Pharmaceutical use of imidazole derivatives

Abstract

To provide a novel pharmaceutical capable of exhibiting strong agonistic activity on an α1A receptor.SOLUTION: There is provided a pharmaceutical comprising, as an active ingredient, a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof. The pharmaceutical of the present invention has superior adrenergic α1A receptor agonistic activity and serves as a prophylactic or therapeutic agent for orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence (wherein R1 represents a hydrogen atom or a C1-C3 alkyl group; and Z is selected from the group consisting of substituted phenylamino groups, substituted phenyloxy groups, substituted phenylthio groups, substituted thienylamino groups and the like).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the medical use of imidazole derivatives. [Background technology]

[0002] Epinephrine and norepinephrine are types of neurotransmitters collectively known as catecholamines. They are primarily secreted from the adrenal medulla and sympathetic nerve endings and are involved in sympathetic nerve signal transmission. The adrenergic receptors involved in the expression of these actions are broadly classified into α-receptors and β-receptors, with α-receptors having two subtypes, α1 and α2. Of these, α1-receptors are further subdivided into three subtypes, α1A-receptors, α1B-receptors, and α1D-receptors, all of which are involved in smooth muscle contraction. Among these, it has been reported that activation of α1A-receptors significantly contributes to an increase in blood pressure (Non-Patent Documents 1 and 2).

[0003] Because α1 receptor activation causes vascular smooth muscle contraction, α1 receptor agonists are used clinically as hypertensive drugs. Currently, midodrine, etilefrine, phenylephrine, etc. are known as α1 receptor agonists in clinical use, but the variety is limited.

[0004] N-((1H-imidazol-4-yl)methyl)-2-(oxazol-5-yl)aniline and 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)isoxazole (Non-Patent Document 3) have been reported as α1 receptor agonists. These compounds have α1A agonist activity, but are structurally different from the compounds of the present invention, which do not have an oxazole ring or isoxazole ring in the biaryl structure. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Circulation 100 2336-2343 1999 [Non-patent document 2] J Pharmacol Exp Ther 274 97-103 1995 [Non-patent document 3] Bioorg Med Chem Lett 12 3449-3452 2002 Summary of the Invention [Problem to be solved by the invention]

[0006] Because activation of α1A receptors plays an important role in increasing blood pressure, an objective of the present invention is to provide a pharmaceutical agent that exhibits a strong agonistic effect on α1A receptors and can be used as a hypertensive drug. That is, an objective of the present invention is to provide a pharmaceutical agent that can be used as an excellent therapeutic or preventive agent for orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence based on α1A receptor activation. [Means for solving the problem]

[0007] In order to solve the above problems, the present inventors have conducted extensive research aimed at creating an adrenergic α1A receptor agonist having a novel structure. As a result, they have found that the compound represented by the following general formula (I) and its pharmacologically acceptable salt have excellent adrenergic α1A receptor agonism, and have completed the present invention.

[0008] According to the present invention, there is provided a pharmaceutical comprising, as an active ingredient, a compound represented by general formula (I) or a pharmacologically acceptable salt thereof. In this specification, pharmaceuticals comprising these compounds or pharmacologically acceptable salts thereof as active ingredients are referred to as "pharmaceuticals of the present invention." The present invention can be embodied in the following embodiments (1) to (16), etc.

[0009] (1) A pharmaceutical comprising, as an active ingredient, a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof: [ka] [In the formula, R 1means a hydrogen atom or a C1 to C3 alkyl group. Z is selected from the group consisting of the following formulas: [ka] (In the formula, R 2 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkyl group. R 3 is selected from the group consisting of the following formulas: [ka] (In the formula, Y represents an oxygen atom or a sulfur atom. R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group. R 5 means a hydrogen atom, a fluorine atom, a C1 to C3 alkyl group, or a C1 to C3 alkoxy group. R 6 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 7 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyclopropyl group. R 8 means a hydrogen atom or a C1 to C3 alkoxy group. R 9 means a hydrogen atom or a C1 to C3 alkyl group. R 10 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyano group. In addition, R 6 is a C1-C3 alkoxy group, R 7 and R 8 is a hydrogen atom, and R 8 is a C1-C3 alkoxy group, R 6 is a hydrogen atom or a fluorine atom, and R 7 is a hydrogen atom.

[0010] (2) The pharmaceutical composition according to (1), which contains, as an active ingredient, a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof: [ka] [In the formula, R 1 means a hydrogen atom or a C1 to C3 alkyl group. Z is selected from the group consisting of the following formulas: [ka] (In the formula, R 2 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkyl group.

[0011] R 3 is selected from the group consisting of the following formulas: [ka] (In the formula, Y represents an oxygen atom or a sulfur atom. R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group. R 5 means a hydrogen atom, a fluorine atom, a C1 to C3 alkyl group, or a C1 to C3 alkoxy group. R 6 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 7 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyclopropyl group. R 8 means a hydrogen atom or a C1 to C3 alkoxy group. R 9 means a hydrogen atom or a C1 to C3 alkyl group. R 10 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyano group. In addition, R 6 is a C1-C3 alkoxy group, R 7 and R 8 is a hydrogen atom, and R8 is a C1-C3 alkoxy group, R 6 is a hydrogen atom or a fluorine atom, and R 7 is a hydrogen atom.)

[0012] However, Z is [ka] and R 2 When is a hydrogen atom, R 3 rather than 3-fluoropyridine attached at the 2-position; Also, Z [ka] and R 2 When is a hydrogen atom, R 3 is not an unsubstituted pyridine attached at the 2-position, an unsubstituted pyrazole attached at the 3-position, or a 3-methoxypyrazole attached at the 4-position;

[0013] Also, Z [ka] and R 2 When is a hydrogen atom, R 3 rather than unsubstituted furan bonded at the 2-position; Also, Z [ka] and R 1 is a C1-C3 alkyl group and R 2 When is a hydrogen atom, R 3 rather than unsubstituted pyrazole attached at the 4-position; Also, Z [ka] When R 3 is not an unsubstituted thiazole bonded at the 5-position.) In addition, R 1Of the two enantiomers that are produced when is a C1-C3 alkyl group, the enantiomer with weaker α1A agonist activity than 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole is excluded.

[0014] (3) R of the compound 3 is the following formula [ka] [wherein Y represents an oxygen atom or a sulfur atom.] R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group. R 5 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 6 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 7 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyclopropyl group. R 8 means a hydrogen atom or a C1 to C3 alkoxy group. R 9 means a hydrogen atom or a C1 to C3 alkyl group. R 10 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyano group. In addition, R 6 is a C1-C3 alkoxy group, R 7 and R 8 is a hydrogen atom, and R 8 is a C1-C3 alkoxy group, R 6 is a hydrogen atom or a fluorine atom, and R 7 is a hydrogen atom.

[0015] However, Z is [ka] When R 3is bonded at position 4 and R at position 3 9 a thiophene substituted with , a pyridine bonded at the 3-position and substituted at the 4-position with a C1-C3 alkyl group, or an unsubstituted pyrazole bonded at the 4-position; Also, Z [ka] When R 3 is bonded at position 4 and R at position 3 9 a thiophene substituted with , a pyridine bonded at the 3-position and substituted at the 4-position with a C1-C3 alkyl group, an unsubstituted pyrazole bonded at the 4-position, an unsubstituted pyrimidine bonded at the 5-position, or a pyrimidine bonded at the 5-position and substituted at the 4-position with a C1-C3 alkyl group;

[0016] Also, Z [ka] and R 2 is a C1-C3 alkyl group, R 3 is bonded at position 4 and R at position 3 9 a thiophene substituted with , an unsubstituted pyrimidine bonded at the 5-position, or a pyrimidine bonded at the 5-position and substituted at the 4-position with a C1-C3 alkyl group; Z is the same as above, and R 2 When is a hydrogen atom, R 3 is neither a pyridine bonded at the 3-position and substituted at the 4-position with a C1-C3 alkyl group nor an unsubstituted pyrazole bonded at the 4-position; Z is the same as above, and R 1 is a C1-C3 alkyl group, and R 2 When is a hydrogen atom, R 3 is neither a 4-cyclopropylpyridine attached at the 3-position nor an unsubstituted pyrimidine attached at the 5-position; Also, Z [ka] When R 3 is bonded at position 4 and R at position 3 9the thiophene bonded at the 3-position and substituted at the 4-position with a C1-C3 alkyl group, the pyridine bonded at the 4-position with an unsubstituted pyrazole bonded at the 4-position, the unsubstituted pyrimidine bonded at the 5-position, or the pyrimidine bonded at the 5-position with an unsubstituted C1-C3 alkyl group at the 4-position. The pharmaceutical agent according to (1) or (2), which is a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof.

[0017] (4) R of the compound 3 is the following formula [ka] [wherein Y represents an oxygen atom or a sulfur atom.] R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group. R 5 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 6 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 7a means a hydrogen atom, a C1-C3 alkoxy group, or a cyclopropyl group. R 7b means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyclopropyl group. R 8 means a hydrogen atom or a C1 to C3 alkoxy group. R 9 means a hydrogen atom or a C1 to C3 alkyl group. R 10 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyano group. In addition, R 6 is a C1-C3 alkoxy group, R 7 and R 8 is a hydrogen atom, and R 8 is a C1-C3 alkoxy group, R 6 is a hydrogen atom or a fluorine atom, and R 7 is a hydrogen atom.

[0018] However, Z is [ka] When R 3 is neither a pyridine bonded at the 2-position and substituted at the 3-position with a C1-C3 alkoxy group nor a pyridine bonded at the 5-position and substituted at the 3-position with a C1-C3 alkoxy group. The pharmaceutical agent according to (3), which is a compound selected from the group consisting of:

[0019] (5) R of the compound 3 is the following formula [ka] [In the formula, R 4 each independently represents a hydrogen atom or a methoxy group. R 5 means a hydrogen atom, a fluorine atom, or a methoxy group. R 6 means a hydrogen atom, a fluorine atom, or a methoxy group. R 7a means a hydrogen atom, a methoxy group, or a cyclopropyl group. R 7b means a hydrogen atom, a methyl group, or a methoxy group. R 8 means a hydrogen atom or a methoxy group. R 9 means a hydrogen atom or a methyl group. R 10 means a hydrogen atom, a methyl group, a methoxy group, or a cyano group. In addition, R 6 When is a methoxy group, R 7a and R 8 is a hydrogen atom, and R 6 When is a fluorine atom, R 8 is a hydrogen atom, and R 8 When is a methoxy group, R 6 is a hydrogen atom or a fluorine atom, and R7a is a hydrogen atom.

[0020] However, Z is [ka] When R 3 rather than 3-methylpyrazole attached at the 4-position; Also, Z [ka] When R 3 is not a 3-position-linked unsubstituted pyridine, a 4-position-linked 3-methylpyrazole, a 3-position-linked 2-methoxypyridine, a 3-position-linked 4-methoxypyridine, or a 2-position-linked unsubstituted thiophene; Also, Z [ka] When R 3 is not an unsubstituted pyrimidine attached at the 5-position, a 3-methylpyrazole attached at the 4-position, a 2-methoxypyridine attached at the 3-position, a 4-methoxypyridine attached at the 3-position, or an unsubstituted thiophene attached at the 2-position;

[0021] Also, Z [ka] and R 2 When is a methyl group, R 3 is not a 3-linked unsubstituted pyridine, a 3-linked 2-methoxypyridine, a 3-linked 4-methoxypyridine, or a 2-linked unsubstituted thiophene; Z is the same as above, and R 2 When is a hydrogen atom, R 3 is not an unsubstituted pyridine attached at the 3-position, a 3-methylpyrazole attached at the 4-position, or an unsubstituted thiophene attached at the 2-position; Z is the same as above, and R 2When is a fluorine atom, R 3 is not an unsubstituted pyridine attached at the 3-position, a 4-methylpyrimidine attached at the 5-position, a 2-methoxypyridine attached at the 3-position, or an unsubstituted thiophene attached at the 2-position; Also, Z [ka] When R 3 is not a 3-position-bonded unsubstituted pyridine, a 4-position-bonded 3-methylpyrazole, a 3-position-bonded 2-methoxypyridine, a 3-position-bonded 4-methoxypyridine, or a 2-position-bonded unsubstituted thiophene. The pharmaceutical composition according to (4), which is a compound selected from the group consisting of:

[0022] (6) R of the compound 3 is the following formula [ka] [In the formula, R 4 each independently represents a hydrogen atom or a methoxy group. R 5 means a hydrogen atom, a fluorine atom, or a methoxy group. R 6 means a hydrogen atom, a fluorine atom, or a methoxy group. R 7a means a hydrogen atom, a methoxy group, or a cyclopropyl group. R 7b means a methoxy group. R 8 means a hydrogen atom or a methoxy group. R 9 means a hydrogen atom or a methyl group. In addition, R 6 When is a methoxy group, R 7a and R 8 is a hydrogen atom, and R 6 When is a fluorine atom, R 8 is a hydrogen atom, and R 7a When is a methoxy group, R6 is a fluorine atom, R 8 is a hydrogen atom. However, Z is [ka] When R 3 is not an unsubstituted pyridine bonded at the 3-position. The pharmaceutical agent according to (5), which is a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof.

[0023] (7) Z of the compound is of the following formula: [ka] The pharmaceutical agent according to (1) or (2), which is a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof.

[0024] (8) Z of the compound is of the following formula: [ka] The pharmaceutical agent according to (1) or (2), which is a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof.

[0025] (9) Z of the compound is of the following formula: [ka] [In the formula, R 2 means a hydrogen atom, a methyl group, or a fluorine atom. and R 3 is the following formula [ka] [In the formula, R 4 means a hydrogen atom or a methoxy group. The pharmaceutical agent according to (7), which is a compound selected from the group consisting of:

[0026] (10) Z of the compound is of the following formula: [ka] and R 3 is the following formula [ka] [In the formula, R 4 means a hydrogen atom or a methoxy group. R 6 means a hydrogen atom or a fluorine atom. R 7a means a hydrogen atom, a methyl group, a methoxy group, or a cyclopropyl group. R 7b means a hydrogen atom, a methyl group, or a methoxy group. In addition, R 6 When is a hydrogen atom, R 7a means a methoxy group or a cyclopropyl group, and R 7a When is a methyl group, R 6 is a fluorine atom, and R 7a When is a cyclopropyl group, R 6 is a hydrogen atom. The pharmaceutical composition according to (8), which is a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof.

[0027] (11) The compound is the following compound: N-((1H-imidazol-4-yl)methyl)-[2,3'-bithiophene]-4'-amine; N-((1H-imidazol-4-yl)methyl)-[2,2'-bithiophene]-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine;

[0028] N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-methylpyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methylthiazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine;

[0029] N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine; 4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole; 4-((2-(furan-2-yl)phenoxy)methyl)-1H-imidazole; 4-((2-(thiophen-2-yl)phenoxy)methyl)-1H-imidazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyridine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine;

[0030] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methylpyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methylpyrimidine;

[0031] 5-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine; (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole; 3-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)pyridine; 4-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)-1H-pyrazole; and 4-(((2-(thiophen-3-yl)phenyl)thio)methyl)-1H-imidazole The pharmaceutical agent according to (1) or (2), which is a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof.

[0032] (12) The compound is the following compound: N-((1H-imidazol-4-yl)methyl)-[2,3'-bithiophene]-4'-amine; N-((1H-imidazol-4-yl)methyl)-[2,2'-bithiophene]-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine;

[0033] N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methylthiazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine;

[0034] N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine;

[0035] 4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole; 4-((2-(thiophen-2-yl)phenoxy)methyl)-1H-imidazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyridine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile; 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine;

[0036] 5-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine; (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole; and 3-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)pyridine The pharmaceutical agent according to (4), which is a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof.

[0037] (13) The compound is the following compound: N-((1H-imidazol-4-yl)methyl)-[2,3'-bithiophene]-4'-amine; N-((1H-imidazol-4-yl)methyl)-[2,2'-bithiophene]-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline;

[0038] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline;

[0039] N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine; 4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine;

[0040] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile; 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine; 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; and 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine The pharmaceutical agent according to (5), which is a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof.

[0041] (14) The pharmaceutical composition according to any one of (1) to (13), for the prevention or treatment of a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence.

[0042] (15) Use of a compound represented by general formula (I) of (1) or (2) or a pharmacologically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence. (16) A method for preventing or treating a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence, comprising administering a therapeutically effective amount of the pharmaceutical agent according to any one of (1) to (13) to a subject patient in need thereof. [Effects of the Invention]

[0043] The pharmaceutical agent of the present invention has excellent adrenergic α1A receptor agonism and is useful as a preventive or therapeutic agent for orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence. DETAILED DESCRIPTION OF THE INVENTION

[0044] In this specification, each term is defined as follows. The term "C1 to C3 alkyl group" refers to a linear or branched alkyl group consisting of 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, and an i-propyl group. The term "C1 to C3 alkoxy group" specifically means an --O--(C1 to C3 alkyl) group, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, and an i-propoxy group. The term "C1 to C6 alkyl group" refers to a straight-chain alkyl group consisting of 1 to 6 carbon atoms.

[0045] The pharmaceutical of the present invention will be explained below. [ka] The compound contained as an active ingredient in the medicament of the present invention is a compound represented by the above general formula (I), wherein R 1 and Z is a compound defined as follows or a pharmacologically acceptable salt thereof.

[0046] R 1 is a hydrogen atom or a C1 to C3 alkyl group.

[0047] Z is selected from the group consisting of the following formulae: [ka] [In the formula, R 2 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkyl group. R 3 is selected from the group consisting of the following formulas: [ka] (In the formula, Y represents an oxygen atom or a sulfur atom. R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group. R 5 means a hydrogen atom, a fluorine atom, a C1 to C3 alkyl group, or a C1 to C3 alkoxy group. R 6 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 7 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyclopropyl group. R 8 means a hydrogen atom or a C1 to C3 alkoxy group. R 9 means a hydrogen atom or a C1 to C3 alkyl group. R 10 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyano group. In addition, R 6 is a C1-C3 alkoxy group, R 7 and R 8 is a hydrogen atom, and R 8 is a C1-C3 alkoxy group, R 6 is a hydrogen atom or a fluorine atom, and R 7 is a hydrogen atom.)

[0048] Preferably, Z is [ka] and R 2 When is a hydrogen atom, R3 rather than 3-fluoropyridine attached at the 2-position; Also, Z [ka] and R 2 When is a hydrogen atom, R 3 is not an unsubstituted pyridine attached at the 2-position, an unsubstituted pyrazole attached at the 3-position, or a 3-methoxypyrazole attached at the 4-position;

[0049] Also, Z [ka] and R 2 When is a hydrogen atom, R 3 rather than unsubstituted furan bonded at the 2-position; Also, Z [ka] and R 1 is a C1-C3 alkyl group and R 2 When is a hydrogen atom, R 3 rather than unsubstituted pyrazole attached at the 4-position; Also, Z [ka] When R 3 is not an unsubstituted thiazole attached at the 5-position.

[0050] In the compound contained as an active ingredient in the medicament of the present invention, the R 3 Among these, groups selected from the group consisting of the following formulae are preferred: [ka] [wherein Y represents an oxygen atom or a sulfur atom.] R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group. R 5means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 6 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 7 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyclopropyl group. R 8 means a hydrogen atom or a C1 to C3 alkoxy group. R 9 means a hydrogen atom or a C1 to C3 alkyl group. R 10 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyano group. In addition, R 6 is a C1-C3 alkoxy group, R 7 and R 8 is a hydrogen atom, and R 8 is a C1-C3 alkoxy group, R 6 is a hydrogen atom or a fluorine atom, and R 7 is a hydrogen atom.

[0051] However, Z is [ka] When R 3 is bonded at position 4 and R at position 3 9 a thiophene substituted with , a pyridine bonded at the 3-position and substituted at the 4-position with a C1-C3 alkyl group, or an unsubstituted pyrazole bonded at the 4-position; Also, Z [ka] When R 3 is bonded at position 4 and R at position 3 9 a thiophene substituted with , a pyridine bonded at the 3-position and substituted at the 4-position with a C1-C3 alkyl group, an unsubstituted pyrazole bonded at the 4-position, an unsubstituted pyrimidine bonded at the 5-position, or a pyrimidine bonded at the 5-position and substituted at the 4-position with a C1-C3 alkyl group;

[0052] Also, Z [ka] and R 2 is a C1-C3 alkyl group, R 3 is bonded at position 4 and R at position 3 9 a thiophene substituted with , an unsubstituted pyrimidine bonded at the 5-position, or a pyrimidine bonded at the 5-position and substituted at the 4-position with a C1-C3 alkyl group; Z is the same as above, and R 2 When is a hydrogen atom, R 3 is neither a pyridine bonded at the 3-position and substituted at the 4-position with a C1-C3 alkyl group nor an unsubstituted pyrazole bonded at the 4-position; Z is the same as above, and R 1 is a C1-C3 alkyl group and R 2 When is a hydrogen atom, R 3 is neither a 4-cyclopropylpyridine attached at the 3-position nor an unsubstituted pyrimidine attached at the 5-position; Also, Z [ka] When R 3 is bonded at position 4 and R at position 3 9 the thiophene bonded at the 3-position and substituted at the 4-position with a C1-C3 alkyl group, the pyridine bonded at the 4-position with an unsubstituted pyrazole bonded at the 4-position, the unsubstituted pyrimidine bonded at the 5-position, or the pyrimidine bonded at the 5-position with an unsubstituted C1-C3 alkyl group at the 4-position.

[0053] In the compound contained as an active ingredient in the medicament of the present invention, the R 3 Among these, groups selected from the group consisting of the following formulae are more preferred: [ka] [wherein Y represents an oxygen atom or a sulfur atom.] R 4each independently represents a hydrogen atom or a C1-C3 alkoxy group. R 5 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 6 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 7a means a hydrogen atom, a C1-C3 alkoxy group, or a cyclopropyl group. R 7b means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyclopropyl group. R 8 means a hydrogen atom or a C1 to C3 alkoxy group. R 9 means a hydrogen atom or a C1 to C3 alkyl group. R 10 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyano group. In addition, R 6 is a C1-C3 alkoxy group, R 7 and R 8 is a hydrogen atom, and R 8 is a C1-C3 alkoxy group, R 6 is a hydrogen atom or a fluorine atom, R 7 is a hydrogen atom. However, Z is [ka] When R 3 is neither a pyridine bonded at the 2-position and substituted at the 3-position with a C1-C3 alkoxy group nor a pyridine bonded at the 5-position and substituted at the 3-position with a C1-C3 alkoxy group.

[0054] The compound contained as an active ingredient in the medicament of the present invention further comprises the R 3 Among these, groups selected from the group consisting of the following formulae are more preferred: [ka] [In the formula, R4 each independently represents a hydrogen atom or a methoxy group. R 5 means a hydrogen atom, a fluorine atom, or a methoxy group. R 6 means a hydrogen atom, a fluorine atom, or a methoxy group. R 7a means a hydrogen atom, a methoxy group, or a cyclopropyl group. R 7b means a hydrogen atom, a methyl group, or a methoxy group. R 8 means a hydrogen atom or a methoxy group. R 9 means a hydrogen atom or a methyl group. R 10 means a hydrogen atom, a methyl group, a methoxy group, or a cyano group. In addition, R 6 When is a methoxy group, R 7a and R 8 is a hydrogen atom, and R 6 When is a fluorine atom, R 8 is a hydrogen atom, and R 8 When is a methoxy group, R 6 is a hydrogen atom or a fluorine atom, R 7a is a hydrogen atom.

[0055] However, Z is [ka] When R 3 rather than 3-methylpyrazole attached at the 4-position; Also, Z [ka] When R 3 is not a 3-position-linked unsubstituted pyridine, a 4-position-linked 3-methylpyrazole, a 3-position-linked 2-methoxypyridine, a 3-position-linked 4-methoxypyridine, or a 2-position-linked unsubstituted thiophene; Also, Z [ka] When R 3 is not an unsubstituted pyrimidine attached at the 5-position, a 3-methylpyrazole attached at the 4-position, a 2-methoxypyridine attached at the 3-position, a 4-methoxypyridine attached at the 3-position, or an unsubstituted thiophene attached at the 2-position;

[0056] Also, Z [ka] and R 2 When is a methyl group, R 3 is not a 3-linked unsubstituted pyridine, a 3-linked 2-methoxypyridine, a 3-linked 4-methoxypyridine, or a 2-linked unsubstituted thiophene; In addition, Z is the same as above, and R 2 When is a hydrogen atom, R 3 is not an unsubstituted pyridine attached at the 3-position, a 3-methylpyrazole attached at the 4-position, or an unsubstituted thiophene attached at the 2-position; In addition, Z is the same as above, and R 2 When is a fluorine atom, R 3 is not an unsubstituted pyridine attached at the 3-position, a 4-methylpyrimidine attached at the 5-position, a 2-methoxypyridine attached at the 3-position, or an unsubstituted thiophene attached at the 2-position; Also, Z [ka] When R 3 is not a 3-position-bonded unsubstituted pyridine, a 4-position-bonded 3-methylpyrazole, a 3-position-bonded 2-methoxypyridine, a 3-position-bonded 4-methoxypyridine, or a 2-position-bonded unsubstituted thiophene.

[0057] In the compound contained as an active ingredient in the medicament of the present invention, the R 3 Among these, groups selected from the group consisting of the following formulae are particularly preferred: [ka] [In the formula, R 4 each independently represents a hydrogen atom or a methoxy group. R 5 means a hydrogen atom, a fluorine atom, or a methoxy group. R 6 means a hydrogen atom, a fluorine atom, or a methoxy group. R 7a means a hydrogen atom, a methoxy group, or a cyclopropyl group. R 7b means a methoxy group. R 8 means a hydrogen atom or a methoxy group. R 9 means a hydrogen atom or a methyl group.

[0058] In addition, R 6 When is a methoxy group, R 7a and R 8 is a hydrogen atom, and R 6 When is a fluorine atom, R 8 is a hydrogen atom, and R 7a When is a methoxy group, R 6 is a fluorine atom, R 8 is a hydrogen atom. However, Z is [ka] When R 3 is not an unsubstituted pyridine bonded at the 3-position.

[0059] In one embodiment of the compound contained as an active ingredient in the medicament of the present invention, Z is represented by the following formula: [ka] and a structure selected from the group consisting of: [ka] A structure in which:

[0060] where R 2 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkyl group.

[0061] Also, R 3 is preferably a group selected from the group consisting of the following formulae: [ka] [In the formula, R 4 means a hydrogen atom or a methoxy group.

[0062] In another embodiment of the compound contained as an active ingredient in the medicament of the present invention, Z is represented by the following formula: [ka] is.

[0063] where R 3 is preferably a group selected from the group consisting of the following formulae: [ka] [In the formula, R 4 means a hydrogen atom or a methoxy group. R 6 means a hydrogen atom or a fluorine atom. R 7a means a hydrogen atom, a methyl group, a methoxy group, or a cyclopropyl group. R 7b means a hydrogen atom, a methyl group, or a methoxy group. In addition, R 6 When is a hydrogen atom, R 7a means a methoxy group or a cyclopropyl group, and R 7a When is a methyl group, R 6 is a fluorine atom, and R 7a When is a cyclopropyl group, R 6 is a hydrogen atom.

[0064] Among the compounds contained as active ingredients in the medicament of the present invention, compounds having a strong α1A agonist effect are preferred. As described above, more preferred substituents Z and R 3 By selecting the above, a compound with a strong α1A agonist effect can be obtained. In addition, from the range of compounds contained as active ingredients in the medicament of the present invention, R 1 Of the two enantiomers that are generated when is a C1-C3 alkyl group, the enantiomer having a weaker α1A agonist activity than 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole (Example 47) is excluded. The enantiomer having a weaker α1A agonist activity than 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole (Example 47) is, for example, an enantiomer having a lower EC 50 In a preferred embodiment of the compound contained as an active ingredient in the pharmaceutical of the present invention, R 1 Of the two enantiomers that are generated when R is a C1-C3 alkyl group, the enantiomer with a weaker α1A agonist effect is excluded. Note that, normally, the enantiomer with an optical rotation of (+) has a stronger α1A agonist effect than the (-) enantiomer. That is, in a preferred embodiment of the compound contained as an active ingredient in the pharmaceutical of the present invention, R 1 Of the two enantiomers that are generated when is a C1-C3 alkyl group, the enantiomer with an optical rotation of (+) is included in the present invention, but the (-) enantiomer is not included.

[0065] Pharmacologically acceptable salts of the compounds represented by general formula (I) contained as active ingredients in the medicament of the present invention are included within the scope of the present invention. Examples of pharmacologic acceptable salts include salts with amino acids (e.g., salts with aspartic acid, glutamic acid, etc.), salts with inorganic acids (e.g., salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc.), and salts with organic acids (e.g., salts with formic acid, acetic acid, trifluoroacetic acid, etc.). The reaction of forming these salts can be carried out according to conventional methods.

[0066] Compounds that are converted into the compound represented by the general formula (I) by reactions with enzymes, gastric acid, etc. under physiological conditions in vivo are included within the scope of compounds contained as active ingredients in the medicament of the present invention, such as compounds in which the imidazole group of the compound represented by the general formula (I) is amidated (e.g., acetamidated).

[0067] The compound represented by general formula (I) contained as an active ingredient in the medicament of the present invention can be produced by the methods shown in the following reaction schemes I to IX, the methods described in the Examples, or a combination of known methods. Compounds used as starting materials or reagents necessary for producing compounds contained as active ingredients in the medicament of the present invention, for which the production method is not specified, are commercially available or can be produced by referring to known methods.

[0068] Reaction scheme I shows the reaction of R 1 is a hydrogen atom and Z is bonded via a nitrogen atom. [Reaction Scheme I] [ka] wherein ring A represents a ring selected from the group consisting of the following formulae: [ka] (In the formula, R 2 means a hydrogen atom, a fluorine atom, or a C1-C3 alkyl group.

[0069] In addition, ring B in the above formula means a ring selected from the group consisting of the following formulae: [ka] [wherein Y represents an oxygen atom or a sulfur atom.] R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group. R 5means a hydrogen atom, a fluorine atom, a C1 to C3 alkyl group, or a C1 to C3 alkoxy group. R 6 means a hydrogen atom, a fluorine atom, or a C1 to C3 alkoxy group. R 7 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyclopropyl group. R 8 means a hydrogen atom or a C1 to C3 alkoxy group. R 9 means a hydrogen atom or a C1 to C3 alkyl group. R 10 means a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group, or a cyano group. In addition, R 6 is a C1-C3 alkoxy group, R 7 and R 8 is a hydrogen atom, and R 8 is a C1-C3 alkoxy group, R 6 is a hydrogen atom or a fluorine atom, R 7 is a hydrogen atom.

[0070] [Process I-1] The compound represented by general formula (1) is reacted with 4-formylimidazole (2) in an appropriate solvent (e.g., N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane, or a mixture thereof) using an additive (e.g., acetic acid, triethylamine, titanium tetraisopropoxide, etc.) to obtain the compound represented by general formula (3). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0071] [Process I-2] A compound of general formula (4) can be obtained by reacting a compound of general formula (3) with a reducing agent (e.g., sodium borohydride, sodium triacetoxyborohydride, etc.) in an appropriate solvent (e.g., N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane, or a mixture thereof). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours. Steps I-1 and I-2 may be carried out consecutively or in one pot without isolation and purification after step I-1.

[0072] Reaction scheme II shows the reaction of R 1 is a C1-C3 alkyl group and Z is bonded via a nitrogen atom.

[0073] [Reaction Scheme II] [ka] wherein ring A and ring B have the same meanings as in reaction scheme I. PG 1 means a protecting group for an imidazolyl group. R 1 means a C1 to C3 alkyl group. X 1 means a bromine atom or a chlorine atom.

[0074] [Process II-1] The compound represented by general formula (1) and the compound represented by general formula (5) are reacted in an appropriate solvent (e.g., N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane, or a mixture thereof) using an additive (e.g., acetic acid, p-toluenesulfonic acid, triethylamine, titanium tetraisopropoxide, molecular sieves, etc.) to obtain the compound represented by general formula (6). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0075] [Process II-2] The compound of general formula (6) is reacted with a Grignard reagent (7) (e.g., methylmagnesium bromide) in a suitable solvent (e.g., tetrahydrofuran) to obtain the compound of general formula (8). The reaction temperature ranges from 0°C to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 24 hours.

[0076] [Process II-3] The compound represented by general formula (9) can be obtained by removing the protecting group of the compound represented by general formula (8) with reference to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)".

[0077] The compound represented by general formula (1) used as a starting material in reaction schemes I and II can be produced by the method shown in reaction scheme III below, the method described in the Reference Examples, or a combination of known methods. [Reaction Scheme III] [ka] [In the ceremony, PG 2 means a protecting group for an amino group or a hydrogen atom. Ring A and ring B have the same meanings as in Reaction Scheme I. M 1 is -B(OH)2 or [ka] means. M 2 means a triC1-C6 alkyltin group. X 2 means a bromine atom or an iodine atom. Furthermore, PG 2 When is a hydrogen atom, the compound represented by the general formula (13) and the compound (1) can be obtained without going through step III-5.

[0078] [Process III-1] A compound represented by general formula (10) and a compound represented by general formula (11) are reacted in an appropriate solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(di-t-butylphosphino)ferrocene]palladium dichloride, etc.) to obtain a compound represented by general formula (13). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0079] [Process III-2] The compound represented by general formula (10) and the compound represented by general formula (12) are reacted in a suitable solvent (e.g., dioxane, toluene, etc.) in the presence or absence of an additive (e.g., potassium fluoride, etc.) using a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium, etc.) to obtain the compound represented by general formula (13). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0080] [Process III-3] The compound represented by general formula (10) is reacted with bis(pinacolato)diboron (14) in a suitable solvent (e.g., dioxane) in the presence of a base (e.g., potassium acetate) using a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium), to obtain the compound represented by general formula (15). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0081] [Process III-4] A compound represented by general formula (15) and a compound represented by general formula (16) are reacted in an appropriate solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(di-t-butylphosphino)ferrocene]palladium dichloride, etc.) to obtain a compound represented by general formula (13). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0082] [Process III-5] PG of the compound represented by general formula (13) 2 When is a protecting group for an amino group, the protecting group can be removed by referring to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)", to obtain a compound of general formula (1).

[0083] Reaction scheme IV shows the reaction of R 1 is a hydrogen atom and Z is bonded via a nitrogen atom, and is an alternative method to Reaction Scheme I.

[0084] [Reaction Scheme IV] [ka] wherein ring A and ring B have the same meanings as in reaction scheme I. M 1 means the same group as in Reaction Scheme III.

[0085] [Process IV-1] The compound of general formula (17) is reacted with 4-formylimidazole (2) in a suitable solvent (e.g., N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane, or a mixture thereof) using an additive (e.g., acetic acid, triethylamine, titanium tetraisopropoxide, etc.) to obtain the compound of general formula (18). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0086] [Process IV-2] A compound of general formula (19) can be obtained by reacting a compound of general formula (18) with a reducing agent (e.g., sodium borohydride, sodium triacetoxyborohydride, etc.) in an appropriate solvent (e.g., N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane, or a mixture thereof). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours. Steps IV-1 and IV-2 may be carried out consecutively or in one pot without isolation and purification after Step IV-1.

[0087] [Process IV-3] The compound represented by general formula (19) and the compound represented by general formula (11) are reacted in an appropriate solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(di-t-butylphosphino)ferrocene]palladium dichloride, etc.) to obtain the compound represented by general formula (4). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0088] Reaction scheme V is a reaction scheme in which R 1 is a hydrogen atom and Z is bonded via an oxygen atom.

[0089] [Reaction Scheme V] [ka] [In the ceremony, PG 1 means the same group as in Reaction Scheme II. X 2 means the same group as in Reaction Scheme III. R 2 means the same group as in Reaction Scheme I. Ring B has the same meaning as in Reaction Scheme I. M 1 and M 2 means the same group as in Reaction Scheme III.

[0090] [Process V-1] The compound represented by general formula (20) and the compound represented by general formula (21) are reacted in a suitable solvent (e.g., tetrahydrofuran, etc.) in the presence of an additive (e.g., triphenylphosphine, etc.) using a Mitsunobu reaction reagent (e.g., diisopropyl azodicarboxylate, etc.) to obtain the compound represented by general formula (22). The reaction temperature is from 0°C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0091] [Process V-2] The compound represented by general formula (23) and the compound represented by general formula (21) are reacted in an appropriate solvent (e.g., N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.) with or without an additive (e.g., potassium iodide, etc.) using a base (e.g., potassium carbonate, sodium carbonate, etc.) to obtain the compound represented by general formula (22). The reaction temperature is from 0°C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0092] [Process V-3] A compound represented by general formula (22) and a compound represented by general formula (11) are reacted in an appropriate solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(di-t-butylphosphino)ferrocene]palladium dichloride, etc.) to obtain a compound represented by general formula (24). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0093] [Process V-4] A compound represented by general formula (22) and a compound represented by general formula (12) are reacted in an appropriate solvent (e.g., dioxane, toluene, etc.) in the presence or absence of an additive (e.g., potassium fluoride, etc.) using a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium, etc.) to obtain a compound represented by general formula (24). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0094] [Process V-5] The compound represented by general formula (25) can be obtained by removing the protecting group of the compound represented by general formula (24) with reference to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)".

[0095] Reaction scheme VI shows the reaction of R 1 is a hydrogen atom and Z is bonded via an oxygen atom, and is an alternative method to Reaction Scheme V.

[0096] [Reaction Scheme VI] [ka] wherein ring B has the same meaning as in reaction scheme I. R 2 means the same group as in Reaction Scheme I. PG 1 means the same group as in Reaction Scheme II.

[0097] [Process VI-1] The compound represented by general formula (26) and the compound represented by general formula (20) are reacted in an appropriate solvent (e.g., tetrahydrofuran, etc.) in the presence of an additive (e.g., triphenylphosphine, etc.) using a Mitsunobu reaction reagent (e.g., diisopropyl azodicarboxylate, etc.) to obtain the compound represented by general formula (24). The reaction temperature is from 0°C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0098] [Process VI-2] The compound represented by general formula (25) can be obtained by removing the protecting group of the compound represented by general formula (24) with reference to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)".

[0099] Reaction Scheme VII shows the reaction of R 1 is a C1-C3 alkyl group and Z is bonded via an oxygen atom.

[0100] [Reaction Scheme VII] [ka] [In the ceremony, PG 1 , X 1 , and R 1 means the same group as in Reaction Scheme II. R 2 means the same group as in Reaction Scheme I. Ring B has the same meaning as in Reaction Scheme I.

[0101] [Process VII-1] The compound of general formula (5) is reacted with a Grignard reagent (7) (e.g., methylmagnesium bromide) in a suitable solvent (e.g., tetrahydrofuran) to obtain the compound of general formula (27). The reaction temperature ranges from 0°C to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 24 hours.

[0102] [Process VII-2] The compound represented by general formula (27) is reacted with a chlorinating agent (e.g., methanesulfonyl chloride) in an appropriate solvent (e.g., chloroform) in the presence or absence of an additive (e.g., triethylamine) to obtain a compound represented by general formula (28). The reaction temperature ranges from 0°C to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 24 hours.

[0103] [Process VII-3] The compound represented by general formula (28) and the compound represented by general formula (26) are reacted in an appropriate solvent (e.g., N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.) with or without an additive (e.g., potassium iodide, etc.) using a base (e.g., potassium carbonate, sodium carbonate, etc.) to obtain the compound represented by general formula (29). The reaction temperature is from 0°C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0104] [Process VII-4] The compound represented by general formula (30) can be obtained by removing the protecting group of the compound represented by general formula (29) with reference to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)".

[0105] The compound represented by general formula (26) used as a starting material in reaction schemes VI and VII can be produced by the method shown in the following reaction scheme VIII, the method described in the Reference Examples, or a combination of known methods. [Reaction Scheme VIII] [ka] [In the ceremony, M 1 means the same group as in Reaction Scheme III. Ring B has the same meaning as in Reaction Scheme I. X 2 means the same group as in Reaction Scheme III.

[0106] [Process VIII-1] A compound represented by general formula (31) and a compound represented by general formula (16) are reacted in an appropriate solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(di-t-butylphosphino)ferrocene]palladium dichloride, etc.) to obtain a compound represented by general formula (26). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0107] Reaction Scheme IX shows the reaction of R 1 is a hydrogen atom and Z is bonded via a sulfur atom.

[0108] [Reaction Scheme IX] [ka] [In the ceremony, PG 1 means the same group as in Reaction Scheme II. R 2 means the same group as in Reaction Scheme I. Ring B has the same meaning as in Reaction Scheme I. M 1 and X 2 means the same group as in Reaction Scheme III.

[0109] [Process IX-1] The compound represented by general formula (32) and the compound represented by general formula (33) are reacted in an appropriate solvent (e.g., N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.) with or without an additive (e.g., potassium iodide, etc.) using a base (e.g., potassium carbonate, sodium carbonate, etc.) to obtain the compound represented by general formula (34). The reaction temperature is from 0°C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0110] [Process IX-2] A compound represented by general formula (34) and a compound represented by general formula (11) are reacted in an appropriate solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(di-t-butylphosphino)ferrocene]palladium dichloride, etc.) to obtain a compound represented by general formula (35). The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time ranges from 30 minutes to 48 hours.

[0111] [Process IX-3] The compound represented by general formula (36) can be obtained by removing the protecting group of the compound represented by general formula (35) with reference to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)".

[0112] Regarding substituents (e.g., hydroxyl group, amino group, carboxy group, etc.) contained in the compound contained as an active ingredient in the medicament of the present invention and in the compound used to produce said compound, it may be effective in producing the compound to introduce an appropriate protecting group into said substituent at the stage of a raw material or intermediate, and if necessary, a protecting group described in the aforementioned "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)" may be appropriately selected and used.

[0113] To isolate and purify the compounds contained as active ingredients in the pharmaceutical of the present invention and the compounds used to produce said compounds from the reaction mixture, commonly used methods can be used. For example, solvent extraction, ion exchange resin, column chromatography using silica gel, alumina, or the like as a carrier, high-performance liquid chromatography (HPLC) fractionation, thin-layer chromatography, scavenger resin, recrystallization, etc. can be used. These isolation and purification methods can be used alone or in combination. Isolation and purification can be performed for each reaction or after completion of several reactions.

[0114] When the compound herein has an asymmetric carbon atom and optical isomers exist, these optical isomers can be resolved by a conventional method for optical resolution of a racemic compound, for example, a method of fractional crystallization in which a compound is recrystallized as a diastereomeric salt with a general optically active compound, or a method of reacting a compound with a general optically active compound to form diastereomers and subjecting the diastereomers to chromatography, etc. Alternatively, each optical isomer can also be resolved by high performance liquid chromatography (HPLC) fractionation using an optically active separation column.

[0115] The compound contained as an active ingredient in the pharmaceutical of the present invention produced in this manner acts as an adrenergic α1A receptor agonist and can therefore be used as a preventive or therapeutic agent for orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence. To prevent or treat a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence, a therapeutically effective amount of the pharmaceutical agent of the present invention can be administered to a patient in need thereof. The subject may be, for example, a human or a non-human mammal, preferably a human.

[0116] The pharmaceutical of the present invention can be administered orally or parenterally, and various dosage forms can be selected depending on the purpose. For example, oral dosage forms include tablets, capsules, powders, and granules, while parenteral dosage forms include patches, liniments, and ointments. When forming into a convenient tablet form, orally ingestible ingredients used in the field can be appropriately selected. Examples include excipients, binders, disintegrants, lubricants, flavoring agents, and anti-aggregating agents. The pharmaceutical of the present invention is typically used as a pharmaceutical composition in which the compound contained as the active ingredient is mixed with the above-mentioned additives.

[0117] The dosage of the medicament of the present invention is not particularly limited and can be selected appropriately. The dosage of the medicament of the present invention is determined appropriately depending on its dosage form, method of use, the patient's age, sex, and other conditions, and the severity of the disease. In the case of oral administration, the daily dose of the compound as the active ingredient contained in the medicament of the present invention is in the range of approximately 0.1 μg to 100 mg per kg of body weight, which can be administered appropriately in 1 to 4 divided doses per day. However, the dosage and frequency of administration are determined depending on relevant circumstances, including the severity of the symptoms to be treated, the type of compound to be administered, and the selected administration route, and therefore the ranges of the dosage and frequency of administration do not limit the scope of the present invention. [Example]

[0118] The present invention will be explained in more detail below with reference to Examples, Reference Examples, and Pharmacological Test Examples, but the technical scope of the present invention is not limited to the contents of these descriptions.

[0119] [Nuclear magnetic resonance spectrum] In the following Examples and Reference Examples, nuclear magnetic resonance (1 H-NMR spectra were measured using an Agilent 400 MR and a Bruker AVANCE NEO 400. Chemical shift values ​​were reported in δ values ​​(ppm) using tetramethylsilane as an internal standard. Splitting patterns were indicated by "s" for singlets, "d" for doublets, "t" for triplets, "q" for quartets, "quint" for quintets, "m" for multiplets, and "br" for broad lines.

[0120] Mass spectrometry was performed by electrospray ionization (ESI) under any of the following measurement conditions A to D. [Measurement condition A] Measurement equipment: Waters ACQUITY UPLC / SQD system Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1 mm x 50 mm) Column temperature: 50℃ Flow rate: 1.5 mL / min UV detection wavelength: 210-400 nm Mobile phase: [A] Water / acetonitrile / formic acid = 97 / 3 / 0.1, [B] Water / acetonitrile / formic acid = 5 / 95 / 0.1 Gradient: [A] / [B] = 95 / 5 to 1 / 99 (1 minute linear gradient)

[0121] [Measurement condition B] Measurement equipment: Agilent LC / MSD 1200 series Column: Xbridge-C18 (1.7 μm, 2.1 mm × 50 mm) Column temperature: 30℃ Flow rate: 1.5 mL / min UV detection wavelength: 214 or 254 nm Mobile phase: [A] 0.1% trifluoroacetic acid in water, [B] acetonitrile Gradient: [A] / [B] = 95 / 5 to 5 / 95 (linear gradient over 2.5 minutes) [Measurement conditions C] Measurement equipment: Agilent LC / MSD 1200 series Column: Xbridge-C18 (1.7 μm, 2.1 mm × 50 mm) Column temperature: 30℃ Flow rate: 1.5 mL / min UV detection wavelength: 214 or 254 nm Mobile phase: [A] 0.1% ammonium bicarbonate aqueous solution, [B] acetonitrile Gradient: [A] / [B] = 95 / 5 to 5 / 95 (linear gradient over 2.5 minutes)

[0122] In the table, methyl group is represented by "Me", ethyl group by "Et", propyl group by "Pr", butyl group by "Bu", trityl group by "Trt", t-butoxycarbonyl group by "Boc", acetyl group by "Ac", N,N-dimethylacetamide by "DMA", tetrahydrofuran by "THF", trifluoroacetic acid by "TFA", 1,1'-bis(diphenylphosphino)ferrocene by "dppf", and 1,1'-bis(di-t-butylphosphino)ferrocene by "dtbpf".

[0123] <Production of Compounds Related to the Present Invention in Which Biaryl Moiety and Imidazole Moiety are Bonded via Nitrogen Atom> Preparation of biarylamine 1 Step III-1 (Reference Examples 1 to 11) [Reference example 1] t-Butyl [2,3'-bithiophene]-4'-ylcarbamate [ka] t-Butyl (4-bromothiophen-3-yl)carbamate (210 mg) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (2.5 mL). 2-thiopheneboronic acid (290 mg), tetrakis(triphenylphosphine)palladium (43.6 mg), and potassium carbonate (41.7 mg) were added. The reaction vessel was purged with argon gas and stirred at 90°C for 4 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0 to 4 / 1) to give the title compound (211 mg). ESI / MS(m / z) 282 (M+H) +

[0124] Compounds were synthesized according to the following reaction scheme, with reference to the method of Reference Example 1. The synthesized compounds and data are shown in Table 1. [ka]

[0125] [Table 1]

[0126] Preparation of biarylamine 2 Step III-2 (Reference Examples 12 to 15) [Reference example 12] t-Butyl (4-(thiazol-2-yl)thiophen-3-yl)carbamate [ka] t-Butyl (4-bromothiophen-3-yl)carbamate (1.1 g) and 2-(tributylstannyl)thiazole (3.0 g) were dissolved in toluene (30 mL), and tetrakis(triphenylphosphine)palladium (464 mg) was added. The reaction vessel was purged with nitrogen gas, and the mixture was stirred overnight at 110° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (pentane / ethyl acetate = 20 / 1) to give the title compound (451 mg). ESI / MS(m / z) 283 (M+H) + .

[0127] Compounds were synthesized according to the following reaction scheme, with reference to the method of Reference Example 12. The synthesized compounds and data are shown in Table 2. [ka]

[0128] [Table 2]

[0129] Preparation of biarylamine 3 Steps III-3 and III-4 (Reference Examples 16 to 36) [Reference example 16] t-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)carbamate [ka] t-Butyl (4-bromothiophen-3-yl)carbamate (3 g) and potassium acetate (3.17 g) were dissolved in 1,4-dioxane (30 mL), and bis(pinacolato)diboron (5.5 g) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (395 mg) were added. The reaction vessel was purged with nitrogen gas, and the mixture was stirred overnight at 100°C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (pentane / ethyl acetate = 10 / 1) to give the title compound (3.2 g). ESI / MS(m / z) 326 (M+H) + .

[0130] [Reference example 17] t-Butyl (4-(3-methylpyridin-2-yl)thiophen-3-yl)carbamate [ka] t-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)carbamate (Reference Example 16, 325 mg) was dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (3 mL), and potassium carbonate (552 mg), 2-bromo-3-methylpyridine (345 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (395 mg) were added. The reaction vessel was then purged with nitrogen gas, and the mixture was stirred overnight at 100°C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (pentane / ethyl acetate = 10 / 1) to give the title compound (250 mg). ESI / MS(m / z) 291 (M+H) + .

[0131] [Reference example 18] t-Butyl 4-iodo-5-methoxy-1H-pyrazole-1-carboxylate [ka] 4-Iodo-3-methoxy-1H-pyrazole (1 g) and 4-dimethylaminopyridine (109 mg) were dissolved in dichloromethane (20 mL), and di-t-butyl dicarbonate (1.46 g) was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (pentane / ethyl acetate = 20 / 1 to 10 / 1) to give the title compound (1.2 g). ESI / MS(m / z) 225 (M+H-boc) + .

[0132] Compounds were synthesized according to the following reaction scheme, with reference to the method of Reference Example 17. The synthesized compounds and data are shown in Table 3. [ka]

[0133] [Table 3-1]

[0134] [Table 3-2]

[0135] Preparation of biarylamine 4 Step III-5 (Reference Examples 37 to 56) [Reference example 37] [2,3'-bithiophene]-4'-amine [ka] t-Butyl[2,3'-bithiophene]-4'-ylcarbamate (Reference Example 1,211 mg) was dissolved in chloroform (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, made basic with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (137 mg). ESI / MS(m / z) 182 (M+H) + .

[0136] Compounds were synthesized according to the following reaction scheme, with reference to the method of Reference Example 37. The synthesized compounds and data are shown in Table 4. [ka]

[0137] [Table 4-1]

[0138] [Table 4-2]

[0139] Production of Compounds Contained as Active Ingredients in the Pharmaceuticals of the Present Invention Steps I-1 and 2 (Examples 1 to 34) [Example 1] N-((1H-imidazol-4-yl)methyl)[2,3'-bithiophene]-4'-amine [ka] [2,3'-bithiophene]-4'-amine (Reference Example 37, 20.0 mg) and 4-formylimidazole (21.2 mg) were dissolved in N,N-dimethylformamide (550 μL) and stirred overnight at 70°C. After cooling to room temperature, methanol (550 μL) and sodium borohydride (10.5 mg) were added and stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was stirred for 30 minutes and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (NH silica; chloroform / methanol = 10 / 1) to give the title compound (13.7 mg). 1 H-NMR (400 MHz, CD3OD) δ 7.61 (d, J = 1.2 Hz, 1H), 7.35 (dd, J = 5.2, 1.1 Hz, 1H), 7.27 (d, J = 3.3 Hz, 1H), 7.22 (dd, J = 3.5, 1.1 Hz, 1H), 7.08 (dd, J = 5.2, 3.5 Hz, 1H), 7.01 (brs, 1H) 6.21 (d, J = 3.3 Hz, 1H), 4.24 (s, 2H). ESI / MS(m / z) 262 (M+H) + .

[0140] Compounds were synthesized according to the following reaction scheme, with reference to the method of Example 1. The synthesized compounds are shown in Table 5, and the data are shown in Table 6. [ka]

[0141] [Table 5-1]

[0142] [Table 5-2]

[0143] [Table 5-3]

[0144] [Table 6-1]

[0145] [Table 6-2]

[0146] [Table 6-3]

[0147] [Example 33] N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline [ka] t-Butyl 4-(2-amino-4-methylphenyl)-5-methoxy-1H-pyrazole-1-carboxylate (Reference Example 35, 117 mg), 4-formylimidazole (111 mg), and acetic acid (0.1 mL) were dissolved in methanol (8 mL) and stirred at 50°C for 48 hours. After cooling to room temperature, sodium cyanoborohydride (109 mg) was added and stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate water / acetonitrile = 80 / 20 to 30 / 70) to give the title compound (16 mg). 1H-NMR (400 MHz, CD3OD) δ 7.60 (s, 1H), 7.53 (s, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.95 (s, 1H), 6.59 (s, 1H), 6.51 (d, J = 7.6 Hz, 1H), 4.25 (s, 2H), 3.85 (s, 3H), 2.26 (s, 3H). ESI / MS(m / z) 284 (M+H) + .

[0148] The compounds were synthesized according to the following reaction scheme, with reference to the method of Example 33. The data are shown in Table 7. [ka]

[0149] [Table 7]

[0150] Production of compounds contained as active ingredients in the pharmaceutical of the present invention Steps II-1 to II-3 (Examples 35 to 40, Reference Examples 57 to 59) [Example 35] N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline [ka] 2-(Pyridin-3-yl)aniline (Reference Example 9, 34 mg), 1-trityl-1H-imidazole-4-carbaldehyde (81 mg), and molecular sieves 3A (90 mg) were suspended in toluene (2 mL) and heated to reflux for 1 day. The reaction solution was filtered while hot, and the residue was washed with toluene. The filtrate and washings were combined and concentrated under reduced pressure to obtain a residue, which was then dissolved in tetrahydrofuran (2 mL). The mixture was cooled to -78°C, and a 1M solution of methylmagnesium bromide in tetrahydrofuran (500 μL) was added dropwise, followed by warming to room temperature. After stirring for 1 hour, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. After filtering off the anhydrous sodium sulfate, the mixture was washed with ethyl acetate. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (hexane / ethyl acetate=1 / 1) to give 2-(pyridin-3-yl)-N-(1-(1-trityl-1H-imidazol-4-yl)ethyl)aniline (52 mg). ESI / MS(m / z) 507 (M+H) + .

[0151] The 2-(pyridin-3-yl)-N-(1-(1-trityl-1H-imidazol-4-yl)ethyl)aniline (52 mg) obtained above was dissolved in formic acid (2 mL) and stirred overnight at room temperature. The reaction solution was washed with hexane, concentrated under reduced pressure, and then azeotroped with chloroform. The resulting residue was dissolved in tetrahydrofuran (2 mL), potassium carbonate (200 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The potassium carbonate was filtered and washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (methanol / chloroform = 1 / 9) to give the title compound (20 mg). 1H-NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.58 (s, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 7.86 (dt, J = 7.9, 1.2 Hz, 1H), 7.51 (s, 1H), 7.49 (ddd, J = 7.9, 4.8, 1.2 Hz, 1H), 7.16 (t, J = 7.1 Hz, 1H), 7.00 (dd, J = 7.1, 1.5 Hz, 1H), 6.91 (s, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.69 (t, J = 7.1 Hz, 1H), 4.56-4.52 (m, 2H), 1.34 (d, J = 5.0 Hz, 3H). ESI / MS(m / z) 265 (M+H) + .

[0152] [Example 36] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline, and [Reference example 57] (-)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline The compound (N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline) prepared in Example 35 was subjected to optical resolution using high performance liquid chromatography (CHIRALPAK IC; hexane / ethanol / diethylamine=900 / 100 / 1) to obtain the title compound. Example 36: 1H-NMR (400 MHz, CD3OD) δ 8.57 (dd, J = 2.2, 0.9 Hz, 1H), 8.51 (dd, J = 5.0, 1.6 Hz, 1H), 7.93 (ddd, J = 7.9, 2.2, 1.6 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.51 (ddd, J = 7.9, 5.0, 0.9 Hz, 1H), 7.17 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 7.02 (dd, J = 7.4, 1.6 Hz, 1H), 6.87 (s, 1H), 6.80-6.72 (m, 2H), 4.61 (q, J = 6.7 Hz, 1H), 1.43 (d, J = 6.7 Hz, 3H). ESI / MS(m / z) 265 (M+H) + . Reference example 57: 1 H-NMR (400 MHz, CD3OD) δ 8.57 (dd, J = 2.3, 0.9 Hz, 1H), 8.51 (dd, J = 4.9, 1.7 Hz, 1H), 7.93 (ddd, J = 7.9, 2.3, 1.7 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.51 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 7.17 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 7.02 (dd, J = 7.4, 1.6 Hz, 1H), 6.87 (s, 1H), 6.81-6.71 (m, 2H), 4.61 (q, J = 6.7 Hz, 1H), 1.43 (d, J = 6.7 Hz, 3H). ESI / MS(m / z) 265 (M+H) + .

[0153] Compounds were synthesized according to the following reaction scheme, with reference to the method of Example 35. The synthesized compounds are shown in Table 8, and the data are shown in Table 9. [ka]

[0154] [Table 8]

[0155] [Table 9]

[0156] [Example 39] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline, and [Reference example 58] (-)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline The compound (N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline) prepared in Example 37 was subjected to optical resolution using high performance liquid chromatography (CHIRALPAK IA; hexane / ethanol / diethylamine=950 / 50 / 1) to obtain the title compound. Example 39: 1 H-NMR (400 MHz, CDCl3) δ 9.55 (brs, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.66 (dd, J = 8.3, 7.6 Hz, 1H), 7.51-7.47 (m, 2H), 7.26 (s, 1H), 7.23 (dd, J = 7.6, 0.7 Hz, 1H), 7.17 (ddd, J = 8.3, 7.3, 1.6 Hz, 1H), 6.86 (s, 1H), 6.73-6.68 (m, 2H), 6.65 (dd, J = 8.3, 0.7 Hz, 1H), 4.76 (quint, J = 6.5 Hz, 1H), 3.65 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H). ESI / MS(m / z) 295 (M+H) + . Reference example 58: 1H-NMR (400 MHz, CDCl3) δ 9.55 (brs, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.66 (dd, J = 8.3, 7.6 Hz, 1H), 7.51-7.47 (m, 2H), 7.26 (s, 1H), 7.23 (dd, J = 7.6, 0.7 Hz, 1H), 7.17 (ddd, J = 8.3, 7.3, 1.6 Hz, 1H), 6.86 (s, 1H), 6.73-6.68 (m, 2H), 6.65 (dd, J = 8.3, 0.7 Hz, 1H), 4.76 (quint, J = 6.5 Hz, 1H), 3.65 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H). ESI / MS(m / z) 295 (M+H) + .

[0157] [Example 40] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline, and [Reference example 59] (-)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline The compound (N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline) prepared in Example 38 was subjected to optical resolution using high performance liquid chromatography (CHIRALPAK IA; hexane / ethanol / diethylamine=950 / 50 / 1) to obtain the title compound. Example 40: 1 H-NMR (400 MHz, CDCl3) δ 8.89 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.48-7.45 (m, 2H), 7.26 (s, 1H), 7.19-7.11 (m, 1H), 6.88 (s, 1H), 6.75-6.67 (m, 2H), 4.75 (quint, J = 6.7 Hz, 1H), 1.60 (d, J = 6.7 Hz, 3H). ESI / MS(m / z) 271 (M+H) + . Reference example 59: 1H-NMR (400 MHz, CDCl3) δ 8.89 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.48-7.45 (m, 2H), 7.26 (s, 1H), 7.19-7.11 (m, 1H), 6.88 (s, 1H), 6.75-6.67 (m, 2H), 4.75 (quint, J = 6.7 Hz, 1H), 1.60 (d, J = 6.7 Hz, 3H). ESI / MS(m / z) 271 (M+H) + .

[0158] Preparation of imidazolylmethylaminoallyl Steps IV-1 and 2 (Reference Example 60) [Reference example 60] N-((1H-imidazol-4-yl)methyl)-4-bromothiophen-3-amine [ka] 4-Bromothiophene-3-amine hydrochloride (50.0 mg) and 4-formylimidazole (44.8 mg) were dissolved in N,N-dimethylformamide (500 μL), sodium triacetoxyborohydride (49.4 mg) was added, and the mixture was stirred at 70°C for 11 hours. Additional sodium triacetoxyborohydride (49.4 mg) was added, and the mixture was stirred at 70°C for 5 hours. Water and saturated sodium bicarbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (NH silica; chloroform / methanol = 10 / 1) to give the title compound (3.9 mg). ESI / MS(m / z) 258, 260 (M+H) + .

[0159] Production of compounds contained as active ingredients in the pharmaceutical of the present invention Step IV-3 (Examples 41 to 43) [Example 41] N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl)thiophen-3-amine [ka] N-((1H-imidazol-4-yl)methyl)-4-bromothiophen-3-amine (Reference Example 60, 3.9 mg) was dissolved in a mixed solvent of 1,4-dioxane (100 μL) and water (50 μL), and 2-furanboronic acid (5.1 mg), tetrakis(triphenylphosphine)palladium (0.9 mg), and potassium carbonate (8.3 mg) were added. The reaction vessel was then purged with argon gas, and the mixture was stirred at 100°C overnight. The reaction solution was filtered through Celite and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (NH silica; chloroform / methanol = 20 / 1) to give the title compound (0.3 mg). 1 H-NMR (400 MHz, CD3OD) δ 7.78 (dd, J = 1.7, 0.8 Hz, 1H), 7.62 (s, 1H), 7.53 (t, J = 1.7 Hz, 1H), 7.22 (d, J = 3.3 Hz, 1H), 7.01 (brs, 1H), 6.68 (dd, J = 1.9, 0.8 Hz, 1H), 6.19 (d, J = 3.3 Hz, 1H), 4.23 (s, 2H). ESI / MS(m / z) 246 (M+H) + .

[0160] Compounds were synthesized according to the following reaction scheme, with reference to the method of Example 41. The synthesized compounds are shown in Table 10, and the data are shown in Table 11. [ka]

[0161] [Table 10]

[0162] [Table 11]

[0163] <Production of Compounds Related to the Present Invention in Which Biaryl Moiety and Imidazole Moiety are Bonded via an Oxygen Atom> Preparation of imidazolyl methoxyallyl 1 Step V-1 (Reference Example 61) [Reference example 61] 4-((2-iodophenoxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide [ka] 4-(Hydroxymethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (307 mg), 2-iodophenol (363 mg), and triphenylphosphine (471 mg) were suspended in tetrahydrofuran (4 mL), and diisopropyl azodicarboxylate (441 μL) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate = 2 / 3) followed by silica gel column chromatography (hexane / ethyl acetate = 1 / 2) to give the title compound (350 mg). ESI / MS(m / z) 408 (M+H) + .

[0164] Preparation of imidazolyl methoxyallyl 2, Step V-2 (Reference Examples 62 to 64) [Reference example 62] 4-((2-bromophenoxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide [ka] 2-Bromophenol (8.7 g) and potassium carbonate (13.8 g) were suspended in dimethyl sulfoxide (100 mL), 4-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (11.2 g) was added, and the mixture was stirred at 100°C for 12 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (pentane / ethyl acetate = 5 / 1 to 2 / 1) to give the title compound (15.1 g). ESI / MS(m / z) 360, 362 (M+H) + .

[0165] Compounds were synthesized according to the following reaction scheme, with reference to the method of Reference Example 62. The synthesized compounds and data are shown in Table 12. [ka]

[0166] [Table 12]

[0167] Production of compounds contained as active ingredients in the pharmaceutical of the present invention Steps V-3 and V-5 (Examples 44 to 65) [Example 44] 4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole [ka] 4-((2-iodophenoxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 61, 61 mg) was dissolved in a mixed solvent of 1,4-dioxane (1 mL) and water (0.5 mL), and 3-thiopheneboronic acid (21 mg), tetrakis(triphenylphosphine)palladium (17 mg), and potassium carbonate (62 mg) were added, followed by stirring at 90°C for 2.5 hours. The reaction solution was filtered through Celite and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 2) to give N,N-dimethyl-4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole-1-sulfonamide (42 mg). ESI / MS(m / z) 364 (M+H) + .

[0168] The N,N-dimethyl-4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole-1-sulfonamide (42 mg) obtained above was dissolved in methanol (1 mL), and 2M hydrochloric acid in methanol (1 mL) was added, followed by stirring at 70°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography (NH silica; chloroform / methanol = 10 / 1) to give the title compound (27 mg). 1 H-NMR (400 MHz, CD3OD) δ 7.70 (d, J = 0.9 Hz, 1H), 7.66 (dd, J = 3.0, 1.3 Hz, 1H), 7.53 (dd, J = 7.5, 1.7 Hz, 1H), 7.46 (dd, J = 5.1, 1.3 Hz, 1H), 7.36 (dd, J = 5.1, 3.0 Hz, 1H), 7.28 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H), 7.20 (dd, J = 8.3, 1.3 Hz, 1H), 7.13 (s, 1H), 7.02 (td, J = 7.5, 1.3 Hz, 1H), 5.09 (s, 2H). ESI / MS(m / z) 257 (M+H) + .

[0169] Compounds were synthesized according to the following reaction scheme, with reference to the method of Example 44. The synthesized compounds are shown in Table 13, and the data are shown in Table 14. [ka]

[0170] [Table 13-1]

[0171] [Table 13-2]

[0172] [Table 14-1]

[0173] [Table 14-2]

[0174] Preparation of the compound contained as an active ingredient in the medicament of the present invention Steps V-4 and V-5 (Example 66) [Example 66] 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine [ka] 4-((2-Bromo-5-methylphenoxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 63, 38 mg), 2-(tributylstannyl)pyrazine (56 mg), and tetrakis(triphenylphosphine)palladium (17 mg) were suspended in toluene (0.7 mL) and stirred at 100°C overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate, silica pre-column with potassium carbonate added). The resulting compound was dissolved in methanol (1 mL), and 2M hydrochloric acid in methanol (1 mL) was added, followed by stirring at 70°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography (NH silica; chloroform / methanol = 10 / 1) to give the title compound (9 mg). 1 H-NMR (400 MHz, CD3OD) δ 9.15-9.05 (m, 1H), 8.64-8.56 (m, 1H), 8.41-8.35 (m, 1H), 7.74-7.62 (m, 2H), 7.19-7.09 (m, 2H) 6.98-6.91 (m, 1H), 5.13 (s, 2H), 2.42 (s, 3H). ESI / MS(m / z) 267 (M+H) + .

[0175] Production of biallylphenol Step VIII-1 (Reference Examples 65 to 75) [Reference example 65] 2-(thiazol-4-yl)phenol [ka] 2-Hydroxyphenylboronic acid (200 mg), 4-bromothiazole (250 mg), tetrakis(triphenylphosphine)palladium (81 mg), and potassium carbonate (606 mg) were suspended in a mixed solvent of 1,4-dioxane (10 mL) and water (5 mL) and stirred at 90°C for 4.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / 1) to give the title compound (195 mg). ESI / MS(m / z) 178 (M+H) + .

[0176] Compounds were synthesized according to the following reaction scheme, with reference to the method of Reference Example 65. The synthesized compounds and data are shown in Table 15. [ka]

[0177] [Table 15]

[0178] Preparation of Compounds Contained as Active Ingredients in the Pharmaceuticals of the Present Invention Steps VI-1 and VI-2 (Examples 67 to 77) [Example 67] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole [ka] 2-(Thiazol-4-yl)phenol (Reference Example 65, 24.3 mg), 4-(hydroxymethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (33.7 mg), and triphenylphosphine (46 mg) were dissolved in tetrahydrofuran (2 mL), and diisopropyl azodicarboxylate (35 μL) was added and stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate = 1 / 1) to give N,N-dimethyl-4-((2-(thiazol-4-yl)phenoxy)methyl)-1H-imidazole-1-sulfonamide (24.1 mg). ESI / MS(m / z) 365 (M+H) + .

[0179] The N,N-dimethyl-4-((2-(thiazol-4-yl)phenoxy)methyl)-1H-imidazole-1-sulfonamide (18.2 mg) obtained above was dissolved in methanol (1 mL), and 2 M hydrochloric acid in methanol (1 mL) was added, followed by stirring at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, then diluted with chloroform, washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off and washed with chloroform. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography (NH silica; chloroform / methanol = 20 / 1) to give the title compound (12.9 mg). 1 H-NMR (400 MHz, CDCl3) δ 9.44 (brs, 1H), 8.84 (s, 1H), 8.18 (brs, 1H), 8.01 (brs, 1H), 7.68-7.65 (m, 1H), 7.31 (ddd, J = 8.3, 7.3, 1.8 Hz, 1H), 7.18-7.01 (m, 3H), 5.23 (s, 2H). ESI / MS(m / z) 258 (M+H) + .

[0180] Compounds were synthesized according to the following reaction scheme, with reference to the method of Example 67. The synthesized compounds are shown in Table 16, and the data are shown in Table 17. [ka]

[0181] [Table 16]

[0182] [Table 17]

[0183] Preparation of imidazolyl methoxyallyl 3 Steps VII-1 and 2 (Reference Examples 76-77) [Reference example 76] 4-(1-hydroxyethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide [ka] 4-Formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (500 mg) was dissolved in tetrahydrofuran (25 mL), and 1 M methylmagnesium bromide in tetrahydrofuran (2.5 mL) was added under ice-cooling. The mixture was stirred at room temperature for 20 hours. Under ice-cooling, saturated aqueous ammonium chloride and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 12 / 1) to give the title compound (540 mg). ESI / MS(m / z) 220 (M+H) +

[0184] [Reference example 77] 4-(1-chloroethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide [ka] 4-(1-Hydroxyethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 76, 45 mg) was dissolved in chloroform (2.5 mL), and triethylamine (47 μL) and methanesulfonyl chloride (21 μL) were added under ice-cooling, followed by stirring for 1.5 hours under ice-cooling. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off and washed with chloroform. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (38 mg). ESI / MS(m / z) 238 (M+H) + .

[0185] [Reference example 78] 2-(Thiophen-2-yl)phenol [ka] 2-Hydroxyphenylboronic acid (1.00 g), tetrakis(triphenylphosphine)palladium (418 mg), and potassium carbonate (3.00 g) were suspended in a mixed solvent of 1,4-dioxane (24 mL) and water (12 mL), and 2-bromothiophene (930 μL) was added and stirred at 90°C for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1) to give the title compound (909 mg). ESI / MS(m / z) 177 (M+H) + .

[0186] Production of compounds contained as active ingredients in the pharmaceutical of the present invention Steps VII-3 and 4 (Examples 78 to 79, Reference Example 79) [Example 78] 4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole [ka] 2-(Thiophen-2-yl)phenol (Reference Example 78, 50 mg) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (65 mg) and 4-(1-chloroethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 77, 36 mg) were added, and the mixture was stirred at room temperature for 1 hour. Potassium iodide (56 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After that, the temperature was raised to 50°C and the mixture was stirred for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 2) to give N,N-dimethyl-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole-1-sulfonamide (24 mg). ESI / MS(m / z) 378 (M+H) + .

[0187] The N,N-dimethyl-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole-1-sulfonamide (23 mg) obtained above was dissolved in methanol (600 μL), and 2 M hydrochloric acid in methanol (600 μL) was added, followed by stirring at 70° C. for 19 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography (NH silica; chloroform / methanol=50 / 1) and thin-layer chromatography (chloroform / methanol=12 / 1) in this order to give the title compound (7.2 mg). 1 H-NMR (400 MHz, CD3OD) δ 7.64-7.60 (m, 2H), 7.52 (dd, J = 3.7, 1.2 Hz, 1H), 7.36 (dd, J = 5.2, 1.2 Hz, 1H), 7.14 (ddd, J = 8.8, 7.2, 1.7 Hz, 1H), 7.09-7.01 (m, 2H), 6.98-6.91 (m, 2H), 5.56 (q, J = 6.4 Hz, 1H), 1.72 (d, J = 6.4 Hz, 3H). ESI / MS(m / z) 271 (M+H) + .

[0188] [Example 79] (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole and [Reference example 79] (-)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole The compound (4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole) prepared in Example 78 was subjected to optical resolution using high performance liquid chromatography (CHIRALPAK IC; hexane / isopropanol / diethylamine=950 / 50 / 1) to obtain the title compound. Example 79: 1 H-NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 7.7, 1.7 Hz, 1H), 7.61 (d, J = 1.1 Hz, 1H), 7.55 (dd, J = 3.7, 1.1 Hz, 1H), 7.35 (dd, J = 5.1, 1.1 Hz, 1H), 7.18 (ddd, J = 8.4, 7.7, 1.7 Hz, 1H), 7.12 (dd, J = 5.1, 3.7 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.01-6.95 (m, 2H), 5.63 (q, J = 6.4 Hz, 1H), 1.80 (d, J = 6.4 Hz, 3H). ESI / MS(m / z) 271 (M+H) + . Reference example 79: 1H-NMR (400 MHz, CDCl3) δ 9.07 (brs, 1H), 7.67 (dd, J = 7.7, 1.6 Hz, 1H), 7.60 (s, 1H), 7.54 (s, 1H), 7.38-7.34 (m, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.12 (dd, J = 5.1, 3.7 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.01-6.95 (m, 2H), 5.63 (q, J = 6.4 Hz, 1H), 1.80 (d, J = 6.4 Hz, 3H). ESI / MS(m / z) 271 (M+H) + .

[0189] <Production of Compounds Related to the Present Invention in Which Biaryl Moiety and Imidazole Moiety are Bonded via a Sulfur Atom> Preparation of imidazolylmethylthioallyl Step IX-1 (Reference Example 80) [Reference example 80] 4-(((2-Bromophenyl)thio)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide [ka] N,N-Dimethylformamide (2.5 mL) and 2-bromobenzenethiol (31 μL) were added to 4-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide hydrochloride (100 mg), potassium iodide (4.2 mg), and potassium carbonate (106.1 mg), and the mixture was stirred at room temperature for 15 hours and at 60°C for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (hexane / ethyl acetate = 1 / 1) and then further purified by thin-layer chromatography (chloroform / ethyl acetate = 9 / 1) to give the title compound (82.1 mg). ESI / MS(m / z) 377 (M+H) + .

[0190] Production of compounds contained as active ingredients in the pharmaceutical of the present invention Steps IX-2 and IX-3 (Examples 80 to 82) [Example 80] 3-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)pyridine [ka] 1,4-Dioxane (1.5 mL) and water (0.3 mL) were added to 4-(((2-bromophenyl)thio)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 80, 20 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (16.4 mg), tetrakis(triphenylphosphine)palladium (6.1 mg), and potassium carbonate (22.1 mg), and the mixture was stirred at 90°C for 15 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (hexane / ethyl acetate=1 / 2) to give N,N-dimethyl-4-(((2-(pyridin-3-yl)phenyl)thio)methyl)-1H-imidazole-1-sulfonamide (25.2 mg). ESI / MS(m / z) 375 (M+H) + .

[0191] Methanol (0.5 mL) and 2M hydrochloric acid in methanol (0.5 mL) were added to the N,N-dimethyl-4-(((2-(pyridin-3-yl)phenyl)thio)methyl)-1H-imidazole-1-sulfonamide (25.2 mg) obtained above, and the mixture was stirred at 70° C. for 10 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography (chloroform / methanol=20 / 1) to give the title compound (6.3 mg). 1H-NMR (400 MHz, CD3OD) δ 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 8.42 (dd, J = 2.4, 0.8 Hz, 1H), 7.77 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.56 (dd, J = 7.6, 1.2 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.46 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.38 (ddd, J = 7.6, 7.6, 1.6 Hz, 1H), 7.32 (ddd, J = 7.6, 7.6, 1.2Hz, 1H), 7.25 (m, 1H), 6.69 (s, 1H), 3.96 (d, J = 0.8 Hz, 2H). ESI / MS(m / z) 268 (M+H) +

[0192] Compounds were synthesized according to the following reaction scheme, with reference to the method of Example 80. The synthesized compounds are shown in Table 18, and the data are shown in Table 19. [ka]

[0193] [Table 18]

[0194] [Table 19]

[0195] <Pharmacological test example> (1) Cultivation of human α1A-adrenergic receptor-expressing cells CHO-K1 cells highly expressing human α1A adrenergic receptor (GeneBLAzer™ ADRA1A-NFAT-bla CHO-K1 Cells) were purchased from ThermoFisher and cultured according to the manufacturer's instructions.

[0196] (2) Ca2+ expression in cells expressing human α1A-adrenergic receptors 2+ Recruitment assay Cultured human α1A-adrenergic receptor-expressing cells were washed with D-PBS and then replaced with loading buffer (DMEM (high-glucose) containing 2 μmol / L Fluo-4 / AM, 1x PowerLoad, and 2.5 mmol / L Probenecid) and incubated for 60 minutes at 37°C in a 5% CO2 incubator. Cells were detached using 0.05% trypsin-EDTA solution and suspended at 500,000 cells / mL in assay buffer (1.15 mol / L NaCl, 0.054 mol / L KCl, 1.8 mmol / L CaCl2, 1 mmol / L MgSO4, 0.11 mol / L glucose, 0.01 mol / L NaH2PO4·2H2O, 0.25 mol / L HEPES, pH 7.3). Test compounds were dissolved in dimethyl sulfoxide and diluted with assay buffer containing 0.3% BSA. The final concentrations of the test compounds were set to range from 0.1 nmol / L to 10 μmol / L. Norepinephrine was used as a reference compound and its final concentration was set to range from 0.01 nmol / L to 100 μmol / L. The cell suspension was dispensed (40 μL per well) onto a 384-well clear-bottom black plate (Corning) coated with poly-D-lysine and allowed to stand for 10 minutes. The plate was then transferred to a fluorescence imaging plate reader (FDSS7000, Hamamatsu Photonics) and measurements were initiated. One minute after the start of measurements, 20 μL of test compound solution or norepinephrine solution (total volume 60 μL per well) was added to each well (final concentrations: 0.1% BSA, 0.1% dimethyl sulfoxide). The change in Fluo-4 fluorescence intensity over time was measured for an additional 5 minutes (Ex 480 nm / Em 540 nm).

[0197] (3) Emax value and EC 50 Calculating values The maximum fluorescence value of the change in fluorescence intensity due to the test compound and norepinephrine was obtained, and this value was normalized by setting the maximum fluorescence value of a well containing no test compound as 0% and the maximum fluorescence value at 100 μmol / L norepinephrine as 100%. The normalized value (% Activation) was used for subsequent analysis. Emax value and EC 50 The concentration-response curve of the test compound was created using 4-parameter logistic regression using XLFit, and the Emax value was the % Activation, EC 50 The values ​​were calculated as the concentration showing a 50% response of the Emax value. The results are shown in Table 20.

[0198] As a result, it was found that all of the compounds of the examples tested this time had a high α1A receptor agonistic effect.

[0199] [Table 20-1]

[0200] [Table 20-2] Comparative compound 1 is compound 14 (N-((1H-imidazol-4-yl)methyl)-2-(oxazol-5-yl)aniline) described in Non-Patent Document 3 (Bioorg Med Chem Lett 12 3449-3452 2002). The compound contained as an active ingredient in the medicament of the present invention has a superior adrenergic α1A receptor agonist effect compared to Comparative Compound 1. [Industrial Applicability]

[0201] Since the pharmaceutical agent of the present invention has excellent adrenergic α1A receptor agonism, it is useful as a preventive or therapeutic agent for orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence.

Claims

1. A pharmaceutical comprising, as an active ingredient, a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof: 【Chemical 1】 [In the formula, R １ is a hydrogen atom or C １ ~C ３ It means an alkyl group. Z is selected from the group consisting of the following formulas: 【Chemistry 2】 (In the formula, R ２ is a hydrogen atom, a fluorine atom, or C １ ~C ３ It means an alkyl group. R ３ is selected from the group consisting of the following formulas: 【Chemistry 3】 (In the formula, Y represents an oxygen atom or a sulfur atom. R ４ are each independently a hydrogen atom or C １ ~C ３ It means an alkoxy group. R ５ represents a hydrogen atom, a fluorine atom, or C １ ~C ３ Alkyl group, or C １ ~C ３ It means an alkoxy group. R ６ is a hydrogen atom, a fluorine atom, or C １ ~C ３ It means an alkoxy group. R ７ is a hydrogen atom, C １ ~C ３ Alkyl group, C １ ~C ３ It means an alkoxy group or a cyclopropyl group. R ８ is a hydrogen atom or C １ ~C ３ It means an alkoxy group. R ９ is a hydrogen atom or C １ ~C ３ It means an alkyl group. R １０ is a hydrogen atom, C １ ~C ３ Alkyl group, C １ ~C ３ It means an alkoxy group or a cyano group. In addition, R ６ is C １ ~C ３ When it is an alkoxy group, R ７ and R ８ is a hydrogen atom, and R ８ is C １ ~C ３ When it is an alkoxy group, R ６ is a hydrogen atom or a fluorine atom, and R ７ is a hydrogen atom.

2. 2. The pharmaceutical composition according to claim 1, comprising, as an active ingredient, a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof: 【Chemistry 4】 [In the formula, R １ is a hydrogen atom or C １ ~C ３ It means an alkyl group. Z is selected from the group consisting of the following formulas: 【Chemistry 5】 (In the formula, R ２ is a hydrogen atom, a fluorine atom, or C １ ~C ３ It means an alkyl group. R ３ is selected from the group consisting of the following formulas: 【Chemistry 6】 (In the formula, Y represents an oxygen atom or a sulfur atom. R ４ are each independently a hydrogen atom or C １ ~C ３ It means an alkoxy group. R ５ represents a hydrogen atom, a fluorine atom, or C １ ~C ３ Alkyl group, or C １ ~C ３ It means an alkoxy group. R ６ is a hydrogen atom, a fluorine atom, or C １ ~C ３ It means an alkoxy group. R ７ is a hydrogen atom, C １ ~C ３ Alkyl group, C １ ~C ３ It means an alkoxy group or a cyclopropyl group. R ８ is a hydrogen atom or C １ ~C ３ It means an alkoxy group. R ９ is a hydrogen atom or C １ ~C ３ It means an alkyl group. R １０ is a hydrogen atom, C １ ~C ３ Alkyl group, C １ ~C ３ It means an alkoxy group or a cyano group. In addition, R ６ is C １ ~C ３ When it is an alkoxy group, R ７ and R ８ is a hydrogen atom, and R ８ is C １ ~C ３ When it is an alkoxy group, R ６ is a hydrogen atom or a fluorine atom, and R ７ is a hydrogen atom.) However, Z is 【Chemistry 7】 and R ２ is a hydrogen atom, R ３ is not a 3-fluoropyridine attached at the 2-position; Also, Z is 【Chemistry 8】 and R ２ is a hydrogen atom, R ３ is not an unsubstituted pyridine attached at the 2-position, an unsubstituted pyrazole attached at the 3-position, or a 3-methoxypyrazole attached at the 4-position; Also, Z is 【Chemistry 9】 and R ２ is a hydrogen atom, R ３ is not an unsubstituted furan attached at the 2-position; Also, Z is 【Chemistry 10】 and R １ is C １ ~C ３ Alkyl group and R ２ is a hydrogen atom, R ３ is not an unsubstituted pyrazole attached at the 4-position; Also, Z is 【Chemistry 11】 When R ３ is not an unsubstituted thiazole bonded at the 5-position. Furthermore, R １ is C １ ~C ３ Of the two enantiomers that result when the alkyl group is present, the enantiomer with a weaker α1A agonist effect than 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole is excluded.

3. R of the compound ３ is the following formula 【Chemistry 12】 wherein Y represents an oxygen atom or a sulfur atom. R ４ are each independently a hydrogen atom or C １ ~C ３ It means an alkoxy group. R ５ is a hydrogen atom, a fluorine atom, or C １ ~C ３ It means an alkoxy group. R ６ is a hydrogen atom, a fluorine atom, or C １ ~C ３ It means an alkoxy group. R ７ is a hydrogen atom, C １ ~C ３ Alkyl group, C １ ~C ３ It means an alkoxy group or a cyclopropyl group. R ８ is a hydrogen atom or C １ ~C ３ It means an alkoxy group. R ９ is a hydrogen atom or C １ ~C ３ It means an alkyl group. R １０ is a hydrogen atom, C １ ~C ３ Alkyl group, C １ ~C ３ It means an alkoxy group or a cyano group. In addition, R ６ is C １ ~C ３ When it is an alkoxy group, R ７ and R ８ is a hydrogen atom, and R ８ is C １ ~C ３ When it is an alkoxy group, R ６ is a hydrogen atom or a fluorine atom, and R ７ is a hydrogen atom. However, Z is 【Chemistry 13】 When R ３ is bonded at the 4th position and R is at the 3rd position ９ Thiophene substituted with C, bonded at the 3-position and C at the 4-position １ ~C ３ not a pyridine substituted with an alkyl group or an unsubstituted pyrazole bonded at the 4-position; Also, Z is 【Chemistry 14】 When R ３ is bonded at the 4th position and R is at the 3rd position ９ Thiophene substituted with C, bonded at the 3-position and C at the 4-position １ ~C ３ Pyridine substituted with an alkyl group, unsubstituted pyrazole bonded at the 4-position, unsubstituted pyrimidine bonded at the 5-position, or unsubstituted pyrimidine bonded at the 5-position and having C at the 4-position １ ~C ３ not a pyrimidine substituted with an alkyl group; Also, Z is 【Chemistry 15】 and R ２ is C １ ~C ３ When it is an alkyl group, R ３ is bonded at the 4th position and R is at the 3rd position ９ substituted thiophene, unsubstituted pyrimidine bonded at the 5-position, or a thiophene bonded at the 5-position and having C at the 4-position １ ~C ３ not a pyrimidine substituted with an alkyl group; Z is the same as above, and R ２ is a hydrogen atom, R ３ is bonded at the 3rd position and C at the 4th position １ ~C ３ neither an alkyl-substituted pyridine nor an unsubstituted pyrazole bonded at the 4-position; Z is the same as above, and R １ is C １ ~C ３ Alkyl group and R ２ is a hydrogen atom, R ３ is neither a 4-cyclopropylpyridine attached at the 3-position nor an unsubstituted pyrimidine attached at the 5-position; Also, Z is 【Chemistry 16】 When R ３ is bonded at the 4th position and R is at the 3rd position ９ Thiophene substituted with C, bonded at the 3-position and C at the 4-position １ ~C ３ Pyridine substituted with an alkyl group, unsubstituted pyrazole bonded at the 4-position, unsubstituted pyrimidine bonded at the 5-position, or unsubstituted pyrimidine bonded at the 5-position and having C at the 4-position １ ~C ３ It is not a pyrimidine substituted with an alkyl group. The pharmaceutical composition according to claim 2, which is a compound selected from the group consisting of:

4. R of the compound ３ is the following formula 【Chemistry 17】 wherein Y represents an oxygen atom or a sulfur atom. R ４ are each independently a hydrogen atom or C １ ~C ３ It means an alkoxy group. R ５ is a hydrogen atom, a fluorine atom, or C １ ~C ３ It means an alkoxy group. R ６ is a hydrogen atom, a fluorine atom, or C １ ~C ３ It means an alkoxy group. R ７ａ is a hydrogen atom, C １ ~C ３ It means an alkoxy group or a cyclopropyl group. R ７ｂ is a hydrogen atom, C １ ~C ３ Alkyl group, C １ ~C ３ It means an alkoxy group or a cyclopropyl group. R ８ is a hydrogen atom or C １ ~C ３ It means an alkoxy group. R ９ is a hydrogen atom or C １ ~C ３ It means an alkyl group. R １０ is a hydrogen atom, C １ ~C ３ Alkyl group, C １ ~C ３ It means an alkoxy group or a cyano group. In addition, R ６ is C １ ~C ３ When it is an alkoxy group, R ７ and R ８ is a hydrogen atom, and R ８ is C １ ~C ３ When it is an alkoxy group, R ６ is a hydrogen atom or a fluorine atom, R ７ is a hydrogen atom. However, Z is 【Chemistry 18】 When R ３ is bonded at the 2nd position and C at the 3rd position １ ~C ３ Pyridine substituted with an alkoxy group or a compound bonded at the 5-position and having C at the 3-position １ ~C ３ It is not a pyridine substituted with an alkoxy group. The pharmaceutical composition according to claim 3, which is a compound selected from the group consisting of:

5. R of the compound ３ is the following formula 【Chemistry 19】 [In the formula, R ４ each independently represents a hydrogen atom or a methoxy group. R ５ means a hydrogen atom, a fluorine atom, or a methoxy group. R ６ means a hydrogen atom, a fluorine atom, or a methoxy group. R ７ａ means a hydrogen atom, a methoxy group, or a cyclopropyl group. R ７ｂ means a hydrogen atom, a methyl group, or a methoxy group. R ８ means a hydrogen atom or a methoxy group. R ９ means a hydrogen atom or a methyl group. R １０ means a hydrogen atom, a methyl group, a methoxy group, or a cyano group. In addition, R ６ is a methoxy group, R ７ａ and R ８ is a hydrogen atom, and R ６ is a fluorine atom, R ８ is a hydrogen atom, and R ８ is a methoxy group, R ６ is a hydrogen atom or a fluorine atom, R ７ａ is a hydrogen atom. However, Z is 【Chemistry 20】 When R ３ is not a 3-methylpyrazole attached at the 4-position; Also, Z is 【Chemical 21】 When R ３ is not an unsubstituted pyridine attached at the 3-position, a 3-methylpyrazole attached at the 4-position, a 2-methoxypyridine attached at the 3-position, a 4-methoxypyridine attached at the 3-position, or an unsubstituted thiophene attached at the 2-position; Also, Z is 【Chemical 22】 When R ３ is not an unsubstituted pyrimidine attached at the 5-position, a 3-methylpyrazole attached at the 4-position, a 2-methoxypyridine attached at the 3-position, a 4-methoxypyridine attached at the 3-position, or an unsubstituted thiophene attached at the 2-position; Also, Z is 【Chemical 23】 and R ２ is a methyl group, R ３ is not a 3-bonded unsubstituted pyridine, a 3-bonded 2-methoxypyridine, a 3-bonded 4-methoxypyridine, or a 2-bonded unsubstituted thiophene; Z is the same as above, and R ２ is a hydrogen atom, R ３ is not an unsubstituted pyridine attached at the 3-position, a 3-methylpyrazole attached at the 4-position, or an unsubstituted thiophene attached at the 2-position; Z is the same as above, and R ２ is a fluorine atom, R ３ is not an unsubstituted pyridine attached at the 3-position, a 4-methylpyrimidine attached at the 5-position, a 2-methoxypyridine attached at the 3-position, or an unsubstituted thiophene attached at the 2-position; Also, Z is 【Chemistry 24】 When R ３ is not an unsubstituted pyridine bonded at the 3-position, a 3-methylpyrazole bonded at the 4-position, a 2-methoxypyridine bonded at the 3-position, a 4-methoxypyridine bonded at the 3-position, or an unsubstituted thiophene bonded at the 2-position. The pharmaceutical composition according to claim 4, which is a compound selected from the group consisting of:

6. R of the compound ３ is the following formula 【Chemistry 25】 [In the formula, R ４ each independently represents a hydrogen atom or a methoxy group. R ５ means a hydrogen atom, a fluorine atom, or a methoxy group. R ６ means a hydrogen atom, a fluorine atom, or a methoxy group. R ７ａ means a hydrogen atom, a methoxy group, or a cyclopropyl group. R ７ｂ means a methoxy group. R ８ means a hydrogen atom or a methoxy group. R ９ means a hydrogen atom or a methyl group. In addition, R ６ is a methoxy group, R ７ａ and R ８ is a hydrogen atom, and R ６ is a fluorine atom, R ８ is a hydrogen atom, and R ７ａ is a methoxy group, R ６ is a fluorine atom, R ８ is a hydrogen atom. However, Z is 【Chemical formula 26】 When R ３ is not an unsubstituted pyridine bonded at the 3-position. The pharmaceutical composition according to claim 5, which is a compound selected from the group consisting of:

7. Z of the compound is of the formula 【Chemical 27】 The pharmaceutical composition according to claim 2, which is a compound selected from the group consisting of:

8. Z of the compound is of the formula 【Chemical Formula 28】 The pharmaceutical composition according to claim 2, which is a compound selected from the group consisting of:

9. Z of the compound is of the formula 【Chemical formula 29】 [In the formula, R ２ means a hydrogen atom, a methyl group, or a fluorine atom. and R ３ is the following formula 【Chemistry 30】 [In the formula, R ４ means a hydrogen atom or a methoxy group. The pharmaceutical composition according to claim 7, which is a compound selected from the group consisting of:

10. Z of the compound is of the formula 【Chemical 31】 and R ３ is the following formula 【Chemical 32】 [In the formula, R ４ means a hydrogen atom or a methoxy group. R ６ means a hydrogen atom or a fluorine atom. R ７ａ means a hydrogen atom, a methyl group, a methoxy group, or a cyclopropyl group. R ７ｂ means a hydrogen atom, a methyl group, or a methoxy group. In addition, R ６ is a hydrogen atom, R ７ａ means a methoxy group or a cyclopropyl group, and R ７ａ is a methyl group, R ６ is a fluorine atom, and R ７ａ is a cyclopropyl group, R ６ is a hydrogen atom. The pharmaceutical composition according to claim 8, which is a compound selected from the group consisting of:

11. The compound is the following compound: N-((1H-imidazol-4-yl)methyl)-[2,3′-bithiophene]-4′-amine; N-((1H-imidazol-4-yl)methyl)-[2,2′-bithiophene]-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-methylpyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methylthiazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine; 4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole; 4-((2-(furan-2-yl)phenoxy)methyl)-1H-imidazole; 4-((2-(thiophen-2-yl)phenoxy)methyl)-1H-imidazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyridine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methylpyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methylpyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine; (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole; 3-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)pyridine; 4-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)-1H-pyrazole; and 4-(((2-(thiophen-3-yl)phenyl)thio)methyl)-1H-imidazole The pharmaceutical composition according to claim 2, which is a compound selected from the group consisting of:

12. The compound is the following compound: N-((1H-imidazol-4-yl)methyl)-[2,3′-bithiophene]-4′-amine; N-((1H-imidazol-4-yl)methyl)-[2,2′-bithiophene]-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methylthiazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine; 4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole; 4-((2-(thiophen-2-yl)phenoxy)methyl)-1H-imidazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyridine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile; 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine; (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole; and 3-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)pyridine The pharmaceutical composition according to claim 4, which is a compound selected from the group consisting of:

13. The compound is the following compound: N-((1H-imidazol-4-yl)methyl)-[2,3′-bithiophene]-4′-amine; N-((1H-imidazol-4-yl)methyl)-[2,2′-bithiophene]-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine; 4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile; 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine; 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; and 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine The pharmaceutical composition according to claim 5, which is a compound selected from the group consisting of:

14. The pharmaceutical agent according to any one of claims 1 to 13, for the prevention or treatment of a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence.

Images