temperature for 5 hours.
Was. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was diethyl ether
The title compound (0.25 g, 0.8
9 mmol, yield 86%) as colorless crystals.N- (2-phenylethyl) -N'-cyano-3- (2
Physicochemical properties of (-thienyl) propenylamidine  Melting point: 164-165 ° C Infrared absorption spectrum (cm^-1, KBr): 2180, 15
80, 1540. Nuclear magnetic resonance spectrum (100MHz,
CDCl₃During):δ (ppm)7.6-7.0 (9H),
6.59 (1H, d, J = 16.4 Hz), 5.82 (1
H, brs), 3.69 (2H, q, J = 7.1 Hz),
2.93 (2H, t, J = 7.1 Hz). Mass spectrometry: m / z 281 (M⁺)

[0019]Example 12  N- (2-nitroxyethyl) -N'-cyano-3-
Production of (2-thienyl) propenylamidine  2-nitroxyethylamine hydrochloride (0.37 g,
2.6 mmol) in methanol (25 ml) and ice-cooled
Under sodium methoxide (0.12 g, 2.28 mmol
l) was added. Furthermore, methyl = N-cyano-3- (2-
Thienyl) propenylimidate (0.2 g, 1.04
mmol) and stirred at room temperature for 6 days. After the reaction, the reaction solution
Was concentrated under reduced pressure, and the residue was added to chloroform (40 ml × 2 times).
Extracted. Remove the chloroform layer with anhydrous sodium sulfate.
After water, the mixture was concentrated under reduced pressure. The residue is purified by silica gel column chromatography.
Subjected to chromatography (Wakogel C-200, 14 g),
Elution was performed with hexane: acetone (5: 1). Elution category
Was concentrated under reduced pressure to give the title compound (0.03
g, 0.11 mmol, yield 11%) as pale yellow crystals.
Was.N- (2-nitroxyethyl) -N'-cyano-3-
Physicochemical properties of (2-thienyl) propenylamidine  Infrared absorption spectrum (cm^-1, CHCl₃): 216
0, 1630, 1550. Nuclear magnetic resonance spectrum (10
0MHz, CDCl₃During):δ (ppm)7.67 (1H,
d, J = 15.8 Hz), 7.48 (1H, d, J = 5.
9 Hz), 7.31 (1H, d, J = 3.8 Hz), 7.0
9 (1H, dd, J = 3.8, 5.9 Hz), 6.64
(1H, d, J = 15.8 Hz), 4.67 (2H, t,
J = 5.5 Hz), 3.80 (2H, q, J = 5.5H)
z). Mass spec: m / z 266 (M⁺)

[0020]Example 13  N-cyano-N '-(2-nitroxyethyl) -2-
Production of benzothiophene carboximidamide  a) Benzothiophene-2-carboxamide (1
g, 5.65 mmol) in dimethyl sulfate (3 g, 23.8 mm).
ol) and stirred at 100-105 ° C for 2 hours. reaction
Thereafter, the reaction solution was concentrated under reduced pressure, and a 30% aqueous solution of sodium carbonate was used.
And extracted with chloroform (50 ml × 2).
The chloroform layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure.
By contraction, methyl = 2-benzothiophenecar
Colorless crystals of crude product of boxiimidate (0.95 g)
As obtained. Subsequently, the crystals were dissolved in dichloromethane (10 m
l) and dissolved in cyanamide (0.41 g, 9.88 mmol)
l) and Na₂HPO₄(0.7 g, 4.94 mmol)
NaH₂PO₄・ 2H₂O (3.08 g, 19.8 mmo
l) and phosphate buffer (pH 5.4, 75 ml)
Stirred overnight at warm. After the reaction, the reaction solution was mixed with chloroform (5
0 ml x 2), and the chloroform layer was dried over anhydrous sodium sulfate.
After dehydration with thorium, the mixture was concentrated under reduced pressure. Silica gel residue
Ram chromatography (Wakogel C-200, 19
0g) and dissolved in hexane: acetone (10: 1).
Issued. The eluted fraction was concentrated under reduced pressure to give methyl =
N-cyano-2-benzothiophene carboximidate
(0.38 g, 1.77 mmol, 31% yield)
Obtained as crystals. b) 2-Nitroxyethylamine salt
The acid salt (0.19 g, 1.33 mmol) was added to methanol (14
of sodium methoxide (0.1 ml) under ice-water cooling.
07 g, 1.3 mmol). Furthermore, methyl = N-si
Ano-2-benzothiophene carboximidate
(0.12 g, 0.56 mmol) and stirred at room temperature for 6 days.
Stirred. After the reaction, the reaction solution is concentrated under reduced pressure, and the residue is
The extract was extracted with LUM (40 ml × 2 times). The chloroform layer
After dehydration with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. Residue
Ricagel column chromatography (Wakogel C-2
Hexane: acetone (5: 1)
Was eluted. The elution category can be determined by concentrating under reduced pressure.
Title compound (0.08 g, 0.28 mmol, yield 50%)
Was obtained as colorless crystals.N-cyano-N '-(2-nitroxyethyl) -2-b
Physicochemical properties of nzothiophene carboximidamide  Melting point: 133-134 ° C Infrared absorption spectrum (cm^-1, KBr): 2180, 16
40, 1570, 1280. Nuclear magnetic resonance spectrum (1
00MHz, CDCl₃During):δ (ppm)8.33 (1H,
s), 7.88 (2H, m), 7.46 (2H, m),
6.34 (1H, brs), 4.71 (2H, m),
3.89 (2H, m). Mass spectrometry: m / z 290 (M⁺)

[0021]Example 14  N-cyano-N '-[2- (2-chlorophenyl) e
Tyl] -3-pyridyl-2-benzyloxyiminoace
Production of tomidine  a) 3-pyridylacetonitrile (25 g, 0.21
mol) under ice-water cooling, 15% ethyl nitrite ethanol solution
(270 ml, 0.43 mol), and
Add Sid (11.5 g, 0.21 mol) and stir at room temperature overnight.
Stirred. After the reaction, ice water and acetic acid (12.6 g,
0.21 mol) was added. The precipitate formed is filtered and washed with water
By purifying, 3-pyridyl-2-hydroxyimi
Noacetonitrile (17.2 g, 0.12 mol, yield 5)
5%) as a powder. Subsequently, this powder (6 g, 4 g
0.8 mmol) with N, N-dimethylformamide (75 m
l), and cooled with ice water, 60% sodium hydride
(1.65 g, 41.4 mmol) and stirred at room temperature for 1 hour.
Stirred. Further, benzyl chloride (5.91 g,
46.8 mmol) and stirred at room temperature for 1.5 hours. Anti
After the reaction, ammonium chloride and water (150 ml) were added to the reaction solution.
In addition, the mixture was extracted with ethyl acetate (300 ml × 2). vinegar
The ethyl acid layer is washed with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate.
After dehydration with thorium, the mixture was concentrated under reduced pressure. Silica gel residue
Ram chromatography (Wakogel C-200, 30
0 g) and dissolved in hexane: ethyl acetate (6: 1).
Issued. The elution fraction is concentrated under reduced pressure
Jil-2-benzyloxyiminoacetonitrile (9.
12g, 38.4 mmol, 94% yield) as colorless crystals
Obtained. Subsequently, the crystals (8 g, 33.8 mmol) were added to methanol.
(600 ml), and sodium methoxide
(0.2 g, 3.7 mmol) and stirred at room temperature overnight.
Was. After the reaction, acetic acid (0.24 g, 4.03 mmol) was added.
Neutralize the reaction solution with
3-pyridyl-2-benzyloxyiminoacetimide
The crude product was obtained. The crude product is then
Dissolved in Toril (30 ml), cyanamide (1.42 g,
33.8 mmol) and Na₂HPO₄(2.4 g, 16.
9 mmol) and NaH₂PO₄・ 2H₂O (10.5 g, 6
7.6 mmol) and a phosphate buffer (pH 5.4, 50 ml).
The mixture was stirred overnight at room temperature. After the reaction, the reaction mixture was washed with ethyl acetate.
(100 ml × 3 times). The ethyl acetate layer becomes saturated
Wash with aqueous NaCl solution and dehydrate with anhydrous sodium sulfate
Then, the mixture was concentrated under reduced pressure. The residue is purified by silica gel column chromatography.
Raffy (Wakogel C-200, 200g),
Elution was performed with hexane: ethyl acetate (3: 1). Elution zone
The mixture is concentrated under reduced pressure to give methyl-N-cyano-3.
-Pyridyl-2-benzyloxyiminoacetimide
G (1.46 g, 4.97 mmol, 15%) with syrup
I got it. b) Methyl = N-cyano-3-pyridyl-
2-benzyloxyiminoacetimidate (0.1
g, 0.34 mmol) in methanol (3 ml).
-(2-chlorophenyl) ethylamine (0.06 g,
0.4 mmol) and stirred at room temperature for 3 hours. After the reaction,
The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
Chromatography (Wakogel C-200, 5 g)
Elution was performed with chloroform: methanol (200: 1).
The eluted fraction was crystallized from diethyl ether after concentration under reduced pressure.
To give the title compound (0.09 g, 0.22 mmol, yield 65)
%) As colorless crystals.N-cyano-N '-[2- (2-chlorophenyl) ethyl
Ru] -3-Pyridyl-2-benzyloxyiminoaceto
Physicochemical properties of amidine  Melting point: 127-129 ° C Infrared absorption spectrum (cm^-1, KBr): 2180, 16
05, 1580, 1560, 1485, 1335, 75
5. Nuclear magnetic resonance spectrum (500 MHz, CDCl
₃During):δ (ppm)8.39 (1H, t, J = 5.8H
z), 8.16 (1H, d, J = 1.8 Hz), 8.08
(1H, dd, J = 1.2, 4.9 Hz), 7.55 (1
H, brd, J = 7.9 Hz), 7.40 to 7.24 (5
H, m), 7.14 to 7.08 (2H, m), 7.08
-7.02 (2H, m), 5.24 (2H, s), 3.
74 (2H, m), 3.02 (2H, t, J = 7.0)
2). Mass spec: m / z 419 ([M + H]⁺)

[0022]Example 15  N-cyano-N '-(2-nitroxyethyl) -3-
Pyridyl-2-benzyloxyiminoacetamidine
And its hydrochloride  2-nitroxyethylamine hydrochloride (0.42 g,
2.95 mmol) in methanol (20 ml) and ice water
Under cooling, sodium methoxide (0.14 g, 2.59 mm
ol). Further methyl = N-sinoa-3-pyridi
Ru-2-benzyloxyiminoacetimidate (0.
57 g, 1.94 mmol) and stirred at room temperature for 6.5 hours.
did. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was
Column chromatography (Wakogel C-200, 5
0 g), and chloroform: methanol (100:
It eluted in 1). The elution category should be concentrated under reduced pressure.
The title compound was obtained as a syrup. More
Is dissolved in 10% methanol solution of hydrogen chloride and concentrated under reduced pressure.
did. The residue is crystallized from methanol / diethyl ether
The title hydrochloride was obtained as a hygroscopic powder.N-cyano-N '-(2-nitroxyethyl) -3-pi
Lysyl-2-benzyloxyiminoacetamidine
Physicochemical properties  Nuclear magnetic resonance spectrum (500 MHz, CDCl
₃During):δ (ppm)8.46 (1H, d, J = 1.8H
z), 8.38 (1H, brd, J = 4.9 Hz), 7.
78 (1H, brd, J = 7.9 Hz), 7.44-7.
32 (5H, m), 7.23 (1H, dd, J = 4.
9,7.9 Hz), 5.28 (1H, s), 4.66 (2
H, m), 3.82 (2H, t, J = 4.9 Hz).N-cyano-N '-(2-nitroxyethyl) -3-pi
Lysyl-2-benzyloxyiminoacetamidine / salt
Physicochemical properties of acid salts  Infrared absorption spectrum (cm^-1, KBr): 2180, 1
690, 1640, 1600, 1280, 1000.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/40 A61K 31/40 31/44 31/44 C07D 209/42 C07D 209/42 213/53 213/53 311/58 311/58 333 / 24 333/24 333/70 333/70 (58) Fields investigated (Int.Cl. ⁶ , DB name) C07D 333/38 C07D 209/42 C07D 213/53 C07D 311/58 C07D 333/24 C07D 333 / 70 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A carboximidamide derivative represented by the following formula (I). Embedded image [Wherein, the substituents are defined as follows.
X is Embedded image Or an acid adduct thereof, Or Or Y represents an acid adduct thereof. (Where R represents a chlorine atom or a hydrogen atom) or — (CH ₂ ) ₂ ONO ₂ . ]