JPH08175995A - Agent for inhibiting production of glucopretein-modifying substance - Google Patents

Abstract

PURPOSE: To obtain a glucoprotein-modifying substance production inhibiting agent containing an aminopyridine compound as an active ingredient, low in toxicity, and useful for preventing and treating diabetic complications, atherosclerois, and various diseases accompanied by aging in mammalians. CONSTITUTION: This inhibiting agent contains an aminopyridine compound (acid adduct salt) of the formula n is 0, 1; z is S, NCN, CHNO2 ; R1 is CN, NR3 R4 , NHCOR3 [R3 , R4 are H, (substituted) (cyclo)alkyl} as an active ingredient, and can orally or parenterally be administered. The inhibiting agent is administered at a dose of 0.05-20mg/kg body weight/day (especially 0.1-4mg/kg body weight/day) in one to several portions a day, when orally administered for an adult.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a glycated protein denatured substance (Advanced Glycation End Products, hereinafter referred to as "A") containing a group of aminopyridine compounds or acid addition salts thereof as an active ingredient.
GE]) production inhibitor.

[0002]

BACKGROUND OF THE INVENTION Non-enzymatic glycation of proteins in vivo (n
It is known that on-enzymatic glycation) directly modifies protein function and causes cell damage via receptors on the cell membrane, and causes various physiological disorders associated with diabetes and arteriosclerosis. That is, glucose in blood non-enzymatically forms a Schiff base with an amino group of a protein, and further produces a rearrangement product by Amadori rearrangement. This Amadori rearrangement product releases active oxygen and is converted into an active intermediate like 3-deoxyglucosone by the action of a trace amount of transition metal, and further reacts with the amino group of the protein, followed by oxidation, condensation and rearrangement. AGE through complicated reactions such as
Is formed. AGE is considered to be a polymer in which a protein (or a degradation product thereof) is cross-linked with a structure derived from sugar. Glycated proteins are also produced in healthy people and increase with age, but in diabetic patients, high glucose concentration in blood causes rapid glycation of proteins, which has a direct effect on protein function and AGE. Receptor-mediated cellular responses lead to various disorders, which are considered to be one of the causes of various diabetic complications. In addition, active oxygen generated when glycated proteins are produced is also considered to cause cell damage.

More specifically, it has been recognized that diabetic cataract is caused by polymerization, insolubilization, fluorescence generation and coloring of crystallin accompanying glycation of crystallin of the ocular lens (J. Biol. Chem., 256 , 5176, 1981), and diabetic neurological disease is thought to be caused by nonenzymatic glycation of neuronal myelin protein (Clin. Endocrinol. M).
etab., 11 , 431, 1982). In addition, the process of AGE generation is also considered to be the cause of aging. For example, senile cataract involves glycation of crystallin of the eye lens,
The production of AGE is also involved in atherosclerosis. In addition, AGE can be used to thicken the basement membrane of thin blood vessels and the thickening of the renal glomerular basement membrane, which causes a decline in renal function due to aging.
Are known to be involved (Science 232 , 162
9, 1986).

[0004]

Under such a background, a substance that inhibits AGE formation of proteins has been searched for, and aminoguanidine has been reported as such a compound (Science 232 , 1629, 1986). Aminoguanidine blocks the active carbonyl group of the Amadori rearrangement product and inhibits the cross-linking polymerization of the Amadori rearrangement product, and is therefore considered to inhibit the transfer of the protein to AGE. However, the action of aminoguanidine cannot be said to be sufficient, and AGE that can achieve a practically satisfactory effect is obtained.
No production inhibitor has been found yet. From these problems, the present inventors have studied compounds useful for preventing and treating the above-mentioned various diseases by inhibiting the production of AGE, and as a result, the applicant has already found that the method disclosed in JP-A-5-29
It was found in 4935 that a group of aminopyridine compounds or acid addition salts thereof, which were reported to be useful as agents for circulatory organs, had an excellent AGE production inhibitory activity and also had an antioxidant effect. The present invention was made based on such findings, and an object of the present invention is to provide an AGE production inhibitor.

[0005]

The present invention has the following general formula (1):

[0006]

Embedded image

(In the formula, n represents 0 or 1. Z is S, N
Indicates CN or CHNO ₂ . R ₁ is CN, NR ₃ R ₄ , CO
NR ₃ R ₄ , NHNR ₃ R ₄ , NHCONHR ₃ , NHSO ₂
Indicates R ₃ or SR ₃ . R ₂ represents H, optionally substituted alkyl or cycloalkyl. R ₃ and R ₄ are the same or different and each represents H, optionally substituted alkyl, cycloalkyl, aryl, optionally substituted acyl or alkoxycarbonyl, and R ₃ and R ₄ are a bond. The heterocycle may be formed with or without the intervening other heteroatom. ) An AGE formation inhibitor containing an aminopyridine compound represented by the formula (4) or an acid addition salt thereof as an active ingredient.

In the compound represented by the general formula (1),
As alkyl, lower alkyl is preferable and it has 1 to 1 carbon atoms.
Alkyl of 7 is preferred. It may be linear or branched, and specifically, methyl, ethyl, n-propyl, iso.
-Propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, 1,2,2-trimethylpropyl, 2-methylpropyl, 1,1-dimethylpropyl and the like are exemplified. In R ₂ , preferably branched alkyl, 1,2,2-trimethylpropyl, 2
-Methylpropyl, 1,1-dimethylpropyl and the like are preferable. Further, the alkyl may be substituted with a hydroxyl group, an amino group or the like.

The cycloalkyl is preferably a cycloalkyl having 5 to 10 carbon atoms. Cycloalkyl includes, in addition to monocycloalkyl exemplified by cyclopentyl, cyclohexyl, cycloheptyl, etc., bicycloalkyl,
Tricycloalkyl, polycycloalkyl and the like are also included. Examples of bicycloalkyl include norbornyl, pinanyl, bicyclo [2,2,2] octyl and the like, and examples of tricycloalkyl and polycycloalkyl include adamantyl and the like. The cycloalkyl may be substituted with an alkyl group or the like. R ₂ is preferably cycloalkyl or bicycloalkyl exemplified by norbornyl, pinanyl, bicyclo [2,2,2] octyl and the like. Examples of the aryl include phenyl and naphthyl. Aryl may be substituted with alkyl, halogen atom, nitro, cyano and the like.

The acyl may be either aliphatic acyl or aromatic acyl. When the acyl is aliphatic acyl, it is preferably lower acyl, and more preferably acyl having 2 to 5 carbon atoms. Either linear or branched,
Specific examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl and the like. Acyl may be substituted with amino, lower alkoxycarbonylamino, carboxy, a heterocyclic group and the like, and examples of the lower alkoxycarbonyl moiety of lower alkoxycarbonylamino and the heterocyclic group include those described below. Examples of the acyl having such a substituent include glycyl, alanyl, valyl, prolyl, methionyl, aspartyl, glutamyl, histidyl, N-ethoxycarbonylalanyl, Nt-butoxycarbonylalanyl and the like. Examples of aromatic acyl include benzoyl, naphthoyl and toluoyl.

The alkoxycarbonyl is preferably an alkoxycarbonyl in which the alkoxy moiety is lower alkoxy, more preferably an alkoxy having 1 to 4 carbon atoms. The alkoxy moiety may be linear or branched. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. The alkoxy moiety may also be aromatic alkoxy. Specific examples of the alkoxycarbonyl in which the alkoxy moiety is aromatic alkoxy include benzyloxycarbonyl and the like.

The hetero ring formed by R ₃ , R ₄ and the nitrogen atom to which they are attached includes a hetero ring formed by forming alkylene or alkenylene with R ₃ and R ₄ . The alkylene is preferably an alkylene having 1 to 4 carbon atoms, and may be linear or branched. Specific examples include methylene, ethylene, trimethylene, propylene, tetramethylene, 1,2-dimethylethylene and the like. Examples of alkenylene include 1-butenylene and 1,3-butadienylene. Specific examples of these heterocyclic groups include, for example, pyrrolidinyl, piperidino, pyrrolinyl, pyrrolyl and the like. Further, a hetero ring may be formed together with R ₃ , R ₄ and the nitrogen atom to which they are bonded via a hetero atom (eg, nitrogen, oxygen, sulfur, etc.), and examples of these hetero ring groups include piperazinyl , Morpholino,
Thiomorpholino, imidazolinyl, imidazolidinyl,
Examples thereof include imidazolyl and pyrazolidinyl. In particular,
Imidazolyl or general formula

[0013]

Embedded image

A group represented by the formula (wherein R ₅ represents H, alkyl, cycloalkyl, acyl, aryl or alkoxycarbonyl) is preferable. As the alkyl, cycloalkyl, acyl, aryl and alkoxycarbonyl of R _5, the above substituents are exemplified.

Substituent R ₁ and Substituent --NH--C (= Z)-
As the combination of the bonding positions of NHR ₂ with respect to the pyridine skeleton, a combination of (6 position, 3 position) or (2 position, 5 position), or a combination of (4 position, 3 position) or (4 position, 5 position) preferable. Further, for the substituent R ₁ , NR ₃ R ₄
Alternatively, a group represented by NHNR ₃ R ₄ (in the formula, R ₃ and R ₄ are the same as above) is preferable. When the compound represented by the general formula (1) has an asymmetric carbon in the molecule, the present invention includes all optical isomers based on the asymmetric carbon and mixtures thereof.

The compound represented by the general formula (1) can be synthesized by various methods.
It can be prepared by the method described in Japanese Patent No. 4935. The acid addition salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmacologically acceptable non-toxic salt, and examples thereof include salts with inorganic acids (hydrochloride, odor, etc.). Hydrohydrates, phosphates, sulfates, etc.), salts with organic acids (acetates, succinates, maleates, fumarates, malates, tartrates, etc.) and the like.

The inhibitor of the present invention comprises a compound represented by the general formula (1) or an acid addition salt thereof, and a suitable pharmacologically acceptable additive (eg carrier, excipient, diluent, etc.). Powders, granules, tablets, capsules, etc.
It can be orally or parenterally administered as a pharmaceutical composition in the form of an injection or the like. In the above formulation, the general formula (1)
The compound represented by and the acid addition salt thereof are mixed in effective amounts. The dose varies depending on the administration route, symptoms, body weight or age of the patient, and when administered orally to an adult patient, for example, 0.05 to 20 mg / Kg body weight / day, particularly 0.1
It is desirable to administer 4 mg / Kg body weight / day in divided doses 1 to several times a day.

[0018]

INDUSTRIAL APPLICABILITY The AGE production inhibitor of the present invention exhibits excellent effects on mammals (eg, mice, rats, rabbits, dogs, cats, humans, etc.) and has low toxicity. Therefore, various diseases associated with AGE, such as diabetic neuropathy, retinopathy, nephropathy, cataract, coronary heart disease, peripheral circulatory disorder, cerebrovascular disorder and other diabetic complications and atherosclerosis. , Prevention of various diseases associated with aging
It is useful as a therapeutic agent. In recent years, the active oxygen species in the glycated proteins are involved (Diabetes 43, 676-683, 19
94), oxidative stress is increased in diabetes, and it has been reported that it is a factor for the development of diabetic complications (Modern Medicine 26 , 1511-1516, 1994), and AGE generation of the present invention. The antioxidant effect of the inhibitor further enhances its value as a prophylactic / therapeutic agent for diabetic complications and the like.

[0019]

The present invention will be described in more detail based on the following Reference Examples and Test Examples, but the present invention is not limited to these Examples. Reference Example 1 (4-amino-3-pyridyl) thiourea hydrochloride 30 ml of concentrated hydrochloric acid was ice-cooled to obtain 3,4-diaminopyridine (10.0
g, 91.6 mmol) was added. After heating at 50-60 ° C for 10-15 minutes, excess hydrochloric acid was distilled off under reduced pressure, and ammonium thiocyanate (13.1 g, 0.17 mol) dissolved in 15 ml of water was added to the residue.
Was added and reacted at 80 ° C. for 4 hours. After cooling to room temperature, the precipitated solid was collected by filtration, washed with water and acetone, and dried to obtain a white solid (16.0 g). ^{IR (KBr): 3250,3100,3000,1630cm -1 1} H-NMR (DMSO-d 6) δppm: 9.67 (1H,
s), 8.40 (1H, s), 8.04 (1H, d, J = 6.8Hz), 8.35-
7.45 (4H, brs), 6.96 (1H, d, J = 7.2Hz) ¹³ C-NMR (DMSO-d ₆ ) δppm: 183.18, 156.0
0, 138.48, 137.10, 121.02, 109.43

Reference Examples 2 to 8 [General Procedure] 3,4-Diaminopyridine (2 g, 18.3)
(mmol) was suspended in 10 ml of anhydrous pyridine under a nitrogen atmosphere. The isothiocyanate (R-NCS) shown in Table 1 below was added dropwise to this at room temperature, and the mixture was stirred. The reaction mixture was purified after distilling pyridine off under reduced pressure. Incidentally, R = t
-Bu, in the case of _{cyclo-Hex, CH (CH 3} ) C (CH 3) 3 derivatives, after which was collected by filtration since the product was precipitated as a white powder, washed (ether), was dried. Table 1 shows the reaction conditions, purification method and yield.

[0021]

[Table 1]

The physical properties of the compounds obtained in Reference Examples 2 to 8 and the salt production method are shown below. Reference Example 2 (a) N- (4-amino-3-pyridyl) -N'-methyl
Ruchiourea ^{IR (KBr): 3200,1620,1540,1260cm -1 1} H-NMR (CDCl 3: MeOH-d 4 = 4: 1) δpp
m: 8.02 (1H, d, J = 5.6Hz), 8.00 (1H, s), 6.68 (1H,
d, J = 5.6Hz), 3.07 (3H, s) (b) N- (4-amino-3-pyridyl) -N'-methyl
Luthiourea hydrochloride N- (4-amino-3-pyridyl) -N'-methylthiourea (1.02 g, 5.60 mmol) was added with 10 ml of methanol to make a homogeneous solution, and then hydrochloric acid-ethanol (1.75 N, 3.2 m
l) was added dropwise under ice cooling and stirred for 1 hour. The precipitate formed from the reaction mixture was collected by filtration, and dried at a reflux temperature of dichloromethane using a crystal drier to give a monohydrochloride (81
6 mg). mp 278-280 ℃ IR (KBr): 3200,1640,1550,1250cm -1 1 H-NMR (D 2 O) δppm: 8.14 (1H, s), 8.04 (1
H, dd, J = 1.0Hz, 7.0Hz), 7.03 (1H, d, J = 7.0Hz),
3.04 (3H, s) ¹³ C-NMR (D ₂ O) δppm: 184.66, 160.69, 143.1
6, 141.35, 121.83, 112.84, 34.32

Reference Example 3 N- (4-amino-3-pyridyl) -N'-ethylthio
Urea white powder ^{IR (KBr): 3200,1640,1540cm -1 1} H-NMR (DMSO-d 6) δppm: 9.20 (1H, s),
8.06 (1H, s), 8.06 (1H, s), 7.92 (1H, d, J = 5.8H
z), 6.70 (1H, d, J = 5.8Hz), 6.28 (2H, s), 3.45 (2
H, q, J = 6.3 Hz), 1.10 (3H, t, J = 7.1 Hz) ¹³ C-NMR (DMSO-d ₆ ) δppm: 181.73, 152.8
9, 143.21, 141.65, 120.76, 109.45, 38.88, 14.02

Reference Example 4 N- (4-amino-3-pyridyl) -N'-n-propyi
Ruchiourea white powder ^{IR (KBr): 3200,1620,1530,1260cm -1 1} H-NMR (DMSO-d 6) δppm: 8.71 (1H, s),
7.91 (1H, s), 7.90 (1H, d, J = 5.5Hz), 7.51 (1H,
s), 6.62 (1H, d, J = 5.5Hz), 5.70 (2H, s), 3.39 (2
H, m), 1.54 (2H, sext, J = 7.2Hz), 0.87 (3H, t, J =
7.4 Hz) ¹³ C-NMR (DMSO-d ₆ ) δppm: 181.66, 150.4
7, 148.93, 147.22, 119.95, 109.72, 45.91, 21.85, 1
1.31

Reference Example 5N- (4-amino-3-pyridyl) -N'-n-butyl
Thiourea White powder IR (KBr): 3200,1620cm^{-1 1} 1 H-NMR (DMSO-d₆) Δppm: 9.50 (1H, s),
8.37 (1H, s), 8.37 (1H, s), 7.97 (1H, d, J = 6.1H
z), 6.91 (2H, s), 6.83 (1H, d, J = 6.1Hz), 3.45 (2
H, m), 1.59-1.25 (4H, m), 0.90 (3H, t, J = 7.2Hz)¹³ C-NMR (DMSO-d₆) Δppm: 182.13, 152.7
8, 143.33, 141.83, 120.98, 109.52, 43.89, 30.64, 1
9.68, 13.81

Reference Example 6 (a) N- (4-amino-3-pyridyl) -N'-t-bu
Chiruchiourea white powder ^{IR (KBr): 3500,2950,1620,1530,1270cm -1 1} H-NMR (DMSO-d 6) δppm: 8.53 (1H, s),
7.94 (1H, s), 7.88 (1H, d, J = 5.5Hz), 7.22 (1H,
s), 6.61 (1H, d, J = 5.5Hz), 5.70 (2H, s), 1.47 (9
H, s) ¹³ C-NMR (DMSO-d ₆ ) δppm: 181.02, 150.4
4,149.26,147.06,120.66,109.75,52.72,28.67 (b) N- (4-amino-3-pyridyl) -N'-t-butyl
Luthiourea dihydrochloride N- (4-amino-3-pyridyl) -N'-t-butylthiourea (962 mg, 4.29 mmol) was suspended in 5 ml of water. 8.58 ml of 1N-hydrochloric acid aqueous solution was added thereto and heated in a hot water bath until a uniform solution was obtained, and then water was distilled off under reduced pressure.
The obtained white crystals were dried at a reflux temperature of dichloromethane using a crystal drier to obtain a white powder of dihydrochloride (1.12).
g) was obtained. mp> 250 ℃ IR (KBr) : 3150,1640,1550,1260cm -1 1 H-NMR (DMSO-d 6) δppm: 9.65 (1H, s),
8.46 (2H, s), 8.02 (1H, d, J = 7.6Hz), 6.96 (1H,
d, J = 7.6 Hz), 1.49 (9H, s) ¹³ C-NMR (DMSO-d ₆ ) δppm: 180.73, 155.7
4, 138.16, 136.43, 121.08, 109.20, 53.00, 28.42

Reference Example 7 N- (4-amino-3-pyridyl) -N'-cyclohexyl
Shiruchiourea white powder ^{IR (KBr): 3400,1640,1560cm -1 1} H-NMR (DMSO-d 6) δppm: 9.70 (1H, s),
8.58 (1H, d, J = 7.6Hz), 8.51 (1H, s), 8.03 (1H,
d, J = 6.7Hz), 7.91 (1H, s), 6.96 (1H, d, J = 6.7H)
z), 1.91 (2H, m), 1.70-1.56 (3H, m), 1.26 (5H,
m) ¹³ C-NMR (DMSO-d ₆ ) δppm: 180.83, 155.5
4,138.16,136.98,121.24,109.25,52.48,31.74,2
4.21, 25.17

Reference Example 8 N- (4-amino-3-pyridyl) -N '-(1,2,2
-Trimethylpropyl) thiourea ¹ H-NMR (DMSO-d ₆ ) δppm: 8.66 (1H, b
s), 7.96 (1H, s), 7.89 (1H, d, J = 5.5Hz), 7.13
(1H, d, J = 8.6Hz), 6.62 (1H, d, J = 5.5Hz), 5.67
(2H, bs), 4.29 (1H, m), 1.05 (3H, d, J = 6.7Hz),
0.90 (9H, s) ¹³ C-NMR (DMSO-d ₆ ) δppm: 181.81, 150.2
2, 148.88, 147.06, 120.51, 109.67, 57.46, 34.33, 2
6.19, 15.24

Reference Example 9 (a) 4-chloro-3-nitropyridine 4-hydroxy-3-nitropyridine (7.0 g, 50.0 mmo
l) was added phosphorus oxychloride (25 ml, 0.27 mol),
The reaction was carried out at ℃ for 1.5 hours. The phosphorus oxychloride was distilled off under reduced pressure, about 100 g of ice was added to the residue, 28% ammonia water was added dropwise to adjust the pH to 7, 100 ml of water was added, and 200 ml of dichloromethane was added.
3 times, and the dichloromethane layer was dried and evaporated under reduced pressure to give a yellow liquid (7.75 g, yield 97.8%).

(B) 3-nitro-4-methylaminopyridi
Down 4-chloro-3-nitropyridine (2.3 g, 15.3 mmol) in dioxane (5ml), and methylamine hydrochloride (1.55
g, 22.9 mmol) and potassium carbonate (4.22 g, 30.5 mmol) were added, and the mixture was stirred under reflux for 1.5 hours, room temperature for 15 hours, and further refluxed for 3 hours. After filtration through Celite, the filtrate was concentrated and subjected to silica gel column chromatography (eluent: chloroform).
After purification, 1.52 g of the desired product was obtained. ^{_{IR (CHCl 3): 3400,2980,1620,1370cm -1}} 1 H-NMR (CDCl 3) δppm: 3.07 (3H, d, J = 4.0H
z), 6.72 (1H, d, J = 6.0Hz), 8.16 (1H, brs), 8.33
(1H, d, J = 6.0Hz), 9.21 (1H, s) (c) 3-amino-4-methylaminopyridine 3-nitro-4-methylaminopyridine 150g platinum oxide in 10ml ethanol solution , Under hydrogen atmosphere,
Stir at room temperature for 7.5 hours. Platinum oxide was filtered off, and the filtrate was concentrated to obtain the desired product (962 mg, yield 80%) as brown crude crystals.

(D) N- (4-methylamino-3-pyri
Zil ) -N'-cyclohexylthiourea 3-amino-4-methylaminopyridine (950 mg, 7.71 m
To a DMF (5 ml) solution of (mol) was added cyclohexyl isothiocyanate (1.09 ml, 7.71 mmol), and the mixture was stirred at room temperature for 1 hour and at 120 ° C for 3 hours. After removing the solvent, the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1) and recrystallized to obtain 98 mg of the desired product as flesh-colored crystals. mp> 250 ℃ IR (KBr) : 3500~3000,2920,1600cm -1 1 H-NMR (CDCl 3) δppm: 1.0-2.1 (10H,
m), 2.89 (3H, d, J = 4.0Hz), 4.1-4.4 (1H, m), 4.
93 (1H, d, J = 4.0Hz), 5.72 (1H, d, J = 6.0Hz), 6.56
(1H, d, J = 6.0Hz), 7.65 (1H, s), 8.10 (1H, s) 8.
26 (1H, d, J = 6.0Hz) ¹³ C-NMR (CDCl ₃ ); 24.5, 25.1, 28.7, 32.
2, 53.8, 105.2, 118.0, 147.4, 149.0, 151.7, 179.9

Instead of the methylamine of Reference Example 9- (b), t-butylamine (Reference Example 10), cyclohexylamine (Reference Example 11) and diethylamine (Reference Example 1)
2) with the corresponding 4-substituted amino-3-
After obtaining the nitropyridine compound, Reference Examples 9- (c) and (d)
According to the method of 1., the following corresponding aminopyridine compound was obtained.

Reference Example 10 N- (4-t-butylamino-3-pyridyl) -N-si
Black hexyl thiourea mp 216-218 ℃ IR (KBr): 3500-3100,2950,2900,1610cm -1 1 H-NMR (CDCl 3) δppm: 1.0-2.1 (19H, m)
4.1-4.4 (1H, m), 4.87 (1H, s), 6.78 (1H, d, J =
6.0Hz), 8.05 (1H, s), 8.13 (1H, d, J = 6.0Hz) ¹³ C-NMR (CDCl ₃ ) δppm: 24.6, 24.7, 29.1,
32.5, 51.4, 54.0, 107.3, 118.9, 149.5, 180.3

Reference Example 11 N- (4-cyclohexylamino-3-pyridyl)-
N'- cyclohexyl thiourea mp 157-159 ℃ IR (KBr): 3500-3000,2900,2800,1600cm -1 1 H-NMR (CDCl 3) δppm: 1.0-2.1 (20H,
m), 3.2-3.4 (1H, m), 4.1-4.4 (1H, m), 4.70 (1
H, d, J = 8.0Hz), 5.72 (1H, brs), 6.57 (1H, d, J =
6.0Hz), 7.50 (1H, brs), 8.09 (1H, s), 8.19 (1
H, d, J = 6.0Hz)

Reference Example 12 N- (4-diethylamino-3-pyridyl) -N'-si
Black hexyl thiourea mp 119-121 ℃ IR (KBr): 2900,2800,1595cm -1 1 H-NMR (CDCl 3) δppm: 1-2.5 (16H, m), 3.
33 (4H, q), 4.1-4.4 (1H, m), 6.00 (1H, d, J = 8.0
Hz), 6.76 (1H, d, J = 6.0Hz), 7.87 (1H, brs), 8.2
1 (1H, s), 8.23 (1H, d, J = 6.0Hz) ¹³ C-NMR (CDCl ₃ ) δppm: 12.7, 24.7, 25.3,
32.6, 45.1, 112.8, 54.2, 121.9, 148.9, 150.1, 151.
0,179.4

Reference Example 13 (a) 4- (1- Imidazolyl ) -3-nitropyridine 1,4-dioxane 10 ml of 4-chloro-3-nitropyridine (2.00 g, 12.6 mmol) and imidazole (2.25 g, 3
(3.0 mmol) is dissolved, 2 ml of triethylamine is added, and 90
After reacting at -100 ° C for 1.5 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 10: 1 v / v) to obtain a yellow liquid (2.31 g, yield). Rate 96.4%). ¹ H-NMR (DMSO-d ₆ ) δppm: 9.32 (1H, s),
9.00 (1H, d, J = 5.3Hz), 8.08 (1H, s), 7.84 (1H,
d, J = 5.3Hz), 7.53 (1H, s), 7.16 (1H, s)

(B) 3-amino-4- (1-imidazole
) 4- (1-Imidazolyl) -3-nitropyridine (2.10 g, 11.0 mmol) was dissolved in 20 ml of pyridine ethanol, the atmosphere was replaced with nitrogen, and then 0.25 g of 10% palladium-carbon was added to replace it with hydrogen. Stir hydrogenated for 3 days. Palladium-
Carbon was filtered off, washed with ethanol, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 8: 1-6: 1 v / v) to obtain a light brown solid (1.62). g, yield 91.6%). ¹ H-NMR (DMSO-d ₆ ) δppm: 8.25 (1H, s),
7.92 (1H, s), 7.87 (1H, d, J = 5.1Hz), 7.44 (1H,
s), 7.14 (1H, s), 7.11 (1H, d, J = 5.1Hz), 5.50-
5.20 (2H, brs)

(C) N- [4- (1-imidazolyl)-
3-Pyridyl] -N'-cyclohexylthiourea 3-amino-4- (1-imidazolyl) pyridine (1.00
g, 5.95 mmol) was dissolved in 5 ml of DMF, and cyclohexyl isothiocyanate (2.5 ml, 17.63 mmol) was added. After reacting for 4 days at room temperature, the reaction solution was directly subjected to column chromatography (eluent; dichloromethane: methanol = 7: 1).
(v / v) was purified and collected, ether was added to crystallize, and the precipitated solid was collected by filtration (0.30 g, yield 16.7).
%). IR (KBr): 3150, 2900, 2850, 1590, 1550, 150
^{0,1080cm -1 1 H-NMR (DMSO} -d 6) δppm: 9.10-8.90 (1
H, brs), 8.57-8.50 (2H, s + d), 7.99 (1H, s), 7.
98-7.85 (1H, brs), 7.55 (1H, d, J = 5.3Hz), 7.48
(1H, s), 7.11 (1H, s), 4.20-3.80 (1H, brs),
2.00-1.00 (10H, m) ¹³ C-NMR (DMSO-d ₆ ) δppm: 181.37, 152.5
4,148.49,140.48,136.59,129.34,128.17,119.0
4, 118.55, 52.81, 31.71, 25.02, 24.45

Reference Example 14 (a) 4- Phenylamino-3-nitropyridine 1,4-dioxane 10 ml of 4-chloro-3-nitropyridine (1.50 g, 9.46 mmol) and aniline (2.0 ml, 21.9 mmo)
l) was dissolved, 2 ml of triethylamine was added, and the temperature was 80-90 ° C.
After reacting for 2 hours at room temperature, the solvent was distilled off under reduced pressure, and hexane was added to the residue.
The solvent was removed by decantation after adding ml, and 10 ml of ether was used in the same manner. The residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate =).
2: 1 v / v) to obtain a yellow solid (1.41 g, yield 68.8%). ¹ H-NMR (DMSO-d ₆ ) δppm: 9.84 (1H, br
s), 9.10 (1H, s), 8.24 (1H, d, J = 6.2Hz), 7.55-
7.28 (5H, m), 6.88 (1H, d, J = 6.2Hz)

[0040](b) 3-amino-4-phenylaminopi
lysine  To a mixed solvent of 15 ml of ethanol and 10 ml of dichloromethane, 4
-Phenylamino-3-nitropyridine (1.40 g, 6.51
mmol) was dissolved, the atmosphere was replaced with nitrogen, and then 10% palladium-carbon was added.
Add 0.10 g of hydrogen and replace with hydrogen, then stir at room temperature overnight.
Elementary addition. Palladium-carbon was filtered off and
The filtrate was concentrated and the residue was purified by silica gel column chromatography.
Matography (eluent; dichloromethane: methanol)
= 2: 1 v / v) to obtain a light brown solid (1.07).
g, yield 88.7%).¹ 1 H-NMR (DMSO-d₆) Δppm: 7.89 (1H, s),
7.64 (1H, d, J = 5.4Hz), 7.58 (1H, brs), 7.35-6.89
(6H, m), 5.20-4.70 (2H, brs)

(C) N- (4-phenylamino-3-pi)
Lysyl) -N'-cyclohexylthiourea 3-amino-4-phenylaminopyridine (1.00 g, 5.
40 mmol) was dissolved in 6 ml of DMF and cyclohexyl isothiocyanate (1.0 ml, 6.8 mmol) was added. After gradually raising the temperature and reacting at 60 ° C. for 1.5 hours, cyclohexyl isothiocyanate (0.5 ml, 3.4 mmol) was further added,
The reaction was carried out at ℃ for 1.5 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent; ethyl acetate), and the fraction containing the desired product was methanol-
Recrystallization from dichloromethane-ether gave a white solid (1.23 g, yield 69.8%). mp 179-182 ° C. ^{(decomposition) IR (KBr): 3150,2900,2850,1590,1500cm -1} 1 H-NMR (DMSO-d 6) δppm: 8.80-8.70 (1
H, brs), 8.30-8.15 (1H, brs), 8.04 (1H, d, J = 5.
6Hz), 7.90 (1H, s), 7.80-7.55 (1H, brs), 7.45
−6.90 (6H, m), 4.20−3.90 (1H, brs), 2.10−1.10
(10H, m) ¹³ C-NMR (DMSO-d ₆ ) δppm: 180.57, 149.1
7, 147.05, 146.08, 140.37, 129.15, 123.35, 122.8
4, 120.98, 108.50, 52.71, 31.90, 25.13, 24.53

(D) N- (4-phenylamino-3-pi)
Lysyl) -N'-cyclohexylthiourea hydrochloride N- (4-phenylamino-3-pyridyl) -N'-cyclohexylthiourea (1.13 g, 3.46 mmol) was dissolved in 50 ml of ethanol, and 1.2 N hydrogen chloride-ethanol (3.0
ml, 3.6 mmol), the solvent was distilled off, ether was added to the residue for solidification, the ether was decanted to remove the solid, and the solid was dried to obtain a white solid (1.04 g, yield 82.8%). IR (KBr): 3300, 2900, 1640, 1590, 1560, 1510c
^{m -1 1 H-NMR (DMSO} -d 6) δppm: 15.4-13.1 (1
H, brs), 9.93 (1H, brs), 9.87 (1H, brs), 8.70 (1
H, s), 8.57 (1H, brd, J = 7.7Hz), 8.14 (1H, d, J =
7.0Hz), 7.60-7.25 (5H, m), 7.05 (1H, d, J = 6.9H
z), 4.20-4.00 (1H, brs), 2.10-1.10 (10H, m) ¹³ C-NMR (DMSO-d ₆ ) δppm: 180.70, 152.2
7,138.10,137.47,137.07,129.64,126.58,124.4
0,123.23,106.97,52.49,31.69,25.16,24.18

Reference Example 15 (a) 4-Pyrrolidin-1-yl-3-nitropyridine 1,4-dioxane 15 ml of 4-chloro-3-nitropyridine (2.02 g, 12.7 mmol) was suspended in an ice bath. After cooling for a while, pyrrolidine (2.1 ml, 25.3 mmol) was added dropwise. After returning to room temperature and stirring for 30 minutes, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate) to obtain a yellow solid (2.34 g, yield 95.4%). ¹ H-NMR (CDCl ₃ ) δppm: 8.72 (1H, s), 8.23
(1H, d, J = 6.2Hz), 6.70 (1H, d, J = 6.2Hz), 3.40-
3.20 (4H, m), 2.10-1.95 (4H, m)

(B) 3-amino-4-pyrrolidine-1-
4-pyrrolidin-1-yl- in 40 ml of irpyridine 1,4-dioxane
3-Nitropyridine (2.10 g, 10.9 mmol) was dissolved, the atmosphere was replaced with nitrogen, 10% palladium-carbon (0.42 g) was added, the atmosphere was replaced with hydrogen, and the mixture was stirred and hydrogenated overnight at room temperature. Palladium-carbon was removed by filtration, washed with 1,4-dioxane, and the filtrate was concentrated to give a brown liquid (1.61 g, yield 90.7).
%). ¹ H-NMR (DMSO-d ₆ ) δppm: 7.80 (1H, s),
7.65 (1H, d, J = 5.2Hz), 6.53 (1H, d, J = 5.3Hz), 4.7
0-4.20 (2H, brs), 3.30-3.10 (4H, m), 2.00-1.7
5 (4H, m)

(C) N- (4-pyrrolidin-1-yl-
3-pyridyl) -N'-cyclohexylthiourea 3-amino-4-pyrrolidin-1-ylpyridine (1.55
g, 5.40 mmol) was dissolved in 10 ml of dichloromethane, and cyclohexyl isothiocyanate (2.6 ml, 18.3 mmol) was added. Since a solid precipitated, 2 ml of DMF was added to dissolve it,
Further, 2 ml of triethylamine was added and the reaction was carried out at room temperature for 3 days. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 10: 1-8: 1 v / v), and the collected solid was recrystallized from dichloromethane to obtain a pale yellow solid. (1.21 g,
Yield 41.8%). ^{IR (KBr): 3150,2950,2850,1600,1510cm -1 1} H-NMR (DMSO-d 6) δppm: 9.00-8.60 (1
H, brs), 7.97 (1H, d, J = 5.8Hz), 7.86 (1H, s), 7.
40-6.80 (1H, brs), 6.51 (1H, d, J = 5.9Hz), 4.25
-3.90 (1H, brs), ca.3.4 (4H), 2.10-1.00 (14H,
m) ¹³ C-NMR (DMSO-d ₆ ) δppm: 181.20, 151.4
4, 149.78, 147.66, 119.34, 109.08, 52.65, 48.39, 3
2.00, 25.07, 24.56

Reference Example 16 (a) 3-Nitro-4-aminopyridine 3-Nitro-4-chloropyridine (5 g, 31.5 mmol) and 26 g of ammonium acetate were mixed and heated at 130 to 140 ° C. for 3 hours. After allowing to cool, the pH was adjusted to 10 with concentrated aqueous ammonia, and the powder that fell out was collected by filtration to obtain the desired product (2.6 g, yield 59%). (b) 3-Nitro-4-acetylaminopyridine The amino compound (1.2 g, 8.63 mmol) of the above (a) was added to 6 ml of pyridine.
Acetyl chloride (0.65 ml,
8.63 mmol) was added slowly. After reacting for 24 hours at room temperature, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 50: 1) to obtain the desired product (1.12 g, yield 72%). IR (KBr): 3350, 1720, 1600, 1350 cm ^-1 (c) 3-amino-4-acetylaminopyridine 40 ml of an ethanol solution of 1 g of the acetylamide compound of (b) above.
200 mg of 10% palladium-carbon was added, and the mixture was reacted under a hydrogen atmosphere at room temperature for 24 hours. The palladium-carbon was filtered off and the solvent was evaporated to give the desired product (900 mg). IR (KBr): 3300, 1695cm ^-1

(D) N-cyclohexyl-N ′-(4-
Acetylamino -3-pyridyl) thiourea Cyclohexylisothiocyanate was added to 10 ml of a pyridine solution of the acetylamino compound (0.9 g, 5.95 mmol) of the above (c).
(0.84ml, 5.95mmol) was added, and it was at room temperature for 48 hours at 50-60 ℃.
And reacted for 14 hours. The solvent was distilled off, and the residue was washed with methanol to obtain the desired product (1 g, yield 57%). ^{IR (KBr): 3200,2850,1680cm -1 1} H-NMR (DMSO-d 6) δppm: 9.61 (1H, b
s), 8.61 (1H, bs), 8.48 (1H, s), 8.25 (1H, d, J
= 5.4Hz), 7.97 (1H, d, J = 5.2Hz), 7.79 (1H, d, J =
5.4Hz), 4.07 (1H, m), 2.13 (3H, s), 1.96-1.92
(2H, m), 1.70-1.57 (3H, m), 1.34-1.17 (5H, m) ¹³ C-NMR (DMSO-d ₆ ) δppm: 180.67 (s), 1
69.32 (s), 149.73 (d), 146.46 (d), 140.12 (s),
126.54 (s), 116.06 (d), 52.89 (d), 31.84 (t),
25.12 (t), 24.56 (t), 23.93 (q)

Reference Example 17 N-cyclohexyl-N '-(4-benzoylamino-
The title compound was obtained according to Reference Example 16 using 3-pyridyl) thioureabenzoyl chloride. ^{IR (KBr): 3200,2900,1650cm -1 1} H-NMR (DMSO-d 6) δppm: 9.89 (1H, b
s), 8.85 (1H, bs), 8.52 (1H, s), 8.39 (1H, d, J
= 5.4Hz), 8.15 (1H, bs), 7.95 (2H, d, J = 6.9Hz),
7.85 (1H, d, J = 5.4Hz), 7.68-7.51 (3H, m), 4.10
(1H, bs), 1.92 (2H, m), 1.67-1.55 (3H, m), 1.3
3-1.21 (5H, m), ¹³ C-NMR (DMSO-d ₆ ) δppm: 180.48 (s), 1
65.34 (s), 149.42 (d), 147.18 (d), 140.54
(S), 133.62 (s), 132.29 (d), 128.56 (d), 127.
56 (d), 117.08 (d), 52.90 (d), 31.76 (t), 25.0
5 (t), 24.47 (t)

Reference Example 18 N- (2-amino-3-pyridyl) -N'-cyclohex
Sylthiourea 2,3-diaminopyridine (1.00 g, 9.16 mmol) was dissolved in 5 ml of pyridine, and cyclohexyl isothiocyanate (4.2 ml, 29.6 mmol) was added. After reacting at room temperature for 4 days, pyridine was distilled off, and the residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 1).
It was purified by 0: 1 v / v). Further, the product was recrystallized from ethanol-ether-hexane to obtain the desired product as white crystals (1.06 g, yield 46.2%). mp 159-160 ° C (decomposition) IR (KBr): 3350, 3250, 3100, 2900, 2850, 163
^{0,1520,1500,1460cm -1 1 H-NMR (CDCl} 3) δppm: 8.50 (1H, brs), 8.0
0 (1H, dd, J = 5.0, 1.7Hz), 7.36 (1H, dd, J = 7.6, 1.
6Hz), 6.68 (1H, dd, J = 7.6, 5.0Hz), 5.70-5.55 (1
H, brd), 5.50-4.90 (2H, brs), 4.33-4.10 (1H, br
t), 2.10-0.95 (10H, m) ¹³ C-NMR (CDCl ₃ ) δppm: 179.30, 155.68, 14
8.11, 136.62, 116.14, 114.28, 53.99, 32.46, 25.2
2, 24.62

3,5-Diaminopyridine (Reference Example 19)
And 2,5-diaminopyridine (Reference Example 20),
The following compounds were synthesized according to the method of Reference Example 18. Reference Example 19 N- (5-amino-3-pyridyl) -N'-cyclohex
Shiruchiourea mp 114-116 ℃ IR (KBr): 3600-3000,2900,2850,1600cm -1 1 H-NMR (DMSO-d 6) δppm: 1.0-2.0 (10H,
m), 3.9-4.2 (1H, m), 5.31 (2H, brs), 7.21 (1H,
s), 7.65 (1H, s), 7.66 (1H, s), 7.68 (1H, s),
9.19 (1H, s) ¹³ C-NMR (DMSO-d ₆ ) δppm: 24.5, 25.1, 31.
8, 52.1, 114.0, 131.7, 136.4, 144.6, 179.3

Reference Example 20 N- (6-amino-3-pyridyl) -N'-cyclohexyl
Shiruchiourea mp 147-149 ℃ IR (KBr): 3500-3000,2900,2850,1630,1600c
^{m -1 1 H-NMR (DMSO} -d 6) δppm: 1.0-2.0 (10H,
m), 3.40 (1H, brs), 4.05 (1H, brs), 5.80 (2H, b
rs), 6.41 (1H, d, J = 8.0Hz), 7.30 (1H, dd, J = 2.0H)
z, 8.0Hz), 7.74 (1H, d, J = 2.0Hz), 8.85 (1H, br
s) ¹³ C-NMR (DMSO-d ₆ ) δppm: 24.5, 25.1, 3
1.9, 52.3, 107.2, 125.1, 135.4, 144.4, 157.3, 180.
Four

Reference Example 21 N- (6-amino-3-pyridyl) -N'-1,2,2
-Trimethylpropylthiourea 2,5-diaminopyridine was used to synthesize the title compound according to Reference Example 8. ^{IR (KBr): 3300,2950,1500cm -1 1} H-NMR (CDCl 3) δppm: 0.85 (9H, s), 1.08
(3H, d, J = 6.7Hz), 4.39 (1H, m), 4.80 (2H, br)
s), 5.55 (1H, d, J = 9.3Hz), 6.55 (1H, d, J = 8.6H)
z), 7.25-7.40 (1H, m), 7.73 (1H, brs), 7.95 (1
H, d, J = 2.6 Hz) ¹³ C-NMR (DMSO-d ₆ ) δppm: 15.3 (q), 26.3
(Q), 34.3 (s), 57.2 (d), 107.2 (d), 125.2
(S), 135.4 (d), 144.3 (d), 157.3 (s), 181.6
(S)

Reference Example 22 (a) S-methyl-N- (4-amino-3-pyridyl)
-N'- Cyanoisothiourea 3,4-diaminopyridine (4 g, 36.6 mmol) was suspended in 100 ml of anhydrous pyridine. In this, S, S'-dimethyl N-cyanodithioiminocarbonate (8.0 g, 55.
(0 mmol) was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was filtered to remove the resulting powder and washed with 100 ml of ether to give crude crystals. Purification was performed by recrystallization (methanol-ether) to obtain the desired product (1.91 g, yield 58%) as a white powder. In addition, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, eluent; chloroform: methanol = 4: 1) to obtain the desired product (2.8 g, total yield 95%).

(B) N ″ -cyano-N ′-(4-amino
Cyclohexylamine (15 ml) was added to the methylthio derivative (2.0 g, 9.65 mmol) obtained from ( -3-pyridyl) -N-cyclohexylguanidine (a), and the mixture was stirred at room temperature for 6 hours, then heated to 70 ° C and further stirred for 24 hours. did. The reaction mixture was distilled under reduced pressure to remove excess cyclohexylamine, and the residue was purified by recrystallization (methanol: ether) to obtain the desired product (1.4 g, yield 56%) as a white powder. Further, it was recrystallized from methanol-ether. ^{IR (KBr): 3300,3150,2900,2190,1630cm -1 1} H-NMR (DMSO-d 6) δppm: 8.22 (1H, s),
7.90 (1H, d, J = 5.5Hz), 7.84 (1H, s), 6.60 (1H,
d, J = 5.5Hz), 5.19 (2H, s), 3.59 (1H, m), 1.06-1.
80 (10H, m) ¹³ C-NMR (DMSO-d ₆ ) δppm: 157.68, 150.6
6, 148.69, 147.57, 117.94, 117.41, 109.66, 50.45,
32.10, 24.96, 24.69

Reference Example 23 (a) 4-amino-3- (1-methylthio-2-nitro)
Ethenylamino) pyridine 3,4-diaminopyridine (6.00 g, 55.0 mmol) and 1,
1-bis (methylthio) -2-nitroethylene (10.0
g, 60.5 mmol) DMF 60 ml and triethylamine 10 ml
And was reacted at 70 ° C. for 5 hours. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (eluent;
Purification with chloroform: methanol = 2: 1 v / v) gave the desired product (1.63 g, yield 13.1%). ¹ H-NMR (DMSO-d ₆ ) δppm: 8.00-7.87 (1H,
brd), 7.75-7.85 (1H, brs), 6.60-6.85 (3H, brs
+ D), 6.53 (1H, s), 2.35 (3H, s)

(B) 4-amino-3- (1-cyclohexyl
Sylamino-2-nitroethenylamino) pyridine After heating the compound (1.60 g, 7.70 mmol) obtained in (a) above and cyclohexylamine (8.0 ml, 69.9 mmol) at 80 ° C for 2 hours, the excess amine was distilled off. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 2: 1 v / v) (crude product 1.0).
g). This was purified by HPLC (column; Asahi Kasei ODP-90, detection; 254 nm, solvent; water: methanol = 50: 50 to methanol), and the desired product (yellow solid, 180 mg, yield)
9.1%) was obtained. IR (KBr): 3400, 3200, 2900, 1600, 1540, 1390c
^{m -1 1 H-NMR (DMSO} -d 6) δppm: 10.50-10.0 (1
H, brs), 9.00-8.40 (1H, brs), 7.98 (1H, d, J = 5.
6Hz), 7.89 (1H, s), 6.66 (1H, d, J = 5.6Hz), 6.34
-6.14 (2H, brs), 5.88-5.68 (1H, brs), 3.85-3.
65 (1H, brs), 2.10-1.15 (10H, m) ¹³ C-NMR (DMSO-d ₆ ) δppm: 155.78, 151.3
8, 148.97, 148.37, 117.16, 109.41, 97.84, 49.12, 3
2.12, 24.83, 23.95

Reference Example 24 N "-cyano-N- (6-amino-3-pyridyl)-
The title compound was synthesized according to Reference Example 22 using N'-cyclohexylguanidine 2,5-diaminopyridine. Yamabuki colored crystals mp 194-196 ° C IR (KBr): 3600-3000, 2900, 2850, 2150, 1590c
^{m -1 1 H-NMR (DMSO} -d 6) δppm: 1.0-2.0 (10H,
m), 3.4-3.8 (1H, m), 5.93 (2H, brs), 6.42 (1
H, d, J = 8.0Hz), 6.53 (1H, d, J = 8.0Hz), 7.19 (1
H, dd, J = 1.0Hz, 8.0Hz), 7.70 (1H, d, J = 1.0Hz),
8.30 (1H, s) ¹³ C-NMR (DMSO-d ₆ ) δppm: 24.8, 25.0, 3
2.1, 50.4, 107.8, 117.9, 122.8, 135.6, 145.2, 158.
0

Reference Example 25 N "-cyano-N- (6-amino-3-pyridyl)-
The title compound was synthesized according to Reference Example 22 using N '-(1,2,2-trimethylpropyl) guanidine 1,2,2-trimethylpropylamine. Orange crystals mp 175-177 ℃ IR (KBr): 3600-3000,2950,2150,1600cm -1 1 H-NMR (DMSO-d 6) δppm: 0.84 (9H, s),
1.01 (3H, d, J = 6.0Hz), 3.6−3.9 (1H, m), 5.96 (2
H, s), 6.10 (1H, d, J = 10.0Hz), 6, 43 (1H, d, J =
8.0Hz), 7.19 (1H, dd, J = 2.0Hz, 8.0Hz), 7.73 (1
H, d, J = 2.0 Hz), 8.55 (1H, s) ¹³ C-NMR (DMSO-d ₆ ) δppm: 15.4, 26.1, 3
4.7, 55.0, 107.8, 117.2, 122.6, 135.4, 145.0, 158.
0,158.6

Reference Example 26 (a) 3-Nitro-6- pyridylcarbonitrile 3-nitro-6-prompyridine (5.62 g, 27.7 mmo)
l), CuCN (3.32 g, 35.7 mmol) and DMF (6 ml) were mixed and reacted at 100-110 ° C for 2 hours. After cooling to room temperature,
After adding methylene chloride and stirring, methylene chloride was recovered. After filtration through Celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1: 3) to obtain a yellow solid (2.74 g, yield 66%). (b) 3-Amino-6- pyridylcarbonitrile 1.01 g of the nitropyridine compound obtained in (a) above is dissolved in 10 ml of dioxane, 0.5 g of 10% palladium-carbon is added, and the mixture is vigorously stirred at room temperature under a hydrogen atmosphere. did. The palladium-carbon was filtered through Celite, washed with ethanol, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1: 3) to obtain a light brown solid (0.71 g, yield 88%).

(C) 3-isothiocyanate-6-pyri
Aminopyridine body obtained in Jill carbonitrile above (b) (0.22g, 1.85mmo
l) is suspended in 10 ml of toluene and thiophosgene (0.16 ml, 2.
1 mmol) was added and the mixture was refluxed for 1 hour. The fraction obtained by distilling off toluene and extracting with methylene chloride was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1).
(80 mg, 27% yield). (d) N- (6-cyano-3-pyridyl) -N'-
(1,2,2-Trimethylpropyl) thiourea Isothiocyanate compound obtained in (c) above (80 mg, 0.5 mmo
l) was dissolved in 1 ml of methylene chloride, 1,2,2-trimethylpropylamine (0.15 ml, 1.12 mmol) was added, and the mixture was reacted at room temperature for several minutes and then subjected to silica gel column chromatography (eluent; hexane: ethyl acetate =). 1: 1) (white solid, 0.13 g, yield 99%). mp 146.0-148.0 ℃ IR (KBr): 3250,3100,2950,2200,1520cm -1 1 H-NMR (DMSO-d 6) δppm: 9.97 (1H, s),
8.79 (1H, d, J = 2.4Hz), 8.56 (1H, dd, J = 8.6, 2.5H
z), 7.99 (1H, d, J = 9.2Hz), 7.90 (1H, d, J = 8.8H)
z), 4.40-4.20 (1H, m), 1.08 (3H, d, J = 6.7Hz),
0.93 (9H, s)

Reference Example 27(a) 3-amino-6-pyridinecarboxamide  0.45 g of 3-amino-6-pyridinecarbonitrile and meta
Nol-3N sodium hydroxide-35% hydrogen peroxide water
Mix 5 ml of (2: 3: 1), stir at room temperature for 30 minutes, and then mix with water.
5 ml was added and the precipitated solid was collected by filtration. Wash with water and acetone
The white solid was dried after purification (0.29 g, 56%).(b) N- (6-carbamoyl-3-pyridyl) -N '
-(1,2,2-Trimethylpropyl) thiourea Carboxamide derivative obtained in (a) above (0.37g, 27mmo
l) and 1,2,2-trimethylpropyl isothiocyanate
(1.15 g, 8.03 mmol) was added to 2 ml of DMF, and 80-90
Reaction was carried out at 0 ° C for 2 nights. DMF was distilled off, and the residue was treated with silica gel.
Column chromatography (eluent; chloroform:
Purified with methanol = 13: 1), methanol-ether
The crystals were recrystallized (0.4 g, yield 53%). White solid m.p. 197-199 ° C IR (KBr): 3200, 2900, 1690, 1530 cm^{-1 1} 1 H-NMR (DMSO-d₆) Δppm: 9.77 (1H, s),
8.74 (1H, d, J = 2.3Hz), 8.32 (1H, dd, J = 8.4, 2.1H
z), 7, 97 (2H, d + s, J = 8.4Hz), 7.82 (1H, d, J = 9.
2Hz), 7.51 (1H, s), 4.45-4.25 (1H, m), 1.08 (3
H, d, J = 6.7Hz), 0.94 (9H, s)

Reference Example 28 (a) 3-Nitro-6-methylaminopyridine 3-Nitro-6-chloropyridine (5 g, 31.5 mmol) was added to 10 ml of a 30% solution of methylamine in ethanol, and the mixture was kept at room temperature for 5 minutes. After the reaction, recrystallized (chloroform-hexane)
The desired product was obtained (yellow crude crystals, yield 4.92 g). (b) 3-Amino-6-methylaminopyridine 400 mg of platinum oxide was added to 40 ml of an ethanol solution of 4 g of the methylamino compound obtained in (a) above, and the mixture was reacted under a hydrogen atmosphere at room temperature for 15 hours, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; chloroform, then chloroform: methanol = 20: 1) to obtain the desired product (brown crystal, 320 mg).

(C) N- (6-methylamino-3-pyri
Zil) -N '-(1,2,2-trimethylpropyl) thio
Ourea 1,2,2-trimethylpropyl isothiocyanate (523 mg, 3.65 mmol) was added to 1.5 ml of a pyridine solution of the amino compound (300 mg, 2.44 mmol) obtained in (b) above, and the mixture was stirred at room temperature.
Stir for 18 hours. The precipitated crystals were collected by filtration, washed with hexane and ether and dried to obtain the desired product (330 mg, yield 51
%). White crystals mp 195-197 ℃ IR (KBr): 3600-3000,2950,1620cm -1 1 H-NMR (CDCl 3) δppm: 0.85 (9H, s), 1.08
(3H, d, J = 6.0Hz), 2.96 (3H, d, J = 5.0Hz), 4.3-
4.5 (1H, m), 4.9 (1H, brs), 5.58 (1H, d, J = 6.0H
z), 6.44 (1H, d, J = 9.0Hz), 7.31 (1H, dd, J = 2.0H)
z, 9.0Hz), 7.43 (1H, brs), 7.99 (1H, d, J = 2.0H
z) ¹³ C-NMR (DMSO-d ₆ ) δppm: 15.4, 26.3, 2
8.2, 34.4, 57.2, 106.8, 124.9, 135.3, 144.1, 157.
1,181.7

Aniline (Reference Example 29), ethylenediamine (Reference Example 30), hydroxyethylamine (Reference Example 3)
1), imidazole (Reference Example 32) and piperidine (Reference Example 33) were used to synthesize the following compounds according to Reference Example 28. Reference Example 29 N- (6-phenylamino-3-pyridyl) -N'-
(1,2,2-Trimethylpropyl) thiourea mp 168-170 ° C IR (KBr): 3500-3100, 3020, 2950, 1600, 1530c
^{m -1 1 H-NMR (CDCl} 3) δppm: 0.87 (9H, s), 1.09
(3H, d, J = 6.0Hz), 4.3-4.6 (1H, m), 5.60 (1H,
d, J = 8.0Hz), 6.91 (1H, d, J = 8.0Hz), 7.01 (1H,
s), 7.3-7.5 (6H, m), 7.65 (1H, s), 8.08 (1H,
d, J = 2.0 Hz) ¹³ C-NMR (DMSO-d ₆ ) δppm: 15.3, 26.3, 3
4.4, 57.2, 109.9, 117.6, 120.2, 127.8, 128.6, 134.
9, 141.8, 142.8, 152.9, 181.4

Reference Example 30 N- [6- (2-aminoethyl) amino-3-pyridy
]]-N '-(1,2,2-trimethylpropyl) thio
Urea mp 138-140 ℃ IR (KBr): 3600-3000,2950,1615,1530cm -1 1 H-NMR (CDCl 3) δppm: 0.85 (9H, s), 1.08
(3H, d, J = 6.0Hz), 2.97 (2H, t, J = 6.0Hz), 3.3-
3.5 (2H, m), 4.3-4.6 (1H, m), 5.27 (1H, brs),
5.56 (1H, d, J = 8.0Hz), 6.46 (1H, d, J = 9.0Hz), 7.
28 (1H, dd, J = 4.0, 9.0Hz), 7.52 (1H, brs), 7.97
(1H, d, J = 4.0Hz)

Reference Example 31 N- [6- (2-hydroxyethylamino) -3-pyriline
Zil] -N '-(1,2,2-trimethylpropyl) thio
Ourea IR (KBr): 3200, 3080, 3000, 2920, 1520, 148
^{0,1190cm -1 1 H-NMR (DMSO} -d 6) δppm: 0.89 (7H, s),
1.03 (3H, d, J = 6.6Hz), 3.30 (2H, t, J = 5.7Hz), 3.53
(2H, t, J = 5.7Hz), 4.20-4.35 (1H, m), 4.60-4.75
(1H, br), 6.48 (1H, d, J = 8.8Hz), 6.48 (1H,
s), 7.13 (1H, d, J = 8.1Hz), 7.38 (1H, dd, J = 8.8,
2.1Hz), 7.81 (1H, d, J = 2.1Hz), 9.00 (1H, s)

Reference Example 32 N- [6- (1-imidazolyl) -3-pyridyl]-
N '-(1,2,2-trimethylpropyl) thiourea IR (KBr): 3400-3200, 2900, 1610, 1180 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δppm: 0.93 (9H, s),
1.07 (3H, d, J = 6.7Hz), 4.25-4.40 (1H, m), 7.11
(1H, s), 7.73−7.77 (1H, brs), 7.75 (1H, d, J =
8.7Hz), 7.90 (1H, s), 8.28 (1H, dd, J = 8.7, 2.5H
z), 8.47 (1H, s), 8.50 (1H, d, J = 2.5Hz), 9.60
(1H, s)

Reference Example 33 N- (6-piperidino-3-pyridyl) -N '-(1,
2,2-trimethyl-propyl) thiourea mp 151-153 ℃ IR (KBr): 3600-3000,2900,1600,1535cm -1 1 H-NMR (CDCl 3) δppm: 0.86 (9H, s), 1.08
(3H, d, J = 6.0Hz), 1.66 (6H, brs), 3.57 (4H, br)
s), 4.3-4.6 (1H, m), 5.63 (1H, d, J = 6.0Hz), 6.
67 (1H, d, J = 8.0Hz), 7.33 (1H, dd, J = 2.0, 8.0H)
z), 7.53 (1H, brs), 8.05 (1H, d, J = 2.0Hz)

Reference Example 34 (a) 2-hydrazino-5-nitropyridine 2-chloro-5-nitropyridine (5 g, 31.5 mmol) and hydrazine (1.74 g, 34.7 mmol) were dissolved in 60 ml of dioxane, and the mixture was dissolved at room temperature in 16 ml. Stir for hours. Precipitated yellow powder (mp19
(8-208 ° C) was collected by filtration to obtain the desired product as a hydrochloride (502 m
g). (b) 6- (2-t-butoxycarbonylhydrazino)
-3 -Nitropyridine 2-hydrazino-5-nitropyridine hydrochloride (1 g, 5.
3 mmol) was suspended in a mixed solvent of 20 ml of dioxane, 1 ml of DMF and 2.5 ml of triethylamine, and 2.4 ml of di-t-butyl dicarbonate was added with stirring. The reaction solution was refluxed for 2 hours, and after the completion, the reaction solution was filtered. The solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 2) to obtain 1.27 g of the desired product as a yellow powder (mp132.5-134 ° C). It was (c) 3-amino-6- (2-t-butoxycarbonyl
Hydrazino) pyridine 6- (2-t-butoxycarbonylhydrazino) -3-
57 mg of platinum oxide was added to a solution of 570 mg of nitropyridine in 10 ml of ethanol. The mixture was vigorously stirred for 1 hour at room temperature under a hydrogen atmosphere. After the completion of the reaction, the reaction solution was filtered, the filtrate was thoroughly washed with ethanol, the filtrate and the washing solution were combined, and the solvent was distilled off to give a brown powder of 3-amino-6- (2-t-butoxycarbonylhydrazino) pyridine. 502 mg was obtained.

(D) N- [6- (2-t-butoxycal
Bonylhydrazino) -3-pyridyl] -N ′-(1,
2,2-Trimethylpropyl) thiourea 3-amino-6- (2-t-butoxycarbonylhydrazino) pyridine (500 mg, 2.2 mmol) and 1,2,2-trimethylpropyl isothiocyanate (351 mg, 2.5 mmo
l) was dissolved in 10 ml of pyridine and stirred at room temperature for 16 hours.
After completion, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate =).
It was purified by 1: 3) to obtain the target product as white powder (mp143-146 ° C). ^{IR (KBr): 3250,2950,1690,1530cm -1 1} H-NMR (DMSO-d 6) δppm: 0.90 (9H, s),
1.04 (3H, d, J = 6Hz), 1.42 (9H, s), 4.29 (1H,
m), 6.48 (1H, d, J = 8Hz), 7.28 (1H, brd), 7.58
(1H, dd, J = 2Hz), 7.94 (1H, d, J = 2.3Hz), 8.07 (1
H, s), 8.78 (1H, s), 9.08 (1H, s) ¹³ C-NMR (DMSO-d ₆ ) δppm: 18.4 (q), 28.
1 (q), 56.0 (q), 79.1 (d), 106.6 (d), 124.7
(D), 133.0 (d), 137.6 (s), 152.3 (s), 156.2
(S), 187.9 (s)

Reference Example 35 N- (6-hydrazino-3-pyridyl) -N '-(1,
2,2-Trimethylpropyl) thiourea N- (6-t-butoxycarbonylhydrazino-3-pyridyl) -N '-(1,2,2-trimethylpropyl)
To a solution of thiourea (150 mg, 0.41 mmol) in ethanol (2 ml) was added at room temperature 3.5 ml of 8.83N hydrochloric acid ethanol solution. After stirring at room temperature for 30 minutes, the mixture was stirred in an ice bath for 30 minutes.
Then, the mixture was allowed to stand for 30 minutes in an ice bath, and the blue powder that had separated out was collected by filtration and dried to obtain 85 mg of the desired product. ^{IR (KBr): 3200,1690,1600,1540cm -1 1} H-NMR (DMSO-d 6) δppm: 0.92 (9H, s),
1.04 (3H, d, J = 6.7Hz), 3.0-4.5 (1H, br), 4.26
(1H, q, J = 6.7Hz), 6.85 (1H, d, J = 9Hz), 7.85 (1
H, dd, J = 2.1, 9.0Hz), 8.07 (1H, d, J = 8.6Hz), 8.2
7 (1H, s), 9.1-9.5 (1H, s), 10.07 (1H, s)

Reference Example 36 N-Hydroxysuccin of t-butoxycarbonylglycine
The following compound was used according to Reference Example 34 using cinimide ester.
I got a compound.(a) N- [6- (2-t-butoxycarbonylglycy
Luhydrazino) -3-pyridyl] -N ′-(1,2,2
-Trimethylpropyl) thiourea IR (KBr): 3400, 1680cm^{-1 1} 1 H-NMR (DMSO-d₆) Δppm: 9.75 (1H, s),
9.09 (1H, s), 8.24 (1H, s), 7.95 (1H, d, J = 2.1H
z), 7.57 (1H, dd, J = 2.0, 8.7Hz), 7.31 (1H, d, J =
9.3Hz), 7.02 (1H, t), 6.57 (1H, d, J = 8.8Hz), 4.
28 (1H, m), 3.62 (2H, d, J = 5.9Hz), 1.39 (9H,
s), 1.04 (3H, d, J = 6.6Hz), 0.90 (9H, s)(b) N- [6- (2-glycylhydrazino) -3-pi
Lysyl] -N '-(1,2,2-trimethylpropyl)
Thiourea hydrochloride IR (KBr): 3400-3100, 1700cm^{-1 1} 1 H-NMR (DMSO-d₆) Δppm: 11.17 (1H,
s), 10.74 (2H, s), 8.50 (1H, s), 8.47-8.39 (4
H, m), 8.13 (1H, dd, J = 2.1, 9.4Hz), 7.20 (1H,
d, J = 9.4Hz), 4.24 (1H, m), 3.86 (2H, d, J = 5.3H)
z), 1.05 (3H, d, J = 6.7Hz), 0.93 (9H, s)¹³ C-NMR (DMSO-d₆) Δppm: 180.71 (s), 1
66.78 (s), 150.16 (s), 141.16 (d), 129.47
(D), 127.87 (s), 110.87 (d), 57.39 (d), 39.50
(T), 34.28 (s), 26.34 (q), 15.18 (q)

Reference Example 37 Using 4-ethoxycarbonylpiperazine, Reference Example 34
The following compound was obtained according to (a) N- [6- (4-ethoxycarbonyl-1-pipet
Razinyl) -3-pyridyl] -N '-(1,2,2-to
Li-methylpropyl) thiourea ^{IR (KBr): 3200,1690cm -1 1} H-NMR (CDCl 3) δppm: 8.08 (1H, d, J = 2.6H
z), 7.43 (1H, bs), 7.38 (1H, dd, J = 2.6, 9.0H
z), 6.67 (1H, d, J = 8.9Hz), 5.59 (1H, d, J = 9.8H)
z), 4.40 (1H, m), 4.18 (2H, q, J = 7.0Hz), 3.60
(8H, s), 1.29 (3H, t, J = 7.1Hz), 1.08 (3H, d, J =
6.7Hz), 0.86 (9H, s) (b) N- [6- (4-ethoxycarbonyl-1-pipet
Razinyl) -3-pyridyl] -N '-(1,2,2-to
Li-methylpropyl) thiourea hydrochloride ^{IR (KBr): 3250,1700cm -1 1} H-NMR (CDCl 3) δppm: 10.74 (1H, bs), 9.0
1 (1H, d, J = 9.0Hz), 7.93 (1H, s), 7.83 (1H, d, J)
= 9.1Hz), 6.95 (1H, d, J = 9.6Hz), 4.35 (1H, m),
4.19 (2H, q, J = 7.1Hz), 3.75 (8H, m), 1.30 (3H,
t, J = 7.1Hz), 1.17 (3H, d, J = 6.7Hz), 1.01 (9H,
s) ¹³ C-NMR (CDCl ₃ ) δppm: 181.24 (s), 155.04
(S), 149.04 (s), 143.45 (d), 129.86 (s), 128.
22 (d), 110.09 (d), 62.00 (t), 58.45 (d), 46.71
(T), 42.54 (t), 34.55 (s), 26.47 (q), 15.29
(Q), 14.54 (q)

Reference Example 38 (a) 2-Acetylamino-5-nitropyridine 2-amino- 5-nitropyridine (4.0 g, 28.8 mmol) in dichloromethane (15 ml) was added to DMAP (176 mg, 31.
6 mmol), triethylamine (4.41 ml, 31.6 mmol) and acetyl chloride (2.16 ml, 31.6 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The mixture suspension was neutralized by adding a 1 M potassium carbonate aqueous solution, extracted with chloroform (three times), dried (magnesium sulfate), removed of the solvent, and subjected to silica gel column chromatography (eluent: chloroform). Recrystallization from chloroform-hexane was performed to obtain the desired product (2.14 g, yield 49%) as a skin-colored powder. (b) 2-Acetylamino - 5-aminopyridine 2-acetylamino-5-nitropyridine (1.0 g, 5.5
100 mg of platinum oxide was suspended in a 2 mmol) ethanol (20 ml) solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour and 30 minutes.
Platinum oxide was removed by Celite filtration, the solvent was distilled off under reduced pressure,
The residue is subjected to silica gel column chromatography (eluate;
Chloroform only to chloroform: methanol = 10:
Purified in 1), the desired product of dark brown crude crystals (170 mg, yield 20
%) Was obtained.

[0075](c) N- (6-acetylamino-3-pi
Lysyl) -N '-(1,2,2-trimethylpropyl)
Thiourea 2-Acetylamino-5-aminopyridine (150 mg, 0.9
9 mmol) in pyridine (1.5 ml) solution, 1,2,2-trimethyl
Cylpropyl isothiocyanate (213mg, 1.49mmol)
Is added dropwise at room temperature for 22 hours, at 50 ° C for 5 hours, and at room temperature for 15 hours.
After stirring for an hour, the solvent was distilled off under reduced pressure. Black residue
Recrystallized from loform-hexane to obtain the desired product as a skin-colored powder (23
2 mg, yield 79%) was obtained. m.p. 197-199 ° C IR (KBr): 3500-3000, 2950, 1670, 1590 cm^{-1 1} 1 H-NMR (DMSO-d₆) Δppm: 0.92 (9H, s),
1.06 (3H, d, J = 6.0Hz), 2.08 (3H, s), 4.32 (1H,
m), 7.53 (1H, d, J = 8.0Hz), 7.84 (1H, dd, J = 1.0,
8.0Hz), 8.01 (1H, d, J = 8.0Hz), 8.35 (1H, d, J = 1.
0Hz), 9.35 (1H, s), 10.42 (1H, s)¹³ C-NMR (DMSO-d₆) Δppm: 15.2, 23.7, 2
6.3, 34.3, 57.2, 112.6, 132.1, 133.2, 142.8, 148.
2, 168.8, 181.0

Reference Example 39 N- (6-benzoylamino-3-pyridyl) -N'-
The title compound was obtained according to Reference Example 38 using 1,2,2-trimethylpropylthioureabenzoyl chloride. mp 168-170 ℃ IR (KBr): 3600-3000,2950,1650,1610cm -1 1 H-NMR (CDCl 3) δppm: 0.87 (9H, s), 1.01
(3H, d, J = 6.0Hz), 4.25 (1H, brs), 7.3-7.6 (4
H, m), 7.8-8.2 (4H, m), 8.41 (1H, s), 9.36 (1
H, s), 10.68 (1H, s)

According to Reference Example 38, 2-methylpropyl isothiocyanate (Reference Example 40), 1-dimethylpropyl isothiocyanate (Reference Example 41) and exo-2-norbornyl isothiocyanate (Reference Example 42) were used. The following compounds were synthesized. Reference Example 40 N- (6-amino-3-pyridyl) -N '-(2-methyi)
Rupuropiru) thiourea ^{IR (KBr): 3300,2950,1550,1350,1280cm -1 1} H-NMR (CDCl 3) δppm: 0.88 (6H, d, J = 6.7H
z), 1.90 (1H, d, hept, J = 6.9, 6.7Hz), 3.43 (2H,
dd, J = 6.9, 5.7Hz), 4.70 (2H, brs), 5.73 (1H, br)
s), 6.55 (1H, dd, J = 8.6, 0.6Hz), 7.32 (1H, dd, J)
= 8.6, 2.6Hz), 7.49 (1H, brs), 7.97 (1H, d, J = 2.6
Hz) ¹³ C-NMR (DMSO-d ₆ ) δppm: 20.1 (q), 27.
5 (d), 51.4 (t), 107.5 (d), 124.7 (s), 135.7
(D), 144.8 (d), 157.6 (s), 181.8 (s)

Reference Example 41 N- (6-amino-3-pyridyl) -N '-(1,1-
Dimethylpropyl) thiourea IR (KBr): 3180, 2950, 1630, 1530, 1250, 1190c
^{m -1 1 H-NMR (CDCl} 3) δppm: 0.82 (3H, t, J = 7.5H
z), 1.43 (6H, s), 1.90 (2H, q, J = 7.5Hz), 4.76
(2H, brs), 5.56 (1H, brs), 6.54 (1H, dd, J = 8.7H
z, 0.4Hz), 7.31 (1H, dd, J = 8.7Hz, 2.6Hz), 7.51
(1H, brs), 7.92 (1H, d, J = 2.6Hz) ¹³ C-NMR (DMSO-d ₆ ) δppm: 8.2 (q), 26.5
(Q), 32.0 (d), 55.2 (s), 107.3 (d), 125.1
(S), 135.9 (d), 144.4 (d), 157.3 (s), 180.9
(S)

Reference Example 42 N- (6-amino-3-pyridyl) -N '-(exo-
2- Norbornyl ) thiourea IR (KBr): 3350, 2950, 1630, 1520, 1400, 1280c
^{m -1 1 H-NMR (DMSO} -d 6) δppm: 1.00-1.75 (8
H, m), 2.15-2.30 (2H, m), 3.70-4.05 (1H, m),
5.82 (2H, brs), 6.39 (1H, d, J = 8.8Hz), 7.32 (1
H, dd, J = 8.8, 2.5Hz), 7.40 (1H, brs), 7.74 (1H,
d, J = 2.5 Hz), 8.77 (1H, brs) ¹³ C-NMR (DMSO-d ₆ ) δppm: 26.0 (t), 27.
9 (t), 35.1 (t), 38.9 (t), 35.2 (d), 41.7
(D), 56.8 (d), 107.1 (d), 125.4 (s), 135.5
(D), 144.5 (d), 157.3 (s), 180.9 (s)

Reference Example 43 (a) N- (6-amino-3-pyridyl) -N '-(d
Xoxo-2-norbornyl) carbodiimide In a solution of the thiourea compound of Reference Example 42 (2 g, 7.62 mmol) in methylene chloride-ethanol (1: 1,100 ml), mercuric oxide (4.95 g, 27.9 mmol), sulfur (0.122 g) , 3.81mmol)
Was added, and the mixture was stirred at room temperature for 3 days. The mercuric oxide, mercuric sulphide and sulfur were filtered over Celite and the Celite was washed with methylene chloride. The filtrate and the washing solution were combined and the solvent was distilled off to obtain the desired product (1.77 g). (b) N- (6-amino-3-pyridyl) -N'-sia
No-N ″-(exo-2-norbornyl) guanidine Cyanamide (0.641 g, 15.27 mmo) in 20 ml of a methylene chloride solution of the carbodiimide derivative (1.743 g, 7.63 mmol) of the above (a).
l) and 1 drop of N, N-diisopropylethylamine were added, and the mixture was stirred at room temperature for 1 day. The solvent was evaporated, the product was purified by silica gel column chromatography (eluent; chloroform-methanol = 10: 1) and then recrystallized (methylene chloride-methanol-ether) to obtain the desired product (1.538 g). White powder mp 180-181 ℃ IR (KBr): 3300, 2900, 2150, 1585, 1490, 1375c
^{m -1 1 H-NMR (CDCl} 3) δppm: 1.00-1.70 (8H,
m), 2.10-2.25 (2H, m), 3.50-3.65 (1H, m), 5.9
2 (2H, brs), 6.41 (1H, d, J = 8.6Hz), 6.45 (1H,
d, J = 5.9Hz), 7.18 (1H, dd, J = 8.6, 2.6Hz), 7.70
(1H, d, J = 2.6Hz), 8.44 (1H, brs)

Reference Example 44 (a) N- [6- [3- (3-benzyloxycarbonyl)
L-5-oxo-4-oxazolidinyl) propionyl
Amino] -3-pyridyl] -N′-cyano-N ″-(d
Xoxo-2-norbornyl) guanidine N- (6-amino-3-pyridyl) -N'-cyano-
N ″-(exo-2-norbornyl) guanidine 922mg
To 3- (S)-(3-benzyloxycarbonyl-5)
A solution of -oxo-4-oxazolidinyl) propionyl chloride (1.06 g, 3.41 mmol) in DMF (1 ml) and triethylamine 0.475 ml in DMF (1 ml) were slowly added dropwise at the same time. After completion of dropping, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; methanol: chloroform = 1: 20) to obtain the desired product (394 mg, yield 21.
2%).

(B) N- [6- (benzyloxycarbo
Nyl-γ-L-glutamylamino) -3-pyridyl]-
N'-cyano-N "-(exo-2-norbornyl)
Anidine [6- [3- (3-benzyloxycarbonyl-5-oxo-4-oxazolidinyl) propionylamino]-
3-Pyridyl] -N'-cyano-N "-(exo-2-
Norbornyl) guanidine (410 mg, 0.76 mmol) in THF1
It was dissolved in 5 ml and 0.75 ml of 1N sodium hydroxide solution was added with stirring at room temperature. Stir at room temperature for 20 minutes,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; methanol: chloroform =
The product was purified by 1: 2) to obtain the desired product (370 mg, yield 92.3%).

(C) N- [6- (γ-L-glutamylmer
Mino) -3-pyridyl] -N'-cyano-N "-(ex
So-2-norbornyl) guanidine N- [6- (benzyloxycarbonyl-γ-L-glutamylamino) -3-pyridyl] -N′-cyano-N ″
-(Exo-2-norbornyl) guanidine (20 mg, 0.0
(375 mmol) and 4 mg of lithium hydroxide were added to 1 ml of water, the atmosphere was sufficiently replaced with nitrogen, and then palladium-carbon was added. Then, after substituting with hydrogen, the mixture was vigorously stirred at room temperature for 2 hours under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered, the filtered product was thoroughly washed with water, the filtrate and the washing solution were combined and neutralized with 1N-hydrochloric acid, and then the solvent was distilled off. The residue is purified by HPLC,
The target substance (6 mg, yield 40%) was obtained as a white powder. mp 200-204 ℃ IR (KBr): 3200,2950,2200,1680cm -1 1 H-NMR (DMSO-d 6) δppm: 10.7 (1H, b
r), 8.15 (1H, d, J = 2.6Hz), 7.99 (1H, d, J = 8.9H)
z), 7.79 (1H, br), 7.60 (1H, dd, J = 2.6, 8.9H
z), 3.70 (1H, br), 3.27 (1H, t, J = 6.3Hz), 2.50
(2H, br), 2.21 (2H, br), 1.91 (2H, q, J = 6.3H
z), 1.00-1.80 (8H, m)

N- (6-amino-obtained in Reference Example 43
3-pyridyl) -N'-cyano-N "-(exo-2-
Norbornyl) guanidine as a raw material and the following Reference Example 4
5 to 50 compounds were obtained. Reference Example 45 N- (6-L-alanylamino-3-pyridyl) -N '
-Cyano-N "-(exo-2-norbornyl) guani
Gin white powder mp 154.0-158.0 ° C ¹ H-NMR (DMSO-d ₆ ) δppm: 8.15 (1H, d, J =
2.7Hz), 8.07 (1H, d, J = 8.9Hz), 7.62 (1H, dd, J = 8.
9, 2.7Hz), 7.02 (1H, d, J = 6.5Hz), 3.55-3.75 (1
H, m), 3.51 (1H, q, J = 6.8Hz), 3.0-3.9 (2H, b
r), 2.15-2.30 (2H, m), 1.23 (3H, d, J = 6.8Hz),
1.00-1.80 (8H, m)

Reference Example 46 N- (6-ethoxycarbonylamino-3-pyridyl)
-N'-cyano-N "-(exo-2-norbornyl)
Hydrochloride white powder mp 144-145 ℃ IR (KBr): 3200,2950,2200,1740cm -1 1 H-NMR (DMSO-d 6) δppm: 10.50 (1H,
s), 9.16 (1H, s), 8.17 (1H, d, J = 1.4Hz), 7.74
(2H, m), 7.18 (1H, d, J = 6.6Hz), 4.18 (2H, q, J =
7.1Hz), 3.68 (1H, m), 2, 24 (2H, m), 1.72-1.07
(8H, m), 1.26 (3H, t, J = 7.1Hz)

Reference Example 47 N- (6-benzyloxycarbonylamino-3-pyridin
Dil) -N'-cyano-N "-(exo-2-norbol
Yl) guanidine hydrochloride white powder mp 152-153 ℃ IR (KBr): 3200,2950,2200,1720cm -1 1 H-NMR (DMSO-d 6) δppm: 10.76 (1H,
s), 9.29 (1H, s), 8.21 (1H, d, J = 2.5Hz), 7.82-
7.71 (2H, m), 7.43 (5H, m), 7.27 (1H, d, J = 6.7H
z), 5.21 (2H, s), 3.70 (1H, m), 2.23 (2H, m),
1.72-1.08 (8H, m)

Reference Example 48 N- [6- (3-hexylureido) -3-pyridyl]
-N'-cyano-N "-(exo-2-norbornyl)
Guanidine colorless needles mp 157-158 ° C IR (KBr): 3400-3100, 2950, 2850, 2118, 167
^{0,1498cm -1 1 H-NMR (DMSO} -d 6) δppm: 9.16 (1H, s),
8.73 (1H, s), 8.04 (1H, br), 8.00 (1H, d, J = 2.5H
z), 7.49 (1H, dd, J = 2.5Hz, 8.9Hz), 7.33 (1H, d,
J = 8.9Hz), 6.75 (1H, d, J = 6.6Hz), 3.61 (1H, br
s), 3.17 (2H, q, J = 6.3Hz), 2.22 (2H, br), 1.55
-1.70 (1H, m), 1.00-1.55 (15H, m), 0.88 (3H,
t, J = 6.3Hz)

Reference Example 49(a) N- [6- (5-methyl-2-oxo-2H-1,
3-dioxol-4-ylmethylamino) -3-pyri
Zil] -N'-cyano-N "-(exo-2-norbol
Nil) guanidine IR (KBr): 3250, 2900, 2200, 1800, 1720cm^{-1 1} 1 H-NMR (DMSO-d₆) Δppm: 8.50 (1H, s),
7.83 (1H, d, J = 2.3Hz), 7.25 (1H, dd, J = 2.4, 8.7H)
z), 7.04 (1H, t, J = 5.7Hz), 6.51 (1H, d, J = 8.7H)
z), 6.52 (1H, s), 4.29 (2H, d, J = 5.6Hz), 3.56
(1H, m), 2.19 (2H, m), 2.15 (3H, s), 1.66-1.0
4 (8H, m)

(B) N- [6- (5-methyl-2-oxo
-2H-1,3-dioxol-4-ylmethylami
No) -3-pyridyl] -N′-cyano-N ″-(exo
2-norbornyl) guanidine hydrochloride pale yellow powder mp 151-152 ℃ IR (KBr): 3200,2900,2150,1800,1730cm -1 1 H-NMR (DMSO-d 6) δppm: 9.07 (1H, s) ，
8.60 (1H, s), 7.94 (1H, d, J = 2.2Hz), 7.78 (1H, d
d, J = 2.0, 9.3Hz), 7.12 (1H, d, J = 6.5Hz), 7.00 (1
H, d, J = 9.3Hz), 4.53 (2H, s), 3.65 (1H, m), 2.2
3 (2H, m), 2.19 (3H, s), 1.71-1.06 (8H, m)

Reference Example 50 N- [6- (2-oxopropylamino) -3-pyridy
]]-N'-cyano-N "-(exo-2-norbornyl
Le) guanidine light yellow crystal mp 117-119 ° C IR (KBr): 3500, 3350, 3200, 3000, 2950, 215
^{0,1720,1590,1610cm -1 1 H-NMR (CDCl} 3) δppm: 7.94 (1H, d, J = 2.0H
z), 7.25 (1H, dd, J = 2.0, 10.0Hz), 7.16 (1H, br
s), 6.54 (1H, d, J = 10.0Hz), 5.50 (1H, t, J = 7.0H)
z), 4.43 (1H, d, J = 8.0Hz), 4.29 (2H, d, J = 7.0H)
z), 3.55-3.7 (1H, m), 2.27 (3H, s), 2.15-2.25
(2H, m), 1.0-1.9 (8H, m)

Reference Example 51 (a) N- (6-methanesulfonylamino-3-pyridyl
) -N '-(1,2,2-trimethylpropyl) calc
Bodiimide N- (6-amino-3-pyridyl) -N '-(1,2,
2-Trimethylpropyl) thiourea (1.26g, 5.29mmo
l) was dissolved in 10 ml of THF under a nitrogen atmosphere, and under ice-cooling, 7.38 ml of triethylamine and methanesulfonyl chloride (0.41 ml, 5.29 mmol) were sequentially added dropwise to this solution. After the dropping was completed, the mixture was stirred at room temperature for 1.5 hours, and then water was added. The reaction solution was extracted with chloroform three times, the extract was dried, and the solvent was evaporated. Silica gel column chromatography of the residue (eluent; chloroform: methanol = 100: 1 to 10: 1)
Was purified by recrystallization from chloroform-ether to obtain the desired product (210 mg, yield 13%). White crystal IR (KBr): 3600-3100, 3000, 2950, 2850, 2100c
^{m -1 1 H-NMR (DMSO} -d 6) δppm: 8.04 (1H, d, J =
2.0Hz), 7.47 (1H, dd, J = 2.0, 8.0Hz), 6.95 (1H,
d, J = 8.0Hz), 3.54 (1H, q, J = 6.0Hz), 3.27 (3H,
s), 1.25 (3H, d, J = 6.0Hz), 0.92 (9H, s) ¹³ C-NMR (DMSO-d ₆ ) δppm: 154.8, 145.8,
137.2, 133.0, 128.3, 113.1, 52.6, 41.5, 34.1, 26.
1, 16.4

(B) N- (6-methanesulfonylamino
-3-Pyridyl) -N'cyano-N "-(1,2,2-
Trimethylpropyl) guanidine N- (6-methanesulfonylamino-3-pyridyl)-
Cyanamide (172 mg, 4.1 mmol) and diisopropylethylamine (711 μl, 4.1 mmol) were added to a solution of N ′-(1,2,2-trimethylpropyl) carbodiimide (121 mg, 0.41 mmol) in chloroform (1 ml), and the mixture was stirred at room temperature for 16 hours. did. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent; chloroform to chloroform: methanol = 5: 1) and recrystallized from chloroform-ether to give the desired product (97 mg, yield 72%). White crystals mp 164-166 ℃ IR (KBr): 3600-3000,2990,2290,2200cm -1 1 H-NMR (DMSO-d 6) δppm: 8.94 (1H, s),
8.11 (1H, d, J = 2.0Hz), 7.58 (1H, dd, J = 2.0, 7.0H
z), 6.95 (1H, d, J = 7.0Hz), 6.73 (1H, d, J = 8.0H)
z), 3.7-3.95 (1H, m), 3.27 (3H, s), 1.06 (3H,
d, J = 6.0Hz), 0.88 (9H, s)

Reference Example 52 N- (6-methylthio-3-pyridyl) -N '-(1,
2,2-trimethyl-propyl) thiourea white powder mp 157.0-158.0 ℃ IR (KBr): 3220,2950,1530,1465,1140cm -1 1 H-NMR (CDCl 3) δppm: 8.36 (1H, d, J = 2.5 H
z), 7.83 (1H, brs), 7.41 (1H, dd, J = 8.7, 2.5H
z), 7.25 (1H, dd, J = 8.7, 0.5Hz), 5.60-5.85 (1
H, brd), 4.25-4.55 (1H, m), 2.58 (3H, s), 1.11
(3H, d, J = 6.7Hz), 0.89 (9H, s)

Reference Examples 53 to 84 The compounds shown in Tables 2 to 6 were synthesized according to the method of Reference Example 38 and the method of Reference Example 1 or 22. Properties of the obtained compound are shown in Tables 2 to 6. In addition, Table 2 to Table 6
In the column of compound (R), the "*" mark indicates the binding position (hereinafter the same).

[0095]

[Table 2]

[0096]

[Table 3]

[0097]

[Table 4]

[0098]

[Table 5]

[0099]

[Table 6]

Reference Example 85 N- (6-aminopyridin-1-oxide-3-yl)
-N'-cyano-N "-(1,2,2-trimethylpro
Pill) guanidine N- (6-amino-3-pyridyl) -N'-cyano-
N "-(1,2,2-trimethylpropyl) guanidine
(1.757 g, 6.749 mmol) was dissolved in a methylene chloride-methanol mixed solvent (4: 1, 25 ml), and m-chloroperbenzoic acid (1.664 g, purity 70%, 6.749 mmol) was added little by little under ice cooling. It was
Stir under ice cooling for 2 hours, add 50 mg of sodium sulfite,
Stir for 10 minutes. Next, 30 ml of 10% potassium carbonate aqueous solution
Was added, and the mixture was extracted with chloroform and dried, and then the solvent was distilled off. Silica gel column chromatography of the residue
(Eluent: chloroform: methanol = 10: 1) and purified by recrystallization from methanol-methylene chloride-ether to obtain the desired product (1.459 g, yield 78.2%). Light brown powder mp 141.0-146.0 ° C ¹ H-NMR (DMSO-d ₆ ) δppm: 8.78 (1H, s),
7.90 (1H, d, J = 2.2Hz), 6.98 (1H, dd, J = 8.8, 2.2H
z), 6.77 (2H, s), 6.77 (1H, d, J = 8.8Hz), 6.61
(1H, d, J = 9.2Hz), 3.65-3.90 (1H, m), 1.01 (3
H, d, J = 6.8Hz), 0.85 (9H, s)

The following compound was obtained in the same manner as in Reference Example 85. Reference Example 86 N- (6-aminopyridin-1-oxide-3-yl)
-N'-cyano-N "-(exo-2-norbornyl)
Guanidine white powder mp 156.0-160.0 ° C ¹ H-NMR (DMSO-d ₆ ) δppm: 8.66 (1H, s),
7.90 (1H, d, J = 2.2Hz), 6.98 (1H, dd, J = 8.9, 2.2H
z), 6.75 (1H, brs), 6.75 (1H, d, J = 8.9Hz), 6.75
(2H, s), 3.45-3.65 (1H, m), 2.10-2.25 (2H, m
m), 1.00-1.70 (8H, m)

Reference Examples 87 to 89 In the same manner as in Reference Example 85, the compounds shown in Table 7 were obtained.

[0103]

[Table 7]

Reference Examples 90 to 95 In the same manner as in Reference Example 44, the compounds shown in Table 8 were obtained.

[0105]

[Table 8]

Formulation Example 1 Tablet (1) Compound of Reference Example 84 10 mg (2) Fine granules for direct compression No. 209 (manufactured by Fuji Chemical Co., Ltd.) 46.6 mg Magnesium aluminometasilicate 20% Corn starch 30% Lactose 50% ( 3) Crystalline cellulose 24.0 mg (4) Carboxymethyl cellulose calcium 4.0 mg (5) Magnesium stearate 0.4 mg (1), (3) and (4) are all passed through a 100 mesh sieve in advance. Each of (1), (3) and (4) and (2) is dried to reduce the water content to a constant value, and then mixed in the above weight ratio using a mixer. (5) was added to the mixed powder which was made uniform in quality, and mixed for a short time (30 seconds), and the mixed powder was compressed into a tablet (punch: 6.3 m).
mφ, 6.0 mmR) to give tablets of 85 mg each. If necessary, the tablets may be coated with a commonly used gastric film-coating agent (for example, polyvinyl acetal diethylaminoacetate) or an edible coloring agent.

Formulation Example 2 Capsule (1) Compound of Reference Example 84 50 g (2) Lactose 935 g (3) Magnesium stearate 15 g The above components were weighed and mixed uniformly, and the mixed powder was made into a hard gelatin capsule. 200 mg each was filled.

Formulation Example 3 Injection (1) Hydrochloride of the compound of Reference Example 84 50 mg (2) Glucose 100 mg (3) Saline 10 ml The above mixture was filtered with a membrane filter and then sterilized again. Aseptically dispense the filtrate into vials,
It was filled with nitrogen gas to give an intravenous injection.

Pharmacological test In order to show the usefulness of the inhibitor of the present invention, the pharmacological test results of representative compounds are shown below. Test Example 1 AGE production inhibitory activity SDS- was used to suppress protein polymer formation according to the method described in the literature (Agric. Biol. Chem., 52 , 1451-1458, 1988).
The AGE production inhibitory activity was measured by the method of PAGE analysis. More specifically, 25 mg / ml of lysozyme, 250 mg / ml of fructose, and a test compound are added to a phosphate buffer containing a mildew-proofing agent and a protease inhibitor in 37
Incubated at 1 ° C for 1 month. After that, SDS-PA
GE was performed and the band density of the lysozyme dimer was analyzed with an image analyzer to calculate the ratio of the dimer in the total lysozyme. The inhibition ratio was calculated by comparing the dimer ratio when the test compound was added with the dimer ratio when the test compound was not added. The inhibitory activity was expressed as a relative ratio (%) of the inhibition rate when the test compound was added to the inhibition rate when the aminoguanidine, which was a positive control compound, was added. The results are shown in Table 9. As shown in Table 9, all the test compounds of the present invention had high AGE.
It showed a production inhibitory activity.

[0110]

[Table 9]

Test Example 2 Antioxidant activity The antioxidant activity of the test compound is an inhibitory effect on the increase in the negative charge of apo B that accompanies the oxidation of LDL (Test A),
The inhibitory effect on the degradation and macromolecularization of apo B (Test B) and the inhibitory effect on foaming of rat macrophages (Test C) were examined. Oxidation of LDL was carried out by adding ¹²⁵ I-labeled human LDL (final concentration 100 μg / ml), final concentration 20 μM CuSO ₄ , in phosphate buffer (PBS),
A test compound having a final concentration of 0 to 10 mM was added, and the mixture was incubated at 37 ° C. overnight. After that, final concentration 1
The reaction was terminated by adding 0 mM EDTA, and each test shown below was performed.

Test A Inhibition of the increase in negative charge associated with LDL oxidation is described in the literature (Proc.
Natl. Acad. Sci. USA 79 , 1712-1716, 1982), and confirmed by agarose gel electrophoresis. For electrophoresis, 0.5% gel containing 0.02% BSA and 0.05M veronal buffer (manufactured by Tsuneko Co., Ltd.) were used and electrophoresis was performed at a constant voltage.
After completion of the electrophoresis, the gel was fixed, dehydrated and dried, and then autoradiography was performed. Since the oxidized LDL has increased mobility, the concentration of the test compound when it migrates to the same position as the non-oxidized LDL was defined as the oxidation inhibitory concentration. The result is shown in FIG.

Test B Decomposition and polymerization of apo B accompanying LDL oxidation are described in the literature (J.
Lipid Res., 28 , 1466-1477, 1987) was referred to, and it was confirmed that the apo B band disappeared in SDS-PAGE. SDS-PAGE was performed under reducing conditions, and 2-15% gradient gel manufactured by Daiichi Pure Chemicals Co., Ltd. was used. After the electrophoresis was completed, the gel was fixed, dried and then autoradiographed. 200 kD molecular weight for non-oxidized LDL
Although a clear apo B band was observed in a, the band disappeared in oxidized LDL, and high molecular weight or low molecular weight was observed. The test compound concentration at which the apo B band can be confirmed was defined as the oxidation inhibitory concentration. The result is shown in FIG. As shown in FIG. 1, all test compounds showed excellent antioxidant activity at low concentrations (<1 mM).

Test C Macrophage foaming associated with LDL oxidation was reported in the literature (Pro.
c. Natl. Acad. Sci. USA 78 , 6499-6503, 1981), and was determined by degrading ¹²⁵ I-labeled LDL with macrophages. As macrophages, adherent cells in rat peritoneal cavity were used. In a tissue culture plate,
1 ml of Dulbecco's modified MEM medium containing macrophages
(Including 10 mM HEPES and 0.1% BSA) and 10
After incubating at 37 ° C. with μl of LDL (corresponding to 1 μg), 200 μl of the culture supernatant was collected after a certain period of time. 100 μl of 20% trichloroacetic acid was added thereto, and the mixture was ice-cooled for 1 hour and then centrifuged, and the radioactivity in the supernatant was measured. The cells were lysed with SDS and the amount of protein was measured. The results were expressed as the radioactivity per protein amount, but in the oxidized LDL, high radioactivity derived from LDL decomposed into the supernatant was observed. The result is shown in FIG. Figure 2
As shown in, the test compound of the present invention shows an excellent antioxidant effect as compared with levoclomacarim or pinacidil known as potassium channel openers, and is equivalent to α-tocopherol generally used as an antioxidant. It became clear that it had an effect.

[Brief description of drawings]

FIG. 1 is a graph showing the antioxidant action of the inhibitor of the present invention (suppression of increase in negative charge of apo B and inhibition of decomposition / polymerization of apo B). In the figure, the upper part is a test for suppressing an increase in the negative charge of apo B, and the lower part is a test for suppressing the decomposition / polymerization of apo B.

FIG. 2 is a graph showing the antioxidant activity (suppression of foaming of macrophages) of the inhibitor of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/44 ACV ADP C07D 401/04 233 401/12 207 405/12 213 // C07D 213/75 213/76 213/77 213/81 213/84 213/89 (C07D 401/04 213: 75 233: 56) (C07D 401/12 207: 16 213: 75) (C07D 405/12 213: 75 317: 36) (72) Inventor Masahiro Eda 2-25-1 Otani Otani, Hirakata City, Osaka Prefecture Midori Cross Central Research Institute Co., Ltd. (72) Kenfumi Nakamura 2-25-1 Otani Invitation, Hirakata City, Osaka Prefecture Midori Cross Central Research Institute (72) Inventor Koichi Yamauchi Invited 2-25-1 Otani, Hirakata City, Osaka Prefecture Midori Cross Central Research Institute Co., Ltd.

Claims (3)

[Claims] 1. A compound of the general formula (In the formula, n represents 0 or 1. Z represents S, NCN or CH.
Indicates NO ₂ . R ₁ is CN, NR ₃ R ₄ , CONR ₃ R ₄ , N
HNR ₃ R ₄ , NHCONHR ₃ , NHSO ₂ R ₃ or SR ₃ is shown. R ₂ represents H, optionally substituted alkyl or cycloalkyl. R ₃ and R ₄ are the same or different and each represents H, optionally substituted alkyl, cycloalkyl, aryl, optionally substituted acyl or alkoxycarbonyl,
In addition, R ₃ and R ₄ may form a hetero ring together with the nitrogen atom to which it is bonded, with or without interposing another hetero atom. ) A glycosylated protein denaturing substance formation inhibitor containing an aminopyridine compound represented by the formula (4) or an acid addition salt thereof as an active ingredient. 2. R ₁ is NR ₃ R ₄ (wherein R ₃ and R
₄ is the same as above), The glycated protein denaturing substance formation inhibitor according to claim 1. 3. The glycated protein denaturing substance formation inhibitor according to claim 1, wherein R ₁ is NHNR ₃ R ₄ (wherein R ₃ and R ₄ are the same as above).