JPH04120079A - Condensed imidazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (ring A may have substituent group and is aromatic 6-membered ring having 1-2 N atoms as a ring constituent atom; R<1> is H, alkyl, aralkyl or aryl; R<2> is H, halogen or NO2; R<3> is group capable of forming anions or group convertible thereinto; X is direct bond or spacer of <=2 atomic chains) or salts thereof. EXAMPLE:2-Butyl-1-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl] methyl} imidazo[4,5-b] pyridine. USE:Having powerful angiotensin II antagonistic and hypotensive action and useful as a remedy for circulatory diseases such as hypertension, cardiopathy and cerebral apoplexy. PREPARATION:For example, a compound expressed by formula II is reacted with an alkylating agent expressed by formula III (W is halogen) in the presence of a base to afford the objective compound expressed by formula I.

Description

[Detailed description of the invention]

[00011

[Industrial Application Field] The present invention relates to novel condensed imidazole derivatives having excellent pharmacological effects and synthetic intermediates thereof. [0002] More particularly, the present invention provides potent angiotensin II
It has an antagonistic effect and a blood pressure lowering effect, and is useful as a therapeutic agent for circulatory system diseases such as hypertension, heart disease, and stroke. It often represents an aromatic six-membered ring containing 1 to 2 nitrogen atoms as ring atoms, R1 represents hydrogen or an optionally substituted alkyl, aralkyl or aryl group, and R2 represents hydrogen, halogen or a nitro group. , R3 represents a group capable of forming an anion or a group capable of converting thereto, X represents a phenylene group and a phenyl group bonded directly or through a spacer having an atomic chain of 2 or less, and n represents 1 or an integer of 2] and salts thereof. [0003]

[Conventional technology]

The renin-angiotensin system, together with the aldosterone system, contributes to systemic blood pressure 7 body fluid volume. Involved in homeostasis regulating functions such as electrolyte balance. Regarding the relationship between the renin-angiotensin system and hypertension, angiotensin I, which has a strong vasoconstrictive effect,
Inhibitors of angiotensin II converting enzyme that produce I (
This has been clarified with the development of anti-ACE drugs. Since angiotensin II constricts blood vessels and increases blood pressure via angiotensin TI receptors on cell membranes, its antagonist, like anti-ACE drugs, can be used to treat hypertension caused by the development of the renin-angiotensin system. Until now, a large number of angiotensin analogues such as saralasin, [5ar1. l1e8] AI■ and the like have been reported to have a strong angiotensin II antagonistic effect. However, it has been reported that peptide antagonists have a short action time when administered parenterally and are ineffective when administered orally [M, A, Ondetti and D,
W. Cushman, Annual Report
ts in Medicinal Chemistry
, 13.82-91 (1978)]. [0004]

[Problem to be solved by the invention]

Non-peptide angiotensin II antagonists are disclosed in Japanese Patent Application Laid-open No. 5
6-71073. Japanese Patent Publication No. 56-71074. Japanese Unexamined Patent Publication No. 1983
-92270. JP-A-58-157768, JP-A-6
3-23868 and Japanese Unexamined Patent Publication No. 1-117876, and A. T. Chiu et al., Eu.
R. J. Pharm., 157.13 (1988
), P., C., Wong et al., J.
PharmcolExp, Ther, 247.1
(1988) and P.C., Wong et al.
, Hypertension, 13.489 (19
89) and others disclose imidazole derivatives having angiotensin II antagonistic activity. However, it is completely unknown that fused imidazole derivatives as shown in the above formula (I) have angiotensin II antagonistic activity. [0005]

[Means to solve the problem]

The present inventors have angiotensin II antagonistic effect,
As a result of our intensive search for compounds useful as therapeutic agents for cardiovascular diseases such as hypertension, heart disease, and stroke, we succeeded in producing a fused imidazole derivative with excellent angiotensin II antagonistic activity, and proceeded with further research to complete the present invention. did. [0006] That is, the present invention provides the formula

[3] [In the formula, term 8 may have a substituent and represents an aromatic six-membered ring containing 1 to 2 nitrogen atoms as ring constituent atoms, and R1 is hydrogen or substituted. R2 represents a hydrogen, halogen or nitro group, a phenyl group and a phenyl group are bonded directly or through a spacer having an atomic chain of 2 or less, and n is an integer of 1 or 2. ] and its salts. [0007] The alkyl group may be linear or 9-branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, L-butyl, pentyl, i
-pentyl, hexyl, heptyl, octyl, etc., and the alkyl group may be substituted with a hydroxyl group, an optionally substituted amino group, a halogen, a lower (C1-4) alkoxy group, etc. (C1-4) alkyl, and the aralkyl group can be methoxy, ethoxy, etc. at any position on the benzene ring)
, lower (C1-4) alkyl (eg, methyl, ethyl, etc.). Examples of the aryl group include phenyl, and the aryl group may have a benzene ring alkoxy (eg, methoxy, ethoxy, etc.), lower (C,) alkyl (eg, methyl, ethyl, etc.). [0008] The aromatic six-membered ring containing one to two nitrogen atoms as ring constituent atoms shown in item 8 includes, for example, a six-membered aromatic heterocyclic ring containing one nitrogen atom such as pyridine, pyrazine, Examples include six-membered aromatic heterocyclic rings containing two nitrogen atoms such as pyrimidine and pyridazine, among which pyridine,
Pyrazine is preferred. Item 8 above may have a substituent, and examples of the substituent include halogen (eg F, C1, Br, etc.), nitro,
cyano, optionally substituted amino groups (e.g., amylamino, etc.), alicyclic amines (e.g., morpholino, piperidino, piperazino, N-phenylpiperazino, etc.)
9 Formula -Y-R [In the formula, Y represents a bond, -〇-1-S- or -(C○)-, and R represents an optionally substituted lower alkyl group (e.g., hydroxyl group, substituted a group represented by the formula -COD [in the formula, D is an optionally substituted alkoxy group (e.g., an alkyl moiety is a hydroxyl group, an optionally substituted amino group, a halogen,
lower (C1-4) alkoxy, which may be substituted with a lower (C1-4) alkoxy group, etc.), an optionally substituted amino group (e.g., amino, N-lower (C1-4)
Alkylamino (e.g., methylamino, etc.), N,N-di-lower (C1-4) alkylamino (e.g., dimethylamino, etc.), N-arylamino (e.g., phenylamino, etc.), alicyclic amino (e.g., morpholino, piperidino, piperazino, N-phenylpiperazino, etc.), a group represented by a halogen (e.g., chloro), or a hydroxyl group. The nitrogen atom in item 8 may be oxidized to form N-oxide. In addition, when item 8 above has a group represented by the formula -COD as a substituent, the compound in which D represents a halogen is a compound in which D represents an optionally substituted alkoxy group or an optionally substituted amino group. It is useful as a synthetic raw material. [0009] R2 represents hydrogen, halogen (eg, chloro, bromo, etc.), or a nitro group, and these may be substituted at either the ortho or meta position. [0010] Examples of the group capable of forming an anion as R3 or the group convertible thereto include carboxyl, lower (C,) alkoxycarbonyl, cyano, tetrazolyl, trifluoromethanesulfonic acid amide (-NH302CF3)
, phosphoric acid, sulfonic acid, etc., and any group that can form an anion or can be converted into an anion under biological or physiological conditions or chemically can be used.
R3 may be substituted at any of the ortho, meta, and para positions. Compounds in which R3 is a group that can chemically form an anion (for example, by oxidation, reduction, or hydrolysis) or a group that can be converted into an anion (for example, cyano, etc.) are useful as synthetic intermediates.

001X indicates that an adjacent phenylene group and a phenyl group are bonded directly or via a spacer with an atomic chain of 2 or less, and as a spacer with an atomic chain of 2 or less, the number of atoms constituting the linear part is Any divalent chain having 1 or 2 valences may be used, and it may have a side chain. Specifically, lower (C,) alkylene, -(CO)-t -0, S
(NH) , (CO) (NH)
, 0 (CH2)S-(CH2)-, -(CH)
= (CH)-, etc. [0012] Among the compounds represented by the above formula (I), compounds represented by the formula
[Wherein, term 8 is 1 to 3 (preferably 1) halogen (preferably C1), lower (C1-4) alkoxy, nitro, amino, N-lower (C1-4) alkylamino,
N,N-dilower(C1-4)alkylamino or formula-
Represents a pyridine or pyrazine ring which may have a substituent such as COD (in the formula, D represents a hydroxyl group or lower (C1-2) alkoxy), R represents a C2-5 alkyl, and R represents hydrogen. and R represents carboxyl or tetrazolyl] is preferred. [0013] (Production method) The compound of the above general formula (I) can be produced, for example, by the method shown below. [0014] Reaction (a)

[C5] ] [0015] reaction (b)

[C6] [In the formula, each symbol has the same meaning as above. ] [0016] reaction (c)

[C7] [wherein A, R1, R2, X and n has the same meaning as above. R4 is optionally substituted represents (C,) alkyl. 1 [0017] reaction (d)

[In the formula, A, R, R, X and n have the same meanings as above. R5
indicates a protecting group that can be removed by acid (eg, triphenylmethyl, methoxymethyl, etc.). ] [0018] The reaction (a) is carried out using an alkylating agent (III) in the presence of a base.
Alkylation is carried out by the action of About 1 to 3 mol of base and 1 to 3 mol of alkylating agent (III) are used per 1 mol of compound (II),
This is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, or ethylmethylketone. Such bases include sodium hydride, potassium L-butoxy, potassium carbonate, and sodium carbonate. Such an alkylating agent (III) can be a substituted halide (
For example, it is used as a chloride, bromide, iodide, etc.), but it may also be used as a substituted sulfonic acid ester (for example, methyl p-toluenesulfonate, etc.). The reaction conditions vary depending on the combination of the base and alkylating agent (III) used, but are generally the same. It is preferable to keep the temperature between ice-cooling and room temperature for about 1 to 10 hours. [0019] In reaction (b), the cyano group substituted on the benzene ring of compound (Ia) is reacted with various azides to convert it into the tetrazole compound (Ib). About 1 to 3 moles of the azide compound are used per mole of compound (Ia), and the reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, toluene, or benzene. Examples of such azide compounds include trialkyltin or triphenyltin azide and hydrazide acid. When using an organic tin azide compound, the reaction is carried out in toluene or benzene for about 10 to 30 hours while heating under reflux. In addition, when reacting hydrazidic acid, sodium azide and ammonium chloride are used in about twice the mole of compound (Ia), and the reaction is carried out in dimethylformamide at about 100 to 130°C for about 1 to 3 days. During this time, it is preferable to accelerate the reaction by adding appropriate amounts of sodium azide and ammonium chloride. [0020] Reaction (C) involves hydrolyzing the ester (Ic) in the presence of an alkali to obtain the carboxylic acid (Id). About 1 to 3 mol of alkali is used per 1 mol of compound (Ic), and alcohols containing water (e.g., methanol,
ethanol, methyl cellosolve, etc.). As such alkali, sodium hydroxide, potassium hydroxide, etc. are used. Further, the reaction is preferably carried out at room temperature to about 100°C for about 1 to 10 hours. [0021] Reaction (d) involves hydrolyzing the protected tetrazole derivative (I e) in the presence of an acid to obtain the deprotected derivative (I b). The reaction is usually carried out in a solvent such as an alcohol containing water (eg, methanol, ethanol, methyl cellosolve, etc.) using an equivalent to excess amount of acid per mole of compound (Ie). As such acids, acetic acid, hydrochloric acid, etc. are used. Further, the reaction is carried out at about 0 to 50°C, 1 to 1
It is preferable to carry out the process for about 0 hours. [0022] Compound (I) thus produced from reaction (a) to reaction (d) can be separated and purified from the reaction solution by conventional separation and purification methods, such as distillation of the reaction solvent, extraction with water or an organic solvent, concentration, and neutralization. It can be easily isolated as a crystal or oil by recrystallization, distillation, column chromatography, etc. [0023] In addition, these compounds (I) can be prepared by conventional methods into salts with physiologically acceptable acids or bases, such as salts with inorganic acids such as hydrochloride, sulfate, and nitrate; It can be converted into salts with organic acids such as succinates and maleates, salts with alkali metals such as sodium salts and potassium salts, and salts with alkaline earth metals such as calcium salts. [0024] Among these compounds, starting compound (II) is, for example, 1
) G, W, H, Cheeseman and R
, F. Cookson, ”The Che
Mistry of Heterocyclic
Chemistry, Condensed Py
razines” Vol, 35. ed, b
y A, Weissberger and E, C,
Taylor, John Wiley & 5on
s, New York (1979), pp, 375
-397.2) R, A, Abramovitch
and J, G, 5aha, ”Advance
in Heterocyclic Chemistry
yPyrazine” Vol. 14. ed.
by A, R, Katritzky and A,
J. Boulton, Acad, Press;
Inc., New York and London
n (1966) pp, 99.3) “The Ch.
Emistry of Heterocyclic C
compounds, Pyrazine and
Its Derivatives” Par
t 1-4. Ed, by R,A,Ab
ranovitch et al., Inte
rscience Publishers Inc.
, New York (1962), 4) Y, C,
Tong, J., Heterocycle, Chem.
,, 12.1127 (1975), 5) M-l5
rael and A, R, Dr, , J, Or
g, Chem, 24.1455 (1959),
6) Ratio Vorbrueggen and K, Kro
likiewicz, 5ynthesis, 198
3.316.7) P, Kumar and C,
V, Ratnam, Indian J, Chem.
, 16B, 531 (1978) and 8) W, V
, Bedenburg, G., Steinmetz a.
nd K, Th1ele, Chem, Ztg,,
103.387 (1979) or a similar method. [0025] Among the starting compounds (III), for the compound (IIIa) where n is 1, a commercially available compound can be used, and a method known in the literature, for example 1) J, R,
E., Hoover, A., W., Chow, R.
J., Stedman, N., M., Hall, H.
, S., Greenberg, M., M., Dola.
n and R, J, Feriauto, J, M
ed. Chem, 7.245 (1964). 2) R, J, 5tedrnan, J,
R, E, Hoover, A, W, Ch.
ow, M, M, Dolan, N.
~'1. Hall and R, J, Feri
auto, J, Med, Chem,, 7.25
1 (1964). 3) H, Gilman and R, D, Gors
ich, J, Am, Chem, Soc,, 7
8.2217 (1956). 4) M, 0rchin and E, 0scar
It can also be easily obtained by halogenomethylation according to the method described in Woolfolk, 67, 122 (1945). [0026] Reaction (e) [In the formula, each symbol has the same meaning as above. ] [0027] Furthermore, among the starting compounds (III), a compound (IIIb) in which n is 2 can be obtained by reacting ). [0028] Compound (IIIa reaction)

embedded image [In the formula, each symbol has the same meaning as above. ] [0029] Compound (I) and its salts produced in this way have low toxicity, strongly suppress the vasoconstrictive and blood pressure increasing effects caused by angiotensin II, and are effective for use in animals, especially mammals (e.g., humans, dogs, rabbits, rats, etc.). ), and is useful not only as a therapeutic agent for hypertension, but also as a therapeutic agent for circulatory system diseases such as heart disease and stroke. When used as such pharmaceuticals, compound (I) and its salts may be used as such or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents to form powders, granules, tablets, capsules, and injections. It can be administered orally or parenterally in the following dosage forms. The dosage varies depending on the target disease, symptoms, subject, administration method, etc., but when administered as a treatment for adult essential hypertension, the daily dose for oral administration is 10 to 100 mg. For intravenous injection, it is preferable to administer a daily dose of 5 to 50 mg divided into 2 to 3 doses. [00301] [00301] [00301] The present invention will be explained in more detail below using formulation examples, working examples, experiments, experimental examples, and reference examples, but it goes without saying that these do not limit the present invention. Examples of abbreviations used in this specification are listed below. Me: Methyl, Et: Ethyl, Pr: Proyl, Bu Nibutyl, Tet: Tetrazolyl, D
MF Nidimethylformamide Formulation Example Compound (I) of the present invention can be used to treat, for example, hypertension, heart disease,
When used as a therapeutic agent for circulatory system diseases such as stroke,
For example, it can be used with the following formulation [0
031] 1. Capsule (1) 2-butyl-1-[[2'-tetrazole-5
-yl)-biphenyl-4-yl]methyl]imidazo[
4,5-b]Pyridine 10mg (2) Lactose
90mg (3) Microcrystalline cellulose
70mg (4) Magnesium stearate 10mg 1 capsule 180mg After mixing 172 of (1), (2), (3) and (4), granulate. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule. [0032] 2. Tablets (1) 2-butyl-1-[[2'-(LH-tetrazol-5-yl)-biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine 10 mg ( 2) Lactose 3
5mg (3) cornstarch
150mg (4) Microcrystalline cellulose
30mg (5)
Magnesium stearate
5mg 1 tablet 230mg After mixing 273 (1), (2), (3), (4) and 172 (5), granulate. The remaining (4) and (5) are added to the granules and compressed into tablets. [0033] 3. Injection (1) 2-butyl-1-[[2'-(LH-tetrazol-5-yl)-biphenyl-4-yl]methyl]imidazo[4,5-b]pyrazine 10 mg ( 2) Inojit
100mg (3) benzyl alcohol
20mg1 ampoule 130
Dissolve mg (1), (2), and (3) in distilled water for injection to a total volume of 2 ml, and seal in an ampoule. The entire process is performed under aseptic conditions. [0034] Reference Example 1 2-Butylimidazo[4,5-b]pyridine 2,3-diaminopyridine (2,2 g), ethylvaleroimidate hydrochloride (8°3 g) and triethylamine (6,5 g)
) was dissolved in ethanol (20ml) and heated under reflux for 12 hours. After concentrating the reaction solution, the residue was extracted with ethyl acetate-water, and the organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography. The resulting crude crystals were recrystallized from isopropyl ether to obtain colorless needles (2.2 g, 63%). Melting point 104-105℃ Elemental analysis value C (%) H as C1oH13N3
(%) N (%) Calculated value: 68.54; 7.48; 23.98 Actual value: 68.59; 7.53; 23.78 [003
5] Reference Example 2 2-Butylimidazo[4,5-b]pyrazine 2,3-diaminopyrazine (2,2g), ethylvaleroimidate hydrochloride (6°6g) and triethylamine (4,0g)
) was dissolved in ethanol (30ml) and heated under reflux for 10 hours. The reaction solution was concentrated, and saturated brine and chloroform were added to separate the layers. After washing the organic layer with water and drying, the solvent was distilled off. The obtained crude crystals were recrystallized from ethyl acetate-methanol to obtain colorless plate crystals (2.1 g, 60%). Melting point 232-233°C Elemental analysis value C9H1°C as N4 (%) H (%) N (%) Calculated value: 61.34; 6.86; 31.79 Actual value: 61.38; 6.93; 31 .64[003
6] Reference Example 3 2-Methylimidazo[4,5-b]pyridine Synthesized in the same manner as in Reference Example 1. IHNMR (200MHz, CDC13) δ: 2
．． 73 (3H, s), 7.24 (LH, dd), 8
．． 01 (LH, dd), 8.33 (LH, dd) [0037] Reference Example 4 2-ethylimidazo[4,5-b]pyridine Synthesized in the same manner as in Reference Example 1. IH-NMR (200 M'Hz, CDCl) δ:
1.57 (3H, t), 3.11 (2H, q), 7
．． 25 (IH, dd). 8,05 (LH,dd), 8.34 (IH,d
) [0038] Reference Example 5 2-Propylimidazo[4,5-b]pyridine Reference Example 1
It was synthesized in the same manner. IHNMR (200MHz, CDCl3)δ
: 1.10(3H,t), 1.93-2.12(2
H, m), 3.05 (2H, q), 7.25 (I
H, dd), 8.05 (LH, dd), 8.
33 (LH, dd) [0039] Reference Example 6 2-propyl-1-[[2'-(N-)lyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b] Pyridine (A) and 2-propyl-3-[[2'-(N-)lytyltetrazole-5
-yl)biphenyl-4-yl]methyl]imidazo[4
,5-b]pyridine (B)2-propylimidazo[4,
5-b] Pyridine (0.81 g) in DMF (5 ml)
Add sodium hydride (60%) to the solution while stirring under ice cooling.
0.22 g) was added and stirred for 15 minutes. Add 4-[2-(N-trityltetrazol-5-yl)phenyl]benzylbromide (3.5 g) to the reaction solution,
Stir at room temperature for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Wash the extract with water and dry (MgSO3)
After that, the solvent was distilled off. The resulting syrup was purified by silica gel column chromatography to obtain brown syrup (A, 0.58 g, 18%) and light brown syrup (
B, 1.2 g, 38%) was obtained. Compound A: , 21 (2H,s), 6.11 (2H,d)
, 6.89-7.00 (8H, m) , 7.0
9 (2H, d), 7.17-7, 36 (IOH
, m), 7.43-7゜49 (2H, m),
7.91-7.95 (LH, m), 8.46 (
LH, dd) I R (Neat) cm': 16
00.1500.1490.1465.1440.14
00.1350.1320.1275°1205, 1
180. 1020. 900.870 Compound B: , 40 (2H,s) , 6.90-6.95 (
8H, m), 7.07 (2H, d), 7.1
8-7.34 (IH, m), 7.41-7.46
(2H, m), 7.88-7.96 (LH, m
), 7.99 (LH, dd), 8.33 (
LH, dd) I R (Neat) cm': 16
00.1500.1450.1425.1400.13
55.1280.1225.1190°1030, 90
5.880 [0040] Reference Example 7 2-Methyl-1-[[2'-(N-)lytyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine, 88 -6.94 (7
H, m), 7.00 (LH, dd), 7.10
(2H, d), 7.17-7, 36 (IOH, m)
, 7.44-7.49 (2H, m), 7,93-
7.98 (LH, m), 8.48 (LH, dd
)IR(Neat)cm': 1605.15
10.1490.1440.1415.1395.13
50.1280.1215°1030.1000.87
5.780.760.740[0041] Reference Example 8 2-Methyl-3-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b] Pyridine was synthesized in the same manner as in Reference Example 6. Light brown syrup (34%) IHNM R (200
MHz, CD C13) δ: 2.41 (3H, s
), 5.37 (2H, s), 6.88-6.95 (8H
, m), 7.08 (2H, d), 7.18-
7.35 (LH, m), 7.43-7.49 (
2H, m), 7.91-7.95 (LH, m)
, 7.98 (LH, dd) , 8.35 (IH
, dd) I R (Neat) cm-1: 1600.1515
．． 1460.1445.1425.1390.1280
．． 1215.750[0042] Reference Example 9 2-ethyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Reference Example 6 It was synthesized in the same manner. Brown syrup (5%) IHNM R (200MH
z, CD Cl 3) δ: 1.41 (3H, t)
, 2.81 (2H, q), 5.21 (2H, s), 6,
'l'l (2H, d), 6.88-6.93
(7H, m), 7.00 (IH, dd), 7
．． 09 (2H, d), 7.18-7.36 (I
OH, m), 7.45-7, 50 (2H, m)
, 7.92-7.96 (LH,m), 8.49
(LH, dd) I R (Nujol) cm-1:
1510.1490.1420.1400.1310.
1280.1030.1000.880°780, 76
0. 745.695 [0043] Reference Example 10 2-ethyl-3-[[2'-(N-)lyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Reference Example It was synthesized in the same manner as in 6. Light brown syrup (32%) IHNMR (200M
Hz, CD Cl 3) δ: 1.32 (3H, t
), 2.71 (2H, q), 5.39 (2H, s), 6
, 89-6.95 (8H, m), 7.07 (2
H, d), 7.19-7.35 (LH, m),
7.43-7.49 (2H, m), 7.90-
7.94 (LH, m), 8.04 (LH, dd), 8
．． 35 (IH, dd) I R (Neat) cm
'21600. 1510. 1495. 1440
．． 1420°900.880.795.750.69
5 [0044] Reference Example 11 2-Butylimidazo[4,5-c]pyridine Synthesized in the same manner as in Reference Example 1. Light brown oil 1400°1280°1230°1025°97 (2H, m), 3.02 (2H, t),
7.50 (LH, d), 8.38 (LH, d
), 8.94 (IH,s)IR(Ne,at)
cm': 1620.1590.1535.146
0.1420.1280.1025.810.755[
Reference Example 12 2-Butyl-3-[[2′-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-c]pyridine In the same manner as Reference Example 6 Synthesized. Light brown oil (6.5%) 90 (2H, m),
2.78 (2H, t), 5.27 (2H, s),
6.82 (2H, d), 6.90-9.94 (8H,
m), 7.11 (2H, d), 7.19-7.36
(8H, m), 7.45-7.51 (2H, m
), 7.68 (LH, dd), 7.93-7
．． 98 (LH, m), 8.44 (LH, d)
, 8.56(IH,d) [0046] Reference Example 13 2-Butyl-1-[[2'-(N-)lyltetrazol-5-yl)nyl-4-yl]methyl]imidazo[
4,5-c] pyridine bifue 91 (2H, m), 2.78 (2H, t),
5.21 (2H, s), 6.78 (2H, d)
, 6.90-7.01 (7H, m) , 7.11
(2H, d), 7.19-7.37 (IOH,
m), 7.44-7.50 (2H, m), 7.
92-7.97 (LH, m), 8.27 (LH
, d), 9.09 (IH,s) [0047] Reference Example 14 2-Butyl-6-methylimidazo[4,5-b]pyridine Synthesized in the same manner as in Reference Example 1. Colorless prism crystal (4
1%) Melting point 156-157℃ IHNMR (200MHz, CDCl3)δ
: 1.00(3H,t), 1.40-1.59(2
H, m), 1.87-2゜02 (2H, m),
2.49 (3H, s), 3.03 (2H, t)
, 7.82 (LH,s) , 8.14 (LH
, 5)-1°I R (KBr) cm, 3300-2200.
1620.1545.1480.1440.1410.
1395.1375°1310, 1275.1255.
1150.990.975.880.860.765.
735[0048] Reference Example 15 2-Butyl-6-methyl-3-[[2'-(N-1 lythyltetrazol-5-yl)biphenyl-4-yl]
Methyl]imidazo[5,4-b]pyridine It was synthesized in the same manner as in Reference Example 6. Colorless syrup (26%)'HNMR
(200MHz, CD C13) δ: 0.88
(3H, 7), 1.24-1.39 (2H, m), 1.
67-1°82 (2H, m), 2.48 (3H
,s), 2.69 (2H,t), 5.38
(2H, s), 6.88-6.96 (8H, m)
, 7.06 (2H, d) , 7.20-7.3
6 (IOH, m), 7.43-7.49 (2H
, m), 7.81 (IH, d), 7.89-
7.93 (LH, m), 8.18 (IH, d)
IR (Neat) cm': 1510.144
0.1420.1390.1365.1355.123
5.1040.1020°1000, 880.745.
695 [0049] Reference Example 16 2-Butyl-6-methyl-1-[[2'-(N-1 lythyltetrazol-5-yl)biphenyl-4-yl]
Methyl]imidazo[4,5-b]pyridine It was synthesized in the same manner as in Reference Example 6. Colorless prismatic crystal (12%) Melting point 1
79-180℃ (decomposition) 91 (2H, m), 2.28 (3H, s), 2.78 (
2H, 7), 5.18 (2H, s), 6.76 (2H,
d), 6.89-6.96 (6H, m), 7.08-7
．． 13 (3H, m), 7.18-7.38 (I
OH, m), 7.45-7.51 (2H, m)
, 7.91-7.95 (IH, m) , 8.33
(LH, d) I R (KBr) cm': 15
10.1495.1460.1440.1400.12
75.1030.1000.880°870, 750.
740.695 [00503 Reference Example 17 2-Amino-6-dimethylamino-3-nitropyridine 2-amino-6-chloro-3-nitropyridine (1,5
g) and a 50% dimethylamine aqueous solution (3.9 g) were dissolved in ethanol (30 ml) and refluxed for 13 hours. The yellow crystals obtained by cooling the reaction solution were filtered and washed with ethanol to obtain yellow plate crystals (1.08 g, 69%).
. Melting point 162-163℃ IHNMR (200MHz, CDCl3) δ
: 3.16 (6H, s), 6.02 (LH, d), 8
．． 17(IH,d) [0051] Reference Example 18 5-dimethylamino-2-propylimidazo[4,5-
b] Pyridine 2-amino-6-dimethylamino-3-nitropyridine (1,07 g) and concentrated ammonium (4
, 2 ml) was dissolved in tetrahydrofuran (20 ml) and water (17 ml), and Na2S204 (6.73 g) was dissolved in tetrahydrofuran (20 ml) and water (17 ml).
A solution of was added in water (25 ml). The reaction solution was stirred at room temperature for 4 hours, further stirred at 50°C for 14 hours, extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off. The obtained product was mixed with polyphosphoric acid (10 g) and butyric acid (1 ml), and the mixture was heated at 130°C for 4 hours, then dissolved in water, the reaction solution was made basic with NaHCO2, and the separated oil was collected. After dissolving in ethyl acetate, washing with water and drying, the solvent was distilled off. The resulting product was purified by silica gel column chromatography to obtain a brown powder (0.4 g, 33%).
. Melting point 159-160°C 1HNMR (200MHz, CDC13) δ:
1.01 (3H, t), 1.74-1.92 (2H,
m), 2.82 (2H, t), 3.11 (6H,
s), 6.46 (LH, d), 7.74 (
LH, d) [0052] Reference Example 19 2-Amino-3-nitro-6-bropylthiopyridine 2
-Amino-6-chloro-3-nitropyridine (1,5g
), propyl mercaptan (1,57 ml) and triethylamine (1,75 g) were dissolved in 1,2-dichloroethane (30 ml) and heated under reflux for 19 hours. The solid obtained by distilling off the solvent of the reaction solution was recrystallized with aqueous ethanol to obtain yellow prism crystals (1.14 g, 62%
). Melting point 72-73℃ IHNMR (200MHz, CDCl3)δ
: 1.05(3H,t), 1.66-1.83(2
H, m), 3.13 (2H97), 6.55 (IH, d
), 8.16 (IH, d) [0053] Reference Example 20 2-propyl-5-propylthioimidazo[4,5-b
] Pyridine Synthesized in the same manner as in Reference Example 18. Brown powder (62%) Melting point 82-83°C IHNMR (200MHz, CD Cl3) δ
: 1.04 (3H, t), 1.05 (3H, t),
1.68-1.85 (2H, m), 1.81-2.
01 (2H, m), 3.00 (2H, t),
3.14 (2H, t), 7.13 (LH, d
), 7.81 (IH, d) [0054] Reference Example 21 2-chloro-5-propylimidazo[4,5-b]pyridine Synthesized in the same manner as in Reference Example 18. Light brown powder (2
2%) Melting point 164-166℃ IHNMR (200MHz, CDCl3)δ
: 1.06 (3H, t), 1.87-2.05 (2H
, m), 3.06 (2H, t), 7.26 (IH
, d) , 7.98 (IH, d) [0055] Reference Example 22 2-Propyl-5-propylthio-3-[[2'-(N
-trityltetrazol-5-yl)biphenyl-4-
yl]methyl]imidazo[4,5-b]pyridine (A)
and 2-propyl-5-propylthio-1-[[2'
-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine (B) 2-propyl-5-propylthioimidazo[4°, 5-
b] To a solution of pyridine (0.77 g) in DMF (5 ml) was hydrogenated f)') rum (60% oily, 0.1
6 g) and stirred at room temperature for 30 minutes. Add [
2'-(N-)lythyltetrazol-5-yl)biphenyl-4-ylcomethylbromide (2.19 g) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness, the resulting residue was dissolved in ethyl acetate, and then washed with water. Dry. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain a light-colored powder (A
. 6g. 67%) and yellow syrup (B. 0.45 g. 19%). Compound A: Melting point 102-106°C, m), 2.67 (2H,t), 3.14
(2H,t), 5.33 (2H,s), 6
．． 89-6.99 (8H, m), 7.06-7,
36 (13H, m), 7゜43-7.50 (2
H, m), 7.83 (LH, d), 7.89
-7.94 (LH,m) Compound B: , m) , 2.75 (2H,t) , 3.32
(2H,t), 5.16 (2H,s), 6
．． 75 (2H, d), 6.83-6.96 (7
H, m), 7.04-7.11 (3H, m),
7.17-7, 37 (IOH, m), 7.42
-7.52 (2H, m), 7.91-7.97
(LH,m)[0056] Reference Example 23 5-chloro-2-propyl-3- [[2' (N-trityltetrazol-5 monoyl) biphenyl-4-yl] methyl] imidazo[4°5-b ] Pyridine, t), 5.33 (2H,s), 6.86
-6,97 (8H,m), 7.08 (2H,d
), 7.21-7.52 (13H, m), 7
．． 92-7.98 (LH. m), 7.96 (LH, d) [0057] Reference Example 24 5-chloro-2-propyl-1-'2' (N-trityltetrazol-5 monoyl) biphenyl -4-yl] methyl] imidazo[4゜5-b] pyridine, t), 5.21 (2H,s), 6.11 (
2H, d), 6.89-6.98 (6H, m),
7.09-7.38 (14H, m), 7.43-7
．． 53 (2H. m), 7.91-7.98 (LH, m) [0058] Reference Example 25 5-dimethylamino-2-propyl-1-[[2'
-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesized in the same manner as in Reference Example 22. Light brown powder (28%
) IHNMR (200MHz, CD Cl 3)
δ: 0.92 (3H, t), 1.68-1.85 (2
H, m), 2.60 (2H, t), 3.08 (6
H,s), 5.25 (2H,s), 6.49
(LH, d), 7.80 (LH, d), 6
．． 88-7.51 (22H, m), 7.88-7
°93 (LH, m) [0059] Reference Example 26 5-methoxy-2-propylimidazo[4,5-b]pyridine Synthesized in the same manner as in Reference Example 5. brown syrup (
95%), 96 (3H,s), 6.45 (I
H,d), 7.81 (LH,d)I R(Nea
t) cm': 1610.1590.1485.
1440.1405.1325.1270.1245.
1220°1200, 1030.810.755[0
060] Reference Example 27 5-Methoxy-2-propyl-1-[[2'-(N-
) Lythyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Reference Example 2
It was synthesized in the same manner as 2. Colorless amorphous powder (33
%), 03 (3H,s), 5.17 (2H,
s), 6.48 (LH, d), 6.76 (
2H, d), 6.89-6.95 (6H, m)
, 7.09 (2H, d) , 7°17-7, 37
(11H, m), 7.45-7.51 (2H,
m), 7.92-7.96 (LH,m)I R(
KB r ) cm': 1580.1500.1
475.1440.1400.1225.1200.1
025.745° June Reference Example 28 5-methoxy-2-propyl-3-[[2'-(N-
Trityltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Reference Example 2
It was synthesized in the same manner as 2. Colorless needle crystals (42%) Melting point
172-173°C (decomposition) IHNMR (200MHz, CDC13) δ:
0.94 (3H, t), 1.79 (2H, m), 2.
64 (2H, q), 3, 89 (3H, s), 5.
31 (2H, s), 6.68 (LH, d),
6.90-6.98 (8H, m), 7.09
(2H, d), 7.18-7.37 (LH. m), 7.44-7.50 (2H, m), 7
．． 89-7.93 (2H,m)IR(KBr)
cm-1: 1595.1490.1440.142
0.1400.1340.1245.1025.810
゜745, 695.690 [0062] Reference Example 29 6-bromo-2-butyl-5-methylimidazo[4,5
-b] Pyridine Synthesized in the same manner as in Reference Example 1. Colorless needle crystals (35%) Melting point 141-143°C 1HNMR (200MHz, CD Cl 3) δ
: 0.96(3H,t), 1.36-1.54(2
H, m), 1.78-1°93 (2H, m), 2.
79 (3H, s), 2.97 (2H, t), 8.1
6(LH,s), 11.53(LH,br s)I
R(KB r ) cm-1: 1610.1570.
1530.1460.1430.1400.1260.
1090.980° [0063] Reference Example 30 6-bromo-2-butyl-5-methyl-3-[[2'
-(N-)lythyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesized in the same manner as in Reference Example 22. Colorless syrup (56
%) 80 (2H, m), 2.68 (2H, t),
2.70 (3H,s), 5.34 (2H,s)
, 6.84-6.94 (8H, m), 7.0
6 (2H, d), 7.19-7.36 (IOH
, m), 7.41-7.52 (2H, m), 7
．． 90-7.94 (IH, m), 8.13 (IH
,s)I R(Neat) cm': 1495.1
450.1400.1360.1240.1040.7
50.700[0064] Reference Example 31 6-bromo-2-butyl-5-methyl-1-[[2'
-(N-)lythyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesized in the same manner as in Reference Example 22. Colorless powder IHNM
R (200MHz, CD C13) δ: 0.90
(3H, t,), 1.30-1.47 (2H, m),
1.76-1°91 (2H, m), 2.74 (2H
,t), 2.75(3H,s), 5.13(2H,
s), 6.73 (2H, d), 6.88-6.
93 (6H, m), 7.10 (2H, d), 7
．． 18-7.37 (IOH, m), 7.45-7
．． 49 (2H, m), 7.51 (IH, s)
, 7.93-7.98 (LH,m)IR(KBr)
cm': 1445.1400.750.700[0
065] Reference Example 32 2-propylimidazo[4,5-b]pyridine 4N-
2-propylimidazo[4,5-b]pyridine (2,5 g) was dissolved in hydrogen peroxide (30%, 3 ml) and acetic acid (1,4 ml) and stirred at 110-120°C for 9 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from methanol-ethyl acetate to obtain colorless prism crystals (1.7 g, 61%). Melting point 193-194℃ Elemental analysis value C (%) H (%) N (%) calculated value as C9H1□N30:
61.00; 6.26; 23.71 Actual value: 6
1.05; 6.23; 23.69t), 7.14(
IH, dd), 7.50 (LH, d), 8.12 (LH
, d) I R (KB r ) cm-1: 3150-
2200.1585.1525.1460.1440.
1420.1270.1235°1205, 1165.
1080.990.780.740 [0066] Reference Example 33 2-propyl-1-[[2'-(N-)lytyltetrazol-5-yl)biphinyl-4-yl]methyl]imidazo[4,5- b] Pyridine 4N-oxide Synthesized in the same manner as in Reference Example 22. Pale yellow oil IHN
M R (200MHz, CDCl3) δ: 0
．． 98 (3H, t), 1.91 (2H, m), 2.81
(2H, q). 5, 23 (2H, s), 6.78-6.95 (
IOH, m), 7.12-7.38 (12H, m
), 7.46-7, 54 (2H, m), 7.
92-7.97 (LH, m), 8.19 (LH
, dd) I R (KB r ) cm': 158
0.1500.1460.1440.1410.137
5.1325.1250.1220, 1060.101
0.1000.900.880.760 [0067] Reference Example 34 2-Propyl-3-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo-4.5- b] Pyridine 4N-oxide Synthesized in the same manner as in Reference Example 22. Pale yellow oil IHN
MR (200MHz, CDCl3) δ:
1.09 (3H, t), 2.02 (2H, m), 3.
08 (2H, t), 5, 59 (2H, s), 6
．． 58 (LH, dd), 6.94-7.52 (
23H, m), 7.86 (LH, d), 7.
90-7.95 (LH, m) I R (Neat) c
m': 1615.1490.1445.1375
．． 1275.1250.1215.1190.880.
850, 750.695 [0068] Reference Example 35 2-cyano-2-propylimidazo[4,5-b]pyridine 2-furoylimidazo[4,5-b]pyridine 4
A solution of N-oxide (2.7 g), methylsilyl cyanide (6 g) and triethylamine (6 g) in acetonitrile (20 ml) was heated under reflux for 15 hours. The syrup obtained by distilling off the solvent of the reaction solution was purified by silica gel column chromatography, and the obtained crude crystals were recrystallized with ethyl acetate to obtain colorless prism crystals (2
．． 2g, 79%). Melting point 166-167°C IH-NMR (200MHz, CDCl) δ:
1.10 (3H, t), 2.00 (2H, m), 3.1
6 (2H, t,), 7, 69 (LH, d), 8.
12 (LH, d) I R (KB r ) cm-1:
2225.1620.1540.1430.1410
．． 1380.1010.850.795° [0069] Reference Example 36 5-cyano-2-propyl-1-[[2'-(N-)
Lythyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesized in the same manner as in Reference Example 6. Colorless needle crystals (25%) Melting point 16
4-165℃ (decomposition) IHNMR (200MHz, CDCl3)δ
: 0.97 (3H, t), 1.83 (2H, m), 2
．． 75 (2H, t), 5, 37 (2H, s), 6
．． 89-6.93 (8H, m), 7.09 (2
H, d), 7.21-7.40 (IOH, m)
, 7.44-7.50 (2H, m), 7゜65
(LH, d), 7.93-7.97 (LH, m
), 8.08 (LH,d)IR(KBr)
cm 1: 2220.1600.1500.147
0.1445.1420.1400.1310.127
0880, 845.810.755.745.700[
Reference Example 37 5-cyano-2-propyl-3-[[2'-(N-
) Lythyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Reference Example 6
It was synthesized in the same manner. Colorless crystals (40%) Melting point 18
8-189℃ (decomposition) IHN MR (200MHz, CDCl3)
δ: 0.97 (3H, t), 1.83 (2H, m),
2.75 (2H,t,), 5,37 (2H,s),
6.89-6.93 (8H, m), 7.09
(2H, d), 7.21-7.40 (IOH, m
), 7.44-7.50 (2H, m), 7゜65 (LH, d), 7.93-7.97 (LH
, m), 8. ,08 (LH,d)I R(KB
r) cm': 2220.1600.1500
．． 1470.1445.1420.1400.1310
．． 1270880, 845.810.755.745.
700[0071] Reference Example 38 2-Propylimidazo[4,5-c]pyridine Reference Example 1
It was synthesized in the same manner as in 1. Light brown oil (91%) IH
-NMR (200MHz, CDC1) δ: 1.01 (
3H,t), 1.92(2H,m), 2.97(2
H, t), 7, 48 (LH, dd), 8.3
4 (LH, d), 8.90 (IH, d) I R
(Neat) cm-1: 1620.1590.14
40.1420.1280.1200.1030.81
0.750[0072] Three reference examples 2-propylimidazo[4,5-c]pyridine 5N-
It was synthesized in the same manner as Oxide Reference Example 32. Brown oil (54%) IHNMR (200MHz, CD
Cl 3) δ: 0.99 (3H, t), 1.88 (
2H, m), 2.92 (2H, t), 7.50 (LH,
d), 8.10 (LH, dd), 8.68 (IH, d)
IR (Neat) cm': 1535.145
0.1265.1130.990.860.805.7
90.770.725 [0073] Reference Example 40 4-Cyano-2-propylimidazo[4,5-c]pyridine Synthesized in the same manner as Reference Example 35. Colorless prismatic crystal (61%) Melting point 178-179°C IHNMR (200MHz, CD C13) δ:
1.07 (3H, t), 1.96 (2H, m), 3
．． 04 (2H, t), 7, 71 (LH, d), 8
．． 50 (LH, d) I R (Neat) cm':
3200-2250.2220.1615.1575.
1530.1420.1280.1260.1215,
1090.1070.1005.835 [0074] Reference Example 41 4-cyano-2-propyl-3-[[2'-(N-)
Lythyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Reference Example 22
It was synthesized in the same manner. Colorless prismatic crystal (4%) melting point
95-97℃, 64 (2H, s), 6.81 (2H, d)
, 6.92-7.98 (6H, m) , 7.13
(2H, d), 7.20-7.37 (IOH,
m), 7.44-7°50 (2H, m), 7
．． 89 (LH, d), 7.91-7.95 (L
H,m), 8.53 (IH,d)I R(KB
r) cm': 2220.1600.1500.
1455.1440.1430.1400.1275.
11951020, 1000.880.820.76
0.740.695[0075] Reference Example 42 4-cyano-2-propyl-1-[[2'-(N-)
Lythyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Reference Example 22
It was synthesized in the same manner. Colorless prismatic crystal (70%) Melting point 121-124℃ IHNMR (200MHz, CD Cl 3) δ
: 1.01 (3H, t), 1.88 (2H, m), 2
．． 84 (2H, t,), 5, 25 (2H, s),
6.11 (2H, d), 6.90-6.94 (
6H, m), 7.10-7.37 (13H, m)
, 7.46-7, 52 (2H, m) , 7゜9
2-7.97 (LH, m), 8.29 (LH,
d) I R (KB r ) cm': 2220.
1600.1580.1495.1440.1395.
1270.1235.12251200, 1030.8
30.745.695 [0076] Example 1 2-Butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]imidazo[4,5-bl pyridine 2-butylimidazo[4,5-b] Pyridine (1,05
Sodium hydride (60% oil, 0.26 g) was added to the DMF (10 ml) solution of g) under water cooling and stirred for 20 minutes. 4-(2-cyanophenyl)benzyl chloride (1.37 g) was added and stirred at room temperature for 2.5 hours. Water and ethyl acetate were added to the reaction solution to separate the layers, and the organic layer was washed with water and dried. The solvent was distilled off and the residue was converted into a brown oil (1,
25g, 57%). IH-NMR (200MHz, CD C13) δ
:0.92(3H,t), 1.34-1.52(2H
, m), 1.75-1.91 (2H,, m), 2.
85 (2H, t), 5.57 (2H, s), 7.22
(LH, d), 7.26 (2H, d), 7.39-
7.53 (5H, m), 7.59-7.67 (LH,
m), 7.73-7.78 (LH, m), 8.03
(LH, dd), 8.36 (LH, dd) I R(n
eat) crn': 2220.1600.1
510.1480.1450.1425.1400.1
280.1240[0077] Example 2 2-Butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]imidazo[4,5-b]pyridine Reaction product obtained in the same manner as in Example 1 The product was purified by silica gel column chromatography to obtain the desired product as a brown oil (0.3 g, 14%). IHNMR (200MHz, CD C13) δ:
0.94 (3H, t), 1.37-1.56 (2H,
m), 1.82-1.97 (2H, m), 2.9
3 (2H, 7), 5.43 (2H, s), 7.13
(IH, d), 7.15 (2H, d), 7.4
2-7.54 (5H, m), 7.61-7.69 (L
H, m), 7.77 (IH, dd), 8.53 (L
H, dd). IR(neat) cm': 2230.161
0.1515.1485.1420.1280. 76
0[0078] Example 3 2-Butyl-3-[[2'-(LH-tetrazole-
5-yl)biphenyl-4-yl]methyl]imidazo[
4,5-b]pyridine2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]imidazo[4,5-
b] Pyridine (1.25g), sodium azide (3,
3g) and ammonium chloride (2.7g) in DMF
(12 ml) and stirred at 115°C for 5 days. Water and ethyl acetate were added to the reaction solution to separate the layers, and the organic layer was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography, and the resulting crude crystals were recrystallized from ethyl acetate-methanol to give a colorless prism product (0.82 g, 59%
) was obtained. Melting point 197-198℃ Elemental analysis value C (%) H as C24H23N7
(%) N (%) Calculated value: 70.40; 5.66; 23.94 Actual value: 70.42; 5.73; 23.641HNM
R (200MHz, d6DMso) δ: 0.86 (3H
,t), 1.25-1.44(2H,m), 1.6
1-1.76 (2H, m), 2.82 (2H, t),
5.52 (2H, s), 7.05 (2H, d), 7.
12 (2H, d), 7.26 (LH, dd). 7.48-7.71 (4H, m), 8.00 (LH,
dd), 8.30 (LH, dd). I R (KB r ) cm': 1600.15
10.1465.1410.1280. 780.76
0[0079] Example 4 2-Butyl-1-[[2'-(LH-tetrazole-
5-yl)biphenyl-4-yl]methyl]imidazo[
4,5-b]pyridine2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]imidazo[4,5-
b] Pyridine (0.3g), sodium azide (0.7g)
8g) and ammonium chloride (0.64g) in DMF
(4 ml) and stirred at 115°C for 7 days. Water was added to the reaction solution, neutralized with IN-hydrochloric acid, and then extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off. The residue was purified by silica gel column chromatography, and the resulting crude crystals were recrystallized from ethyl acetate-methanol to obtain colorless crystals (77 mg, 22%). Melting point 137-139℃ Elemental analysis CHN -0,4H20C (%)
H (%) N (%) Calculated value: 69.18; 5.76; 23.53 Actual value: 69.42; 5.93; 23.331 HNM R
(200MHz, CD C13) δ: 0.85 (3
H, t), 1.22-1.42 (2H, m), 1.
59-1.74 (2H, m), 2.66 (2H, t)
, 5.26 (2H, s), 6.69 (2H, d),
6.97 (2H, d), 7.02 (IH. dd), 7.31-7.36 (IH, m), 7.4
1 (LH, dd), 7.49-7.60 (2H, m)
, 7.90-7.94 (LH, m). 8.19 (IH, dd). I R (KB r ) cm': 1610.15
10.1480.1450.1415.1280. 7
80. 760 [0080] Example 5 2-Butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]imidazo[4,5-b]pyrazine 2-butylimidazo[4,5-b]pyrazine (0 ,35
Sodium hydride (60% oil, 88 mg) was added to the DMF (5 ml) solution of g) while cooling on ice, and the mixture was stirred for 15 minutes. Add 4-(2-cyanophenyl) to the mixture.
Benzyl chloride (0.46 g) was added and stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent was distilled off. The product was purified by silica gel column chromatography to obtain the desired product as a pale brown oil (0.36 g, 49%). 1HNMR (200MH2, CDC13) δ: 0.90
(3H, t), 1.28-1.43 (2H, m),
1.73-1.89C2H,m), 2.79(2H,
t), 5.38 (2H, s), 7.26 (2H, d)
, 7.43-7.55 (4H, m), 7.60-7
．． 75 (2H, m), 8.26 (IH9d), 8.
50 (LH, d). [0081] Example 6 2-Butyl-1-[[2'-(LH-tetrazole-
5-yl)biphenyl-4-yl]methyl]imidazo[
4,5-b]pyrazine2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]imidazo[4,5-
b] Pyrazine (0,36g), sodium azide (0,
96 g) and ammonium chloride (0.79 g) in DM
The mixture was stirred in F (5 ml) at 115°C for 5 days. Water and ethyl acetate were added to the reaction solution to separate the layers, and the organic layer was washed with water, dried, and concentrated. The product was purified by silica gel column chromatography to give colorless powder crystals (0.12 g,
29%). Melting point 102-104℃ Elemental analysis CHN -0,4H20C (%)
H (%) N (%) Calculated value: 66.14; 5.50; 26.83 Actual value: 66.44; 5.47; 26.56.82
(2H, m), 2.80 (2H, t), 5.45 (2
H,s), 7.03(2H,d), 7.10(2H
, d), 7.36 (LH. dd), 7.47-7.62 (2H, m), 7.9
7 (LH, dd), 8.25 (LH, d), 8.3
8 (LH, d). I R(KB r ) cm-1: 1570.14
95.1450.1420.1400.1360.12
00.845.775[0082] Example 7 2-Methyl-3-[[2'-(LH-tetrazole-
5-yl)biphenyl-4-yl]methyl]imidazo[
4,5-b]pyridine2-methyl-3-[[2'-(
N-)lythyltetrazol-5-yl)biphenyl-4
-yl]methyl]imidazo[4,5-b]pyridine (0
, 89 g) was dissolved in ethanol (15 ml) containing IN HCI (3 ml) and stirred at room temperature for 3 hours. The reaction solution was neutralized by adding IN NaOH and concentrated to dryness. The resulting syrup was dissolved in chloroform, washed with water, and dried (MgSO3). The syrup obtained by distilling off the solvent was purified by silica gel column chromatography, and the obtained crude crystals were recrystallized from methanol-ethyl acetate to obtain colorless prism crystals (0.29 g, 53%).
I got it. Melting point: 251-254°C (decomposition) Elemental analysis: C2, Hl. C (%) H (%) N (%) Calculated value as N7: 68.65 : 4.66 : 26.6
9 Actual value: 68.58; 4.75; 26.
571HNM R (200MHz, DM S Od
6) δ: 2.51 (3H, s), 5.51 (2H,
s), 7.05 (2H, d), 7.14 (2H, d)
, 7.26 (LH, dd) , 7.50-7.7
1 (4H, m), 7.98 (IH, dd), 8
．． 30 (LH, dd) I R (KB r ) cm-1
: 1600.1465.1420.1400.135
0.1290.1240.1040.985°960,
855. 800.780.755 [0083] Example 8 2-Methyl-1-(I[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine implementation Synthesized in the same manner as in Example 7. Colorless needle crystals (41%) Melting point 180-182°C Elemental analysis C2□H1□N71.C as IH2o
%) H (%) N (%) Calculated value: 65.14; 5.00;
25.32 Actual value: 65.31;
4.94; 25.034H, m), 7.1
9 (LH, dd), 7.49-7.70 (4H
, m), 7.93 (LH, dd), 8.34
(LH, dd) I R (KB r) cm':
1600.1510.1415.1280.775.7
55[0084] Example 9 2-Methyl-3-[[2'-(LH-tetrazole-
5-yl)biphenyl-4-yl]methyl]imidazo[
4,5-b]pyridine Synthesized in the same manner as in Example 7. Colorless needle crystals (66%) Melting point 149-150℃ (decomposition) Elemental analysis value C (%) H (%) N (%) Calculated value as C22H19N71/2EtOAC: 61.15; 5.45; 23.0
4 Actual value: 67.52; 5.37; 23.1
31HNMR (200MHz, DMSOd6) δ: 1
．． 26 (3H, t), 2.84 (2H, q), 5.51
(2H,s), 7.04 (2H,d), 7.1
2 (2H, d), 7.26 (LH, dd),
7.48-7.71 (4H, m), 8.01
(LH, dd) , 8.31 (IH, dd) I R (KB r ) cm': 1600.15
00.1460.1420.1400.1280.12
50.1040.800°775,755 [0085] Example 10 2-ethyl-1-[[2'-(LH-tetrazole-
5-yl)biphenyl-4-yl]methyl]imidazo[
4,5-b]pyridine Synthesized in the same manner as in Example 7. Colorless crystals (13%) Melting point: 141-143°C (decomposed) Elemental analysis: C22H19N7.0. C (%) H (%) N (%) Calculated value as IC6H1゜○: 67.15 ; 5.44 ; 24.2
5 Actual value: 67.28; 5.36; 23.
991HNMR (200MHz, DMSOC6) δ:
1.29 (3H, t), 2.88 (2H, q), 5.5
2 (2H, s), 7.06 (4H, s), 7.
19 (IH, dd), 7.49-7.70 (4
H, m), 7.93 (IH, dd), 8.3
5 (LH, dd) I R (KB r ) cm'
: 1605.1510.1480.1455.141
0.1280.780.755 [0086] Example 11 2-propyl-3-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesize in the same manner as in Example 7. Colorless plate crystals (59%) Melting point 207-208℃ (decomposed) Elemental analysis C23H2, C as N7/0.2H20
(%) H (%) N (910) Calculated value:
69.22; 5.40: 24.57 Actual value:
69.59; 5.35; 24.381H-NM
R (200MHz, DMS○-d6) δ: 0.93
(3H, t), 1.72 (2H, m), 2.80 (2
H,t,), 5.52 (2H,s), 7.05
(2H, d) , 7.12 (2H, d) , 7
．． 26 (LH, dd), 7.50-7.72 (
4H, m), 8.01 (LH, dd), 8.2
8 (LH, dd) I R (KB r ) cm-1: 1600.150
5.1465.1410.1280.1225.775
．． 760[0087] Example 12 2-Propyl-1-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine 4N-oxide Example 7 It was synthesized in the same manner. Colorless needle crystals (28%) Melting point 19
2-195℃ (decomposition) Elemental analysis value C23H2□N70・0, 7 H2C
As C (%) H (%) N (%) Calculated value: 65.14 ; 5.32 : 23.1
2 Actual value: 65.19; 5.12; 23.1
3, 5.55 (2H, s), 7.08 (4H,
s), 7.17 (LH, dd), 7.48-
7.71 (5H, m), 8.14 (LH, d)
I R (KB r ) cm': 1450.141
0.1245.1220.780.735 [0088] Example 13 2-Butyl-1-[[2'-(LH-tetrazole-
5-yl)biphenyl-4-yl]methyl]imidazo[
4,5-c]pyridine Synthesized in the same manner as in Example 7. Colorless leaf pieces (4 Melting point 146-147℃ Elemental analysis value CHN-0, C (%) as 2H20 H
(%) N (%) Calculated value: 69.78 ; 5.71 ; 23.7
3 Actual measurement value: 69.88; 5.69; 23.4
97%) 1,78 (2H, m), 2.84 (2H, t)
, 5.53 (2H,s) , 7.06 (4H
,s), 7.46-7,69 (5H,m),
8.29 (LH, d), 8.89 (IH, s) I R (KB r ) cm': 1615.15
15.1475.1450.1400.825.755
[0089] Example 14 2-Butyl-3-[[2'-(IH-tetrazole-
5-yl)biphenyl-4-yl]methyl]imidazo[
4,5-c]pyridine Synthesized in the same manner as in Example 7. Colorless crystal (30%) Melting point 116-117℃ Elemental analysis value CHN ・C (%) as 0.2H20
H (%) N (%) Calculated value: 69.78; 5.71; 23.7
3 Actual measurement value: 69.49; 5.83; 23.9
11,90 (2H,m), 2.93 (2H,t
), 5.38 (2H,s), 6.59 (2
H, d), 6.75 (2H, d), 7.17
-7, 42 (3H, m), 7.71 (LH, d)
, 7.11-1.82 (LH, m) , 8.24
(LH, d), 9.00 (IH, br s),
9.95 (LH, br s) I R (KBr) cm-
1: 1500.1470.1415.825.765
[0090] Example 15 2-Butyl-6-methyl-3-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[5,4-b]pyridine Example 7 It was synthesized in the same manner. Colorless needle crystals (77%) Melting point 136-14
0℃ Elemental analysis value CH=N ・25 as 0.3H20
2o7 C (%) H (%) N (%) Calculated value: 70.01 ; 6.02 ; 22.8
6 Actual value: 70.01; 5.96; 22.
611HNM R (200MHz, CD C13)
δ: 0.86 (3H, t), 1.22-1.40 (
2H, m), 1.55-1.70 (2H, m),
2.30 (2H, s), 2.47 (2H, t)
, 5.35 (2H,s) , 6.78 (2H
, d) , 6.91 (2H, d) , 6.99
(LH, d). 7, 31-7.36 (IH, m), 7.57-7
, 65 (2H, m), 7.94-8.01 (L
H,m), 8.05 (IH,d)IR(KBr
) cm': 1600.1500.1450.139
5.880.750[0091] Example 16 2-Butyl-6-methyl-1-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[5,4-b ] Pyridine Synthesized in the same manner as in Example 7. Colorless crystals (75%) Melting point 152-153
℃ Elemental analysis value CHN ・C (%) as 0.4H20
H (%) N (%) Calculated value: 69.71 ; 6.04 ; 22.7
6 Actual value: 69.11; 6.00; 22.5
31HNMR (200MHz, CD C13) δ
: 0.82(3H,t), 1.20-1.39(2
H, m), 1.57-1.72 (2H, m), 2
．． 36 (2H, s), 2.61 (2H, t)
, 5.24 (2H,s) , 6.73 (2H,
d), 6.98 (2H, d), 7.27-7
, 35 (2H, m), 7.44-7.58 (2
H, m), 7.89 (LH, dd), 8.0
5 (LH, d) I R (KB r ) Cm':
1615.1560.1515.1485.1450
．． 1410.1280.1000.870°785,7
60 [0092] Example 17 5-chloro-2-propyl-1-[[2'-(LH-
Tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine 5-chloro-2-
Propyl-1-[[2'-(N-)lythyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]hyde(026g) in methanol (8ml) , IN HCI (0,6m1
) and stirred at room temperature for 1 hour. The product obtained by concentrating the reaction solution to dryness was purified by silica gel column chromatography to give a pale yellow powder (0.12 g, 68%
) was obtained. Elemental analysis value CHCIN 1.5H2o (%
) H (%) N (%) Calculated value: 60.46 ; 5.07 ; 21.4
6 Actual value: 60.12; 4.59; 21.
18[0093] Example 18 5-chloro-2-propyl-3-[[2'-(LH
-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesized in the same manner as in Example 17. White crystals (71%) Melting point 232-
234℃ Elemental analysis value CHCIN 1/2H20 (
%) H (%) N (%) Calculated value: 6
2.94; 4.82; 22.34 Actual value:
63.24:4.62;21.17,5.32 (
2H,s), 6.85-7.00 (4H,m)
, 7.14 (LH, d) , 7.30-7.38
(IH, m), 7.43-7.61 (3H, m
), 7, 83-7.91 (IH,m) [0094] Example 19 5-dimethylamino-2-propyl-3-[[2'-
(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pynodine was synthesized in the same manner as in Example 17. Light brown powder (57%) Melting point: 264-266°C Elemental analysis: C2, H26N81. C( as lH2O
%) H (%) N (%) Calculated value: 65.51; 6.20; 24.4
5 Actual value: 65.63; 5.83; 24.0
51HNMR (200MH2, CDC13) δ: 0
．． 75 (3H, t), 1.39-1.57 (2H, m)
, 2.23 (2H, 7), 3.02 (6H, s)
, 5.20 (2H,s) , 6.26 (LH,
d), 6.87 (LH, d), 6.82 (
2H, d), 6.95 (2H, d), 7.3
3-7, 37 (LH, m), 7.49-7.60
(2H, m), 7.84-7.89 (LH, m
)[0095] Example 20 2-propyl-5-propylthio-3-[[2'-(
LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Example 17
It was synthesized in the same manner. Pale yellow crystals (70%) Melting point 2
19-222℃ Elemental analysis value C (%) as CHNS・1/2H20
H (%) N゛ (%) Calculated value: 65.25; 5.90; 20.4
9 Actual value: 64.95; 5.71; 20.3
21HNMR (200MH2, CDC13) δ: 0.
83 (3H, t), 0.91 (3H, t), 1.50-
1.70 (4H, m), 2.39 (2H, t),
3.04 (2H,t), 5.32 (2H,s
), 6.81-7.04 (6H, m), 7.
33-7.39 (IH, m), 7.54-7, 6
4 (2H, m), 7.90-7.97 (18,
m) [0096] Example 21 2-propyl-5-propylthio-1-[[2'-(
IH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Example 17
It was synthesized in the same manner. Pale yellow powder (66%) Elemental analysis value C (%) as C26H2゜N7S・315H20
H (%) N (%) Calculated value: 65.00 ; 5.92 ; 20.4
1 Actual measurement value: 65.00; 5.62; 20.1
81HNMR (200MH2, CDC13) δ: 0.
83 (3H, t), 0.95 (3H, t), 1.54-
1.73 (4H, m), 2.52 (2H, t),
3.04 (2H,t), 5.15 (2H,s
), 6.69 (2H,d), 6.89 (2
H, d), 6.93 (LH, d), 7.22
-7.53 (4H, m), 7.14-'7.81
(LH,m)[0097] Example 22 5-methoxy-2-propyl-1-[[2'-(LH
-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesized in the same manner as in Example 17. Colorless prismatic crystal (66%) Melting point 1
91-192℃ (decomposition) Elemental analysis value C (%) H (%) N (%) Calculated value as C24H23N70・1/2H20: 66.34 ; 5.57 ; 22.5
7 Actual measurement value: 66.44; 5.42; 22.
62 (3H, s), 5.25 (2H, s),
6.54 (LH, d), 6.71 (2H, d)
, 6.97 (2H, d), 7.25-7.3
4 (2H, m), 7.46-7, 59 (2H,
m), 7.91-7.95 (LH,m)I R(
KB r ) cm-1: 1600.1590.15
00.1480.1450.1435.1405.13
60.13401295, 1225. 1200.
1035.805.755 [0098] Example 23 5-Methoxy-2-propyl-3-[[2'-(LH
-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesized in the same manner as in Example 17. Colorless prismatic crystal (65%) Melting point 2
58-260℃ (decomposition) Elemental analysis value C (%) H (%) N (%) Calculated value as C24H23N70-0.3H20: 66.90; 5.50; 22.7
5 Actual value: 67.06; 5.40; 22.9
0 (3H, s), 5.42 (2H, s), 6
．． 67 (LH, d), 7.06 (2H, d)
, 7.19 (2H, d), 7.49-7.72
(4H, m), 7.91 (IH, d) I R (KB r ) cm-1: 1600.159
0.1455.1435.1405.1355.134
5.1260.12001100, 1020.1005
．． 875.850.815.775.745.725 [
[0099] Example 24 6-bromo-2-butyl-5-methyl-3-[[2'
-(LH-tetrazol-5-yl)biphenyl-4-
yl]methyl]imidazo[5,4-b]pyridine Synthesized in the same manner as in Example 17. Colorless prismatic crystal (76%)
Melting point 230-231℃ (decomposition) Elemental analysis value C25H24B r N 7 as C (%
) H (%) N (%) Calculated value: 59. n; 4.81; 19.52
Actual value: 59.70; 4.71; 19.62
'HNMR (200MHz, CDC13) δ: 0.8
4 (3H, t), 1.19-1.38 (2H, m),
1.53-1-68 (2H, m), 2.49 (
2H,t), 2.66 (3H,s), 5.3
8 (2H, s), 6.86 (2H, d),
6.97 (2H, d), 7.33-7.39 (
2H, m), 7.57-7, 68 (2H, m)
, 7.96-8.00 (LH,m)IR(KB
r) cm': 1595.1575.1500
．． 1460.1400.1360.1270.990.
945°895, 770.745.725 [0100] Example 25 6-bromo-2-butyl-5-methyl-1-[[2'
-(LH-tetrazol-5-yl)biphenyl-4
-yl]methyl]imidazo[5,4-b]pyridine Synthesized in the same manner as in Example 17. Colorless prismatic crystal (54%
) Melting point 141-143℃ (decomposition) Elemental analysis value CHBrN-0, C as IC4H80℃
(%) H (%) N (%) Calculated value: 59.68; 4.89: 19.1
8 Actual value: 59.64; 5.01; 18.
871HNMR (200MHz, CDC13) δ: 0
．． 88 (3H, t), 1.24-1.45 (2H, m
), 1.62-1.77 (2H, m), 2.51
(3H,s), 2.64 (2H,t), 5
．． 25 (2H, s), 6.73 (2H, d)
, 6.95 (2H, d) , 7.27-7, 33
(LH, m), 7.51-7.61 (3H, m
), 7.94-7.99 (LH,m)I R(K
B r ) cm-1: 1600.1500.148
0.1450.1400.1370.1275.970
．． '115゜October Example 26 Lowcyano 2-propyl-1-[[2'-(LH-
Tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesized in the same manner as in Example 7. Colorless crystals (91%) Melting point 233-23
4℃ (decomposition) Elemental analysis value C24H2oN8・0.4H20
(%) H (%) N (%) Calculated value:
67.40; 4.90; 26.20 Actual value:
67.44; 4.76; 25.96, 5.61
(2H,s), 7.08 (4H,s), 7.
4'/-1,71 (4H, m), 7.84 (LH
, d), 8.18 (IH, d) [0102] Example 27 Low cyano 2-propyl-3-[[2'-(LH-
Tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine Synthesized in the same manner as in Example 7. Colorless crystal (71%) elemental analysis value C24
C (%) H (%) N (%) as H2oN8 68.56; 4.79; 26.6568.64:
5.03; 26.56 Calculated value: Actual value: , 5.56 (2H, s), 7.06 (2H,
d), 7.13 (2H, d), 7.49-7
．． 71 (4H, m), 7.89 (IH, d)
, 8.23 (LH,d)I R(KB r ) c
m': 2250.1600.1570. '15
00.1475.1460.1405.1370.12
701240. 1220. 1090. 1060.
995. 930.830.770. 760 [010
3] Example 28 Ethyl 2-propyl-1-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]
imidazo[4,5-b]pyridine-5-carboxylade 5-cyano-2-propyl-1-[[2'-(LH-
1 of tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine (1,0g)
A 5% ethanol-hydrochloric acid (10 ml) solution was heated under reflux for 2.5 hours, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography, and the obtained crude crystals were recrystallized from ethyl acetate to give colorless needle crystals (0.77 g
, 64%). Melting point 164-166℃ (decomposition) Elemental analysis value C26H2, N7021/4C4H802
As C (%) H (%) N (%) Calculated value: 65.05 ; 5.66 ; 19.67
Actual value: 65.28; 5.36; 1
9.701H-NMR (200MHz, DMS〇-d6
) δ: 0.96 (3H, t), 1.36 (3H, t
), 1.78 (2H, m), 2.88 (2H, t)
, 4.36 (2H, q), 5.59 (2H, s)
, 7.07 (4H,s) , 7.48-7.71
(4H, m), 7.97 (LH, d), 8
．． 07 (LH, d) I R (KB r ) cm-1
: 1725.1445.1420.1400.130
0.1255.1120.760[0104] Example 29 Ethyl 2-propyl-3-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]
Imidazo[4,5-b]pyridine-5-carboxylade Synthesized in the same manner as in Example 28. Colorless prism crystal (9
2%) Melting point 212-213℃ (decomposition) Elemental analysis value C (%) as C26H2, N702
H (%) N (%) Calculated value: 66.79; 5.39: 20.9
7 Actual value: 66.89; 5.37; 20.
86, 2.81 (2H,t), 4.38 (2H
,q), 5.57 (2H,s), 7.06
(2H, d) , 7.14 (2H, d) , 7.
50-7.71 (4H, m). 8,03 (IH,d), 8.16 (IH,d)
IR(KBr) am': 1710.16
00.1500.1460.1410.1370.12
80.1260.12351120, 860.760 [0105] Example 30 2-propyl-1-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b ] Ethyl pyridine-5-carboxylate 2-
Furopyru 1-[[2'-(LH-tetrazole-5
-yl)biphenyl-4-yl]methyl]imidazo[4
,5-b]pyridine-5-carboxyl) (0,4
g), IN aqueous sodium hydroxide solution (2.6ml)
The mixture was dissolved in methanol (5 ml) containing 100 ml of alcohol, and the mixture was heated under reflux for 2 hours. The residue obtained by distilling off the solvent was dissolved in water, and I
N MCI (2,6 ml) was added to acidify the precipitated crystals, which were recrystallized with methanol to give colorless needle crystals (0,6 ml).
2g, 53%) was obtained. Melting point 211-213℃ Elemental analysis value C24H2, N70℃ 1.7H20 C (%) H (%) N (%) Calculated value: 61.32; 5.23; 20.8
6 Actual value: 61.52; 5.05; 20.
62, 5.59 (2H, s), 7.08 (4H
,s), 7.48-7.71 (4H,m),
7.97 (LH, d), 8.07 (IH, d)
I R (KB r ) cm': 1720.16
00.1460.1410.1380.1320.13
00.1235.760° [0106] Example 31 2-propyl-3-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine- 5-Carboxylic acid Synthesized in the same manner as in Example 30. Colorless needle crystals (46%) Melting point 15
1-152℃ Elemental analysis value CHNo. C (%) as 0.5H20
H (%) N (%) Calculated value: 64.28; 4.94: 21.8
6 Actual value: 64.61; 5.25; 21.
511H-NMR (200MHz, DM S〇-
d6) δ: 0.92 (3H, t), 1.72 (2H
, m), 2.81 (2H, t), 5.59 (2H,
s), 7.05 (2H, d), 7.13 (
2H, d), 7.49-7.71 (4H, m)
, 8.01 (LH, d) , 8.14 (LH,
d) I R (KB r ) cm': 1720.
1600.1500.1480.1455.1410.
1380.1310.1260 [0107] Example 32 4-cyano-2-propyl-1-[[2'-(LH-
Tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-c]pyridine Synthesized in the same manner as in Example 17. Colorless needle crystals (87%) Melting point 225-
230℃ (decomposition) Elemental analysis value C24H2oN83.4H20 as C(
%) H (%) N (%) Calculated value: 59
．． 84; 5.61; 23.26 Actual value: 5
9.97; 5.34; 23.17'HNMR (20
0MHz, DMSOd6) δ: 0.98 (3H, t)
, 1.81 (2H, m), 2.94 (2H, t), 5
．． 59 (2H, s), 6.98 (2H, d)
, 7.10 (2H, d) , 7.23-7.67
(3H, m), 7.52-7.57 (IH, m
), 7.95 (LH,d), 8.46 (I
H, d) I R (KB r ) cm '2222
0. 1600. 1580. 1500. 1450
．． 1440. 1400. 1350. 1270,
1200.830.810.780.755[0108
] Example 33 4-cyano-2-propyl-3-[[2'-(LH-
Tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-c]pyridine Synthesized in the same manner as in Example 17. Colorless prismatic crystal (62%) Melting point 24
2-243℃ (decomposition) Elemental analysis value C24H2oN8 as C (%) H (%) N (%) Calculated value: 68.56; 4.79; 26.6
5 Actual value: 68.17; 4.50; 26.
391HNMR (200MHz, DMSOd6) δ:
0.93 (3H, 7), i, 75 (2H, m), 2.8
6 (2H, t), 5.78 (2H, s), 7.
01 (2H, d), 7.09 (2H, d),
7.51-7.71 (4H, m), 8.02
(LH, d) , 8.52 (LH, d)I R(K
B r ) cm-1: 2220.1600.156
5.1500.1460.1425.1405.127
0.1190, 1135.985.840.770.
750[0109] Example 34 Ethyl 2-propyl-1-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]
Imidazo[4,5-c]pyridine-4-carboxylade Synthesized in the same manner as in Example 28. Colorless leaf pieces (70%)
Melting point 218-219℃ (decomposition) Elemental analysis value C (%) H (%) N (%) Calculated value as C26H2,N702・0.2H20: 66.29; 5.43; 20.81
Actual value: 66.16; 5.42; 20.97
, 2.86 (2H,t) , 4.39 (2H,q
), 5.59 (2H,s), 7.06 (4
H, s), 7.488, 35 (LH, d) -1゜I R(KB r ) cm, 1730.160
0.1460.1440.1400°835,755 [01101 7,71 (4H, m), 7.80 (LH, d)
. 1305, 1235. 1180. 1145 Example 35 2-Propyl-1-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-c]pyridine-4-carboxylic acid Example 30 and It was synthesized in the same manner. Colorless needle crystals (78%) Melting point 17
9-181℃ (decomposition) Elemental analysis value CHN○ ・CHN○・0.5H20 C (%) H (%) N (%) Calculated value: 62.54 : 5.49 ; 21.5
5 Actual value: 62.25; 5.22; 21.
421H-NMR (200MHz, DMS〇-d6)
δ: 0.95 (3H, 7), 1.73 (2H, m)
, 2.87 (2H, t), 5.60 (2H, s)
, 7.07 (4H,s) , 7.48-7.71
(4H, m), 7.81 (LH, d), 8
．． 37 (LH, d) I R (KB r) cm'
: 1650.1605.1405.1370.135
0 [0111] Experimental Example 1 Effect of inhibiting angiotensin-II binding to angiotensin receptor [Experimental method] Douglas et al.'s method [Endocrinology
, 102. 685-696 (1978)]
Angiotensin II (A-II)-receptor binding inhibition experiments were conducted by modifying the method. A-I from the cortex of the bovine adrenal gland
I receptor membrane isolates were prepared. Compound of the present invention (10-6 or 10'M) and 125
■-Angiotensin II (125I-AII) (1
, 85kBq150μm) was added to the receptor membrane fraction and incubated for 1 hour at room temperature. 125 of binding and free
-A-Filter ■■ (Whatman GF/B
filter) and bound to the receptor.
The radioactivity of 5■-A-■■ was measured. [Actual and Experimental Results] Actual and experimental results regarding the compounds of the present invention are shown in Table 1. [0112] Experimental Example 2 Inhibitory effect of the compound of the present invention on A-II pressor reaction action [Experimental method] Jcl: SD flat (9 weeks old, male) was used. In fact, under Maeda pendoparbital NA anesthesia, indwelling cannulae were placed in the femoral artery and vein, and the animals were kept without food and with free access to water until just before the experiment. In fact, during the experiment, the arterial cannula was connected to a blood pressure transducer, and mean blood pressure was recorded using a polygraph. A-I I serves as a control before drug administration
The pressor response due to intravenous administration of (100 ng/kg) was determined. The drug is administered orally, and at the latter measurement point A
-II was administered intravenously, and the pressor response was determined in the same manner, and the response before and after administration of the drug was compared to determine the inhibition rate. [Experimental Results] [0113] Table 1 Example Binding Inhibition Effect (%) Pressor Inhibition Effect (p, o, ) No. 1 NT NT NT NT NT NT NT +++ NT NT +++ NT NT NT NT NT NT *1: +++ ≧70% 〉 ++ ≧50% *2: NT ot ested

Claims (1)

[Claims] Formula [Chem. 1] ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, ring A may have a substituent and contains 1 to 2 nitrogen atoms as ring constituent atoms represents a six-membered aromatic ring, R^1 is hydrogen or optionally substituted alkyl,
Indicates an aralkyl or aryl group, R^2 is hydrogen,
Represents a halogen or nitro group, R^3 represents a group that can form an anion or a group that can be converted into an anion, and X represents that a phenylene group and a phenyl group are bonded directly or through a spacer with 2 or less atomic chains. and n is 1 or 2
[indicates an integer] or a salt thereof.