JP2007091755A - Amine compound and use thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide new amine compounds which are efficacious against diseases such as a viral infectious disease with HIV, rheumatism, and cancer metastasis. <P>SOLUTION: The invention relates to the amine compounds which are represented by the general formula (1) or pharmacologically acceptable salts thereof. [A<SB>1</SB>and A<SB>2</SB>are each independently (substituted) imidazole group, at least one is N-(carboxylmethyl)imidazole or N-(ethoxycarbonylmethyl)imidazole. W is a (substituted)benzene ring. X is CH<SB>2</SB>. D is a group represented by formula (6).]. [Q is CH<SB>2</SB>, NR<SB>12</SB>, R<SB>12</SB>is H or methyl group in the formula (6). Y is a group represented by formula (7)]. [m<SB>3</SB>is an integer of 0-6. R<SB>18</SB>, R<SB>19</SB>are each H in the formula (7). B is a group represented by formula (8)]. [R<SB>25</SB>, R<SB>26</SB>are each a (substituted) 1-15C alkyl group in the formula (8)]. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention relates to an amine compound or a pharmacologically acceptable salt thereof or a prodrug thereof, and particularly relates to an amine compound having antiviral activity based on an antagonistic action against the chemokine receptor CXCR4. Furthermore, the present invention relates to drugs for related diseases such as rheumatic diseases and cancer metastasis diseases based on these compounds as active ingredients, particularly based on antagonism to the chemokine receptor CXCR4.

There are reverse transcriptase inhibitors and protease inhibitors for the treatment of acquired immune deficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) infection, but the emergence of drug-resistant HIV mutants lost therapeutic effect (For example, refer nonpatent literature 1). In addition, multi-drug combination therapy using these combinations has many conditions to be observed when taking, is complicated, has a large number to be taken, and has various side effects (for example, see Non-patent Document 2). In particular, protease inhibitors are known to be more likely to cause the emergence and selection of resistant strains if they are not maintained at almost 100%, despite complicated internal use and many side effects. (For example, refer nonpatent literature 3).

In addition, vaccine development has been attempted because many viral diseases have been extinguished or significantly alleviated by vaccines in the past, but HIV is considered to be extremely difficult due to frequent mutations (for example, non- (See Patent Document 4).

As mentioned above, several compounds having anti-HIV activity have been reported, but they have a novel anti-retroviral activity and can resist the development of resistance. At present, the development of antiviral agents that can be attached to is strongly desired.

Among cytokines, those showing chemotaxis to leukocytes are called chemokines, which are secreted proteins and are classified as CXC-chemokines, CC-chemokines, C-chemokines, CX3C-chemokines by the N-terminal cysteine (Cys) sequence. The number is said to be about 30. There are several subtypes of these chemokine receptors. Among them, CXC4 having CXC-chemokine SDF-1α as a ligand is used as a co-receptor during infection of T cell-directed HIV host cells. (For example, see Non-Patent Document 5 and Non-Patent Document 6). HIV
Envelope protein gp120 enters via binding to CXCR4 on the host cell surface. That is, a drug having an antagonistic action on CXCR4 is expected as an anti-HIV drug based on a novel mechanism of invasion inhibition, and as a low molecular drug, three compounds, AMD3100 (for example, see Non-Patent Document 7), T22 (for example, Non-Patent Document 8), ALX40-4C (for example, see Non-Patent Document 9) have been reported.

  On the other hand, CXCR4 has been shown to be associated with various diseases other than HIV infection. For example, rheumatic diseases (for example, see Patent Document 1), cancer metastasis (for example, see Non-Patent Document 10), and the like have been reported.

As a therapeutic agent for these diseases, development of a novel low-molecular-weight drug having a CXCR4 antagonistic action and low toxicity and side effects that can be used for a long period of time is strongly desired.
International Publication No. 00/06086 Pamphlet Latest Medicine, Vol. 53, No. 9, p. 2031 (1998) Nikkei Science, October issue, page 29 (1998) Molecular Medicine, Vol. 36, No. 9, pp. 1012 (1999) Nikkei Science, October issue, 42 pages (1998) Science, 272, 872 (1996) Nature (382), 829 (1996) Journal of Experimental Medicine (J. Exp. Med), 186, 1383 (1997) Journal of Experimental Medicine (J. Exp. Med), 186, 1389 (1997) Journal of Experimental Medicine (J. Exp. Med), 186, 1395 (1997) Nature, 410, 50 (2001)

  An object of the present invention is to provide a drug having a novel chemical structure and a prodrug thereof having an excellent antiretroviral action, an excellent CXCR4 antagonistic action against SDF-1α, and a high safety. It is in.

The present inventors have already conducted research to develop a compound having a novel chemical structure that has an excellent antiretroviral action and is useful as an excellent CXCR4 antagonist against SDF-1α. Show protective properties in cells inoculated by and thus AIDS and AIDS−
Powerful CXCR4 indicated as having potential for treatment of related complications, etc.
A group of amine compounds has been discovered and filed (PCT / JP03 / 11381) that have shown antagonistic activity and are therefore shown to have potential for the treatment of rheumatoid and cancer metastases, etc. After that, more useful compounds were found. The object of the present invention is to provide a compound of the general formula (1) defined below, which has antiviral activity mainly consisting of HIV and has CXCR4 antagonistic activity, and further from the compound of the general formula (1). A drug for the treatment of patients with viral infection and for the treatment of patients with rheumatism, cancer, etc. is provided.

The present invention relates to a compound represented by the following general formula (1), a pharmacologically acceptable salt thereof, or a prodrug thereof.

In formula (1)
n _1, n _2, n ₃ is an integer of 0 to 3.
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, or an optionally substituted carbon group having 2 to 15 carbon atoms. Or an alkynyl group having 2 to 15 carbon atoms which may be substituted, or a cyclic alkyl group having 3 to 15 carbon atoms which may be substituted. In this case, R ₅ and R ₆ may form a carbonyl group together with the carbon atom to which they are bonded.
A ₁ and A ₂ are each a hydrogen atom, an independently substituted monocyclic or polycyclic heteroaromatic ring, and a partially substituted polycyclic heteroaromatic which may be substituted A ring, an optionally substituted monocyclic or polycyclic aromatic ring, an optionally substituted polycyclic aromatic ring, an optionally substituted heterocycle, or A group represented by the following formula (2) is shown.

In formula (2)
R ₇ , R ₈ , R ₉ and R ₁₀ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl group having 2 to 15 carbon atoms, or a substituted group. An optionally substituted alkynyl group having 2 to 15 carbon atoms or an optionally substituted cyclic alkyl group having 3 to 15 carbon atoms is shown.
W represents an optionally substituted benzene ring or any group represented by the following formula (10) or formula (11).

In the formula (10), R ₃₀ is a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl group having 2 to 15 carbon atoms, or an optionally substituted carbon number 2 -15 alkynyl group or C3-C15 cyclic alkyl group, methanesulfonyl group, p-toluenesulfonyl group, phenyl group, acyl group, carboxyl group and cyano group which may be substituted.
m ₇ represents an integer of 0 to 2.
T ₁ and T ₂ represent CH ₂ or CO.
T ₃ and T ₄ represent T ₃ = NH and T ₄ = CO, or T ₃ = CO and T ₄ = NH.
X represents an optionally substituted monocyclic or polycyclic heteroaromatic ring, an optionally substituted monocyclic or polycyclic aromatic ring, O, CH ₂ , NR ₁₁ , CHR ₃₅ , or the following formula ( 3) shows a group represented by formula (12).
R ₁₁ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl group having 2 to 15 carbon atoms, or an optionally substituted alkynyl group having 2 to 15 carbon atoms. ,
Or the C3-C15 cyclic alkyl group which may be substituted is shown.
R ₃₅ represents a carboxyl group or an alkoxycarbonyl group.
In formula (3)
m ₁ represents an integer of 1 or 2.

In the formula (12), T ₅ represents an oxygen atom or a sulfur atom.
R ₃₁ and R ₃₂ may represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ₃₁ and R ₃₂ may be bonded to each other to form a ring.

D represents a group represented by the above formula (4) or the following formula (6).
In formula (4)
R ₁₃ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl group having 2 to 15 carbon atoms, or an optionally substituted alkynyl group having 2 to 15 carbon atoms. Or a C3-C15 cyclic alkyl group which may be substituted, or a group represented by the following formula (5).

In formula (5)
m ₂ represents an integer of ₂ to 4.
R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl group having 2 to 15 carbon atoms, or a substituted group. An optionally substituted alkynyl group having 2 to 15 carbon atoms or an optionally substituted cyclic alkyl group having 3 to 15 carbon atoms is shown.

In formula (6)
Q is a single bond when X is O described above, a single bond when X is NR ₁₁ , or a group represented by the above formula (3), wherein X may be a monocyclic or polycyclic group. A cyclic heteroaromatic ring, an optionally substituted monocyclic or polycyclic aromatic ring, CH ₂ , or a single bond, S, O when represented by formula (3) or formula (12) , NR ₁₂ , or a group represented by the formula (13).

R ₁₂ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl group having 2 to 15 carbon atoms, or an optionally substituted alkynyl group having 2 to 15 carbon atoms. , Or an optionally substituted cyclic alkyl group having 3 to 15 carbon atoms, methanesulfonyl group, p-toluenesulfonyl group, phenyl group, acyl group, carboxyl group, cyano group, or group represented by formula (15) Indicates.
R ₃₄ is an optionally substituted alkyl group having 1 to 15 carbon atoms, and optionally substituted 3 carbon atoms.
~ 15 cyclic alkyl group, phenyl group.
Y represents a group represented by the following formula (7).

In formula (7)
m ₃ represents an integer of 0-6.
R ₁₈ and R ₁₉ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl group having 2 to 15 carbon atoms, or an optionally substituted carbon number. 2 to 15 alkynyl group, an optionally substituted cyclic alkyl group having 3 to 15 carbon atoms, or an optionally substituted aromatic ring, wherein R ₁₂ and R ₁₈ form a ring; It may be.
m ₄ and m ₅ represent an integer of 0 to 2.
R ₂₀ , R ₂₁ , R ₂₂ and R ₂₃ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl group having 2 to 15 carbon atoms, or a substituted group. An optionally substituted alkynyl group having 2 to 15 carbon atoms or an optionally substituted cyclic alkyl group having 3 to 15 carbon atoms is shown.
z is a C3-C15 cyclic alkylene group which may be substituted, a monocyclic or polycyclic heteroaromatic ring which may be substituted, or a partly saturated polycyclic which may be substituted. A cyclic heteroaromatic ring, an optionally substituted monocyclic or polycyclic aromatic ring, an optionally substituted polycyclic aromatic ring, or a substituted Or a heterocycle, S, O, NR ₁₂ , S═O, O═S═O, or formula (16).

B represents any group represented by the following formula (8) or formula (14).
In formula (8)
Q ₁ represents S, O, or NH, and Q ₂ represents S, O, NR ₂₇ .
R ₂₄ and R ₂₇ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl group having 2 to 15 carbon atoms, or an optionally substituted carbon number. 2 to 15 alkynyl group, an optionally substituted cyclic alkyl group having 3 to 15 carbon atoms, or an optionally substituted aromatic ring, wherein R ₂₄ and R ₂₇ form a ring; It may be.
R ₂₅ and R ₂₆ are each independently a hydrogen atom when X is CH _2, an optionally substituted alkyl group having 1 to 15 carbon atoms, or an optionally substituted cyclic group having 3 to 15 carbon atoms. Represents an alkyl group, an alkenyl group having 2 to 15 carbon atoms which may be substituted with 1 to 3 double bonds, or an alkynyl group having 2 to 15 carbon atoms which may be substituted with 1 to 3 triple bonds. In addition, R ₂₅ and R ₂₆ may form a ring, and in some cases, a hetero atom, a cyclic alkyl group, an aromatic ring, a heteroaromatic ring, or a heterocyclic ring are combined to form a ring. You may do it.
R ₂₅ and R ₂₆ are each independently a hydrogen atom, a substituent represented by the following formula (9), an optionally substituted alkyl group having 1 to 15 carbon atoms, or a substituent when X is not CH _2. A cyclic alkyl group having 3 to 15 carbon atoms which may be substituted, an alkenyl group having 2 to 15 carbon atoms which may be substituted including 1 to 3 double bonds, or 1 to 3 carbon atoms which are substituted. Represents an alkynyl group having 2 to 15 carbon atoms, and R ₂₅ and R ₂₆ may form a ring, in which case a heteroatom, a cyclic alkyl group, an aromatic ring, a heteroaromatic ring And may be bonded via a heterocyclic ring to form a ring.
In formula (9)
m ₆ is 0 or 1, Q ₃ is CH or N when m ₆ = 0, Q ₄ is N, S, or O, and when m ₆ = 1, Q ₃ and Q ₄ are respectively Independently represents CH or N.
G is an alkylene group having 1 to 15 carbon atoms which may be substituted, and 2 carbon atoms which may be substituted.
-15 alkenylene groups are shown.
R ₂₈ is an alkyl group having 1 to 15 carbon atoms substituted at any position other than a nitrogen atom that may be present on the ring, an optionally substituted alkenyl group having 2 to 15 carbon atoms, A C2-C15 alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group,
A hydroxyalkoxy group, a halogen atom, an amino group, an alkylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, an alkylcarbamoyl group, a saturated heterocyclic ring, a heteroaromatic ring, and m ₆ = 1 and Q ₃ When Q ₄ is CH at the same time, it may be a hydrogen atom.
R ₂₉ represents a hydrogen atom or a group similar to R _24, and may combine with G to form a ring.

In formula (14), R ₃₃ is the same as R ₁₂ described above.
In addition, in the case where one or two or more asymmetric carbons that may be present in the compound represented by the general formula (1) are one, a pure optically active substance represented by an absolute configuration R or S, Mixtures, racemates, and optically pure diastereomers, racemates, or combinations of these in any ratio, if any, are present. Good.
In addition, the terms used in this specification are defined as follows and are used alone or in combination.
The alkyl group is a saturated hydrocarbon group which may be linear, branched or cyclic, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, pentyl group, And neopentyl group.
An alkenyl group is a hydrocarbon group having a double bond in any of linear, branched, or cyclic, such as an allyl group, 1-butenyl group, 2-butenyl group, isobutenyl group, cyclohexenyl group, and the like. Can be mentioned.
The alkynyl group is a hydrocarbon group having a triple bond in any of linear, branched or cyclic, and examples thereof include a propynyl group and a 1-butynyl group.
The cyclic alkyl group represents a cyclic hydrocarbon group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or the like.
The aromatic ring means an aromatic ring made of hydrocarbon. Examples of the monocyclic ring include a benzene ring, and examples of the polycyclic type include a naphthalene ring and an anthracene ring. Examples of the partially saturated polycyclic aromatic ring include dihydronaphthalene ring, tetralin ring, and indane ring. Heteroaromatic ring means an aromatic ring that contains one or more of nitrogen, oxygen and sulfur atoms in the ring, and in the case of a single ring, for example, pyrrole ring, furan ring Thiophene ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, imidazole ring, pyrazole ring, oxazole ring, thiazole ring, thiadiazole ring, oxadiazole ring, triazole ring, etc. Examples include quinoline ring, isoquinoline ring, benzimidazole ring, indazole ring, benzthiazole ring, benzoxazole ring, indole ring, benzfuran ring, benzothiophene ring and the like.
Examples of the partially saturated polycyclic heteroaromatic ring include a tetrahydroisoquinoline ring and a tetrahydroquinoline ring. The heterocyclic ring means a saturated ring containing one or more of any one of nitrogen atom, oxygen atom and sulfur atom in the ring, and examples thereof include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and the like. .
An alkylene group is a hydrocarbon group connecting two groups to the end, and examples thereof include an ethylene group, a propylene group, an isopropylene group, a butylene group, an isobutylene group, and a 2,2-dimethylethylene group.
The alkenylene group is a group having a double bond in alkylene, and examples thereof include a propenylene group, a 2-butenylene group, and a 1,3-butadienylene group.
An alkynylene group is a group having a triple bond in an alkylene group, and examples thereof include a propynylene group and a butynylene group.
The acyl group is a hydrogen atom, an alkyl group, a monocyclic or polycyclic heteroaromatic ring, or a group in which a monocyclic or polycyclic aromatic ring is bonded via a carbonyl group, and these groups May be substituted at any position, and examples thereof include formyl group, acetyl group, benzoyl group, trifluoroacetyl group and the like.
B is represented by R ₂₅ (R ₂₆ ) N-, R ₂₅ and R ₂₆ may form a ring, and R ₂₅ and R ₂₆ are directly bonded to form a nitrogen atom to which they are bonded. Ring represents, for example, a pyrrolidine ring, piperidine ring, hexamethyleneimine ring, heptamethyleneimine ring, etc., and R ₂₅ and R ₂₆ are bonded via a hetero atom and the ring is bonded together with the nitrogen atom to which they are bonded. When formed, it represents a morpholine ring, a piperazine ring or the like, and when forming a ring via an aromatic ring, examples thereof include a tetrahydroisoquinoline ring and a dihydroindole ring.
When R ₂₅ and / or R ₂₆ is a group represented by the above formula (8) and R ₂₉ and G form a ring, R ₂₅ and R ₂₆ are, for example, a tetralinyl group, Indanyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group and the like are represented.
“Optionally substituted” included in the expression of each substituent is a hydroxyl group, thiol group, formyl group, carboxyl group, sulfonyl group, amino group, amide group, carbamoyl group, cyano group, alkoxy group, alkoxy Carbonyl group, alkylamino group, acylamino group, alkoxycarbonylamino group, alkylthio group, aminosulfonyl group, dialkylaminosulfonyl group, methanesulfonyl group, p-toluenesulfonyl group, phenyl group, halogen atom, morpholino group, tetrahydrofuranyl group, 5-methyl-2-oxo-1,3-dioxol-4-yl group, 3-oxo-1,3-dihydro-isobenzofuranyl group, acyloxy group, alkoxycarbonyloxy group, tetrazol-5-yl group Indicates replacement. Here, the alkoxy group means that an alkyl group, cyclohexyl group, or cinnamyl group which may be substituted via an oxygen atom is bonded, the acylamino group is an alkyl group, or a phenyl group is an amino group via a carbonyl group. An acyloxy group means that an alkyl group is bonded to an oxygen atom via a carbonyl group, and an alkoxycarbonyloxy group means that an alkoxy group is bonded to an oxygen atom via a carbonyl group. Represents that In addition, the “optionally substituted” group in A ₁ and A ₂ includes an alkyl group in addition to the aforementioned groups.
A prodrug is a precursor substance that becomes an effective drug after chemical or biochemical metabolism after being administered to a living body, and is a cyclic compound such as a heterocyclic ring contained in the compound represented by the general formula (1). A compound in which one or more groups that are metabolized and eliminated in a living body, such as an alkoxycarbonyl group, a dialkylaminosulfone group, etc., are bonded to medium N or chain N, or represented by the general formula (1) A compound in which one or more ester groups, amide groups, etc. using alcohol or carboxylic acid, which may be contained in the compound, are bonded.
Examples of the pharmacologically acceptable salt include trifluoroacetate, hydrochloride, acetate, sulfate, nitrate, lactate, maleate, methanesulfonate, toluenesulfonate, and tartrate. Citrate, oxalate, malonate, succinate, fumarate, propionate, butyrate, glucuronate, terephthalate, phosphate and the like. Preferred examples include hydrochloride, maleate, tartrate, citrate, and more preferably tartrate.

The following compounds can be illustrated as an amine compound of this invention.
2-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -ethanol [Compound No. 1]
[4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1H-benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 2]
[4- (6-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 3]
[4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 4]
[4- (5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 5]
4-{[N- (1H-imidazol-2-ylmethyl) -amino] -methyl-N- (4-dipropylamino-butyl) -benzamide [Compound No. 6]
2- (4-Dipropylamino-butyl) -5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -2,3- Dihydro-isoindol-1-one [Compound No. 7]
2- (4-Dipropylamino-butyl) -6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -2,3- Dihydro-isoindol-1-one [Compound No. 8]
N- (4-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N-methyl-N ′, N′-dipropyl-butane-1,4-diamine [Compound No. 9 ]
N-methyl-N- [4-({[1- (1-methyl-1H-imidazol-2-ylmethyl) -1H-imidazol-2-ylmethyl] -amino} -methyl) -benzyl-N ′, N ′ -Dipropylbutane-1,4-diamine [Compound No. 10]

[4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1H-inden-2-yl) -butyl] -dipropyl-amine [Compound No. 11]
1- (4-dipropylaminobutyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl) -Urea [Compound No. 12]
[4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1-methyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 13]
3- (3-Dipropylaminopropyl) -8-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-
Imidazol-2-ylmethyl) -amino] -methyl} -3,4-dihydro-1H-benzo [e] [1,4] diazepine-2,5-dione [Compound No. 14]
4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -N- (4-dipropylaminomethyl-phenyl) -Benzamide [Compound No. 15] 4-{[(5-Ethyl-pyridin-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -N- (4-di Propylaminomethyl-phenyl) -benzamide [Compound No. 16]
[4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -3,4-dihydro-1H-isoquinolin-2-yl) -butyl] -dipropyl-amine [
Compound No. 17]
[3- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1-methyl-1H-benzimidazol-2-yl) -benzyl] -dipropyl-amine [Compound No. 18]
6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -5,6,7,8-tetrahydro-imidazo [1,2- a] Pyridine-2-carboxylic acid (4-dipropylamino-butyl) -amide [Compound No. 19]
N- (4-dipropylamino-butyl) -4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5-methyl-pyridin-2-ylmethyl) -amino] -methyl} -benzamide [ Compound No. 20]

N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl ) -Methanesulfonamide [Compound No. 21]
N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl ) -4-Methyl-benzenesulfonamide [Compound No. 22]
N-ethyl-N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ', N'- Dipropyl-butane-1,4-diamine [Compound No. 23]
N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N-phenyl-N ′, N′- Dipropyl-butane-1,4-diamine [Compound No. 24]
N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl ) -Acetamide [Compound No. 25]
1- (4-Dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl ) -1-Methyl-urea [Compound No. 26]
1- (4-Dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl ) -1,3-Dimethyl-urea [Compound No. 27]
N-methyl-N- [4-({(1-methyl-1H-imidazol-2-ylmethyl)-[1- (toluene-4-sulfonyl) -1H-imidazol-2-ylmethyl] -amino} -methyl) -Benzyl] -N ″, N ″ -dipropyl-butane-1,4-diamine [Compound No. 28]
[4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1-methyl-1H-benzimidazol-2-yl) -benzyl] -dipropyl-amine [Compound No. 29]
6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -imidazo [1,2-a] pyridine-2-carboxylic acid (4 -Dipropyl) -amino-butyl) -amide [Compound No. 30]

N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ', N'-dipropyl-N- (2,2,2-trifluoro-ethyl) -butane-1,4-diamine [Compound No. 31]
N- (4-{[(1-Methanesulfonyl-1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N-methyl-N '', N ''-Dipropyl-butane-1,4-diamine [Compound No. 32]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionitrile [Compound No. 33]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid methyl ester [Compound No. 34]
1- (4-Dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl ) -Thiourea [Compound No. 35]
{3- [6- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl) -pyridin-2-yl] -Propyl} -dipropyl-amine [Compound No. 36]
N- (4-Dipropylamino-butyl) -2,2,2-trifluoro-N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) ) -Amino] -methyl} -benzyl) -acetamide [Compound No. 37]
[4- (5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1,3-dihydro-isoindol-2-yl) -butyl] -dipropyl-amine [Compound No. 38]
{4- (1E)-[2- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl) -vinyl] -Benzyl} -dipropyl-amine [Compound No. 3
9]
{[4-((1Z) -2- {4-[(dipropylamino) -methyl] -phenyl} -vinyl) -phenyl] -methyl}-(imidazol-2-ylmethyl)-[(1-methylimidazole -2-yl) -methyl] -amine [Compound No. 40]

{[4-((1E) -2- {4- [2- (dipropylamino) -ethyl] -phenyl} -vinyl) -phenyl] -methyl}-(imidazol-2-ylmethyl)-[(1- Methylimidazol-2-yl) -methyl] -amine [Compound No. 41]
{[4-((1E) -2- {4-[(dipropylamino) -methyl] -phenyl} -vinyl) -phenyl] -methyl}-
Bis- (imidazol-2-ylmethyl) -amine [Compound No. 42]
[4- (6-{[(1H-imidazol-2-yl-methyl)-(1-methyl-imidazol-2-yl-methyl) -amino] -methyl} -benzothiazol-2-yl) -benzyl] -Dipropyl-amine [Compound No. 43]
(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl- (4-piperidin-1-ylbutyl) amine [Compound No. 44]
2- (2- (4-Dipropylamino-butyl) -6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benz Imidazole-1-yl) -ethanol [Compound No. 45]
[3- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -propyl] -dipropyl-amine [Compound No. 46]
[4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1-isopropyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 47]
[5- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -pentyl] -dipropyl-amine [Compound No. 48]
N- (4-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzyl) -N-methyl-N ′ , N'-Dipropyl-butane-1,4-diamine [Compound No. 49]
N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino]- Methyl} -benzyl) -methanesulfonamide [Compound No. 50]

3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid [Compound No. 51]
(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -cyanamide [ Compound No. 52]
(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -formamide [ Compound No. 53]
[(4-{[(1-Carboxymethyl-1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino -Butyl) amino] -acetic acid [Compound No. 54]
[4- (1-Benzyl-6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1H-benzimidazol-2-yl ) -Butyl] -dipropyl-amine [Compound No. 55]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid ethyl ester [Compound No. 56]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-
Imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -amino] -propionic acid isopropyl ester [Compound No. 57]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid benzyl ester [Compound No. 58]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid butyl ester [Compound No. 59]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester [Compound No. 60]

3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid 1-ethyl-propoxycarbonyloxymethyl ester [Compound No. 61]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid 1- (cyclohexyloxycarbonyloxy) -ethyl ester [Compound No. 62]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid methoxycarbonyloxymethyl ester [Compound No. 63]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid ethoxycarbonyloxymethyl ester [Compound No. 64]
2,2-Dimethyl-propionic acid 3-[(4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)- Amino] -methyl} -benzyl) -amino] -propionyloxymethyl ester [Compound No. 65]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid 3-oxo-1,3-dihydro-isobenzofuran-1-yl ester [Compound No. 66]
Hexanoic acid 3-[(4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Benzyl) -amino] -propionyloxymethyl ester [Compound No. 67]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid 3-cyclopentyl-propionyloxymethyl ester [Compound No. 68]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid diethylcarbamoyloxymethyl ester [Compound No. 69]
3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -propionic acid t-butoxycarbonylmethyl ester [Compound No. 70]

3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -Amino] -N-ethyl-propionamide [Compound No. 71]
3-[(4-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid [Compound No. 72]
3-[(4-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid ester [Compound No. 73 ]
3-[(4-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid 5-methyl-2-propionate Oxo- [1,3] dioxol-4-ylmethyl ester [Compound No. 74]
3-[(4-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid 1- (cyclohexyloxycarbonyl Oxy) -ethyl ester [Compound No. 75]
2,2-Dimethyl-propionic acid 3-[(4-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) -amino]- Propionyloxymethyl ester [Compound No. 76]
3-[(4-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid 3-oxo-1, 3-Dihydro-isobenzofuran-1-yl ester [Compound No. 77]
3-[(4-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid diethylcarbamoyloxymethyl ester [ Compound No. 78]
3-[(4-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) -amino] -N-ethyl-propionamide [compound No. 79]
(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-[2- (4-piperidin-1-yl-butyl) -3-propyl-3H-benzimidazol-5- Ilmethyl] -amine [Compound No. 80]

3-[(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-
Amino] -methyl] -benzyl)-(4-piperidin-1-yl-butyl) -amino] -propionic acid [Compound No. 81]
[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino ] -Acetonitrile [Compound No. 82]
[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino ] -Acetic acid methyl ester [Compound No. 83]
[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino ] -Acetic acid [Compound No. 84]
3-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -Amino] -propionic acid 1-isopropoxycarbonyloxy-ethyl ester [Compound No. 85]
3-[(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid methyl ester [compound no. 86]
[(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid methyl ester [Compound No. 87]
[(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid [Compound No. 88]
[(4-Dipropylamino-butyl)-([[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino]- Acetic acid benzyl ester [Compound No. 89]
[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino ] -Acetic acid 2-morpholin-4-yl-ethyl ester [Compound No. 90]

[[4- (Dipropyl-amino) -butyl]-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -Amino] -acetic acid ethyl ester
[Compound No. 91]
[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino ] -Acetic acid 2-methoxy-ethyl ester [Compound No. 92]
[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino ] -Cinnamyl acetate [Compound No. 93]
[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino ] -Acetic acid 2- (2-hydroxy-
Ethoxy) -ethyl ester [Compound No. 94]
(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -carbamic acid t-Butyl ester [Compound No. 95]
N- (2-chloro-4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -N-methyl-N ′ , N'-Dipropyl-butane-1,4-diamine [Compound No. 96]
[(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid ethyl ester [Compound No. 97]
[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino ] -Acetic acid 3,7,11-trimethyl-dodeca-2,6,10-trienyl ester [Compound No. 98]
2-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -Amino] -N, N-dimethyl-acetamide [Compound No. 99]
[(4-[[Bis- (1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid [Compound No. 100 ]

[(4-[[Bis- (1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid ethyl ester [Compound No. .101]
[(4-Dipropylamino-butyl)-([[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino]- Acetic acid- (R)-(-)-tetrahydrofuran-2-ylmethyl ester [Compound No. 102]
([4-[(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -methyl-amino] -butyl] -Propyl-amino) -acetic acid [Compound No. 103]
([4- [Carboxymethyl- (4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -amino] -butyl ] -Propyl-amino) -acetic acid [Compound No. 104]
(2-[[(1-Carboxymethyl-1H-imidazol-2-ylmethyl)-(4-[[(4-dipropylamino-butyl) -methyl-amino] -methyl] -benzyl) -amino] -methyl ] -Imidazol-1-yl) -acetic acid [Compound No. 105]
(2-[[(4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -Imidazol-1-yl) -acetic acid [Compound No. 106]
4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -N- (1H-imidazol-2-ylmethyl) -N- (1-methyl-1H-imidazol-2-ylmethyl)- Benzamide [Compound No.107]
2-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -Amino] -malonic acid diethyl ester [Compound No. 108]
(2- {2-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl-amino]- Ethoxy} -ethyl) -dipropyl-amine [Compound No. 109]
N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ', N'-dipropyl-N- (1H-tetrazol-5-ylmethyl) -butane-1,4-diamine [Compound No. 110]

5-dipropylamino- (2S)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl -Amino] -pentanoic acid ethyl ester [Compound No. 111]
5-dipropylamino- (2S)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl -Amino] -pentanoic acid [Compound No. 112]
(2S) -Dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl -Amino] -pentanoic acid ethyl ester [Compound No. 113]
(2S) -Dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl -Amino] -pentanoic acid [Compound No. 114]
5-dipropylamino- (2R)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl -Amino] -pentanoic acid ethyl ester [Compound No. 115]
5-dipropylamino- (2R)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl -Amino] -pentanoic acid [Compound No. 116]
(2R) -Dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl -Amino] -pentanoic acid ethyl ester [Compound No. 117]
(2R) -Dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl -Amino] -pentanoic acid [Compound No. 118]
[(4-Dipropylamino-butyl) -methyl-amino]-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -Phenyl) -acetic acid ethyl ester [Compound No. 119]
[(4-Dipropylamino-butyl) -methyl-amino]-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -Phenyl) -acetic acid [Compound No. 120]

2-{[(4-Dipropylamino-butyl) -methyl-amino] -methyl} -5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)- Amino] -methyl} -benzoic acid ethyl ester [Compound No. 121]
2-{[(4-Dipropylamino-butyl) -methyl-amino] -methyl} -5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)- Amino] -methyl} -benzoic acid [Compound No. 122]
The present invention relates to a CXCR4 antagonist comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The CXCR4 antagonist or a salt thereof in the present invention is used for treatment or prevention of viral diseases such as AIDS, treatment of cancer, rheumatism or the prevention thereof.

The pharmacologically acceptable salt may be any salt that can form a salt with the amine compound represented by the above formula (1) and is pharmacologically acceptable. For example, trifluoroacetate, hydrochloride, acetate, sulfate, nitrate, lactate, maleate, methanesulfonate, toluenesulfonate, tartrate, citrate, oxalate, malonate, Examples thereof include succinate, fumarate, propionate, butyrate, glucuronate, terephthalate, and phosphate. Preferred examples include hydrochloride, maleate, tartrate, citrate, and more preferably tartrate.
These compounds may optionally form hydrates or solvates.

In addition, in the case where one or two or more asymmetric carbons that may be present in the compound represented by the general formula (1) are one, a pure optically active substance represented by an absolute configuration R or S, Mixtures, racemates, and optically pure diastereomers, racemates, or combinations of these in any ratio, if any, are present. Good.

The pharmaceutical preparation comprising the compound of the present invention represented by the general formula (1) or a pharmacologically acceptable salt thereof as an active ingredient is usually a pharmacologically acceptable carrier, excipient, or dilution known per se. Agent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, colorant, sweetener, thickener, corrigent, solubilizer, other additives, specifically water, vegetable oil , Alcohols such as ethanol or benzyl alcohol, glycols, glycerol triacetate, gelatin, lactose, starch and other carbohydrates, magnesium stearate, potassium stearate, talc, lanolin, petrolatum, macrogol, crystalline cellulose, hydroxypropyl cellulose, etc. , Tablets, powders, granules, capsules, pills, suppositories, injections, eye drops, liquids, troches, aerosols Agents, suspensions, emulsions, can be administered by the form such as syrup orally or parenterally. The dosage may vary depending on the type and degree of disease, the compound to be administered and the route of administration, the age, sex, and body weight of the patient, but in the case of oral administration, usually 0.1 to 5000 mg, particularly 1 to 3000 mg may be administered per adult. preferable. In the case of a prodrug, it is particularly preferable to administer 1 to 5000 mg.

The novel amine compound according to the present invention or a pharmacologically acceptable salt thereof, or a prodrug thereof can provide a novel CXCR4 antagonist. The novel CXCR4 antagonist of the present invention has a CXCR4 antagonistic action, and exhibits an excellent effect as a therapeutic or preventive drug for diseases such as viral infections such as HIV, rheumatism, or cancer metastasis based on the CXCR4 antagonistic action.

First, the production method of the CXCR4 antagonist of the present invention will be specifically described by production examples of the compound of the present invention. Hereinafter, commercially available products (for example, manufactured by Tokyo Kasei Co., Ltd. (Tokyo), manufactured by Kanto Chemical Co., Inc. (Tokyo), etc.) that are readily available to those skilled in the art are used as reagents unless otherwise indicated.

Production Example 1: 2-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-
Synthesis of methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -amino] -ethanol [Compound No. 1]

Example 1-1: Synthesis of 4- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -benzaldehyde
773 mg of 4- (aminomethyl) -benzoic acid methyl hydrochloride (manufactured by Aldrich) was dissolved in 50 ml of THF, and 300 mg of lithium aluminum hydride was gradually added under ice cooling. The mixture was stirred at room temperature for 3 hours and then ice-cooled, and a concentrated aqueous sodium hydroxide solution was gradually added until no bubbles appeared. Celite filtration was performed using chloroform as a solvent, and the filtrate was concentrated and dried. 10 ml of purified water and 10 ml of THF
After dissolving in ice and cooling with ice, 1.26 g of N-carboethoxyphthalimide and 900 mg of sodium carbonate were added. After stirring at room temperature for 4 hours, THF was distilled off, and chloroform was added for extraction. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was further vacuum dried. Next, this compound was dissolved in 20 ml of chloroform, 5.0 g of manganese dioxide (chemically treated product) was added, and the mixture was stirred at room temperature for 3 hours. After filtration through Celite, the filtrate was concentrated and purified by silica gel column chromatography (chloroform / methanol) to obtain 259 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 266 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 4.92 (2H, s), 7.58 (2H, d, J = 8.3 Hz), 7.72-7.76 (2H, m), 7.83-7.89 (4H, m), 9.98 (1H, s).

Example 1-2: Synthesis of N, N-dipropylbutane-1,4-diamine
N- (4-aminobutyl) carbamic acid t-butyl ester (Tokyo Kasei Co., Ltd.) 500 mg is dissolved in methanol 10 ml, propionaldehyde (Tokyo Kasei Co., Ltd.) 0.418 ml, sodium cyanoborohydride 404 mg and trimethyl orthoacetate 1.60. g was added and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off, chloroform was added, washed with distilled water and saturated brine, and dried over anhydrous sodium sulfate. After the solution was concentrated to dryness and dried, 4.0 ml of methanol and 4.0 ml of 4 mol / l hydrogen chloride / dioxane solution were added and stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off and dioxane was added to wash the residue to obtain 654 mg of the hydrochloride of the title compound.
MS (FAB, Pos.): M / z = 173 [M + H] ⁺

Example 1-3: Synthesis of 2- {4-[(4-dipropylamino-butyl-amino) -methyl] -benzyl} -isoindole-1,3-dione Compound obtained in Example 1-1 103 mg was dissolved in 10 ml of anhydrous methanol, and 114 mg of the hydrochloride of the compound obtained in Example 1-2 was added. Triethylamine 0.108ml and anhydrous magnesium sulfate 3g were added there, and it stirred at room temperature for 1 hour. The anhydrous magnesium sulfate was removed by Celite filtration, methanol was distilled off, and the residue was dried with a vacuum pump. This was dissolved in 10 ml of anhydrous methanol, and 22.0 mg of sodium borohydride was gradually added under ice cooling. This was returned to room temperature and stirred for 1 hour. After completion of the reaction, methanol was distilled off, and water and chloroform were added to extract the organic layer. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol / water) to obtain 60.3 mg of the title compound as a pale yellow viscous liquid.
MS (FAB, Pos.): M / z = 420 [M + H] ⁺

Example 1-4: [4- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -benzyl]-(4-dipropylamino-butyl) -carbamic acid t-butyl ester Synthesis 60.3 mg of the compound obtained in Example 1-3 was dissolved in chloroform, and 47.0 mg of di-t-butyl dicarbonate was added thereto. After stirring at room temperature for 30 minutes, the mixture was concentrated and purified by silica gel column chromatography (chloroform / methanol) to obtain 70.0 mg of the title compound as a colorless viscous liquid.
MS (FAB, Pos.): M / z = 522 [M + H] ⁺

Example 1-5: (4-Aminomethyl-benzyl)-(4-dipropylamino-butyl) -carbamic acid t-
Synthesis of butyl ester 3.0 ml of 40% methylamine / methanol solution was added to 70.0 mg of the compound obtained in Example 1-4.
Stir at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off, 1 mol / l aqueous sodium hydroxide solution and chloroform were added, and the aqueous layer was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 65.5 mg of the title compound as a colorless viscous liquid.

Example 1-6: Synthesis of (4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -carbamic acid-t-butyl ester 0.78 g of the compound obtained in Example 1-5 was dissolved in 20 ml of methanol, 214 mg of 2-imidazolecarboxaldehyde was added, and the mixture was stirred at room temperature for 17 hours. After the solvent was distilled off, the residue was vacuum-dried, dissolved in 15 ml of methanol, 217.8 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 45 minutes. 10 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes.
Saturated saline was added to the reaction solution, extracted with chloroform, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 1.01 g of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 472 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3Hz), 1.26-1.49 (17H, m), 2.32-2.35 (6H, m), 3.12 (1H, brs), 3.21 (1H, brs), 3.79 (2H, brs), 3.92 (2H, brs), 4.12 (1H, brs), 4.13 (1H, brs), 6.99 (2H, s), 7.20 (2H, brs), 7.25 (2H, d, J = 7.5Hz).

Example 1-7: (4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} Synthesis of (benzyl) -carbamic acid t-butyl ester 231 mg of the compound obtained in Example 1-6 was dissolved in anhydrous methanol 5.0 ml, sodium cyanoborohydride 61.6 mg, acetic acid 2.00 ml, 1-methyl-2- Imidazolecarboxaldehyde (80.9 mg) was added, and the mixture was stirred at room temperature for 6 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / methanol / water) to obtain 197 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 566 [M + H] ⁺

Example 1-8: N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ′, N Synthesis of '-dipropylbutane-1,4-diamine 197 mg of the compound obtained in Example 1-7 was dissolved in 1.0 ml of methanol, 3.0 ml of 10% hydrogen chloride / methanol solution was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off to obtain 159 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 466 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.87 (6H, t, J = 7.3 Hz), 1.59-1.67 (8H, m), 2.87 (2H, brs), 2.94-2.97 (4H, m), 3.01 (2H, brs), 3.66 (3H, s), 3.69 (2H, s), 4.03 (4H, s), 4.13 (2H, s), 7.34 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.2Hz), 7.40 (1H, d, J = 2.0Hz), 7.41 (1H, d, J = 2.0Hz), 7.53 (2H, s).

Example 1-9: 2-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -methyl} -benzyl) -amino] -ethanol [Compound No. 1] 209 mg of the compound obtained in Example 1-8 was dissolved in 8.4 ml of anhydrous methanol. [1,4] Dioxane-2,5-diol 54.0 mg and sodium cyanoborohydride 56.6 mg were added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 19.5 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution (1.0 ml) was added, and the mixture was extracted with chloroform. Dried over magnesium sulfate. Evaporate the solvent,
The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 175.8 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 510 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.1 Hz), 1.64-1.68 (6H, m), 1.78-1.82 (2H, m), 3.00 -3.08 (10H, m), 3.71 (3H, s), 3.74 (4H, s), 4.09 (2H, s), 4.17 (2H, s), 4.30 (2H, q, J = 13.9Hz), 7.41 ( 2H, d, J = 7.8Hz), 7.48 (4H, d, J = 5.6Hz), 7.61 (2H, s).

Production Example 2: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1H-benzimidazol-2-yl ) -Butyl] -dipropyl-amine [Compound No. 2]

Example 2-1: Synthesis of methyl 4-amino-3-{(5-t-butoxycarbonylamino) -pentanoyl} -aminobenzoate
1.45 g of 5-t-butoxycarbonylaminovaleric acid, 1.74 g of WSCI hydrochloride and 1.25 g of HOBt were dissolved in 20 ml of DMF and stirred for 15 minutes. To this was added 1.00 g of methyl 3,4-diaminobenzoate (Lancaster) and stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with saturated aqueous ammonium chloride and 1 mol / l aqueous sodium hydroxide, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 1.46 g of the title compound.
MS (FAB, Pos.): M / z = 365 [M + H] ⁺

Example 2-2: Synthesis of 2- (4-dipropylamino-butyl) -3H-benzimidazole-5-carboxylic acid methyl ester 1.46 g of the compound obtained in Example 2-1 was dissolved in 7.3 ml of methanol. To this, 7.3 ml of 4 mol / l hydrogen chloride / dioxane solution was added and stirred at 40 ° C. overnight. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was vacuum dried. This was dissolved in 15 ml of methanol, 0.597 ml of triethylamine, 1.0 ml of trimethyl orthoformate and 0.309 ml of propionaldehyde were added and stirred at room temperature for 30 minutes. To this, 272 mg of sodium cyanoborohydride was added and stirred at room temperature for 30 minutes. Further, 0.310 ml of propionaldehyde and 270 mg of sodium cyanoborohydride were added and stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (315 mg) as a brown oily substance.
MS (FAB, Pos.): M / z = 332 [M + H] ⁺

Example 2-3 Synthesis of {4- [6-Chloromethyl-1- (toluene-4-sulfonyl) -1H-benzimidazol-2-yl] -butyl} -dipropyl-amine 108 mg of lithium aluminum hydride in 60 ml of THF 60 ml of a THF solution of the compound 315 mg obtained in Example 2-2 was added dropwise thereto and stirred at room temperature for 1 hour. After completion of the reaction, sodium sulfate decahydrate was added until no foaming occurred, and a 1 mol / l aqueous sodium hydroxide solution was added little by little until a white precipitate was formed. After filtration, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum. The residue was dissolved in 10 ml of dichloromethane, and 263 μl of triethylamine and 364 mg of p-toluenesulfonyl chloride were added and stirred at room temperature for 2.5 hours. After completion of the reaction, it was washed with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 113 mg of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 476 [M + H] ⁺

Example 2-4: [4- (6-Aminomethyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-
Synthesis of amine 113 mg of the compound obtained in Example 2-3 was dissolved in 2.0 ml of DMF, 69.0 mg of potassium phthalimide was added, and the mixture was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with water. After extraction with chloroform, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was vacuum-dried. The residue was dissolved in 1.5 ml of 40% methylamine / methanol solution, and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, and washed with water and 1 mol / l sodium hydroxide aqueous solution. After extraction with chloroform, the extract was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 39.8 mg of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 303 [M + H] ⁺

Example 2-5: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1H-benzimidazole-2 Synthesis of -yl) -butyl] -dipropyl-amine [Compound No. 2] 39.8 mg of the compound obtained in Example 2-4 was dissolved in 1.0 ml of methanol, 13.3 mg of 2-imidazolecarboxaldehyde, and trimethyl orthoformate 0.030 ml was added and stirred at room temperature for 30 minutes. To this, 10.5 mg of sodium borohydride was added little by little and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with water, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure.
This was dissolved in 1.0 ml of methanol, 63.2 mg of 1-methyl-2-imidazolecarboxaldehyde, 0.023 ml of acetic acid, 0.030 ml of trimethyl orthoformate, and 23.2 mg of sodium cyanoborohydride were added and stirred at room temperature for 30 minutes. To this, 0.045 ml of acetic acid was added and stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 27.6 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 477 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.89 (3H, t, J = 7.3 Hz), 1.63-1.69 (4H, m), 1.70-1.81 (2H, m), 1.94-2.01 (2H , m), 2.84-3.00 (4H, m), 3.03-3.09 (2H, m), 3.19-3.23 (2H, m), 3.72 (3H, s), 3.90 (2H, s), 4.13 (2H, s ), 4.21 (2H, s), 4.41 (2H, t, J = 7.3Hz), 7.49 (1H, s), 7.53 (1H, s), 7.59 (1H, d, J = 8.4Hz), 7.64-7.66 (3H, m), 7.81 (1H, s), 10.50 (1H, s).

Production Example 3: [4- (6-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine Synthesis of [Compound No.3]

Example 3-1: Synthesis of methyl 4-amino-3-propylamino-methyl benzoate
2.01 g of methyl 3,4-diaminobenzoate was dissolved in 40 ml of DMF, and 2.00 g of potassium carbonate and 1.4 ml of methyl iodide were added thereto, followed by stirring at room temperature for 22 hours. After completion of the reaction, the solvent was distilled off under reduced pressure.
The residue was dissolved in ethyl acetate, washed with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1.06 g of the title compound.
MS (FAB, Pos.): M / z = 209 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.05 (3H, t, J = 7.3 Hz), 1.71 (2H, sext., J = 7.3 Hz), 3.12 (2H, t, J = 7.1 Hz), 3.86 (3H, s), 6.69 (1H, d, J = 8.1Hz), 7.35 (1H, s), 7.45 (1H, d, J = 8.1Hz).

Example 3-2: Synthesis of methyl 4- (5-t-butoxycarbonylamino-pentanoylamino) -3-propylamino-benzoate
574 mg of 5-t-butoxycarbonylaminovaleric acid, 690 mg of WSCI hydrochloride and 487 mg of HOBt were dissolved in 10 ml of chloroform and stirred at room temperature for 30 minutes. To this was added 503 mg of the compound obtained in Example 3-1, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 540 mg of the title compound as a colorless viscous product.
MS (FAB, Pos.): M / z = 408 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.97 (3H, t, J = 7.3 Hz), 1.37 (9H, s), 1.37-1.46 (2H, m), 1.51-1.66 (4H, m), 2.37 (2H, t, J = 7.3Hz), 2.93 (2H, q, J = 6.6Hz), 3.04 (2H, q, J = 7.1Hz), 3.81 (3H, s), 5.14 (1H, br), 6.83 (1H, br), 7.16 (1H, s), 7.20 (1H, d, J = 8.1Hz), 7.45 (1H, d, J = 8.1Hz), 9.24 (1H, s).

Example 3-3: Synthesis of 2- (4-dipropylamino-butyl) -3-propyl-3H-benzimidazole-5-carboxylic acid methyl ester 540 mg of the compound obtained in Example 3-2 in 10 ml of methanol After dissolution, 5.0 ml of 4 mol / l hydrogen chloride / dioxane solution was added and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in methanol, and an anion exchange resin (Amberlite IRA-410) was added for neutralization. The solvent was distilled off.
This was dissolved in 12 ml of methanol, 0.425 ml of acetic acid and 135 mg of sodium cyanoborohydride were added thereto and cooled to 0 ° C. Propionaldehyde 0.114ml was added here and it stirred at room temperature for 1 hour. The mixture was cooled again to 0 ° C., 132 mg of sodium cyanoborohydride and 0.115 ml of propionaldehyde were added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform.
The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 361 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 374 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.88 (6H, t, J = 7.3 Hz), 1.00 (3H, t, J = 7.3 Hz), 1.49 (4H, q, J = 7.5 Hz), 1.74 -1.82 (4H, m), 1.87 (2H, sext., J = 7.6Hz), 1.91-2.09 (4H, m), 2.93-3.01 (4H, m), 3.00 (2H, t, J = 7.1Hz) , 3.09 (2H, t, J = 7.6Hz), 3.96 (3H, s), 4.15 (2H, t, J = 7.6Hz), 7.66 (1H, d, J = 8.5Hz), 7.96 (1H, d, J = 8.5Hz), 8.08 (1H, s).

Example 3-4: Synthesis of [2- (4-dipropylamino-butyl) -3-propyl-3H-benzimidazol-5-yl] -methanol Lithium aluminum hydride 138 mg was suspended in THF 7.0 ml After cooling to ° C., Example 3-3
7.0 ml of a THF solution of 361 mg of the compound obtained in 1 above was added dropwise and stirred at 0 ° C. for 1 hour. After completion of the reaction, sodium sulfate decahydrate was added until it no longer foamed. A 1 mol / l aqueous sodium hydroxide solution was added thereto until a white solid precipitated. The solid was filtered off, the solvent was distilled off from the filtrate under reduced pressure, and the residue was vacuum-dried to obtain 302 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 346 [M + H] ^{+
1 H-NMR (500MHz, DMSO} -d 6):. Δ = 0.82 (6H, t, J = 7.3Hz), 0.89 (3H, t, J = 7.3Hz), 1.37 (4H, sext, J = 7.3Hz ), 1.50 (2H, quint., J = 7.3Hz), 1.70-1.81 (4H, m), 2.29 (4H, t, J = 7.3Hz), 2.39 (2H, t, J = 7.1Hz), 2.84 ( 2H, t, J = 7.6Hz), 4.11 (2H, t, J = 7.3Hz), 4.59 (2H, d, J = 5.2Hz), 5.16 (1H, t, J = 5.5Hz), 7.09 (1H, d, J = 8.2Hz), 7.42 (1H, s), 7.45 (1H, d, J = 8.2Hz).

Example 3-5: 2- [2- (4-Dipropylamino-butyl) -3-propyl-3H-benzimidazole-5-
Synthesis of [Ilmethyl] -isoindole-1,3-dione 302 mg of the compound obtained in Example 3-4 was dissolved in 6.0 ml of toluene, and 275 mg of triphenylphosphine and 193 mg of phthalimide were added and cooled to 0 ° C. To this, 452 mg of a 40% diethyl azodicarboxylate / toluene solution was added dropwise, and then stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with water, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 174 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 475 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.79-0.83 (6H, m), 0.86 (3H, t, J = 7.3Hz), 1.31-1.40 (4H, m), 1.46-1.51 (2H , m), 1.63-1.80 (4H, m), 2.29 (4H, br), 2.39 (2H, br), 2.83 (2H, t, J = 7.6Hz), 4.12 (2H, t, J = 7.3Hz) , 4.87 (2H, s), 7.08 (1H, d, J = 8.3Hz), 7.46-7.48 (2H, m), 7.83-7.89 (2H, m), 7.90-7.93 (2H, m).

Example 3-6: [4- (6-Aminomethyl-1-propyl-1H-benzimidazol-2-yl) -butyl]-
Synthesis of Dipropyl-Amine 173 mg of the compound obtained in Example 3-5 was dissolved in 1.8 ml of 40% methylamine / methanol solution and stirred at room temperature for 17 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 130 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 345 [M + H] ⁺

Example 3-7: [4- (6-{[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -butyl] -dipropyl Synthesis of -amine [Compound No. 3] 130 mg of the compound obtained in Example 3-6 was dissolved in 3.0 ml of methanol, 0.130 ml of trimethyl orthoformate and 37.3 mg of 2-imidazole carboxaldehyde were added, and the mixture was stirred for 1 hour. 0 ℃
Cooled to. To this was added 21.5 mg of sodium borohydride, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 16.4 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 505 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.91 (6H, t, J = 7.3 Hz), 0.99 (3H, t, J = 7.3 Hz), 1.66-1.71 (4H, m), 1.78- 1.82 (4H, m), 1.83-1.96 (2H, m), 2.97-3.00 (4H, m), 3.08-3.16 (2H, m), 3.25 (2H, t, J = 7.2Hz), 3.87 (2H, s), 4.16 (4H, s), 4.54 (2H, t, J = 7.7Hz), 7.52-7.55 (1H, m), 7.61 (3H, s), 7.64-7.70 (1H, m), 8.43 (1H , s), 10.31 (1H, br).

Production Example 4: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazole Synthesis of 2-yl) -butyl] -dipropyl-amine [Compound No. 4]

Example 4-1: [4- (6-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine Synthesis of 130 mg of the compound obtained in Example 3-6 in 3.0 ml of methanol, 0.130 ml of trimethyl orthoformate and 37.3 mg of 2-imidazole carboxaldehyde were added, and the mixture was stirred for 1 hour, then 0 ° C.
Cooled to. To this was added 21.5 mg of sodium borohydride, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 64.0 mg of the title compound as a pale yellow oil.

Example 4-2: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H- Synthesis of benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 4] 64.0 mg of the compound obtained in Example 4-1 was dissolved in 1.3 ml of methanol, 0.065 ml of acetic acid, 1-
16.6 mg of methyl-2-imidazole carboxaldehyde was added and cooled to 0 ° C. To this was added 14.2 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 30.0 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 519 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.91 (6H, t, J = 7.3 Hz), 0.99 (3H, t, J = 7.3 Hz), 1.66-1.74 (4H, m), 1.78- 1.84 (4H, m), 1.93 (2H, t, J = 7.3Hz), 2.94-3.00 (4H, m), 3.13 (2H, br), 3.26 (2H, t, J = 7.3Hz), 3.73 (3H , s), 3.90 (2H, s), 4.13 (2H, s), 4.21 (2H, s), 4.53 (2H, t, J = 7.6Hz), 7.53-7.55 (3H, m), 7.63 (2H, s), 7.70 (1H, d, J = 8.2Hz), 8.41 (1H, s), 10.48 (1H, br).

Production Example 5: [4- (5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazole Synthesis of -2-yl) -butyl] -dipropyl-amine [Compound No. 5]

Example 5-1: Synthesis of 3-nitro-4-propylamino-benzonitrile
3-Nitro-4-aminobenzonitrile (1.12 g) was dissolved in DMF (20 ml), 60% sodium hydride (411 mg) was added, and the mixture was stirred at room temperature for 30 minutes. To this was added 805 μl of 1-iodopropane and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
After filtration, the solvent was distilled off under reduced pressure to obtain 1.58 g of a crude product of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 206 [M + H] ⁺

Example 5-2: Synthesis of 3-amino-4-propylamino-benzonitrile 1.58 g of the compound obtained in Example 5-1 and 7.81 g of stannous chloride dihydrate were dissolved in 170 ml of ethanol. Heated to ° C. To this, 144 mg of sodium borohydride was added little by little, and the mixture was stirred at 60 ° C. for 2 hours. After completion of the reaction, water was added, neutralized with a 1 mol / l aqueous sodium hydroxide solution, and ethanol was distilled off under reduced pressure. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1.18 g of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 176 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.04 (3H, t, J = 7.6 Hz), 1.70 (2H, sext., J = 7.3 Hz), 3.13 (2H, q, J = 7.1 Hz), 6.58 (1H, d, J = 8.1Hz), 6.94 (1H, s), 7.17 (1H, d, J = 8.1Hz).

Example 5-3: Synthesis of [4- (5-cyano-2-propylamino-phenylcarbamoyl) -butyl] -t-butyl carbamate
1.57 g of 5-t-butoxycarbonylaminovaleric acid, 1.98 g of WSCI hydrochloride and 1.39 g of HOBt were dissolved in 31 ml of chloroform and stirred at room temperature for 30 minutes. This was added dropwise to 10 ml of a chloroform solution of the compound 1.18 g obtained in Example 5-2, and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was removed by silica gel column chromatography (chloroform / ethyl acetate) to remove only the highly polar substance, thereby obtaining 2.52 g of a mixture containing the title compound as a yellow oily substance.
MS (FAB, Pos.): M / z = 375 [M + H] ⁺

Example 5-4: Synthesis of 2- (4-dipropylamino-butyl) -1-propyl-1H-benzimidazole-5-carbonitrile 2.52 g of the compound obtained in Example 5-3 was dissolved in 20 ml of methanol. Then, 12 ml of 4 mol / l hydrogen chloride / dioxane solution was added and stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure.
This was dissolved in 40 ml of methanol, added with 0.250 ml of acetic acid and 1.21 ml of propionaldehyde and cooled to 0 ° C. To this was added 1.39 g of sodium cyanoborohydride, and the mixture was stirred at room temperature for 13 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1.41 g of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 341 [M + H] ⁺

Example 5-5: [4- (5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H- Synthesis of benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 5] After suspending 588 mg of lithium aluminum hydride in 30 ml of THF and cooling to 0 ° C., the compound obtained in Example 5-4 30 ml of a 1.40 g THF solution was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour. After completion of the reaction, sodium sulfate decahydrate was added until it no longer foamed. A 1 mol / l aqueous sodium hydroxide solution was added thereto until a white solid precipitated. The solid was filtered off, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol).
This was dissolved in 12 ml of methanol, 0.78 ml of trimethyl orthoformate and 228 mg of 2-imidazole carboxaldehyde were added and stirred for 1 hour, and then cooled to 0 ° C. To this was added 188 mg of sodium borohydride, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 1 mol / l hydrochloric acid, and the aqueous layer was washed with chloroform. A 1 mol / l aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate).
This is dissolved in methanol 6.0 ml, acetic acid 0.20 ml, sodium cyanoborohydride 50.0 mg
Was added. To this, 59.8 mg of 1-methyl-2-imidazolecarboxaldehyde was added little by little, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate). This was treated with hydrochloric acid to give 242 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 519 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.89-0.95 (9H, m), 1.67-1.94 (10H, m), 2.96-3.00 (4H, m), 3.12-3.13 (2H, m) , 3.26 (2H, t, J = 7.3Hz), 3.72 (3H, s), 3.91 (2H, s), 4.13 (2H, s), 4.21 (2H, s), 4.41 (2H, t, J = 7.3 Hz), 7.49 (1H, s), 7.52 (1H, s), 7.64 (2H, s), 7.72 (1H, d, J = 8.5Hz), 7.82 (1H, s), 7.90 (1H, d, J = 8.5Hz), 10.61 (1H, s).

Production Example 6: Synthesis of 4-{[N- (1H-imidazol-2-ylmethyl) -amino] -methyl-N- (4-dipropylamino-butyl) -benzamide [Compound No. 6]

Example 6-1: Synthesis of 4-{[t-butoxycarbonyl- (1H-imidazol-2-ylmethyl) -amino] -methyl} -benzoic acid 10.0 g of commercially available bromomethylbenzoic acid methyl ester (manufactured by Aldrich) After dissolving in 100 ml of DMF, 9.70 g of potassium phthalimide (manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was concentrated, water was added, and the mixture was extracted with chloroform. After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 12.9 g of a white solid. 7.56 g of this was dissolved in 100 ml of methanol, hydrazine monohydrate (manufactured by Nacalai Tesque) was added and 6.25 ml was added at 60 ° C. for 1.5
Stir for hours. After completion of the reaction, the precipitated solid was filtered off and the solvent was distilled off. Water was added thereto, and the mixture was extracted with chloroform and washed with a 0.3 mol / l aqueous sodium hydroxide solution and saturated brine. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. 120 ml of methanol and 2.35 g of 2-imidazole carboxaldehyde (Aldrich) were added thereto and stirred at room temperature for 2 days. After completion of the reaction, the precipitated solid was collected by filtration. The liquid layer was concentrated to dryness, washed with 30 ml of anhydrous methanol, and the solid was filtered off. This solid and the previously collected solid were combined and suspended in 86 ml of methanol, and 1.42 g of sodium borohydride was added under ice cooling. This was stirred at room temperature for 1 hour and the solvent was distilled off. After adding water, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, concentration under reduced pressure and drying were performed to obtain 4.32 g of a colorless oil. 4.28 g of this was dissolved in 65 ml of DMF, 8.90 ml of di-t-butyl dicarbonate was added, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off, and 43 ml of THF, 43 ml of methanol and 43 ml of 1 mol / l aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off, 5.0 ml of water was added, 1 mol / l hydrochloric acid was carefully added, and the acid precipitate was collected by filtration and dried to give 4.87 g of the title compound.
Was obtained as a white solid.
MS (FAB, Pos.): M / z = 332 [M + H] ⁺

Example 6-2: Synthesis of [4- (4-Dipropylamino-butylcarbamoyl) -benzyl]-(1H-imidazol-2-ylmethyl) -carbamic acid t-butyl ester Obtained in Example 1-2 203 mg of the compound was dissolved in 5.0 ml of DMF and 5.0 ml of chloroform, and 0.374 ml of triethylamine, 382 mg of WSCI hydrochloride, 200 mg of HOBt and 463 mg of the compound obtained in Example 6-1 were added and stirred at room temperature for 23 hours. After completion of the reaction, the solvent was distilled off, chloroform was added, and the mixture was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol / water) to obtain 168 mg of the title compound as a colorless foam.
MS (FAB, Pos.): M / z = 486 [M + H] ⁺

Example 6-3: Synthesis of 4-{[N- (1H-imidazol-2-ylmethyl) -amino] -methyl-N- (4-dipropylamino-butyl) -benzamide [Compound No. 6] 117 mg of the compound obtained in 6-2 was dissolved in 1.2 ml of methanol, 1.2 ml of 4 mol / l hydrogen chloride / dioxane solution was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in water and purified with a solid phase extraction column (Seppack, tC18, manufactured by Waters) to obtain 118 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 386 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.89 (6H, t, J = 7.3 Hz), 1.54-1.62 (2H, m), 1.61-1.83 (6H, m), 2.93-3.01 (4H , m), 3.00-3.01 (2H, m), 3.30 (2H, dd, J = 6.1,12.3Hz), 4.37 (2H, s), 4.52 (2H, s), 7.62-7.64 (4H, m), 7.92 (2H, d, J = 8.1Hz), 8.71 (1H, d, J = 4.4Hz).

Production Example 7: 2- (4-Dipropylamino-butyl) -5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of 2,3-dihydro-isoindol-1-one [Compound No. 7]

Example 7-1: Synthesis of 4-methylphthalic acid dimethyl ester
3.00 g of 4-methylphthalic acid was dissolved in 60 ml of methanol, 9.62 g of WSCI hydrochloride and 3.07 g of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction solution to stop the reaction, followed by extraction with chloroform. The organic layer was washed with water, 1 mol / l hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2.54 g of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 209 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 2.42 (3H, s), 3.89 (3H, s), 3.91 (3H, s), 7.33 (1H, dd, J = 1.7, 8.6 Hz), 7.47 ( 1H, d, J = 1.2Hz), 7.68 (1H, d, J = 7.8Hz).

Example 7-2: Synthesis of 4- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -phthalic acid dimethyl ester 202 mg of the compound obtained in Example 7-1 was added to carbon tetrachloride. After dissolving in 7.1 ml, 205 mg of N-bromosuccinimide and 15.8 mg of 2,2′-azobisisobutyronitrile were added and heated to reflux for 20 hours. Carbon tetrachloride (7.0 ml) and N-bromosuccinimide (51.3 mg) were added, and the mixture was further heated under reflux for 4 hours. After cooling, water was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was dissolved in 5.8 ml of DMF, 359 mg of potassium phthalimide was added, and the mixture was stirred at room temperature for 16 hours. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 226 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 354 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 3.88 (3H, s), 3.90 (3H, s), 4.89 (2H, s), 7.60 (1H, dd, J = 1.8, 8.1 Hz), 7.71 ( 1H, d, J = 7.9Hz), 7.74 (2H, dd, J = 2.9, 5.5Hz), 7.75 (1H, m), 7.87 (2H, dd, J = 2.9, 5.5Hz).

Example 7-3: Synthesis of 4- (t-butoxycarbonylamino-methyl) -phthalic acid dimethyl ester The compound 909 mg obtained in Example 7-2 was suspended in 22 ml of methanol and hydrazine monohydrate 0.13 ml. Was added dropwise and heated to reflux for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, followed by extraction with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was dissolved in 15 ml of DMF, 0.54 ml of triethylamine and 851 mg of di-t-butyl dicarbonate were added, and the mixture was stirred at room temperature for 15 hours. After the solvent was distilled off, extraction was performed with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane / ethyl acetate), thereby obtaining the subject compound (779 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 324 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.47 (9H, s), 3.90 (3H, s), 3.91 (3H, s), 4.38 (2H, d, J = 6.1 Hz), 4.94 (1H, br), 7.46 (1H, d, J = 8.5Hz), 7.61 (1H, d, J = 1.5Hz), 7.72 (1H, d, J = 7.8Hz).

Example 7-4: Synthesis of 4- (t-butoxycarbonylamino-methyl) -phthalic acid 76.4 mg of the compound obtained in Example 7-3 was dissolved in 4.5 ml of methanol, and 1 mol / l aqueous sodium hydroxide solution 2.3 ml was added dropwise and stirred at room temperature for 2 hours. The residue obtained by neutralizing by adding 2.3 ml of 1 mol / l hydrochloric acid and evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol) to obtain 65.3 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 296 [M + H] ^+
1 H-NMR (500 MHz, CD ₃ OD): δ = 1.45 (9H, s), 4.30 (2H, s), 7.45 (1H, d, J = 7.6 Hz), 7.80 (1H, s), 7.88 (1H , d, J = 8.1Hz).

Example 7-5: [2- (4-Di-n-propylamino-butyl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -carbamic acid t-butyl ester Synthesis of 123 mg of the compound obtained in Example 7-4 was dissolved in 5.0 ml of xylene, and a solution of 83.4 mg of the compound obtained in Example 1-2 in 5.0 ml of xylene was added dropwise and heated to reflux for 63 hours. Water was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 88.4 mg of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 432 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.4 Hz), 1.40-1.50 (6H, m), 1.47 (9H, m), 1.64-1.70 (2H, m), 2.34 (4H, t, J = 7.4Hz), 2.42 (2H, t, J = 7.5Hz), 3.69 (2H, t, J = 7.3Hz), 4.45 (2H, d, J = 6.1Hz), 5.04 ( 1H, br), 7.62 (, 1H.d, J = 7.5Hz), 7.76 (1H, d, J = 0.8Hz), 7.79 (1H, d, J = 7.6Hz).

Example 7-6: N- [2- (4-Dipropylamino-butyl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -acetamide and N- [2- (4 Synthesis of -Dipropylamino-butyl) -3-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -acetamide 86.5 mg of the compound obtained in Example 7-5 was dissolved in 2.0 ml of acetic acid And heated to 60 ° C. To this solution, 130 mg of zinc powder was added in several portions and heated to reflux for 10 hours. The mixture was allowed to cool to room temperature, filtered through celite, concentrated, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 66.1 mg of the title compound mixture as a yellow oily substance.
1-oxo isomer MS (FAB, Pos.): M / z = 360 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.39-1.48 (6H, m), 1.65-1.68 (2H, m), 2.07 (3H, s), 2.32 (4H, m), 2.43 (2H, t, J = 7.3Hz), 3.61 (2H, t, J = 7.3Hz), 4.34 (2H, s), 4.52 (2H, d, J = 5.8Hz), 6.14 (1H, br), 7.33 (1H, d, J = 7.8Hz), 7.38 (1H, s), 7.74 (1H, d, J = 7.8Hz).
3-oxo isomer MS (FAB, Pos.): M / z = 360 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.39-1.48 (6H, m), 1.65-1.68 (2H, m), 2.05 (3H, s), 2.32 (4H, m), 2.43 (2H, t, J = 7.3Hz), 3.62 (2H, t, J = 7.3Hz), 4.35 (2H, s), 4.51 (2H, d, J = 5.8Hz), 6.14 (1H, br), 7.40 (1H, s), 7.47 (1H, dd, J = 1.6,7.7Hz), 7.70 (1H, d, J = 1.0Hz).

Example 7-7: 2- (4-Dipropylamino-butyl) -5-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -2,3-dihydro-isoindol-1-one 1 mol / l hydrochloric acid was added to 66.1 mg of the compound obtained in Example 7-6, and the mixture was heated to reflux for 18 hours. The concentrated residue was dissolved in methanol, and an anion exchange resin (Amberlite IRA-410) was added to adjust the pH to 8. The resin was filtered off, the residue obtained by distilling off the solvent of the filtrate was dissolved in 2.0 ml of methanol, 0.070 ml of trimethyl orthoformate and 28.8 mg of 2-imidazolecarboxaldehyde were added, and the mixture was stirred at room temperature for 20 hours. The solution was cooled to 0 ° C., 22.7 mg of sodium borohydride was added, the temperature was raised to room temperature, and the mixture was stirred for 3 hours. Water was added to stop the reaction, and the mixture was extracted with chloroform.
The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (13.4 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 398 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.39-1.52 (6H, m), 1.64-1.70 (2H, m), 2.34-2.36 (4H, m ), 2.44 (2H, t, J = 7.3Hz), 3.62 (2H, t, J = 7.2Hz), 3.89 (2H, s), 3.94 (2H, s), 4.34 (2H, s), 7.00 (2H , s), 7.39 (1H, d, J = 6.7Hz), 7.40 (1H, s), 7.76 (1H, d, J = 8.1Hz).

Example 7-8: 2- (4-dipropylamino-butyl) -5-{[(1H-imidazol-2-ylmethyl)-(1-
Synthesis of methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -2,3-dihydro-isoindol-1-one [Compound No. 7] 20.3 mg of the compound obtained in Example 7-7 The mixture was dissolved in 2.0 ml of methanol, 6.8 mg of 1-methyl-2-imidazolecarboxaldehyde and 6.4 mg of sodium cyanoborohydride were added, the pH was adjusted to 4 with acetic acid, and the mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 24.0 mg of the hydrochloride of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 492 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.4 Hz), 1.39-1.52 (6H, m), 1.65 (2H, m), 2.33-2.36 (4H, m), 2.44 (2H, t, J = 7.4Hz), 3.51 (2H, s), 3.59 (3H, s), 3.60 (2H, s), 3.63 (2H, t, J = 7.5Hz), 3.77 (2H, s ), 4.37 (2H, s), 6.90 (1H, d, J = 1.5Hz), 7.01 (1H, d, J = 1.2Hz), 7.09 (1H, br), 7.12 (1H, br), 7.48 (1H , s), 7.57 (1H, d, J = 8.8Hz), 7.82 (1H, d, J = 7.8Hz).

Production Example 8: 2- (4-Dipropylamino-butyl) -6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of 2,3-dihydro-isoindol-1-one [Compound No. 8]

Example 8-1: 2- (4-Dipropylamino-butyl) -6-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -2,3-dihydro-isoindol-1-one 1 mol / l hydrochloric acid was added to 66.1 mg of the compound obtained in Example 7-6, and the mixture was heated to reflux for 18 hours. The concentrated residue was dissolved in methanol, and an anion exchange resin (Amberlite IRA-410) was added to adjust the pH to 8. The resin was filtered off, the residue obtained by distilling off the solvent of the filtrate was dissolved in 2.0 ml of methanol, 0.070 ml of trimethyl orthoformate and 28.8 mg of 2-imidazolecarboxaldehyde were added, and the mixture was stirred at room temperature for 20 hours. The solution was cooled to 0 ° C., 22.7 mg of sodium borohydride was added, the temperature was raised to room temperature, and the mixture was stirred for 3 hours. Water was added to stop the reaction, and the mixture was extracted with chloroform.
The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol) to obtain 22.9 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 398 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.39-1.52 (6H, m), 1.65-1.71 (2H, m), 2.33-2.36 (4H, m ), 2.44 (2H, t, J = 7.3Hz), 3.64 (2H, t, J = 7.3Hz), 3.89 (2H, s), 3.93 (2H, s), 4.37 (2H, s), 7.00 (2H , s), 7.39 (1H, d, J = 7.8Hz), 7.46 (1H, d, J = 7.8Hz), 7.86 (1H, s).

Example 8-2: 2- (4-dipropylamino-butyl) -6-{[(1H-imidazol-2-ylmethyl)-(1-
Synthesis of methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -2,3-dihydro-isoindol-1-one [Compound No. 8] 15.1 mg of the compound obtained in Example 8-1 After dissolving in 1.5 ml of methanol, 5.0 mg of 1-methyl-2-imidazolecarboxaldehyde and 4.8 mg of sodium cyanoborohydride were added, the pH was adjusted to 4 with acetic acid, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 16.5 mg of the hydrochloride of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 492 [M + H] ^{+
1 H-NMR (500MHz, CDCl} 3): δ = 0.85 (6H, t, J = 7.4Hz), 1.39-1.52 (6H, m), 1.65-1.71 (2H, m), 2.33-2.36 (4H, m ), 2.44 (2H, t, J = 7.3Hz), 3.54 (2H, s), 3.57 (2H, s), 3.59-3.63 (2H, m), 3.61 (3H, s), 3.76 (2H, s) , 4.37 (2H, s), 6.88 (1H, s), 6.89 (1H, s), 7.01 (1H, s), 7.02 (1H, s), 7.41 (1H, dd, J = 0.6,7.7Hz), 7.59 (1H, dd, J = 1.6,7.7Hz), 7.94 (1H, d, J = 0.8Hz).

Production Example 9: N- (4-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N-methyl-N ′, N′-dipropyl-butane-1,4-diamine [ Synthesis of Compound No. 9]

Example 9-1: Synthesis of 4-{[(4-dipropylamino-butyl) -methyl-amino] -methyl} -benzonitrile 185 mg of the compound obtained in Example 1-2 was dissolved in 3.7 ml of anhydrous methanol. Then, 154 mg of 4-formylbenzonitrile was added. 0.351 ml of trimethyl orthoformate was added and stirred at room temperature. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was removed under reduced pressure.
This was dissolved in 9.2 ml of anhydrous methanol and 0.134 ml of 36% aqueous formaldehyde solution was added.
201 mg of sodium cyanoborohydride was added. The mixture was adjusted to pH = 5 with acetic acid and stirred at room temperature for 24 hours. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain the title compound (296 mg) as a colorless oil.
MS (FAB, Pos.): M / z = 302 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3Hz), 1.40-1.51 (8H, m), 2.17 (3H, s), 2.33-2.40 (8H, m), 3.51 (2H, s), 7.44 (2H, dd, J = 0.5, 6.6Hz), 7.60 (2H, dd, J = 2.0, 6.6Hz).

Example 9-2: N- (4-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N-methyl-N ′, N′-dipropyl-butane-1,4- Synthesis of Diamine [Compound No. 9] 13.2 g of the compound obtained in Example 9-1 was dissolved in 530 ml of ethanol, and 133 ml of 1 mol / l sodium hydroxide aqueous solution and 1.3 g of Raney nickel were added thereto. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere.
After the reaction, it was filtered through Celite. The solvent was distilled off. Extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 580 ml of anhydrous methanol, and 5.07 g of 2-imidazole carboxaldehyde and 14.4 ml of trimethyl orthoformate were added. Stir at room temperature for 3 hours. 3.32 g of sodium borohydride was added under ice cooling. Stir at room temperature for 2 hours. Water was added and the solvent was distilled off. Extracted with chloroform. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 13.0 g of the title compound as a hydrochloride as a white solid.
MS (FAB, Pos.): M / z = 386 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.63-1.81 (8H, m), 2.63 (3H, d, J = 4.6 Hz), 2.94 3.06 (8H, m), 4.36 (2H, s), 4.53 (2H, s), 7.67-7.71 (6H, m), 10.39 (1H, brs), 11.13 (1H, brs).

Production Example 10: N-methyl-N- [4-({[1- (1-methyl-1H-imidazol-2-ylmethyl) -1H-imidazol-2-ylmethyl] -amino} -methyl) -benzyl-N Synthesis of ', N'-dipropylbutane-1,4-diamine [Compound No. 10]

Example 10-1: Synthesis of 2-hydroxymethyl-1-methylimidazole
42.1 g of 1-methylimidazole and 5.00 g of paraformaldehyde were heated and stirred at 120 ° C. for 3 hours.
13.0 g of paraformaldehyde was added, and the mixture was stirred at 120 ° C. for 8 hours. The mixture was further stirred at 120 ° C. for 3 hours. 40 ml of isobutyl acetate was added and refluxed at 135 ° C. for 3 hours. 40 ml of isobutyl acetate was added and the mixture was stirred and allowed to cool. Cooled to room temperature, filtered, washed with ethyl acetate and dried to give 36.2 g of the title compound as a white solid.

Example 10-2: Synthesis of 2-chloromethyl-1-methylimidazole hydrochloride 56.1 g of the compound obtained in Example 10-1 was added in small portions under ice cooling to 119 ml of thionyl chloride. After dropping, the mixture was refluxed at 65 ° C. for 15 minutes. Excess thionyl chloride was distilled off under reduced pressure and further azeotropically distilled off with toluene to obtain 82.4 g of the hydrochloride of the title compound as a yellow solid.

Example 10-3: N-methyl-N- [4-({[1- (1-methyl-1H-imidazol-2-ylmethyl) -1H-imidazol-2-ylmethyl] amino} -methyl) -benzyl- Synthesis of N ′, N′-dipropylbutane-1,4-diamine [Compound No. 10] 39.1 mg of the compound obtained in Example 9-2 was dissolved in 0.80 ml of DMF, and the mixture was cooled in a nitrogen atmosphere under ice cooling. While stirring, 12.2 mg of 60% sodium hydride was added. After returning this to room temperature and stirring for 30 minutes, 16.9 mg of the compound obtained in Example 10-2 was added and stirred at room temperature for 3 hours. The reaction was stopped by adding 18 μl of water under ice cooling. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, water was added, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 44.0 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 480 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.4 Hz), 1.40-1.52 (8H, m), 2.15 (3H, s), 2.34 (4H, t, J = 2.2 Hz), 2.37 (2H, t, J = 5.8Hz), 2.39 (2H, t, J = 16.5Hz), 3.45 (2H, s), 3.47 (3H, s), 3.81 (2H, s), 3.94 ( 2H, s), 6.75 (1H, d, J = 1.2Hz), 6.86 (1H, d, J = 1.2Hz), 6.93 (1H, d, J = 1.2Hz), 7.01 (1H, d, J = 1.5 Hz), 7.26 (2H, s), 7.27 (2H, s).

Production Example 11: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1H-inden-2-yl) -Butyl] -dipropyl-amine [Compound No. 11]

Example 11-1: Synthesis of 4- (t-butyldiphenylsilyloxy) -butan-1-ol
4.0 g of 1,4-butanediol was dissolved in 120 ml of DMF, 3.02 g of imidazole and 12.2 g of t-butyldiphenylchlorosilane were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was directly concentrated under reduced pressure, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (6.56 g) as a colorless oil.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 1.05 (9H, s), 1.63-1.71 (4H, m), 2.05 (1H, t, J = 5.1 Hz), 3.66 (2H, dt, J = 5.1 , 5.9Hz), 3.70 (2H, t, J = 5.9Hz), 7.37-7.45 (6H, m), 7.67 (4H, d, J = 8.5Hz).

Example 11-2: Synthesis of 4- (t-butyldiphenylsilyloxy) butyraldehyde 6.56 g of the compound obtained in Example 11-1 was dissolved in 262 ml of dichloromethane, and 32.8 g of molecular sieves 4A, N-methylmorpholine- 7.02 g of N-oxide and 702 mg of tetrapropylammonium pearlate were added and stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.86 g) as a colorless oil.

Example 11-3: Synthesis of 5-bromo-2- [4- (t-butyldiphenylsilyloxy) butylidene] indan-1-one
2.50 g of 5-bromoindanone was dissolved in 75 ml of THF, and 11.8 ml of 1 mol / l lithium bistrimethylsilylamide / hexane solution was added with stirring at −78 ° C., followed by stirring for 30 minutes. Subsequently, a solution of the compound 3.86 g obtained in Example 11-2 in 15 ml of THF was slowly added, and the mixture was further stirred for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved again in 75 ml of DMF, and 2.71 g of methanesulfonyl chloride and 2.63 g of triethylamine were added with stirring under ice cooling, and the mixture was warmed to room temperature and stirred for 1 hour. Subsequently, 3.97 g of 1,8-diazabicyclo [5,4,0] undec-7-ene was added and stirred at 70 ° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure, a saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / diethyl ether) to obtain 4.56 g of the title compound as a brown oil.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 1.06 (9H, s), 1.77 (2H, quint., J = 6.1 Hz), 2.42 (2H, dt, J = 6.1, 7.6 Hz), 3.62 (2H , s), 3.71 (2H, t, J = 7.1Hz), 6.88 (1H, t, J = 7.6Hz), 7.34-7.44 (7H, m), 7.54 (1H, d, J = 8.3Hz), 7.64 (4H, d, J = 8.1Hz), 7.71 (1H, d, J = 8.3Hz).

Example 11-4: Synthesis of 5-bromo-2- [4- (t-butyldiphenylsilyloxy) butyl] indan-1-one 4.56 g of the compound obtained in Example 11-3 was dissolved in 136 ml of THF, While stirring at -78 ° C., 8.76 ml of 1 mol / l K-selectride / THF solution was added and stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / diethyl ether) to obtain 2.03 g of the title compound as a yellow oil.

Example 11-5: Synthesis of 5-bromo-2- [4- (t-butyldiphenylsilyloxy) butyl] indan-1-ol After dissolution, 0.442 g of sodium borohydride was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1.54 g of the title compound as a yellow oil.

Example 11-6: Synthesis of [4- (5-Bromo-1-methoxymethoxy-1-indan-2-yl) -butoxy] -t-butyldiphenylsilane 1.54 g of the compound obtained in Example 11-5 Was dissolved in 46.2 ml of DMF, and 235 mg of 60% sodium hydride and 592 mg of chloromethyl methyl ether were added with stirring under ice cooling, followed by stirring at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1.64 g of the title compound as a yellow oil.

Example 11-7: Synthesis of 3- (5-bromo-1-methoxymethoxy-indan-2-yl) butyraldehyde 1.64 g of the compound obtained in Example 11-6 was dissolved in 49.2 ml of THF, and 1 mol / l 4.69 ml of tetrabutylammonium fluoride / THF solution was added and stirred at room temperature for 3 hours. The reaction solution was directly concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum. The residue was dissolved again in 41 ml of dichloromethane, and 5.15 g of molecular sieves 4A, 1.10 g of N-methylmorpholine-N-oxide and 109 mg of tetrapropylammonium pearlatenate were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (
Purification with hexane / ethyl acetate) afforded 0.574 g of the title compound as a pale yellow oil.

Example 11-8: Synthesis of 5-bromo-2- (3-dipropylaminobutyl) -1-methoxymethoxy-indane 574.0 mg of the compound obtained in Example 11-7 was converted to 28.7 ml of 1,2-dichloroethane. The mixture was dissolved, and 266.3 mg of di-n-propylamine and 743.6 mg of sodium triacetoxyborohydride were added with stirring at room temperature, followed by stirring for 20 hours. A 1 mol / l aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (552.4 mg) as a yellow oily substance.

Example 11-9: Synthesis of 5-cyano-2- (3-dipropylaminobutyl) -1-methoxymethoxy-indane 552 mg of the compound obtained in Example 11-8 was dissolved in 1.67 ml of DMF and cyanated. 94.3 mg of zinc and 61.8 mg of tetrakistriphenylphosphine palladium were added, and the mixture was stirred at 80 ° C. for 48 hours. Chloroform was added to the reaction solution, washed with 7% aqueous ammonia solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (436.8 mg) as a yellow oily substance.

Example 11-10: Synthesis of 5-aminomethyl-2- (3-dipropylaminobutyl) -1-methoxymethoxy-indane 436 mg of the compound obtained in Example 11-9 was dissolved in 21.8 ml of THF, hydrogen 138.7 mg of lithium aluminum halide was added, and the mixture was stirred at room temperature for 24 hours. Ethyl acetate, methanol, and 10% aqueous sodium potassium tartrate solution were added to the reaction solution, and the mixture was stirred for 1 hour. The mixture was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 189.7 mg of the title compound as a yellow oil.

Example 11-11: Synthesis of 2- [2- (4-dipropylaminobutyl) -1-methoxymethoxy-indan-5-ylmethyl] -isoindole-1,3-dione Obtained in Example 11-10 189 mg was dissolved in 5.6 ml of DMF, 108.5 mg of potassium carbonate and 172.0 mg of carboethoxyphthalimide were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (253 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 493 [M + H] ⁺

Example 11-12: Synthesis of 2- [2- (4-dipropylamino-butyl) -3H-inden-5-ylmethyl] -isoindole] -1,3-dione obtained in Example 11-11 113.0 mg of compound was dissolved in 2.2 ml of dioxane and stirred at room temperature for 24 hours. The reaction solution was directly concentrated under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 98.8 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 449 [M + H] ⁺

Example 11-13: Synthesis of [4- (6-aminomethyl-1H-inden-2-yl) -butyl] -dipropyl-amine 82.0 mg of the compound obtained in Example 11-12 was dissolved in 4.1 ml of methanol. Then, 0.082 ml of hydrazine monohydrate was added, and the mixture was heated to reflux for 3 hours. The reaction solution was directly concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (40.1 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 301 [M + H] ⁺

Example 11-14: Synthesis of [4- (6-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -1H-inden-2-yl) -butyl] -dipropyl-amine Example 11 The compound 40.1 mg obtained in -13 was dissolved in 2.0 ml of methanol, 19.2 mg of 2-imidazolecarboxaldehyde and 42.5 mg of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 15.1 mg of sodium borohydride was added under ice cooling, and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was directly concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (27.3 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 380 [M + H] ⁺

Example 11-15: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1H-indene-2- Synthesis of (yl) -butyl] -dipropyl-amine [Compound No. 11] 27.3 mg of the compound obtained in Example 11-14 was dissolved in 1.37 ml of methanol, 9.0 mg of sodium cyanoborohydride, 1-methyl-2 -11.8 mg of imidazole carboxaldehyde was added, it adjusted to pH = 4 with acetic acid, and it stirred at room temperature for 3 hours. The reaction solution was directly concentrated under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 31.5 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 475 [M + H] ^+
1 H-NMR (500 Mz, DMSO-d ₆ + D ₂ O): δ = 0.90 (6H, t, J = 7.3 Hz), 1.60-1.68 (8H, m), 2.96-3.31 (8H, m), 3.69 (5H, m), 4.01-4.15 (6H, m), 6.52 (1H, s), 7.05-7.62 (7H, m).

Production Example 12: 1- (4-Dipropylaminobutyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl } -Phenyl) -urea [Compound No. 12]

Example 12-1: Synthesis of 1- (4-cyano-phenyl) -3- (4-dipropylaminobutyl) -urea 581.4 mg of the compound obtained in Example 1-2 was dissolved in 17 ml of anhydrous toluene, 485.7 mg of 4-vinylideneaminobenzonitrile (manufactured by Aldrich) was added. Stir at room temperature for 1.5 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (478 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 317 [M + H] ^{+
1 H-NMR (500MHz, CDCl} 3): δ = 0.88 (6H, t, J = 7.3Hz), 1.43-1.59 (8H, m), 2.37-2.44 (6H, m), 3.25 (2H, dd, J = 6.1, 11.2Hz), 6.06 (1H, br), 6.90 (1H, br), 7.48 (2H, d, J = 8.8Hz), 7.54 (2H, d, J = 8.8Hz).

Example 12-2: Synthesis of 1- (4-aminomethylmethylphenyl) -3- (4-dipropylaminobutyl) -urea 466.4 mg of the compound obtained in Example 12-1 was dissolved in 14 ml of anhydrous THF, Ice-cooled. Thereto was added 223.1 mg of lithium aluminum hydride. Stir at room temperature for 2.5 hours. The reaction was stopped with ethyl acetate. An aqueous sodium potassium tartrate solution was added and stirred. Extracted with chloroform. Washed with saturated brine. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (195 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 321 [M + H] ⁺

Example 12-3: 1- (4-dipropylaminobutyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-
Synthesis of amino] -methyl} -phenyl) -urea 195.6 mg of the compound obtained in Example 12-2 was dissolved in 7.8 ml of anhydrous methanol, and 88.4 mg of 2-imidazole carboxaldehyde and 0.200 ml of trimethyl orthoformate were added at room temperature. For 14 hours. Thereto was added 69.2 mg of sodium borohydride. Stir at room temperature for 1.5 hours. After the reaction
The solvent was removed under reduced pressure. Water was added and extracted with chloroform. Washed with saturated brine. Dried over magnesium sulfate. The solvent was distilled off. The residue was subjected to silica gel column chromatography (
Purification with chloroform / methanol) afforded 101 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 401 [M + H] ⁺

Example 12-4: 1- (4-dipropylaminobutyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -methyl} -phenyl) -urea [Compound No. 12] 101 mg of the compound obtained in Example 12-3 was dissolved in 4.0 ml of anhydrous methanol. 41.8 mg of 1-methyl-2-imidazolecarboxaldehyde and 47.1 mg of sodium cyanoborohydride were added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 20 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate). Hydrochloric acid treatment gave 80.3 mg of the hydrochloride salt of the title compound as a white solid.
MS (FAB, Pos.): M / z = 495 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.89 (6H, t, J = 7.3 Hz), 1.46 (2H, quint., J = 6.9 Hz), 1.63-1.69 (6H, m), 2.94 -2.99 (4H, m), 3.01-3.06 (2H, m), 3.09 (2H, m), 3.57 (2H, s), 3.69 (3H, s), 4.04 (2H, s), 4.11 (2H, s ), 6.64 (1H, br), 7.20 (2H, d, J = 8.7Hz), 7.30 (2H, d, J = 8.7Hz), 7.55 (2H, dd, J = 2.0, 6.4Hz), 7.64 (2H , s), 9.01 (1H, brs), 10.09 (1H, br), 14.67-14.74 (2H, br).

Production Example 13: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-methyl-1H-benzimidazole Synthesis of 2-yl) -butyl] -dipropyl-amine [Compound No. 13]

Example 13-1: Synthesis of 4-amino-3- (5-t-butoxycarbonylamino-pentanoylamino) benzoic acid methyl ester
1.45 g of 5-t-butoxycarbonylamino-valeric acid (manufactured by Aldrich), 1.74 g of WSCI hydrochloride and 1.25 g of HOBt were dissolved in 20 ml of DMF and stirred for 15 minutes. To this was added 1.00 g of methyl 3,4-diaminobenzoate, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with saturated aqueous ammonium chloride and 1 mol / l aqueous sodium hydroxide, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 1.46 g of the title compound.
MS (FAB, Pos.): M / z = 365 [M + H] ⁺

Example 13-2: Synthesis of 2- (4-amino-butyl) -3-methyl-3H-benzimidazole-5-carboxylic acid methyl ester 366 mg of the compound obtained in Example 13-1 was dissolved in 7.0 ml of DMF. Then, 44.3 mg of 60% sodium hydride was added and stirred for 1 hour. Thereafter, 222 μl of methyl iodide was added little by little and stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with saturated sodium bicarbonate, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure.
This was dissolved in 5.0 ml of methanol, 5.0 ml of 4 mol / l hydrogen chloride / dioxane solution was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 218.9 mg of the title compound as a light brown oil.
MS (FAB, Pos.): M / z = 262 [M + H] ⁺

Example 13-3: Synthesis of 2- (4-dipropylamino-butyl) -3-methyl-3H-benzimidazole-5-carboxylic acid methyl ester 219 mg of the compound obtained in Example 13-2 was added to 4.2 ml of methanol. Into this solution, 200 μl of acetic acid and 170.9 mg of sodium cyanoborohydride were added, 180 μl of propionaldehyde was added little by little, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 305 mg of the title compound as a brown oil.
MS (FAB, Pos.): M / z = 346 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.82 (6H, t, J = 7.3 Hz), 1.37 (4H, sext., J = 7.3 Hz), 1.51 (4H, quint., J = 7.3 Hz), 1.78 (4H, quint., J = 7.6Hz), 2.26-2.37 (4H, br), 2.40-2.49 (2H, br), 2.89-2.94 (2H, m), 3.81 (3H, s), 3.88 (3H, s), 7.62 (1H, d, J = 8.3Hz), 7.80 (1H, d, J = 8.3Hz), 8.13 (1H, s).

Example 13-4: Synthesis of [2- (4-dipropylamino-butyl) -3-methyl-3H-benzimidazol-5-yl] -methanol 120 mg of lithium aluminum hydride was suspended in 3.0 ml of THF. The mixture was cooled to 0 ° C., and 4.5 ml of a THF solution of the compound 305 mg obtained in Example 13-3 was added dropwise thereto. It returned to room temperature and stirred for 2 hours. After completion of the reaction, sodium sulfate decahydrate was added little by little until it no longer foamed. A 1 mol / l aqueous sodium hydroxide solution was added thereto until a white solid precipitated. The solid was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / ethyl acetate).
To give 246 mg of the title compound as a brown oil.
MS (FAB, Pos.): M / z = 318 [M + H] ⁺

Example 13-5: Synthesis of 2- [2- (4-dipropylamino-butyl) -3-methyl-3H-benzimidazol-5-ylmethyl] -isoindole-1,3-dione Example 13-4 The compound 245 mg obtained by the above was dissolved in chloroform 5.0 ml, methanesulfonyl chloride 177 mg and triethylamine 107 μl were added thereto, and the mixture was stirred at room temperature for 2 hours. To this was added 65.2 mg of lithium chloride and stirred overnight. After completion of the reaction, the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off.
This was dissolved in 3.0 ml of DMF, 164 mg of potassium phthalimide was added, and the mixture was stirred at room temperature for 3 days.
After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with water, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol / water) to obtain 232 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 447 [M + H] ⁺

Example 13-6: Synthesis of [4- (6-Aminomethyl-1-methyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine 232 mg of the compound obtained in Example 13-5 It was dissolved in 3.0 ml of% methylamine / methanol solution and stirred at room temperature for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with a 1 mol / l aqueous sodium hydroxide solution. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol / water) to obtain 17.0 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 317 [M + H] ⁺

Example 13-7: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-
Synthesis of (Ilmethyl) -amino] -methyl} -1-methyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 13] 17.0 mg of the compound obtained in Example 13-6 After dissolving in 0.5 ml of methanol, 20 μl of trimethyl orthoformate and 6.4 mg of 2-imidazole carboxaldehyde were added and stirred at room temperature for 1 hour. After cooling to 0 ° C., 6.0 mg of sodium borohydride was added to return to room temperature and stirred for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure.
This was dissolved in 1.0 ml of methanol, 18.0 mg of 1-methyl-2-imidazolecarboxaldehyde, 20 μl of acetic acid and 12.5 mg of sodium cyanoborohydride were added and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 19.2 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 491 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.91 (6H, t, J = 7.3 Hz), 1.67-1.71 (4H, m), 1.76-1.86 (2H, m), 1.87-1.96 (2H , m), 2.96-3.04 (2H, m), 3.08-3.14 (2H, m), 3.25 (2H, t, J = 7.3Hz), 3.74 (3H, s), 3.89 (2H, s), 4.07 ( 3H, s), 4.13 (2H, s), 4.21 (2H, s), 7.51-7.54 (3H, m), 7.63 (2H, s), 7.68 (1H, d, J = 8.4Hz), 8.29 (1H , s).

Production Example 14: 3- (3-Dipropylaminopropyl) -8-{[(1H-imidazol-2-ylmethyl)-(1-
Synthesis of methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -3,4-dihydro-1H-benzo [e] [1,4] diazepine-2,5-dione [Compound No. 14]

Example 14-1: Synthesis of 2- [5-t-butoxycarbonylamino-2- (9H-fluoren-9-ylmethoxycarbonylamino) -pentanoylamino] -terephthalic acid dimethyl ester
1.46 g 2-amino-terephthalic acid dimethyl ester (Merck) and 3.18 g 5-t-butoxycarbonylamino-2- (9H-fluoren-9-ylmethoxycarbonylamino) -valeric acid (Watanabe Chemical) Dissolved in 30 ml of anhydrous pyridine. It was cooled to -15 ° C and 0.718 ml of phosphorus oxychloride was added. Stir at room temperature for 1 hour. After the reaction, it was poured into ice water. Extracted with ethyl acetate. Washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It dried with magnesium sulfate and the solvent was distilled off. Azeotropic with toluene. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 3.33 g of the title compound as white crystals.
MS (FAB, Pos.): M / z = 646 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.44 (9H, s), 1.62-1.64 (2H, m), 1.79-1.84 (1H, m), 2.06-2.18 (1H, m), 3.20-3.21 (2H, br), 3.83 (3H, s), 3.95 (3H, s), 4.28 (1H, t, J = 7.1Hz), 4.37 (1H, t, J = 7.3Hz), 4.43 (1H, d, J = 5.1Hz), 4.52 (1H, dd, J = 6.8,10.4Hz), 5.21 (1H, d, J = 6.3Hz), 7.32 (2H, t, J = 6.1Hz), 7.40 (2H, t, J = 7.6Hz), 7.66 (2H, d, J = 7.3Hz), 7.70 (2H, d, J = 7.3Hz), 7.77 (3H, d, J = 7.8Hz), 8.10 (1H, d, J = 8.3Hz), 9.32 (1H, s), 11.56 (1H, s).

Example 14-2: Synthesis of 2- (2-amino-5-t-butoxycarbonylamino-pentanoylamino) -terephthalic acid dimethyl ester 236.0 mg of the compound obtained in Example 14-1 was added to 4.7 ml of anhydrous DMF. After dissolution, 4.7 ml of diethylamine was added thereto and stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 194.7 mg of the title compound as a colorless viscous solid.
MS (FAB, Pos.): M / z = 424 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.43 (9H, s), 1.64-1.72 (4H, m), 3.17-3.19 (2H, m), 3.58-3.61 (1H, m), 3.94 (3H , s), 3.97 (3H, s), 7.76 (1H, dd, J = 1.7, 8.3Hz), 8.02 (1H, s), 8.11 (1H, d, J = 8.1Hz)
, 9.41 (1H, s), 12.08 (1H, s).

Example 14-3: 3- (3-t-butoxycarbonylamino-propyl) -2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [e] [1,4] diazepine-8 —Synthesis of Carboxylic Acid Ethyl Ester 303.8 mg of the compound obtained in Example 14-2 and 138.4 mg of sodium t-butoxide (manufactured by Wako) were dissolved in 6.0 ml of anhydrous THF and stirred at 60 ° C. for 15 hours. After the reaction, water was added and extracted with chloroform.
After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 36.6 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 392 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.41 (9H, s), 1.43 (1H, br), 1.65-1.82 (2H, m), 2.05-2.11 (1H, m), 3.18 (2H, d , J = 6.6Hz), 3.77 (1H, d, J = 6.1Hz), 3.96 (3H, s), 4.88 (1H, brs), 7.13 (1H, brs), 7.73 (1H, s), 7.90 (1H , dd, J = 1.5,8.0Hz), 8.04 (1H, d, J = 8.3Hz), 8.66 (1H, brs).

Example 14-4: [3- (8-Hydroxymethyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [e] [1,4] diazepin-3-yl) -propyl Synthesis of] -carbamic acid t-butyl ester 35.1 mg of the compound obtained in Example 14-3 was dissolved in 1.0 ml of anhydrous THF, 6.8 mg of lithium aluminum hydride was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, an aqueous sodium potassium tartrate solution was added and stirred vigorously at room temperature. Extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 16.9 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 364 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.90 (1H, d, J = 6.3 Hz), 1.42 (9H, s), 1.62 (2H, br), 2.03-2.05 (1H, m), 3.14 3.15 (2H, m), 3.68 (1H, dd, J = 5.6,11.7Hz), 4.70 (2H, t, J = 3.9Hz), 6.87-6.96 (1H, m), 7.04 (1H, d, J = 6.6Hz), 7.11 (1H, d, J = 7.3Hz), 7.83 (1H, d, J = 8.1Hz), 8.94 (1H, br).

Example 14-5: Synthesis of 3- (3-dipropylaminopropyl) -8-hydroxymethyl-3,4-dihydro-1H-benzo [e] [1,4] diazepine-2,5-dione 224 mg of the compound obtained in 14-4 was dissolved in 2.2 ml of methanol, and 2.2 ml of 4 mol / l hydrogen chloride / dioxane solution was added. Stir at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure. Treated with anion exchange resin (Amberlite IRA-410).
This was dissolved in 5.1 ml of anhydrous methanol. Propionaldehyde 0.104 ml, trimethyl orthoformate 0.158 ml and sodium cyanoborohydride 121 mg were added. Stir at room temperature for 21 hours.
After the reaction, the solvent was distilled off under reduced pressure. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (36.0 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 348 [M + H] ⁺

Example 14-6: Synthesis of 2- (1-methyl-1H-imidazol-2-ylmethyl) -isoindole-1,3-dione 83.50 g of the compound obtained in Example 10-2 was suspended in 250 ml of DMF. At −30 ° C., 49.00 g of sodium t-butoxide was added. Furthermore, 95.0 g of phthalimide potassium salt was added. After this, 70 ° C
For 2 hours. After the reaction, it was poured into 800 ml of water, and the precipitated crystals were filtered, washed with water and dried to obtain 101.5 g of the title compound as a white solid.

Example 14-7: Synthesis of C- (1-methyl-1H-imidazol-2-yl) -methylamine 5.89 g of the compound obtained in Example 14-6 was suspended in 118 ml of methanol. Thereto, 1.89 ml of hydrazine monohydrate was added and heated under reflux for 2.5 hours. After allowing to cool, the precipitate was filtered through Celite. The filtrate was distilled off under reduced pressure. This gave 898.5 mg of the title compound as a yellow oil.
MS (EI): m / z = 111 [M] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.99 (2H, br), 3.63 (3H, s), 3.90 (2H, s), 6.81 (1H, d, J = 1.2 Hz), 6.92 (1H, d, J = 1.2Hz).

Example 14-8: 3- (3-dipropylaminopropyl) -8-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} Synthesis of 3,4-dihydro-1H-benzo [e] [1,4] diazepine-2,5-dione [Compound No. 14] 36.0 mg of the compound obtained in Example 14-5 was added to 0.6 ml of chloroform. After dissolution, 180 mg of manganese dioxide (chemically treated product) was added and stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off by filtration through Celite.
This was dissolved in 1.4 ml of anhydrous methanol, 16.7 mg of the compound obtained in Example 14-7 and 0.033 ml of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 16 hours. Thereto was added 11.3 mg of sodium borohydride, and the mixture was stirred at room temperature for 4 hours. Water was added and the solvent was distilled off under reduced pressure. Extracted with chloroform.
It dried with magnesium sulfate and the solvent was depressurizingly distilled.
This was dissolved in 1.2 ml of anhydrous methanol, 14.4 mg of 2-imidazole carboxaldehyde,
18.9 mg of sodium cyanoborohydride was added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 2 days. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol). Hydrochloric acid treatment gave 19.4 mg of the hydrochloride salt of the title compound as a white solid.
MS (FAB, Pos.): M / z = 521 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.87-0.90 (6H, m), 1.61-1.64 (4H, m), 1.79-1.83 (4H, m), 2.96-3.00 ( 4H, m), 3.07-3.08 (2H, m), 3.76 (3H, s), 4.03 (1H, br), 4.10 (2H, br), 4.24 (4H, s), 7.53-7.55 (1H, m) , 7.61-7.63 (4H, m), 7.65 (2H, s).

Production Example 15: 4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(1-methyl-1H-imidazole-2-
Ylmethyl) -amino] -methyl} -N- (4-dipropylaminomethyl-phenyl) -benzamide [
Synthesis of Compound No. 15]

Example 15-1: Synthesis of (4-nitro-benzyl) -dipropyl-amine
4-Nitrobenzylamine hydrochloride was desalted to obtain 3.94 g of a free form. This was dissolved in 80 ml of anhydrous methanol, 5.88 g of sodium cyanoborohydride, 7.18 ml of trimethyl orthoformate and 4.67 ml of propionaldehyde were added, and the mixture was stirred at room temperature for 2 hours in a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2.61 g of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 237 [M + H] ⁺

Example 15-2: Synthesis of 4-dipropylaminomethyl-aniline 2.61 g of the compound obtained in Example 15-1 was dissolved in 25 ml of methanol, 13 ml of THF, 261 mg of activated carbon.
Then, 26.1 mg of iron trichloride hexahydrate was added and refluxed for 30 minutes. The temperature was returned to room temperature, 1.88 ml of hydrazine monohydrate was added, and the mixture was refluxed for 3 hours. After completion of the reaction, the mixture was filtered through Celite, extracted with chloroform, washed with distilled water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified through silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (865 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 207 [M + H] ⁺

Example 15-3: [4- (4-Dipropylaminomethyl-phenylcarbamoyl) -benzyl] -carbamic acid t-butyl ester synthesis Commercially available 4- (t-butoxycarbonylamino-methyl) -benzoic acid (Watanabe Chemical) 1.16 g) was dissolved in 20 ml of chloroform, and WSCI hydrochloride 1.21 g, HOBt 963 mg and the compound 865 mg obtained in Example 15-2 were added and stirred at room temperature overnight. After completion of the reaction, 1 mol / l aqueous sodium hydroxide solution was added and stirred for a while. This was extracted with chloroform, washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 545 mg of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 440 [M + H] ⁺

Example 15-4: Synthesis of 4-aminomethyl-N- (4-dipropylaminomethyl-phenyl) -benzamide 545 mg of the compound obtained in Example 15-3 was dissolved in 10 ml of anhydrous methanol to obtain 4 mol / l chloride. Hydrogen / dioxane solution 10.0ml was added and it stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. To this was added a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 389 mg of the title compound as colorless crystals.
MS (FAB, Pos.): M / z = 340 [M + H] ⁺

Example 15-5: Synthesis of N- (4-dipropylaminomethyl-phenyl) -4-{[(1-methyl-1H-imidazol-2-ylmethyl) amino] methyl} -benzamide In Example 15-4 389 mg of the obtained compound was dissolved in 10 ml of anhydrous methanol, 188 μl of trimethyl orthoformate and 139 mg of 2-imidazolecarboxaldehyde were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. Next, 43.4 mg of sodium borohydride was added to the ice bath and stirred at room temperature for 2.5 hours.
After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified through silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (346 mg) as a yellow solid.
MS (FAB, Pos.): M / z = 440 [M + H] ⁺

Example 15-6: Synthesis of 3,5-dimethyl-pyridine-2-carboxaldehyde
1.29 g of 2,3,5-trimethyl-pyridine (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in 15.0 ml of dichloromethane. After the reaction solution was cooled to 0 ° C., 2.53 g of m-chloroperbenzoic acid was added and stirred at room temperature for 1.5 hours. A 1 mol / l aqueous sodium hydroxide solution was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off, and the resulting residue was dissolved in 25.0 ml of dichloromethane. To the reaction solution, 2.8 ml of trifluoroacetic anhydride was added and heated to reflux for 3.5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off. The obtained residue was dissolved in 60.0 ml of methanol. After the reaction solution was cooled to 0 ° C., 12.5% sodium methoxide / methanol solution was added to adjust to pH = 10, and the mixture was stirred at room temperature for 16.5 hours. After the solvent was distilled off, distilled water was added and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off. The resulting residue was dissolved in 30.0 ml of chloroform. To the reaction solution was added 6.10 g of manganese dioxide (chemically treated product), and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered through celite. The solvent of the filtrate was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 1.14 g of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 136 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 2.40 (3H, s), 2.63 (3H, s), 7.43 (1H, brs), 8.48 (1H, brs), 10.16 (1H, s).

Example 15-7: 4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) amino] methyl} -N- (4-dipropylamino Synthesis of methyl-phenyl) -benzamide [Compound No. 15] 155 mg of the compound obtained in Example 15-5 was dissolved in 3.0 ml of anhydrous methanol, 33.7 mg of sodium cyanoborohydride, 0.50 ml of acetic acid, Example 15- 58.0 mg of the compound obtained in 6 was added and stirred at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform. A 1 mol / l sodium hydroxide aqueous solution was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 174 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 553 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.88 (6H, t, J = 7.5 Hz), 1.65-1.76 (4H, m), 2.37 (3H, s), 2.40 (3H , s), 2.92-2.98 (4H, m), 3.75 (3H, s), 3.84 (2H, s), 4.16 (2H, s), 4.18 (2H, s), 4.28 (2H, s), 7.51 ( 2H, d, J = 8.4Hz), 7.54 (1H, d, J = 2.0Hz), 7.54-7.55 (1H, m), 7.56 (1H, s), 7.57 (1H, d, J = 2.1Hz), 7.85 (2H, d, J = 8.5Hz), 7.87 (1H, s), 7.88 (1H, d, J = 2.1Hz), 8.16 (1H, d, J = 2.0Hz), 8.53 (1H, s).

Production Example 16: 4-{[(5-Ethyl-pyridin-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -N- (4-dipropylaminomethyl- Synthesis of phenyl) -benzamide [Compound No. 16]

Example 16-1: Synthesis of 5-ethyl-pyridine-2-carboxaldehyde
2.31 g of 5-ethyl-2-methyl-pyridine (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in 25.0 ml of dichloromethane.
After the reaction solution was cooled to 0 ° C., 4.43 g of m-chloroperbenzoic acid was added and stirred at room temperature for 2.5 hours. After adding 1 mol / l sodium hydroxide aqueous solution to the reaction solution and extracting with chloroform,
The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off.
This was dissolved in 40.0 ml of dichloromethane. To the reaction solution, 5.6 ml of trifluoroacetic anhydride was added and heated to reflux for 3.5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off.
This was dissolved in 80.0 ml of methanol. After the reaction solution was cooled to 0 ° C., 12.5% sodium methoxide / methanol solution was added to adjust to pH = 10, and the mixture was stirred at room temperature for 16.5 hours. After the solvent was distilled off, distilled water was added and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off.
This was dissolved in 50.0 ml of chloroform. Manganese dioxide (chemically treated product) 7.44g in the reaction solution
And stirred at room temperature for 18 hours. The reaction solution was filtered through celite. The solvent of the filtrate was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 515.6 mg of the title compound as a yellow oil.
MS (FAB, POS.): M / z = 136 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.31 (3H, t, J = 7.6 Hz), 2.77 (2H, q, J = 7.6 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.91 (1H, d, J = 7.8Hz), 10.06 (1H, s).

Example 16-2: 4-{[(5-Ethyl-pyridin-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -N- (4-di Synthesis of Propylaminomethyl-phenyl) -benzamide [Compound No. 16] 191 mg of the compound obtained in Example 15-5 was dissolved in anhydrous methanol 4.0 ml, sodium cyanoborohydride 41.5 mg, acetic acid 0.50 ml, Example 71.4 mg of the compound obtained in 16-1 was added, and the mixture was stirred at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform. A 1 mol / l sodium hydroxide aqueous solution was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 222 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 553 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.88 (6H, t, J = 7.3 Hz), 1.20 (3H, t, J = 7.6 Hz), 1.66-1.77 (4H, m ), 2.77 (2H, q, J = 7.6Hz), 2.91-2.98 (4H, m), 3.78 (3H, s), 3.86 (2H, s), 4.18 (2H, s), 4.22 (2H, s) , 4.28 (2H, s), 7.51 (2H, s), 7.52 (2H, d, J = 8.4Hz), 7.57 (2H, d, J = 8.7Hz), 7.87 (2H, d, J = 8.2Hz) , 7.88 (2H, d, J = 8.7Hz), 7.98 (1H, d, J = 8.2Hz), 8.37 (1H, dd, J = 2.0,8.2Hz), 8.68 (1H, d, J = 1.8Hz) .

Production Example 17: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -3,4-dihydro-1H- Synthesis of isoquinolin-2-yl) -butyl] -dipropyl-amine [Compound No. 17]

Example 17-1: Synthesis of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one
5.47 g of 5-bromoindanone was suspended in 71 ml of benzene, 14 ml of concentrated sulfuric acid was added, and the mixture was vigorously stirred. Thereto was slowly added 2.52 g of sodium azide. Stir at room temperature for 30 minutes. Ethyl acetate was added and the mixture was washed with water and saturated brine. Dried over magnesium sulfate. The solvent was distilled off.
The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 2.25 g of the title compound as a white solid.
MS (FAB, Pos.): M / z = 226,228 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 2.99 (2H, t, J = 6.8 Hz), 3.57 (2H, dt, J = 2.9, 6.7 Hz), 6.23 (1H, br), 7.40 (1H, s), 7.50 (1H, dd, J = 2.0,8.3Hz), 7.93 (1H, d, J = 8.3Hz).

Example 17-2: Synthesis of 1- (6-bromo-3,4-dihydro-1H-isoquinolin-2-yl) -2,2,2-trifluoro-ethanone Compound obtained in Example 17-1 2.253 g was dissolved in anhydrous THF 11 ml, and 55.4 ml of 1 mol / l borane THF complex / THF solution (manufactured by Kanto Chemical Co., Inc.) was added thereto. Heated to reflux overnight. After allowing to cool, methanol was added and the solvent was distilled off. 1 mol / l hydrochloric acid was added and the mixture was heated to reflux for 3 hours. After reaction, cool with ice to 1 mol / l
Aqueous sodium hydroxide and 27% aqueous ammonia were added. Extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 40 ml of anhydrous dichloromethane, 1.53 ml of triethylamine was added, and the mixture was ice-cooled. Thereto was added 1.55 ml of trifluoroacetic anhydride. Stir at room temperature for 1 hour. After the reaction, a saturated aqueous sodium hydrogen carbonate solution was added. Extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.23 g of the title compound as a white solid.
MS (FAB, Pos.): M / z = 308,310 [M + H] ⁺

Example 17-3: Synthesis of 1,2,3,4-tetrahydro-isoquinoline-6-carbonitrile 2.23 g of the compound obtained in Example 17-2 was dissolved in 27 ml of NMP. Cuprous cyanide (1.56 g) was added and the mixture was heated to reflux for 4 hours. After the reaction, the mixture was ice-cooled and water and aqueous ammonia were added. Extracted with chloroform. Dried over magnesium sulfate. The solvent was removed under reduced pressure. Dissolved in diethyl ether, 4 mol / l hydrogen chloride / dioxane solution was added. The precipitate was filtered and washed with diethyl ether. Heat drying gave 1.95 g of the hydrochloride salt of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 159 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 3.06 (2H, t, J = 6.4 Hz), 3.34-3.36 (2H, m), 4.32 (2H, t, J = 4.6 Hz), 7.45 ( 1H, d, J = 8.1Hz), 7.71 (1H, dd, J = 1.7,7.8Hz), 7.76 (1H, s).

Example 17-4: Synthesis of (4,4-diethoxy-butyl) -dipropyl-amine
1.33 g of 4,4-diethoxy-butylamine (Aldrich) was dissolved in 53 ml of anhydrous methanol. Thereto were added propionaldehyde 1.23 ml, trimethyl orthoformate 2.45 ml, and sodium cyanoborohydride 1.40 g, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.03 g of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 246 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3Hz), 1.21 (6Ht, J = 7.0Hz), 1.42-1.48 (4H, m), 1.49-1.54 (2H, m), 1.59-1.64 (2H, m), 2.36-2.39 (4H, m), 2.44 (2H, t, J = 7.5Hz), 3.50 (2H, quint., J = 7.1Hz), 3.65 (2H, quint., J = 7.1Hz), 4.50 (1H, t, J = 5.6Hz).

Example 17-5: Synthesis of 4-dipropylamino-butyraldehyde 1.03 g of the compound obtained in Example 17-4 was dissolved in 10 ml of THF, and 10 ml of 1 mol / l hydrochloric acid was added thereto. Stir at room temperature for 17 hours. The solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off to obtain 697 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 172 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.6 Hz), 1.39-1.46 (4H, m), 1.77 (2H, quint., J = 7.1 Hz), 2.32-2.36 (4H, m), 2.40-2.46 (2H, m), 9.76 (1H, s).

Example 17-6: Synthesis of 2- (4-dipropylamino-butyl) -1,2,3,4-tetrahydro-isoquinoline-6-carbonitrile 439 mg of the compound obtained in Example 17-3 was dissolved in 1 mol / l Dissolved in aqueous sodium hydroxide solution. This was extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 6.7 ml of anhydrous dichloromethane, and 331 mg of the compound obtained in Example 17-5 and 1.23 g of sodium triacetoxyborohydride were added and reacted at room temperature for 2 days. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (220 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 314 [M + H] ⁺

Example 17-7: [4- (6-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -3,4-dihydro-1H-isoquinolin-2-yl) -butyl] -dipropyl Synthesis of amine 220 mg of the compound obtained in Example 17-6 was dissolved in 8.8 ml of anhydrous THF, and 106 mg of lithium aluminum hydride was added. Stir at room temperature for 2 hours. After the reaction, ethyl acetate was added. An aqueous sodium potassium tartrate solution was added and stirred. Extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 8.3 ml of anhydrous methanol. 100 mg of 2-imidazole carboxaldehyde and 0.23 ml of trimethyl orthoformate were added and stirred at room temperature for 16 hours. 79.4 mg of sodium borohydride was added. Stir at room temperature for 6 hours. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 104 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 398 [M + H] ⁺

Example 17-8: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole-2-
Synthesis of (Ilmethyl) -amino] -methyl} -3,4-dihydro-1H-isoquinolin-2-yl) -butyl] -dipropyl-amine [Compound No. 17] 104 mg of the compound obtained in Example 17-7 The resultant was dissolved in anhydrous methanol (4.0 ml), and 1-methyl-2-imidazolecarboxaldehyde (42.9 mg) and sodium cyanoborohydride (49.0 mg) were added.
The pH was adjusted to 5 with acetic acid. Stir at room temperature for 16.5 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 115 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 492 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.64-1.70 (4H, m), 1.72-1.76 (2H, m), 1.85 -1.86 (2H, m), 2.99-3.03 (4H, m), 3.08-3.12 (2H, m), 3.18-3.27 (4H, m), 3.68 (3H, s), 3.70 (4H, s), 4.09 (2H, s), 4.19 (2H, s), 4.20 (1H, d, J = 18.9Hz), 4.45 (1H, d, J = 15.7Hz), 7.06 (1H, d, J = 8.1Hz), 7.17 (1H, d, J = 8.4Hz), 7.21 (1H, s), 7.48 (2H, s), 7.60 (2H, s).

Production Example 18: [3- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-methyl-1H-benzimidazole Synthesis of 2-yl) -benzyl] -dipropyl-amine [Compound No. 18]

Example 18-1: Synthesis of methyl 3-dipropylaminomethyl-benzoate
831 mg of methyl 3-bromomethylbenzoate was dissolved in 12.5 ml of DMF, 971 μl of dipropylamine was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 858 mg of the title compound as a brown solid.

Example 18-2: Synthesis of 3-dipropylaminomethyl-benzoic acid 858 mg of the compound obtained in Example 18-1 was dissolved in 18 ml of methanol, and 9.0 ml of 1 mol / l aqueous sodium hydroxide solution was added thereto at room temperature. Stir overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 1 mol / l hydrochloric acid, chloroform was added, sodium chloride was added to make the aqueous layer a saturated saline solution, extracted with chloroform, then with anhydrous sodium sulfate. Dried. After filtration, the solvent was distilled off under reduced pressure, and the residue was vacuum-dried to obtain 781 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 236 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.72 (4H, sext., J = 7.3 Hz), 2.51 (4H, quint., J = 1.8 Hz), 3.62 (2H, s), 4.40 (3H, s), 7.60 (1H, d, J = 7.8Hz), 7.95 (1H, d, J = 7.0Hz), 8.00 (1H, d, J = 7.8 Hz), 8.17 (1H, s), 10.70 (1H, br).

Example 18-3: Synthesis of 4-amino-3- (3-dipropylaminomethyl-benzoylamino) -benzoic acid methyl ester 300 mg of the compound obtained in Example 18-2 and 365 mg of WSCI hydrochloride and 260 mg of HOBt were mixed with chloroform. Dissolved in 6.0 ml and stirred for 1 hour. To this was added 198 mg of methyl 3,4-diaminobenzoate and stirred for 2 hours. Since solid precipitated, 2.0 ml of DMF was added and the mixture was further stirred for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 381 mg of the title compound as a brown oil.
MS (FAB, Pos.): M / z = 384 [M + H] ⁺

Example 18-4: Synthesis of 4-amino-3-[(3-dipropylaminomethyl-benzoyl) -methyl-amino] -benzoic acid methyl ester 380 mg of the compound obtained in Example 18-3 was added to 7.6 ml of DMF To this, 60% sodium hydride (60.0 mg) was added, and the mixture was stirred for 1 hour. Thereafter, 213 mg of methyl iodide was added little by little, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol / water) to obtain 83.0 mg of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 398 [M + H] ⁺

Example 18-5: Synthesis of 2- (3-dipropylaminomethyl-phenyl) -3-methyl-3H-benzimidazole-5-carboxylic acid methyl ester 83.0 mg of the compound obtained in Example 18-4 was dissolved in methanol. After dissolving in 1.0 ml, 1.0 ml of 4 mol / l hydrogen chloride / dioxane solution was added and stirred at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in methanol, and made into a free form with an anion exchange resin (Amberlite IRA-410). The resin was filtered off, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 44.0 mg of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 380 [M + H] ⁺

Example 18-6: Synthesis of 2- (3-dipropylaminomethyl-phenyl) -3-methyl-3H-benzimidazole-5-carbaldehyde 16.5 mg of lithium aluminum hydride was suspended in 1.2 ml of THF and 0 After cooling to 0 ° C., 1.0 ml of a THF solution of 44.0 mg of the compound obtained in Example 18-5 was added dropwise at 0 ° C. for 2 hours. After completion of the reaction, sodium sulfate decahydrate was added until it no longer foamed. A 1 mol / l aqueous sodium hydroxide solution was added thereto until a white solid precipitated. The solid was filtered off and the filtrate was evaporated under reduced pressure.
This was dissolved in 1.0 ml of dichloromethane, and 105 mg of manganese dioxide (chemically treated product) was added thereto, followed by stirring at room temperature for 19 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 28.0 mg of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 350 [M + H] ⁺

Example 18-7: [3- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl1H-imidazol-2-ylmethyl) -amino] -methyl} -1-methyl-1H-benz Synthesis of Imidazol-2-yl) -benzyl] -dipropyl-amine [Compound No. 18] 31.2 mg of the compound obtained in Example 18-6 was dissolved in 1.0 ml of methanol, 30 μl of acetic acid, 1-methyl-2- 15.4 mg of aminomethylimidazole was added and stirred at room temperature for 2 hours. To this was added 22.7 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 15 hours. Further, 18.0 mg of 2-imidazole carboxaldehyde was added and stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 25.6 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 525 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.88 (6H, t, J = 7.3 Hz), 1.70-1.83 (4H, m), 2.97-3.07 (4H, br), 3.75 (3H, s ), 3.93 (2H, s), 4.15 (2H, s), 4.17 (3H, s), 4.23 (2H, s), 4.47 (2H, d, J = 4.9Hz), 7.54-7.55 (2H, m) , 7.57 (1H, d, J = 8.3Hz), 7.65 (2H, s), 7.74 (1H, d, J = 8.3Hz), 7.81 (1H, t, J = 8.1Hz), 7.99 (1H, d, J = 8.1Hz), 8.03 (1H, d, J = 7.8Hz), 8.32 (1H, s), 8.40 (1H, s).

Production Example 19 6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -5,6,7,8-tetrahydro-imidazo [ Synthesis of 1,2-a] pyridine-2-carboxylic acid (4-dipropylamino-butyl) -amide [Compound No. 19]

Example 19-1: Synthesis of 6-cyano-imidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester
Dissolve 2.45 g of 2-amino-5-cyanopyridine in 30 ml of ethanol, and add 3-bromo-2-oxo-
3.90 g of propionic acid ethyl ester was added and the mixture was heated to reflux for 7 hours. The concentrated residue was dissolved in a minimum amount of 10% hydrogen chloride / methanol solution, and the pH was adjusted to 8 with saturated aqueous sodium hydrogen carbonate solution. The precipitate was collected by filtration to give 3.81 g of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 216 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.33 (3H, t, J = 7.1 Hz), 4.33 (2H, q, J = 7.1 Hz), 7.61 (1H, dd, J = 1.7, 9.6 Hz) , 7.81 (1H, ddd, J = 0.7,1.0,9.6Hz), 8.61 (1H, d, J = 0.7Hz), 9.36 (1H, dd, J = 1.0,1.7Hz).

Example 19-2: Synthesis of 6-cyano-imidazo [1,2-a] pyridine-2-carboxylic acid (4-dipropylamino-butyl) -amide 263 mg of the compound obtained in Example 1-2 was dissolved in dichloromethane Dissolved in 4.0 ml, 1.08 ml of 15% trimethylaluminum / hexane solution was added dropwise thereto and stirred at room temperature for 15 minutes. To this solution, 300 mg of the compound obtained in Example 19-1 was added and further stirred for 20 hours. Heat this to 40 ° C,
After further stirring for 7 hours, 1 mol / l hydrochloric acid was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol) to obtain 237 mg of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 342 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 3.7 Hz), 1.43-1.73 (8H, m), 2.39-2.50 (6H, m), 3.50 (2H, dd, J = 6.3, 6.8Hz), 7.35 (1H, dd, J = 1.7,9.6Hz), 7.51 (1H, br), 7.66 (1H, ddd, J = 0.7,1.0,9.6Hz), 8.26 (1H, d, J = 0.5Hz), 8.64 (1H, dd, J = 1.0,1.7Hz).

Example 19-3: Synthesis of 6-aminomethyl-5,6,7,8-tetrahydro-imidazo [1,2-a] pyridine-2-carboxylic acid (4-dipropylamino-butyl) -amide Raney nickel in ethanol was added to a solution of the compound obtained in 19-2 in 40.2 mg in ethanol (20 ml), and 1 mol / l sodium hydroxide aqueous solution (2.0 ml) was added. The mixture was stirred at room temperature for 14 hours in a hydrogen atmosphere. The catalyst was removed by Celite filtration, and the residue obtained by evaporating the solvent under reduced pressure was dissolved in chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 40.1 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 350 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.5 Hz), 2.03-2.13 (2H, br), 2.34-2.38 (4H, m), 2.44 (2H, t, J = 7.2Hz), 2.75-2.82 (2H, m), 2.85 (2H, dd, J = 6.2,12.4Hz), 2.97 (1H, ddd, J = 3.5,5.5,16.9Hz), 3.40 (2H, dd, J = 6.8,13.4Hz), 3.67 (1H, dd, J = 10.3,12.2Hz), 4.18 (1H, ddd, J = 1.1,5.2,12.4Hz), 7.06 (1H, br), 7.40 (1H, s ).

Example 19-4: 6-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -5,6,7,8-tetrahydro-imidazo [1,2-a] pyridine-2-carboxylic acid Synthesis of (4-dipropylamino-butyl) -amide 28.3 mg of the compound obtained in Example 19-3 was dissolved in 1.0 ml of methanol, and 0.030 ml of trimethyl orthoformate and 11.7 mg of 2-imidazole carboxaldehyde were added at room temperature. Stir for 3 hours. After this solution was cooled to 0 ° C., 4.6 mg of sodium borohydride was added, the temperature was raised to room temperature, and the mixture was further stirred for 15 minutes. The reaction was stopped by adding water and extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (30.5 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 430 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.2 Hz), 1.41-1.48 (6H, m), 1.50-1.52 (2H, m), 1.56-1.59 (2H, m ), 2.04-2.11 (2H, br), 2.33-2.36 (4H, m), 2.41 (2H, t, J = 7.3Hz), 2.61 (1H, dd, J = 8.1,12.0Hz), 2.70-2.76 ( 2H, m), 2.91 (1H, ddd, J = 3.6, 5.5, 16.9Hz), 3.38 (2H, dd, J = 6.8, 13.4Hz)
, 3.61 (1H, dd, J = 10.0,12.4Hz), 3.91 (2H, d, J = 2.2Hz), 4.12 (1H, dd, J = 5.0,12.4Hz), 7.00 (2H, s), 7.14 ( 1H, br), 7.31 (1H, s).

Example 19-5: 6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -5,6,7,8-tetrahydro- Synthesis of imidazo [1,2-a] pyridine-2-carboxylic acid (4-dipropylamino-butyl) -amide [Compound No. 19] 19.6 mg of the compound obtained in Example 19-4 was added to 2.0 ml of methanol. After dissolution, 6.2 mg of 1-methyl-2-imidazolecarboxaldehyde and 5.9 mg of sodium cyanoborohydride were added, the pH was adjusted to 4 with acetic acid, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / ethyl acetate), and further treated with hydrochloric acid to obtain 22.0 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3 Hz), 1.40-1.69 (9H, m), 2.05 (4H, br), 2.13-2.18 (1H, m), 2.35 (2H, d, J = 4.5Hz), 2.35 (2H, t, J = 7.8Hz), 2.42 (2H, t, J = 7.3Hz), 2.50-2.60 (3H, m), 2.80-2.84 (1H , m), 2.93-2.97 (1H, m), 3.40 (2H, dd, J = 6.6,13.4Hz), 3.47-3.49 (2H, m), 3.56 (2H, d, J = 2.7Hz), 3.62- 3.66 (2H, m), 3.73 (3H, s), 4.18 (1H, dd, J = 4.0,12.5Hz), 6.95 (1H, d, J = 1.2Hz), 7.03-7.04 (3H, m), 7.39 (1H, s), 12.39 (1H, br).

Production Example 20: N- (4-Dipropylamino-butyl) -4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5-methyl-pyridin-2-ylmethyl) -amino] -methyl } -Benzamide [Compound No. 20] Synthesis

Example 20-1: Synthesis of t-butyl-4- (4- {dipropylamino} butylcarbamoyl) benzylcarbamate
4- (t-Butoxycarbonylamino-methyl) -benzoic acid (558 mg) was dissolved in chloroform (9.0 ml). A chloroform solution (3.0 ml) containing 652 mg of the compound was slowly added and stirred at room temperature for 12 hours. After completion of the reaction, 7.0 ml of 1 mol / l hydrochloric acid was added, and the aqueous layer was extracted with chloroform. The organic layer was washed with 1 mol / l aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound 715 mg was obtained as a yellow oil.

Example 20-2: Synthesis of 4- (aminomethyl) -N- (4- {dipropylamino} butyl) benzamide 715 mg of the compound obtained in Example 20-1 was dissolved in 7.0 ml of methanol at room temperature. 7.0 ml of 4 mol / l hydrogen chloride / dioxane solution was added and stirred for 2 hours. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform and washed with a 1 mol / l sodium hydroxide aqueous solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (559 mg) as a yellow oil.

Example 20-3: Synthesis of N- (4-dipropylamino-butyl) -4-{[(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzamide Example 20-2 538 mg of the compound obtained in 1 above was dissolved in 10 ml of anhydrous methanol, 600 μl of trimethyl orthoformate was added at room temperature under a nitrogen atmosphere, and 2.0 ml of methanol solution of 240 mg of 1-methyl-2-imidazolecarboxaldehyde was added. After stirring at room temperature for 36 hours, 140 mg of sodium borohydride was added under ice cooling, and the mixture was returned to room temperature and stirred for 1 hour. After completion of the reaction, water was added with stirring under ice cooling. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, water was added, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 782 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 400 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.4 Hz), 1.39-1.45 (4H, m), 1.56 (2H, quint., J = 6.9 Hz), 1.65 (2H , quint, J = 6.9Hz), 2.36 (4H, t, J = 2.2Hz), 2.44 (2H, t, J = 6.9Hz), 3.45 (2H, dt, J = 6.6,6.6Hz), 3.63 (3H , s), 3.83 (2H, s), 3.87 (2H, s), 6.78 (1H, brs), 6.82 (1H, d, J = 1.2Hz), 6.94 (1H, d, J = 1.2Hz), 7.40 (2H, d, J = 8.1Hz), 7.71 (1H, dd, J = 1.7,3.8Hz), 7.28 (1H, dd, J = 1.7,3.8Hz).

Example 20-4: Synthesis of 5-methyl-2-pyridine aldehyde By the same operation as in Example 15-6, 439 mg of the title compound was obtained using 2,5-lutidine as a starting material.
MS (FAB, Pos.): M / z = 122 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 2.46 (3H, s), 7.67 (1H, dd, J = 1.4, 7.9 Hz), 7.89 (1H, d, J = 7.9 Hz), 8.62 (1H, d, J = 1.4Hz), 10.05 (1H, s).

Example 20-5: N- (4-dipropylamino-butyl) -4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5-methyl-pyridin-2-ylmethyl) -amino] Synthesis of -methyl} -benzamide [Compound No. 20] 782 mg of the compound obtained in Example 20-3 was dissolved in 12 ml of anhydrous methanol, and 380 mg of sodium cyanoborohydride and 1.5 ml of acetic acid were added. To this was added 2.0 ml of a methanol solution of the compound 289 mg obtained in Example 20-4 at −10 ° C., and the mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere. After completion of the reaction, water was added to stop the reaction. The solvent was distilled off under reduced pressure, chloroform and a 1 mol / l aqueous sodium hydroxide solution were added to the residue to adjust the pH of the aqueous layer to about 10, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 316 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 505 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.83 (6H, t, J = 7.3 Hz), 1.41 (4H, qt, J = 2.4, 6.4 Hz), 1.55 (2H, quint., J = 7.1 Hz) ), 1.65 (2H, quint., J = 7.3Hz), 2.32 (3H, s), 2.35 (4H, t, J = 2.4Hz), 2.44 (2H, t, J = 7.1Hz), 3.45 (2H, dt, J = 5.6,6.8Hz), 3.49 (3H, s), 3.65 (3H, s), 3.69 (2H, s), 3.70 (2H, s), 6.94 (1H, brt, J = 5.0Hz), 6.77 (1H, d, J = 1.2Hz), 6.90 (1H, d, J = 1.2Hz), 7.24 (1H, d, J = 7.8Hz), 7.38 (2H, d, J = 8.3Hz), 7.46 ( 1H, dd, J = 1.7,8.0Hz), 7.69 (2H, d, J = 8.6Hz), 8.37 (1H, d, J = 1.5Hz).

Production Example 21: N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino]- Synthesis of methyl} -benzyl) -methanesulfonamide [Compound No. 21]

Example 21-1: Synthesis of 4-{[t-Butoxycarbonyl- (1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} benzoic acid methyl ester 4-{[ Dissolve 5.0 g of t-butoxycarbonyl- (1H-imidazol-2-ylmethyl) -amino] -methyl} benzoic acid in 150 ml of DMF, add 1.45 g of 60% sodium hydride and 2.70 ml of methyl iodide, and add 18% at room temperature. Stir for hours. The reaction solution was added to a saturated aqueous ammonium chloride solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 2.31 g of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 360 [M + H] ⁺

Example 21-2: Synthesis of (4-hydroxymethylbenzyl)-(1-methyl-1H-imidazol-2-ylmethyl) carbamic acid-t-butyl ester 1.0 g of lithium aluminum hydride was suspended in 95.1 ml of THF. A solution prepared by dissolving 3.17 g of the compound obtained in Example 21-1 in 95.1 ml of THF was slowly added dropwise at room temperature, and the mixture was further stirred for 1 hour. Ethyl acetate, methanol, and 10% aqueous sodium potassium tartrate solution were added to the reaction solution, and the mixture was stirred for 1 hour. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (1.37 g) as a brown oily substance.
MS (FAB, Pos.): M / z = 360 [M + H] ⁺

Example 21-3: Synthesis of (4-formyl-1-benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) -carbamic acid-t-butyl ester Compound 1.37 obtained in Example 21-2 g was dissolved in 68.5 ml of ethyl acetate, 13.7 g of manganese dioxide (chemically treated product) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (1.37 g) as a brown oily substance.
MS (FAB, Pos.): M / z = 485 [M + H] ⁺

Example 21-4: Synthesis of {4-[(4-dipropylaminobutylamino) -methyl] -benzyl}-(1-methyl-1H-imidazol-2-ylmethyl) -carbamic acid t-butyl ester The compound 1.28 g obtained in 21-3 was dissolved in 38.6 ml of methanol, 0.669 g of the compound obtained in Example 1-2 and 1.28 ml of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 2.5 hours. Under ice cooling, 0.441 g of sodium borohydride was added and stirred at room temperature for 0.5 hour. The reaction solution was directly concentrated under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (1.71 g) as a brown oily substance.
MS (FAB, Pos.): M / z = 486 [M + H] ⁺

Example 21-5: (4-{[(4-Dipropylamino-butyl) -methanesulfonyl-amino] -methyl} -benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) -carbamic acid t Synthesis of -Butyl Ester 182.6 mg of the compound obtained in Example 21-4 was dissolved in 5.3 ml of dichloromethane, 0.105 ml of triethylamine and 43.6 μl of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 0.5 hour. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (148.0 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 564 [M + H] +

Example 21-6: N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino Synthesis of] -methyl} -benzyl) -methanesulfonamide [Compound No. 21] 148.0 mg of the compound obtained in Example 21-5 was dissolved in 2.9 ml of methanol, and 4 mol / l hydrogen chloride /
Dioxane solution (2.9 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure,
To the residue was added a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum.
This was dissolved in 6.09 ml of methanol, 43.4 mg of 2-imidazolecarboxaldehyde and 33.0 mg of sodium cyanoborohydride were added, the pH was adjusted to 5 with acetic acid, and the mixture was stirred at room temperature for 15 hours. The reaction solution was directly concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 102.4 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 544 [M + H] ^+
1 H-NMR (500 Mz, DMSO-d ₆ + D ₂ O): δ = 0.89 (6H, t, J = 7.3 Hz), 1.43-1.62 (8H, m), 2.90-3.11 (8H, m), 2.96 (3H, s), 3.69 (5H, s), 4.06 (2H, s), 4.13 (2H, s), 4.27 (2H, s), 7.27 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.1Hz), 7.50 (2H, s), 7.61 (2H, s).

Production Example 22: N- (4-Dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino]- Synthesis of methyl} -benzyl) -4-methyl-benzenesulfonamide [Compound No. 22]

Example 22-1: (4-{[(4-Dipropylamino-butyl)-(toluene-4-sulfonyl) -amino] -methyl} -benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) ) -Carbamic acid t-butyl ester 182.0 mg of the compound obtained in Example 21-4 was dissolved in dichloromethane 5.3 ml, triethylamine 0.104 ml and p-toluenesulfonyl chloride 107.2 mg were added, and the mixture was stirred at room temperature for 0.5 hour. did.
Water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (219 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 640 [M + H] ⁺

Example 22-2: N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino ] -Methyl} -benzyl) -4-methyl-benzenesulfonamide [Compound No. 22] 219.5 mg of the compound obtained in Example 22-1 was dissolved in 4.3 ml of methanol, and 4 mol / l hydrogen chloride /
Dioxane solution (4.3 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure,
A 1 mol / l aqueous sodium hydroxide solution was added to the residue, extracted with chloroform, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum.
This was dissolved in 9.2 ml of methanol, 56.7 mg of 2-imidazole carboxaldehyde and 43.1 mg of sodium cyanoborohydride were added, adjusted to pH = 5 with acetic acid, and stirred at room temperature for 15 hours. The reaction solution was directly concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 164.4 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 620 [M + H] ^+
1 H-NMR (500 Mz, DMSO-d ₆ + D ₂ O): δ = 0.88 (6H, t, J = 7.3 Hz), 1.26-1.60 (8H, m), 2.42 (3H, s), 2.83-3.06 (8H, m), 3.63 (3H, s), 3.69 (2H, s), 4.05 (2H, s), 4.13 (2H, s), 4.23 (2H, s), 7.21 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.0Hz), 7.46 (2H, d, J = 8.0Hz), 7.50 (2H, s), 7.61 (2H, s), 7.75 (2H, d, J = 8.3 Hz).

Production Example 23: N-ethyl-N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ′ Of N, N'-Dipropyl-butane-1,4-diamine [Compound No. 23]

Example 23-1: Synthesis of 4- (t-butoxycarbonylamino-methyl) -benzoic acid methyl ester
4-Aminomethylbenzoic acid methyl ester hydrochloride was desalted to obtain 20.2 g of a free form. This was dissolved in anhydrous chloroform (400 ml), triethylamine (34.1 ml) and di-t-butyl dicarbonate (32.0 g) were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, distilled water was added and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 35.7 g of the title compound as colorless crystals.
MS (FAB, Pos.): M / z = 266 [M + H] ⁺

Example 23-2: Synthesis of (4-hydroxymethyl-benzyl) -carbamic acid t-butyl ester 35.7 g of the compound obtained in Example 23-1 was dissolved in 800 ml of anhydrous THF, and lithium aluminum hydride 10.2 in an ice bath. g was added and stirred for 2 days under a nitrogen atmosphere. After completion of the reaction, methanol and then aqueous sodium potassium tartrate solution were added and stirred overnight. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 29.2 g of the title compound as colorless crystals.

Example 23-3: Synthesis of (4-formyl-benzyl) -carbamic acid t-butyl ester 17.6 g of the compound obtained in Example 23-2 was dissolved in 400 ml of chloroform, and 88.2 g of manganese dioxide (chemically treated product) was obtained. And stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through Celite and the solvent was distilled off to obtain 20.4 g of the title compound as colorless crystals.

Example 23-4: Synthesis of {4-[(4-dipropylamino-butylamino) -methyl] -benzyl} -carbamic acid t-butyl ester 9.25 g of the compound obtained in Example 1-2 was dissolved in anhydrous methanol After dissolving in 200 ml, trimethyl orthoformate (8.81 ml) and the compound obtained in Example 23-3 (12.6 g) were added, and the mixture was stirred at room temperature for 1 hour and a half in a nitrogen atmosphere. Next, 2.03 g of sodium borohydride was added to the ice bath and stirred at room temperature for 2 hours. After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 19.3 g of the title compound as a colorless oil.

Example 23-5: Synthesis of (4-{[(4-Dipropylamino-butyl) -ethyl-amino] -methyl} -benzyl) -carbamic acid t-butyl ester Compound obtained in Example 23-4 289 mg was dissolved in anhydrous methanol (6.0 ml), sodium cyanoborohydride (92.8 mg), acetic acid (1.00 ml) and acetaldehyde (61.3 μl) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform. A 1 mol / l sodium hydroxide aqueous solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 311 mg of the title compound as a pale yellow oil.

Example 23-6: N- (4-aminomethyl-benzyl) -N-ethyl-N ′, N′-dipropyl-butane-1,4-
Synthesis of Diamine 311 mg of the compound obtained in Example 23-5 was dissolved in 1.0 ml of anhydrous methanol, and 4 mol / l hydrogen chloride /
A dioxane solution (3.0 ml) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. To this was added a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 219 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 320 [M + H] ⁺

Example 23-7: Synthesis of N-ethyl-N- (4-{[(1H-imidazol-2-ylmethyl) amino] methyl} benzyl) -N ', N'-dipropyl-butane-1,4-diamine 219 mg of the compound obtained in Example 23-6 was dissolved in 5.0 ml of anhydrous methanol, 112 μl of trimethyl orthoformate and 72.4 mg of 2-imidazole carboxaldehyde were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. Next, 12.3 mg of sodium borohydride was added in an ice bath and stirred at room temperature for 1 hour. After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 317 mg of the title compound as a yellow oil.

Example 23-8: N-ethyl-N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} benzyl) -N Synthesis of ', N'-dipropyl-butane-1,4-diamine [Compound No. 23] 317 mg of the compound obtained in Example 23-7 was dissolved in 6.0 ml of anhydrous methanol, 74.8 mg of sodium cyanoborohydride, 1.00 ml of acetic acid and 105 mg of 1-methyl-2-imidazole carboxaldehyde were added and stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform. A 1 mol / l sodium hydroxide aqueous solution was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 318 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 494 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.3 Hz), 1.62-1.68 (6H, m ), 1.76-1.78 (2H, m), 2.92-3.02 (4H, m), 3.05-3.08 (2H, m), 3.62 (2H, s), 3.69 (2H, s), 3.71 (3H, s), 3.74 (2H, s), 4.10 (2H, s), 4.17 (2H, s), 4.17-4.19 (1H, m), 4.26-4.29 (1H, m), 7.41 (2H, d, J = 7.9Hz) , 7.48 (2H, d, J = 8.7Hz), 7.49 (2H, s), 7.61 (2H, s).

Production Example 24: N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N-phenyl-N ′ Of N, N'-Dipropyl-butane-1,4-diamine [Compound No. 24]

Example 24-1 Synthesis of N′-phenyl-N, N-dipropyl-butane-1,4-diamine 357.7 mg of the compound obtained in Example 17-5 was dissolved in 14 ml of anhydrous methanol. Thereto were added 0.209 ml of aniline and 0.686 ml of trimethyl orthoformate, and the mixture was stirred at room temperature for 3 hours. Thereto was added 237.2 mg of sodium borohydride, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (165.2 mg) as a colorless oil.
MS (FAB, Pos.): M / z = 249 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3 Hz), 1.41-1.49 (4H, m), 1.52-1.58 (2H, m), 1.63 (2H, quint., J = 7.1Hz), 2.35-2.39 (4H, m), 2.44 (2H, t, J = 7.1Hz), 3.12 (2H, t, J = 6.8Hz), 6.60 (2H, dd, J = 1.0,8.5 Hz), 6.68 (1H, t, J = 7.3Hz), 7.17 (2H, t, J = 7.3Hz).

Example 24-2: Synthesis of 4-{[(4-Dipropylamino-butyl) -phenyl-amino] -methyl} -benzonitrile 152.5 mg of the compound obtained in Example 24-1 was added to 6.1 ml of anhydrous DMF. After dissolution, 299.0 mg of cesium carbonate and 184.0 mg of 4-bromomethyl-benzonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) were added, and the mixture was stirred at 60 ° C. overnight, and further stirred at 80 ° C. for 24 hours. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (88.8 mg) as a colorless oil.
MS (FAB, Pos.): M / z = 363 [M + H] ⁺

Example 24-3: N- (4-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N-phenyl-N ′, N′-dipropyl-butane-1,4- Synthesis of Diamine 88.8 mg of the compound obtained in Example 24-2 was dissolved in 3.5 ml of anhydrous THF. Thereto was added 36.4 mg of lithium aluminum hydride, and the mixture was stirred at room temperature for 4 hours. The mixture was further stirred at 60 ° C. for 2 hours. After the reaction, ethyl acetate was added. An aqueous sodium potassium tartrate solution was added and stirred. Extracted with chloroform. Dried over magnesium sulfate. The solvent was removed under reduced pressure.
This is dissolved in anhydrous methanol 3.5 ml, 2-imidazole carboxaldehyde 34.6 mg,
0.079 ml of trimethyl orthoformate was added and stirred at room temperature for 13 hours. Thereto was added 27.2 mg of sodium borohydride. Stir at room temperature for 2 hours. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 45.5 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 448 [M + H] ⁺

Example 24-4: N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N-phenyl- Synthesis of N ′, N′-dipropyl-butane-1,4-diamine [Compound No. 24] 45.5 mg of the compound obtained in Example 24-3 was dissolved in 1.8 ml of anhydrous methanol. 1-methyl-2-imidazole carboxaldehyde 16.5mg, sodium cyanoborohydride 18.9mg
Was added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 24 hours. After the reaction, the solvent was distilled off, and a 1 mol / l aqueous sodium hydroxide solution was added, followed by extraction with chloroform. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 32.7 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 542 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.90 (6H, t, J = 7.1 Hz), 1.60-1.67 (8H, m), 2.96-2.99 (4H, m), 3.04 -3.07 (2H, m), 3.43 (2H, t, J = 7.1Hz), 4.03 (2H, s), 4.11 (2H, s), 4.49 (2H, s), 6.66 (3H, br), 7.10 ( 2H, d, J = 7.9Hz), 7.15 (2H, t, J = 7.9Hz), 7.23 (2H, d, J = 7.9Hz), 7.45 (2H, s), 7.58 (2H, s).

Production Example 25: N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino]- Synthesis of methyl} -benzyl) -acetamide [Compound No. 25]

Example 25-1: (4-{[(4-Dipropylamino-butyl) -acetamino] -methyl} -benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) -carbamic acid t-butyl ester The compound 182.6 mg obtained in Example 21-4 was dissolved in chloroform 7.0 ml, triethylamine 0.133 ml and acetic anhydride 73.5 mg were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (253.2 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 528 [M + H] ⁺

Example 25-2: N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino ] -Methyl} -benzyl) -acetamide [
Synthesis of Compound No. 25] 237.9 mg of the compound obtained in Example 25-1 was dissolved in 4.7 ml of methanol, and 4 mol / l hydrogen chloride /
4.7 ml of dioxane solution was added and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure,
A 1 mol / l aqueous sodium hydroxide solution was added to the residue, extracted with chloroform, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum.
This was dissolved in 9.6 ml of methanol, 74.5 mg of 2-imidazole carboxaldehyde and 56.7 mg of sodium cyanoborohydride were added, adjusted to pH = 5 with acetic acid, and stirred at room temperature for 20 hours. The reaction solution was directly concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 186.1 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 508 [M + H] ^+
1 H-NMR (500 Mz, DMSO-d ₆ + D ₂ O): δ = 0.90 (6H, t, J = 7.3 Hz), 1.49-1.67 (8H, m), 2.00 (3H, s), 2.9
5-3.04 (6H, m), 3.17-3.24 (2H, m), 3.67 (3H, s), 3.70 (2H, s), 4.07 (2H, m), 4.15 (2H, m), 4.43 (2H, s), 4.49 (2H, s), 7.08 (1H, d, J = 8.1Hz), 7.11 (1H, d, J = 8.1Hz), 7.29 (1H, d, J = 8.1Hz), 7.34 (1H, d, J = 8.1Hz), 7.49 (2H, s), 7.60 (2H, s).

Production Example 26: 1- (4-Dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino]- Synthesis of methyl} -phenyl) -1-methyl-urea [Compound No. 26]

Example 26-1: Synthesis of 3- (4-cyano-phenyl) -1- (4-dipropylamino-butyl) -1-methyl-urea 1.23 ml of acetic anhydride was ice-cooled, and 0.604 ml of formic acid was added thereto. added. This was stirred at 50 ° C. for 2 hours. After the reaction, the mixture was allowed to cool, and 1.0 ml of anhydrous THF was added thereto. This was ice-cooled, and 2.0 ml of a THF solution containing 896.0 mg of the compound obtained in Example 1-2 was added thereto, followed by stirring at room temperature for 30 minutes. After the reaction, the solvent was distilled off.
This was dissolved in 30 ml of anhydrous THF, and 592 mg of lithium aluminum hydride was added to it, and 1
Heated to reflux for 2 hours, then 2 hours. After adding ethyl acetate, aqueous sodium potassium tartrate solution was added and stirred at room temperature. Extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 30 ml of toluene, 910.9 mg of 4-isocyanate-benzonitrile (manufactured by Aldrich) was added, and the mixture was stirred at room temperature for 14 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (97.6 mg) as a colorless oil.
MS (FAB, Pos.): M / z = 331 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.41-1.53 (6H, m), 1.61-1.68 (4H, m), 2.36-2.40 (4H, m ), 2.45 (2H, t, J = 7.1Hz), 3.03 (3H, s), 3.36 (2H, t, J = 7.6Hz), 6.78 (1H, br), 7.50-7.53 (2H, m), 7.55 -7.57 (2H, m).

Example 26-2: 1- (4-dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino Synthesis of] -methyl} -phenyl) -1-methyl-urea [Compound No. 26] 97.6 mg of the compound obtained in Example 26-1 was dissolved in 4.0 ml of ethanol and 1.0 ml of 1 mol / l sodium hydroxide aqueous solution was dissolved. Was added. Raney nickel 10 mg was added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction, it was filtered through Celite. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was removed under reduced pressure.
This was dissolved in 3.4 ml of methanol. 2-Imidazolecarboxaldehyde (36.5 mg) and trimethyl orthoformate (0.082 ml) were added, and the mixture was stirred at room temperature for 16.5 hours. Thereto, 28.4 mg of sodium borohydride was added and stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 4.0 ml of methanol, and 39.6 mg of 1-methyl-2-imidazolecarboxaldehyde and 45.2 mg of sodium cyanoborohydride were added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 22 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 76.8 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 509 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.88 (6H, t, J = 7.3 Hz), 1.51-1.55 (2H, m), 1.60-1.70 (6H, m), 2.92-2.96 (4H , m), 2.94 (3H, s), 3.03-3.06 (2H, m), 3.32 (2H, t, J = 7.2Hz), 3.58 (2H, s), 3.69 (3H, s), 4.04 (2H, s), 4.11 (2H, s), 7.25 (2H, d, J = 8.7Hz), 7.42 (2H, d, J = 8.5Hz), 7.56 (2H, dd, J = 2.0, 7.1Hz), 7.64 ( 2H, s), 8.30 (1H, s) 10.24 (1H, s), 14.79 (2H, br).

Production Example 27: 1- (4-Dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino]- Synthesis of methyl} -phenyl) -1,3-dimethyl-urea [Compound No. 27]

Example 27-1: Synthesis of 1- (4-cyano-phenyl) -3- (4-dipropyl-butyl) -1,3-dimethyl-urea 197.3 mg of the compound obtained in Example 26-1 was dissolved in anhydrous THF Dissolved in .0ml. 27.5 mg of 60% sodium hydride was added. Stir at room temperature for 1.5 hours. Add 0.045 ml of methyl iodide and add 2 at room temperature.
Stir for hours. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (37.8 mg) as a colorless oil.
MS (FAB, Pos.): M / z = 345 [M + H] ⁺

Example 27-2: 1- (4-Dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino ] -Methyl} -phenyl) -1,3-dimethyl-
Synthesis of Urea [Compound No. 27] 37.8 mg of the compound obtained in Example 27-1 was dissolved in 1.5 ml of ethanol. 0.4 ml of 1 mol / l sodium hydroxide aqueous solution was added. Raney nickel (3.8 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After the reaction, the mixture was filtered through celite, and the solvent was distilled off. Extracted with chloroform. The solvent was distilled off.
This was dissolved in 1.2 ml of methanol. Thereto, 12.9 mg of 2-imidazole carboxaldehyde and 0.029 ml of trimethyl orthoformate were added. Stir at room temperature for 3 days. Thereto was added 10.1 mg of sodium borohydride. Stir at room temperature for 4 hours. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off.
This was dissolved in 1.6 ml of methanol. 14.8 mg of 1-methyl-2-imidazolecarboxaldehyde and 16.8 mg of sodium cyanoborohydride were added. The pH was adjusted to 5 with acetic acid. 1 at room temperature
Stir overnight. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added. Extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 39.5 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 523 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.43-1.48 (2H, m), 1.54-1.57 (2H, m), 1.63-1.71 (4H , m), 2.47 (3H, s), 2.89-3.06 (6H, m), 3.00 (3H, s), 3.11 (2H, t, J = 7.3Hz), 3.65 (3H, s), 3.70 (3H, s), 4.11 (2H, s), 4.19 (2H, s), 7.06 (2H, d, J = 8.4Hz), 7.35 (2H, d, J = 8.5Hz), 7.53 (2H, dd, J = 2.0) , 6.8Hz), 7.63 (2H, s), 10.45 (1H, br), 14.80 (1H, br), 14.92 (1H, br).

Production Example 28: N-methyl-N- [4-({(1-methyl-1H-imidazol-2-ylmethyl)-[1- (toluene-4-sulfonyl) -1H-imidazol-2-ylmethyl] -amino } -Methyl) -benzyl] -N ″, N ″ -dipropyl-butane-1,4-diamine [Compound No.28]

Example 28-1: N-methyl-N ″, N ″ -dipropyl-N- [4-({[1- (toluene-4-sulfonyl) -1H-imidazol-2-ylmethyl] -amino}- Synthesis of (methyl) -benzyl] -butane-1,4-diamine The compound 568 mg obtained in Example 9-2 was dissolved in 11 ml of anhydrous THF, and 157 mg of 60% sodium hydride was added with stirring under ice-cooling in a nitrogen atmosphere. The mixture was returned to room temperature and stirred for 1 hour. P-
Toluenesulfonyl chloride 315 mg of THF solution 2.0 ml was slowly added dropwise, and the mixture was stirred with ice cooling for 30 minutes. After completion of the reaction, the mixture was neutralized by adding 220 μl of acetic acid while stirring under ice-cooling, water was added to stop the reaction, and the temperature was returned to room temperature. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, 1 mol / l aqueous sodium hydroxide solution was added to adjust the pH of the aqueous layer to about 10, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain 678 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 540 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 6.3 Hz), 1.42-1.52 (8H, m), 2.16 (3H, s), 2.18-2.41 (8H, m), 2.42 (3H, s), 3.46 (2H, s), 3.76 (2H, s), 4.03 (2H, s), 6.98 (1H, d, J = 1.7Hz), 7.22 (1H, dd, J = 2.0, 6.3Hz), 7.25 (1H, dd, J = 2.0, 4.2Hz), 7.29 (2H, dd, J = 0.7, 2.0Hz), 7.30 (2H, dd, J = 0.7, 2.0Hz), 7.42 (1H, d, J = 1.7Hz), 7.76 (1H, dd, J = 2.0,2.0Hz), 7.79 (1H, dd, J = 2.0,2.0Hz).

Example 28-2: N-methyl-N- [4-({(1-methyl-1H-imidazol-2-ylmethyl)-[1- (toluene-4-sulfonyl) -1H-imidazol-2-ylmethyl] -Amino} -methyl) -benzyl] -N ', N'-
Synthesis of dipropyl-butane-1,4-diamine [Compound No. 28] 307 mg of the compound obtained in Example 28-1 was dissolved in 6.0 ml of anhydrous DMF, and 175 mg of potassium carbonate was added at room temperature under a nitrogen atmosphere. Under cooling, 107 mg of the compound obtained in Example 10-2 was added and added at room temperature to 2
Stir for hours. After stirring at 60 ° C. for 22 hours, the mixture was allowed to cool, and water was added under ice cooling to stop the reaction. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, water was added, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate.
After filtration, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 49.3 mg of the title compound as a brown oil.
MS (FAB, Pos.): M / z = 634 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.41-1.51 (8H, m), 2.15 (3H, s), 2.33-2.39 (8H, m), 2.41 (3H, s), 3.43 (3H, s), 3.45 (2H, s), 3.70 (2H, s), 3.71 (2H, s), 3.85 (2H, s), 6.79 (1H, d, J = 1.2Hz), 6.92 (1H, d, J = 1.2Hz), 6.98 (1H, d, J = 1.7Hz), 7.23 (1H, dd, J = 7.0, 8.2Hz), 7.26 (1H, dd, J = 0.6, 2.9Hz), 7.27 (2H, dd, J = 0.6, 0.6Hz), 7.27 (2H, dd, J = 0.6, 4.1Hz), 7.40 (1H, d, J = 1.7Hz), 7.57 (1H, dd, J = 1.8,2.0Hz), 7.79 (1H, dd, J = 1.7,2.0Hz).

Production Example 29: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-methyl-1H-benzimidazole Synthesis of 2-yl) -benzyl] -dipropyl-amine [Compound No. 29]

Example 29-1: Synthesis of 3,4-diaminobenzonitrile
3.00 g of 3-nitro-4-aminobenzonitrile was dissolved in 300 ml of ethanol, and 20.7 g of stannous chloride dihydrate was added thereto and heated to 60 ° C. To this, 348 mg of sodium borohydride was added little by little, and the mixture was stirred at 60 ° C. overnight. After completion of the reaction, 300 ml of water was added and neutralized with 5 mol / l sodium hydroxide aqueous solution. Ethanol was distilled off under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was recrystallized to obtain 1.11 g of the title compound as brown crystals.
MS (EI): m / z = 133 [M] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 6.68 (1H, d, J = 8.1 Hz), 6.95 (1H, s), 7.05 (1H, d, J = 8.1 Hz).

Example 29-2: Synthesis of methyl 4-dipropylaminomethyl-benzoate
831 mg of methyl 4-bromomethylbenzoate was dissolved in 12.5 ml of DMF, 971 μl of dipropylamine was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off to obtain 883 mg of the title compound as a brown solid.

Example 29-3: Synthesis of 4-dipropylaminomethyl-benzoic acid 883 mg of the compound obtained in Example 29-2 was dissolved in 18 ml of methanol, and 9.0 ml of 1 mol / l sodium hydroxide aqueous solution was added thereto at room temperature. Stir overnight. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 1 mol / l hydrochloric acid, extracted with chloroform, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain 820 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 236 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.74 (4H, sext., J = 7.3 Hz), 2.92 (4H, br), 4.38 (2H , d, J = 4.6Hz), 7.78 (2H, d, J = 8.0Hz), 8.00 (1H, d, J = 8.0Hz), 10.85 (1H, br).

Example 29-4: Synthesis of N- (2-amino-5-cyano-phenyl) -4-dipropylaminomethyl-benzamide 1.01 g of the compound obtained in Example 29-3, 973 mg of WSCI hydrochloride, and 894 mg of HOBt The product was dissolved in 30 ml of chloroform and stirred for 2 hours. To this was added 445 mg of the compound obtained in Example 29-1, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 613 mg of the title compound as an orange solid.
MS (FAB, Pos.): M / z = 351 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3 Hz), 1.48 (4H, sext., J = 7.3 Hz), 2.38 (4H, t, J = 7.3 Hz), 3.62 (2H, s), 4.43 (3H, br), 6.83 (1H, d, J = 8.3Hz), 7.37 (1H, d, J = 8.3Hz), 7.49 (2H, d, J = 8.1Hz), 7.52 (1H, s), 7.80 (1H, br), 7.84 (1H, d, J = 8.1Hz).

Example 29-5: Synthesis of 2- (4-dipropylaminomethyl-phenyl) -3-methyl-3H-benzimidazole-5-carbonitrile 613 mg of the compound obtained in Example 29-4 was dissolved in 18 ml of THF. To this, 105 mg of 60% sodium hydride was added. Thereafter, 373 mg of methyl iodide was added little by little and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with water, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 160 mg of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 347 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.88 (6H, t, J = 7.3 Hz), 1.50 (4H, sext., J = 7.3 Hz), 2.41 (4H, t, J = 7.3 Hz), 3.64 (2H, s), 3.93 (3H, s), 7.55 (2H, d, J = 8.3Hz), 7.57 (1H, d, J = 8.3Hz), 7.72 (2H, d, J = 8.3Hz), 7.74 (1H, s), 7.86 (1H, d, J = 8.3Hz).

Example 29-6: Synthesis of [4- (6-Aminomethyl-1-methyl-1H-benzimidazol-2-yl) -benzyl] -dipropyl-amine 64.0 mg lithium aluminum hydride suspended in 5.0 ml THF The mixture was cooled to 0 ° C., 5.0 ml of a THF solution of the compound 155 mg obtained in Example 29-5 was added dropwise thereto, and the mixture was stirred at 0 ° C. for 1 hour. After completion of the reaction, sodium sulfate decahydrate was added until it no longer foamed. A 1 mol / l aqueous sodium hydroxide solution was added thereto until a white solid precipitated. The solid was filtered off, the filtrate was evaporated under reduced pressure, and the residue was dried in vacuo to give 93.5 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 351 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.94 (6H, t, J = 7.3 Hz), 1.71-1.89 (4H, m), 2.98 (2H, s), 3.13-3.20 (2H, m ), 3.23-3.30 (2H, m), 3.99 (3H, s), 4.64 (2H, s), 7.67 (1H, d, J = 8.3Hz), 7.78 (2H, d, J = 8.3Hz), 7.87 (1H, d, J = 8.3Hz), 8.05 (2H, d, J = 8.3Hz), 8.35 (1H, s).

Example 29-7: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole-2-
Synthesis of (Ilmethyl) -amino] -methyl} -1-methyl-1H-benzimidazol-2-yl) -benzyl] -dipropyl-amine [Compound No. 29] 93.5 mg of the compound obtained in Example 29-6 It melt | dissolved in methanol 4.0ml, Trimethyl orthoformate 100microliter and 2-imidazole carboxaldehyde 31.7mg were added, and it stirred at room temperature for 1 hour. After cooling to 0 ° C., 13.2 mg of sodium borohydride was added. After returning to room temperature, the mixture was stirred for 30 minutes.
After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure.
This was dissolved in 4.0 ml of methanol, 100 μl of acetic acid and 61.0 mg of 1-methyl-2-imidazolecarboxaldehyde were added, and the mixture was stirred at room temperature for 30 minutes. To this, 53.6 mg of sodium cyanoborohydride was added and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 38.4 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 525 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.89 (6H, t, J = 7.3 Hz), 1.72-1.82 (4H, m), 2.94-3.02 (4H, m), 3.75 (3H, s ), 3.94 (2H, s), 4.13 (3H, s), 4.16 (2H, s), 4.24 (2H, s), 4.48 (2H, d, J = 5.6Hz), 7.53-7.54 (2H, m) , 7.59 (1H, d, J = 8.5Hz), 7.64 (2H, s), 7.75 (1H, d, J = 8.5Hz), 8.04 (2H, d, J = 8.7Hz), 8.07 (2H, d, J = 8.7Hz), 8.33 (1H, s).

Production Example 30: 6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -imidazo [1,2-a] pyridine-2- Synthesis of carboxylic acid (4-dipropyl) -amino-butyl) -amide [Compound No. 30]

Example 30-1: Synthesis of 6-amino-pyridine-3-carboxaldehyde
1.02 g of 2-amino-5-cyanopyridine was dissolved in 40 ml of THF, 637 mg of lithium aluminum hydride was added, and the mixture was stirred at room temperature for 2 hours. Water was added to stop the reaction, and a saturated aqueous sodium sulfate solution was added, followed by Celite filtration. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.04 g of the title compound as a yellow solid.
MS (EI): m / z = 122 [M] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 6.51 (1H, dd, J = 0.7,8.9 Hz), 7.19 (2H, br), 7.75 (1H, dd, J = 2.4,8.9 Hz), 8.43 (1H, dd, J = 0.5,2.2Hz), 9.66 (1H, s).

Example 30-2: Synthesis of 6-formyl-imidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester 3-bromo-2 -Oxo-propionic acid ethyl ester 0.33 ml was added and stirred at room temperature for 18 hours. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 230 mg of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 219 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.46 (3H, t, J = 7.0 Hz), 4.49 (2H, q, J = 7.0 Hz), 7.73-7.79 (2H, m), 8.33 (1H, d, J = 0.5Hz), 8.72 (1H, dd, J = 1.0,1.7Hz), 9.99 (1H, s).

Example 30-3: 6-{[(1-Methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -imidazo [1,2-a] pyridine-2-carboxylic acid (4-dipropylamino) Synthesis of (butyl) -amide 0.32 ml of a 15% trimethylaluminum / hexane solution was added dropwise to a 2.0 ml solution of the compound 72.0 mg obtained in Example 1-2 and stirred at room temperature for 15 minutes. To this, 2.0 ml of a dichloromethane solution of 41.8 mg of the compound obtained in Example 30-2 was added dropwise and stirred at room temperature for 20 hours. 1 mol / l hydrochloric acid was added dropwise to the solution to stop the reaction, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
40.2 mg of 65.2 mg of the resulting residue was dissolved in 2.0 ml of methanol, 0.040 ml of trimethyl orthoformate was added, and a solution of compound 20.0 mg obtained in Example 14-7 in 1.0 ml of methanol was added dropwise at room temperature. Stir for 4 hours. After cooling this to 0 ° C., 6.8 mg of sodium borohydride was added,
The mixture was warmed to room temperature and stirred for 30 minutes. Water was added to stop the reaction, and the concentrated residue was extracted with chloroform. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate.
The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 34.7 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 440 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3Hz), 1.43-1.48 (4H, m), 1.55-1.57 (2H, m), 1.63-1.66 (2H, m ), 2.37 (4H, t, J = 7.3Hz), 2.46 (2H, br), 3.48 (2H, tt, J = 6.3, 6.9Hz), 3.64 (3H, s), 3.85 (2H, s), 3.89 (2H, s), 6.82 (1H, d, J = 1.2Hz), 6.94 (1H, d, J = 1.2Hz), 7.26 (1H, dd, J = 1.7,9.3Hz), 7.41 (1H, t, J = 5.8Hz), 7.50 (1H, d, J = 9.3Hz), 8.08 (1H, d, J = 0.6Hz), 8.10 (1H, d, J = 1.1Hz).

Example 30-4: 6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -imidazo [1,2-a] pyridine- Synthesis of 2-carboxylic acid (4-dipropyl) -amino-butyl) -amide [Compound No. 30] 34.7 mg of the compound obtained in Example 30-3 was dissolved in 3.0 ml of methanol to give 2-imidazole carboxaldehyde 9.1. mg and sodium cyanoborohydride (9.9 mg) were added, the pH was adjusted to 4 with acetic acid, and the mixture was stirred at room temperature for 45 hours. Saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 23.6 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 520 [M + H] +
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.26-1.48 (4H, m), 1.51-1.56 (2H, m), 1.61-1.67 (2H, m ), 2.34-2.37 (4H, m), 2.44 (2H, t, J = 7.3Hz), 3.48 (2H, tt, J = 6.4, 6.9Hz), 3.56 (2H, s), 3.57 (2H, s) , 3.65 (3H, s), 3.66 (2H, s), 6.92 (1H, d, J = 1.2Hz), 7.03 (1H, d, J = 1.2Hz), 7.08 (1H, s), 7.14 (1H, s), 7.39 (1H, br), 7.39 (1H, dd, J = 1.5, 9.5Hz), 7.54 (1H, d, J = 9.3Hz), 8.11 (1H, d, J = 0.7Hz), 8.23 ( 1H, d, J = 0.7Hz), 12.41 (1H, br).

Production Example 31: N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ′, N′- Synthesis of dipropyl-N- (2,2,2-trifluoro-ethyl) -butane-1,4-diamine [Compound No.31]

Example 31-1: (4-{[(4-Dipropylaminobutyl)-(2,2,2-trifluoroacetyl) -amino] -methyl} -benzyl)-(1-methyl-1H-imidazole- Synthesis of 2-ylmethyl) -carbamic acid t-butyl ester 222 mg of the compound obtained in Example 21-4 was dissolved in 4.4 ml of anhydrous dichloromethane, and 0.071 ml of triethylamine was added. The mixture was ice-cooled, 0.072 ml of trifluoroacetic anhydride was added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction, it was washed with water. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 178.6 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 582 [M + H] ⁺

Example 31-2: N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ′, N Synthesis of '-dipropyl-N- (2,2,2-trifluoro-ethyl) -butane-1,4-diamine [Compound No. 31] 178.6 mg of the compound obtained in Example 31-1 was added to anhydrous THF. Dissolved in 9 ml. 1.72 ml of 1 mol / l borane THF complex / THF solution was added and heated to reflux for 18.5 hours. After the reaction, methanol was added and the solvent was distilled off. 1 mol / l hydrochloric acid was added and the mixture was heated to reflux for 3 hours. The mixture was neutralized with 1 mol / l sodium hydroxide aqueous solution and extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 5.2 ml of anhydrous methanol. 2-imidazole carboxaldehyde 40.4mg
, 52.8 mg of sodium cyanoborohydride was added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 18 hours. After the reaction, the solvent was distilled off, and a 1 mol / l aqueous sodium hydroxide solution was added, followed by extraction with chloroform. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 138.7 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 548 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.90 (6H, t, J = 7.3 Hz), 1.47-1.48 (2H, m), 1.57-1.64 (6H, m), 2.94 -3.00 (6H, m), 3.21-3.23 (2H, m), 3.69 (6H, s), 3.74 (3H, s), 4.06 (2H, s), 4.14 (2H, s), 7.20 (2H, d , J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.48 (2H, s), 7.59 (2H, s).

Production Example 32: N- (4-{[(1-Methanesulfonyl-1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N Of 2-Methyl-N '', N ''-dipropyl-butane-1,4-diamine [Compound No.32]

Example 32-1 N- [4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl] -N-methyl- N``, N ''-dipropyl-butane-1,4-
Synthesis of Diamine 26.7 mg of the compound obtained in Example 9-2 was dissolved in 0.35 ml of anhydrous THF, and 350 μl of triethylamine and 50 μl of a THF solution of 9.20 mg of 1-methyl-2-imidazolecarboxaldehyde were added. To this was added 31.3 mg of sodium triacetoxyborohydride, and the mixture was stirred for 24 hours under a nitrogen atmosphere at room temperature. After completion of the reaction, water was added, the solvent was distilled off under reduced pressure, chloroform and 1 mol / l sodium hydroxide aqueous solution were added to the residue to adjust the pH of the aqueous layer to 10, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate). Obtained as an oil.
MS (FAB, Pos.): M / z = 480 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.41-1.52 (8H, m), 2.16 (3H, s), 2.36-2.44 (8H, m), 3.46 (2H, s), 3.55 (5H, s), 3.62 (2H, s), 3.67 (2H, s), 6.87 (1H, d, J = 1.2Hz), 6.99 (1H, d, J = 1.2Hz) ), 7.10 (2H, s), 7.27 (2H, d, J = 8.0Hz), 7.35 (1H, d, J = 8.0Hz).

Example 32-2: N- (4-{[(1-Methanesulfonyl-1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) Synthesis of —N-methyl-N ″, N ″ -dipropyl-butane-1,4-diamine [Compound No. 32] 125 mg of the compound obtained in Example 32-1 was dissolved in anhydrous chloroform and a nitrogen atmosphere was obtained. At room temperature, 60 μl of triethylamine was added, and 25 μl of methanesulfonyl chloride was added and stirred. After completion of the reaction, water and methanol were added to stop the reaction. Water was added and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 87.7 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 558 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.32-1.51 (8H, m), 2.15 (3H, s), 2.33-2.41 (8H, m), 3.39 (3H, s), 3.44 (2H, s), 3.45 (3H, s), 3.76 (2H, s), 3.89 (2H, s), 4.05 (2H, s), 6.79 (1
H, d, J = 1.2Hz), 6.91 (1H, d, J = 1.2Hz), 6.98 (1H, d, J = 1.7Hz), 7.16 (2H, d, J = 8.0Hz), 7.24 (2H, d, J = 8.0Hz), 7.30 (1H, d, J = 1.7Hz).

Production Example 33: 3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl } -Benzyl) -amino] -propionitrile [Compound No. 33]

Example 33-1: (4-{[(2-cyano-ethyl)-(4-dipropylamino-butyl) -amino] -methyl}-
Synthesis of benzyl) -carbamic acid t-butyl ester 260 mg of the compound obtained in Example 23-4 was dissolved in 5.0 ml of methanol, 1.0 ml of distilled water and 87.4 μl of acrylonitrile were added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 332 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 445 [M + H] ⁺

Example 33-2: Synthesis of 3-[(4- (aminomethyl-benzyl)-(4-dipropylamino-butyl) -amino) -propionitrile 331 mg of the compound obtained in Example 33-1 It melt | dissolved in THF1.0ml, 4 mol / l hydrogen chloride / dioxane solution 6.0ml was added, and it stirred at room temperature for 20 minutes. After completion of the reaction, the solvent was distilled off. To this was added a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 235 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 345 [M + H] ⁺

Example 33-3: 3-[(4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-
Synthesis of amino] -methyl} -benzyl) amino] -propionitrile 235 mg of the compound obtained in Example 33-2 was dissolved in 5.0 ml of anhydrous methanol, and 112 μl of trimethyl orthoformate and 72.1 mg of 2-imidazole carboxaldehyde were added. Stir overnight at room temperature under a nitrogen atmosphere. Next, 25.8 mg of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 309 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 425 [M + H] ⁺

Example 33-4: 3-[(4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(5-methyl-cyanopenta-1,3-dienylmethyl) -amino] Synthesis of -methyl} -benzyl) -amino] -propionitrile 141 mg of the compound obtained in Example 33-3 was dissolved in 3.0 ml of anhydrous methanol, 31.3 mg of sodium cyanoborohydride, 1.00 ml of acetic acid, 1-methyl -2-Imidazolecarboxaldehyde (40.2 mg) was added, and the mixture was stirred at room temperature for 4 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform. A 1 mol / l sodium hydroxide aqueous solution was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with tartaric acid to obtain 159 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 519 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.89 (6H, t, J = 7.3 Hz), 1.43-1.46 (2H, m), 1.55-1.61 (6H, m), 2.42 (2H, t, J = 6.7Hz), 2.64-2.66 (4H, m), 2.92-2.97 (6H, m), 3.51 (3H, s), 3.53 (2H, s), 3.55 (2H, s), 3.61 (4H, s), 4.22 (6H, s), 6.86 (1H, d, J = 1.2Hz), 7.05 (2H, s), 7.11 (1H, d, J = 1.2Hz), 7.
28 (2H, d, J = 8.4Hz), 7.31 (2H, d, J = 8.4Hz).

Production Example 34: 3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl } -Benzyl) -amino] -propionic acid methyl ester [Compound No. 34]

Example 34-1: Synthesis of 3-[(4-amino-methyl-benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid methyl ester 128 mg of the compound obtained in Example 33-1 Dissolved in 1.0 ml of anhydrous methanol, 4 mol / l hydrogen chloride /
A dioxane solution (3.0 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the solvent was distilled off. To this was added a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified through silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (40.6 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 378 [M + H] ⁺

Example 34-2: 3-[(4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-
Synthesis of amino] -methyl} -benzyl) -amino] -propionic acid methyl ester 40.0 mg of the compound obtained in Example 34-1 was dissolved in 1.0 ml of anhydrous methanol, 17.4 μl of trimethyl orthoformate, 2-imidazole carboxaldehyde 11.2 mg was added and stirred overnight at room temperature under a nitrogen atmosphere. Next, 4.00 mg of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 48.2 mg of the title compound as a colorless oil.

Example 34-3: 3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -methyl} -benzyl) -amino] -propionic acid methyl ester [Compound No. 34] 48.2 mg of the compound obtained in Example 34-2 was dissolved in 1.0 ml of anhydrous methanol, and 9.90 mg of sodium cyanoborohydride 100 μl of acetic acid and 12.8 mg of 1-methyl-2-imidazolecarboxaldehyde were added, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform. A 1 mol / l sodium hydroxide aqueous solution was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 56.1 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 552 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.62-1.69 (6H, m), 1.74-1.83 (2H, m), 2.92 -3.06 (10H, m), 3.17-3.22 (2H, m), 3.64 (3H, s), 3.72 (3H, s), 3.75 (2H, s), 4.10 (2H, s), 4.19 (2H, s ), 4.26-4.34 (2H, m), 7.41 (2H, d, J = 8.2Hz), 7.465 (1H, s), 7.467 (1H, s), 7.50 (2H, d, J = 8.1Hz), 7.60 (2H, s).

Production Example 35: 1- (4-Dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino]- Synthesis of methyl} -phenyl) -thiourea [Compound No. 35]

Example 35-1: Synthesis of 1- (4-cyano-phenyl) -3- (4-dipropylamino-butyl) -thiourea 656.8 mg of the compound obtained in Example 1-2 was dissolved in 19.7 ml of anhydrous toluene. Then, 793.0 mg of 4-isothiocyanate-benzonitrile (manufactured by Aldrich) was added, and the mixture was heated to reflux for 18.5 hours. The solvent was distilled off after standing_to_cool. Water was added and extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off. Silica gel column chromatography (chloroform / ethyl acetate)
To give 314.4 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 333 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.83 (6H, t, J = 7.3 Hz), 1.34-1.41 (4H, m), 1.55 (2H, quint., J = 6.8 Hz), 1.71 (2H , quint., J = 6.6Hz), 2.28 (4H, t, J = 7.8Hz), 2.42 (2H, t, J = 6.3Hz), 3.62 (2H, br), 7.39 (2H, br), 7.65 ( (2H, d, J = 8.8Hz).

Example 35-2: Synthesis of 1- (4-dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl) -thiourea Example 35 314.4 mg of the compound obtained in -1 was dissolved in 12.6 ml of anhydrous THF, 144 mg of lithium aluminum hydride was added, and the mixture was stirred overnight at room temperature. Heated to reflux for 2 hours. After the reaction, ethyl acetate was added. Sodium potassium tartrate aqueous solution was added and stirred overnight. Extracted with chloroform.
It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 6.4 ml of methanol, and 137.4 mg of 2-imidazole carboxaldehyde and 0.312 ml of trimethyl orthoformate were added. Stir at room temperature for 2 hours. 107.8 mg of sodium borohydride was added and stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 93.8 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 417 [M + H] ⁺

Example 35-3: 1- (4-dipropylamino-butyl) -3- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino Synthesis of] -methyl} -phenyl) -thiourea [Compound No. 35] 93.8 mg of the compound obtained in Example 35-2 was dissolved in 3.8 ml of anhydrous methanol, 38.5 mg of 1-methyl-2-imidazolecarboxaldehyde, cyano 43.4 mg of sodium borohydride was added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 13.5 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 86.6 mg of the title compound as a hydrochloride as a white solid.
MS (FAB, Pos.): M / z = 511 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.91 (6H, t, J = 7.3 Hz), 1.56-1.68 (8H, m), 2.99-3.02 (4H, m), 3.06 -3.09 (2H, m), 3.50 (2H, br), 3.66 (2H, s), 3.70 (3H, s), 4.04 (2H, s), 4.12 (2H, s), 7.26 (2H, d, J = 8.5Hz), 7.40 (2H, d, J = 8.3Hz), 7.50 (2H, s), 7.61 (2H, s).

Production Example 36: {3- [6- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl) -pyridine- Synthesis of 2-yl] -propyl} -dipropyl-amine [Compound No. 36]

Example 36-1: Synthesis of 2-chloro-6-p-tolylpyridine
1.00 g of 4-methylphenylboronic acid, 3.27 g of 2,6-dichloropyridine, 0.255 g of tetrakis (triphenylphosphine) palladium (0) and 3.12 g of potassium phosphate were dissolved in 35 ml of toluene and 6.0 ml of water. After stirring at 80 ° C. for 15 hours under a nitrogen atmosphere, the organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Crude purification was performed by silica gel column chromatography (chloroform) to obtain 4.02 g of a mixture containing the title compound.

Example 36-2: Synthesis of 2- (4-bromomethyl-phenyl) -6-chloro-pyridine To a solution of 4.02 g of the mixture obtained in Example 36-1 in 45 ml of carbon tetrachloride, 1.31 g of N-bromosuccinimide And 2,2′-azobisisobutyronitrile (0.121 g) were added, and the mixture was refluxed for 30 minutes, cooled to room temperature, and the solid was filtered off. The organic layer was washed successively with 1 mol / l sodium hydroxide aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to obtain 5.72 g of a mixture containing the title compound.

Example 36-3: Synthesis of 2- [4- (6-chloro-pyridin-2-yl) -benzyl] -isoindole-1,3-dione 5.72 g of the mixture obtained in Example 36-2 and phthalimide Dissolve 2.04g potassium in 30ml DMF,
After stirring at room temperature for 24 hours, the solid was filtered off. After the solvent was distilled off, the residue was dissolved in chloroform, washed with an aqueous sodium hydrogen carbonate solution, the aqueous layer was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain 1.56 g of the title compound as a colorless solid.
MS (FAB, Pos.): M / z = 349 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 4.90 (2H, s), 7.25 (1H, d, J = 7.8Hz), 7.53 (2H, d, J = 8.5Hz), 7.60 (1H, d, J = 7.8Hz), 7.68 (1H, t, J = 7.8Hz), 7.72 (2H, dd, J = 3.2,5.4Hz), 7.86 (2H, dd, J = 2.9,5.4Hz), 7.94 (2H, d, J = 8.3Hz).

Example 36-4: Synthesis of 2- {4- [6- (3-dipropylamino-propyl) -pyridin-2-yl] -benzyl} -isoindole-1,3-dione
A solution of 158 mg of 2-propenyldipropylamine in 1.0 ml of anhydrous THF was ice-cooled, and 2.06 ml of 0.5 mol / l 9-borabicyclo- [3,3,1] -nonane (9-BBN) / THF solution was added dropwise. Gradually warm up to room temperature 5
After stirring for hours, 210 mg of [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (PdCl ₂ (dppf)) and 300 mg of the compound obtained in Example 36-3 were combined with DMF3. 0.06 ml was added, and 0.86 ml of a 3 mol / l aqueous solution of cesium fluoride was added. After stirring at 80 ° C. for 23 hours, the mixture was heated to 100 ° C. and stirred for 2 hours. After cooling to room temperature, the solid was filtered off and evaporated. The concentrate was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 44.0 mg of the title compound as a light brown liquid.
MS (FAB, Pos.): M / z = 456 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3 Hz), 1.42-1.70 (4H, m), 1.98-2.16 (2H, m), 2.40-2.80 (6H, m ), 2.86 (2H, t, J = 7.6Hz), 4.90 (2H, s), 7.08 (1H, d, J = 7.3Hz), 7.50 (1H, d, J = 7.8Hz), 7.52 (2H, d , J = 8.5Hz), 7.63 (1H, t, J = 7.8Hz), 7.72 (2H, dd, J = 3.2,5.6Hz), 7.86 (2H, dd, J = 3.2,5.4Hz), 7.93 (2H , d, J = 8.3Hz).

Example 36-5: Synthesis of {3- [6- (4-aminomethyl-phenyl) -pyridin-2-yl] -propyl} -dipropyl-amine 40.0 mg of the compound obtained in Example 36-4 After adding 44 mg of hydrazine monohydrate to the 2.0 ml solution and stirring at 60 ° C. for 1.5 hours, the solvent was distilled off. The residue was dissolved in chloroform, filtered through Celite and evaporated to give 30.1 mg of the title compound as an amber liquid.

Example 36-6: {3- [6- (4-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl) -pyridin-2-yl] -propyl} -dipropyl-amine Synthesis To a solution of compound 30.1 mg obtained in Example 36-5 and 2-imidazole carboxaldehyde 10.1 mg in anhydrous methanol 0.50 ml was added trimethyl orthoformate 0.029 ml, stirred at room temperature for 14 hours, then sodium borohydride 17.0 mg And stirred for 30 minutes. The solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and evaporated to give 30.4 mg of the title compound.

Example 36-7: {3- [6- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl)- Synthesis of Pyridin-2-yl] -propyl} -dipropyl-amine [Compound No. 36] 0.50 ml of anhydrous methanol containing 30.4 mg of the compound obtained in Example 36-6 and 11.6 mg of 1-methyl-2-imidazolecarboxaldehyde 4 drops of acetic acid was added to the solution, 17 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 29 hours. After the reaction, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain 23.0 mg of the title compound as a pale yellow viscous liquid. This was treated with hydrochloric acid to give 28.3 mg of the hydrochloride of the title compound as a colorless solid.
MS (FAB, Pos.): M / z = 500 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.88 (6H, t, J = 7.3 Hz), 1.46 (4H, sext., J = 7.6 Hz), 1.97 (2H, quint., J = 7.6 Hz) , 2.40 (4H, t, J = 7.6Hz), 2.53 (2H, t, J = 7.3Hz), 2.86 (2H, t, J = 7.6Hz), 3.49 (2H, s), 3.59 (3H, s) , 3.66 (2H, s), 3.75 (2H, s), 6.89 (1H, d, J = 2.2Hz), 7.01 (1H, d, J = 2.0Hz), 7.10 (1H, d, J = 7.1Hz) 7.10 (1H, br), 7.15 (1H, br), 7.51 (2H, d, J = 8.3Hz), 7.53 (1H, d, J = 7.8Hz), 7.65 (1H, t, J = 7.8Hz) , 7.99 (2H, d, J = 8.3Hz), 12.40 (1H, s).

Production Example 37: N- (4-dipropylamino-butyl) -2,2,2-trifluoro-N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole) Synthesis of -2-ylmethyl) -amino] -methyl} -benzyl) -acetamide [Compound No. 37]

Example 37-1: N- (4-dipropylamino-butyl) -2,2,2-trifluoro-N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H Synthesis of -imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -acetamide [Compound No. 37] 166.6 mg of the compound obtained in Example 21-4 was dissolved in 5.0 ml of anhydrous dichloromethane, and 0.052 ml of triethylamine was obtained. Was added. The mixture was ice-cooled, 0.052 ml of trifluoroacetic anhydride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, it was washed with water. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 2.4 ml of methanol, 2.4 ml of 4 mol / l hydrogen chloride / dioxane solution was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 6.5 ml of anhydrous methanol. 2-imidazole carboxaldehyde 49.0mg
64.1 mg of sodium cyanoborohydride was added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 3 days. After the reaction, the solvent was distilled off, and a 1 mol / l aqueous sodium hydroxide solution was added, followed by extraction with chloroform. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 84.9 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 562 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.90 (6H, dt, J = 3.1,7.3 Hz), 1.57-1.67 (8H, m), 2.95-3.03 (6H, m) , 3.24 (1H, m), 3.35 (1H, m), 3.69 (3H, s), 3.71 (2H, s), 4.07 (2H, d, J = 5.8Hz), 4.15 (2H, d, J = 8.7 Hz), 4.57 (1H, s), 4.63 (1H, s), 7.12-7.17 (2H, m), 7.31-7.35 (2H, m), 7.45 (2H, s), 7.58 (2H, s).

Production Example 38: [4- (5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1,3-dihydro-isoindole Synthesis of 2-yl) -butyl] -dipropyl-amine [Compound No. 38]

Example 38-1: [4- (5-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -1,3-dihydro-isoindol-2-yl) -butyl] -dipropyl-amine Synthesis of 24.3 mg of the compound obtained in Example 7-7 in 2.0 ml of THF was added 1 mol / l borane THF complex / 0.41 ml of THF solution, and the mixture was heated to reflux for 16 hours. After cooling to 0 ° C., methanol was added to stop the reaction, and the mixture was concentrated. To the residue was added 4.0 ml of 1 mol / l hydrochloric acid, and the mixture was heated to reflux for 3 hours. After allowing to cool to room temperature, 5 ml of a 1 mol / l aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (12.5 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 384 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.88 (6H, t, J = 7.3Hz), 1.42-1.48 (4H, m), 1.49-1.60 (4H, m), 2.36-2.39 (4H, m ), 2.45 (2H, t, J = 7.3Hz), 2.72 (2H, t, J = 7.3Hz), 3.76 (2H, s), 3.88-3.90 (6H, m), 6.98 (2H, s), 7.10 -7.15 (3H, m).

Example 38-2: [4- (5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-
Synthesis of (Ilmethyl) -amino] -methyl} -1,3-dihydro-isoindol-2-yl) -butyl] -dipropyl-amine [Compound No. 38] 12.5 mg of the compound obtained in Example 38-1 To a 2.0 ml solution of methanol, 4.4 mg of 1-methyl-2-imidazolecarboxaldehyde and 4.2 mg of sodium cyanoborohydride were added, the pH was adjusted to 4 with acetic acid, and the mixture was stirred at room temperature for 8 hours. The residue obtained by concentrating the solution was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (7.7 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 478 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.4 Hz), 1.42-1.48 (4H, m), 1.49-1.60 (4H, m), 2.35 (4H, m), 2.45 (2H, t, J = 7.3Hz), 2.72 (2H, t, J = 7.3Hz), 3.43 (2H, s), 3.54 (3H, s), 3.62 (2H, s), 3.67 (2H, s ), 3.90 (4H, s), 6.87 (1H, d, J = 1.5Hz), 7.00 (1H, d, J = 1.2Hz), 7.08 (1H, s), 7.12 (1H, s), 7.15 (1H , d, J = 8.0 Hz), 7.23-7.24 (3H, m), 12.38 (1H, br).

Production Example 39: {4- (1E)-[2- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl ) -Vinyl] -benzyl} -dipropyl-amine [
Synthesis of Compound No. 39]

Example 39-1 Synthesis of methylene-triphenyl-λ ⁵ -phosphane 6.00 g of methyltriphenylphosphinium bromide was suspended in 50 ml of THF. The reaction solution was cooled to 0 ° C., 1.46 g of sodium amide was added, and the mixture was heated to reflux for 3 hours. The reaction solution was cooled to room temperature and then filtered through celite. The filtrate was concentrated under reduced pressure to obtain 1.92 g of the title compound as a yellow-red solid.

Example 39-2: Synthesis of 2- (4-vinyl-benzyl-isoindole) -1,3-dione 0.99 g of the compound obtained in Example 1-1 was dissolved in 30 ml of THF. The reaction solution was cooled to 0 ° C., 1.66 g of the compound obtained in Example 39-1 was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 0.78 g of the title compound as a white solid.
^{1 H-NMR (500MHz, CDCl} 3): δ = 4.83 (2H, s), 5.23 (1H, dd, J = 1.0,10.0Hz), 5.71 (1H, dd, J = 1.0,16.6Hz), 6.67 ( 1H, dd, J = 6.8,10.7Hz), 7.35-7.40 (4H, m), 7.70-7.72 (2H, m), 7.83-7.85 (2H, m).

Example 39-3: 4- {2- [4- (1E)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)
Synthesis of -phenyl] -vinyl} -benzaldehyde 760 mg of the compound obtained in Example 39-2, p-bromobenzaldehyde 690 mg, tri-o-tolylphosphine 103 mg, palladium acetate 39 mg were suspended in xylene 15 ml and triethylamine 15 ml, The mixture was stirred at 130 ° C for 63 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure.
Distilled water was added to the resulting residue, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / dichloromethane) to obtain 0.91 g of a yellowish white solid.
MS (FAB, Pos.): M / z = 368 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 4.86 (2H, s), 7.11 (1H, d, J = 16.2Hz), 7.22 (1H, d, J = 16.2Hz), 7.45 (2H, d, J = 8.3Hz), 7.50 (2H, d, J = 8.3Hz), 7.64 (2H, d, J = 8.5Hz), 7.71-7.73 (2H, m), 7.85-7.87 (4H, m), 9.99 ( 1H, s).

Example 39-4: 2- {4- (1E)-[2- (4-dipropylaminomethyl-phenyl) -vinyl] -benzyl}-
Synthesis of isoindole-1,3-dione 650 mg of the compound obtained in Example 39-3 was dissolved in 40 ml of 1,2-dichloroethane. After adding 0.29 ml of n-dipropylamine and 600 mg of sodium triacetoxyborohydride to the reaction solution, the mixture was stirred at room temperature for 18 hours, then added with 0.29 ml of n-dipropylamine and stirred at 50 ° C. for 1 hour, 600 mg of sodium triacetoxyborohydride was added and stirred at 50 ° C. for 20 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. A 1 mol / l aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain the title compound (646 mg) as a white solid.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.44-1.51 (4H, m), 2.35-2.38 (4H, m), 3.54 (2H, s), 4.85 (2H, s), 7.05 (2H, d, J = 1.7Hz), 7.30-7.46 (8H, m), 7.70-7.73 (2H, m), 7.84-7.86 (2H, m).

Example 39-5: {4- (1E)-[2- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} Synthesis of -phenyl) -vinyl] -benzyl} -dipropyl-amine [Compound No. 39] 630 mg of the compound obtained in Example 39-4 was dissolved in 5.0 ml of chloroform and 10 ml of methanol. To the reaction solution, 1.0 ml of hydrazine monohydrate was added and heated to reflux for 1 hour. After cooling the reaction solution to room temperature, the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, distilled water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 12 ml of methanol. To the reaction solution, 219 mg of 2-imidazolecarboxaldehyde and 0.39 ml of trimethyl orthoformate were added and stirred at room temperature for 16 hours. After the reaction solution was cooled to 0 ° C., 135 mg of sodium borohydride was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, distilled water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 12 ml of methanol. To the reaction solution, 1-methyl-2-imidazole carboxaldehyde (156 mg) and trimethyl orthoformate (0.24 ml) were added, and the mixture was stirred at room temperature for 15 hours. After the reaction solution was cooled to 0 ° C., 83 mg of sodium borohydride was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, distilled water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 449 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 497 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.88 (6H, t, J = 7.3 Hz), 1.70 (4H, tq, J = 7.3, 7.6 Hz), 2.96 (4H, t, J = 7.6 Hz), 3.17 (2H, s), 3.72 (3H, s), 4.07 (2H, s), 4.15 (2H, s), 4.31 (2H, s), 7.28 (2H, d, J = 9.9
Hz), 7.35 (2H, d, J = 8.1Hz), 7.50 (2H, s), 7.52-7.57 (4H, m), 7.62 (2H, s), 7.69 (2H, d, J = 8.2Hz).

Production Example 40: {[4-((1Z) -2- {4-[(dipropylamino) -methyl] -phenyl} -vinyl) -phenyl] -methyl}-(imidazol-2-ylmethyl)-[( Synthesis of 1-methylimidazol-2-yl) -methyl] -amine [Compound No. 40]

Example 40-1: Synthesis of 4-((1Z) -2- {4-[(1,3-dioxo [c] azolin-2-yl) -methyl] -phenyl} -vinyl) -benzaldehyde Example 39 The compound obtained in -3, 0.76 g, p-bromobenzaldehyde 0.69 g, tri-o-tolylphosphine 103 mg, and palladium acetate 39 mg were suspended in xylene 15 ml and triethylamine 15 ml and stirred at 130 ° C. for 63 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure.
Distilled water was added to the resulting residue, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / dichloromethane) to give the title compound 25 mg
Was obtained as a colorless oil.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 4.87 (2H, s), 5.55 (2H, m), 7.72-7.88 (8H, m), 7.25-7.48 (4H, m), 10.02 (1H, s) ).

Example 40-2: 2-{[4-((1Z) -2- {4-[(dipropylamino) -methyl] -phenyl} -vinyl) -phenyl] -methyl} -benzo [c] azoline- Synthesis of 1,3-dione 25 mg of the compound obtained in Example 40-1 was dissolved in 3.0 ml of 1,2-dichloroethane. To the reaction solution, 0.019 ml of n-dipropylamine and 36 mg of sodium triacetoxyborohydride were added and stirred at room temperature for 62 hours, then 0.019 ml of n-dipropylamine and 36 mg of sodium triacetoxyborohydride were added, and the mixture was stirred at 50 ° C. Then, 0.019 ml of n-dipropylamine and 36 mg of sodium triacetoxyborohydride were added, and the mixture was heated to reflux for 3 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. A 1 mol / l aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (27.0 mg) as a colorless oily substance.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.44-1.50 (4H, m), 2.36-2.39 (4H, m), 3.55 (2H, s), 4.86 (2H, s), 5,37 (1H, d, J = 1.2Hz), 5.44 (1H, d, J = 1.2Hz), 7.22-7.47 (6H, m), 7.70-7.74 (2H, m) , 7.84-7.87 (2H, m).

Example 40-3: {[4-((1Z) -2- {4-[(dipropylamino) -methyl] -phenyl} -vinyl) -phenyl] -methyl}-(imidazol-2-ylmethyl)- [(1-Methylimidazol-2-yl) -methyl]-
Synthesis of amine [Compound No. 40] 110 mg of the compound obtained in Example 40-2 was dissolved in 6.0 ml of methanol. To the reaction solution, 0.5 ml of hydrazine monohydrate was added and heated to reflux for 1 hour. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Distilled water was added to the resulting residue and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 3.0 ml of methanol, 16.4 mg of 2-imidazole carboxaldehyde and 28 μl of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 16.5 hours. After the reaction solution was cooled to 0 ° C., 9.7 mg of sodium borohydride was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, distilled water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 2.0 ml of methanol, 9.5 mg of 1-methyl-2-imidazolecarboxaldehyde and 14 μl of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 65 hours. After the reaction solution was cooled to 0 ° C., 4.1 mg of sodium borohydride was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, distilled water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (3.9 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 497 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3Hz), 1.49 (4H, tq, J = 7.3,7.6Hz), 2.39 (4H, t, J = 7.6Hz) , 3.50 (2H, s), 3.56 (3H, s), 3.59 (2H, s), 3.63 (2H, s), 3.71 (2H, s), 5.42 (1H, d, J = 1.2Hz), 5.44 ( 1H, d, J = 1.2Hz), 6.88-7.47 (12H, m).

Production Example 41: {[4-((1E) -2- {4- [2- (dipropylamino) -ethyl] -phenyl} -vinyl) -phenyl] -methyl}-(imidazol-2-ylmethyl)- [(1-Methylimidazol-2-yl) -methyl]-
Synthesis of amine [Compound No. 41]

Example 41-1: 2-{[4-((1E) -2- {4- [2- (dipropylamino) -ethyl] -phenyl} -vinyl) -phenyl] -methyl} -benzo [c] Synthesis of azoline-1,3-dione In a nitrogen atmosphere, 1.05 g of methoxymethyltriphenylphosphonium chloride was suspended in 25 ml of THF. After the reaction solution was cooled to 0 ° C., 1.52 ml of a 2 mol / l lithium diisopropylamide / heptane / THF / ethylbenzene solution was added and stirred at room temperature for 1.5 hours to adjust ylide. Under a nitrogen atmosphere, 400 mg of the compound obtained in Example 39-4 was suspended in 20 ml of THF. The reaction solution was 0 ° C
After cooling to 0, ylide was added and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (chloroform / ethyl acetate).
This was dissolved in 10 ml of 1,4-dioxane. To the reaction solution was added 3.0 ml of 1 mol / l hydrochloric acid, and the mixture was heated to reflux for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. A 1 mol / l aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 6.0 ml of 1,2-dichloroethane. To the reaction solution, 0.057 ml of n-dipropylamine and 106 mg of sodium triacetoxyborohydride were added and stirred at room temperature for 66 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform.
The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (chloroform / ethyl acetate).
To give 55 mg of the title compound as a white solid.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 0.82-0.94 (6H, m), 1.44-1.65 (4H, m), 2.48 (4H, t, J = 7.6 Hz), 4.85 (2H, s), 7.04 (2H, d, J = 3.9Hz), 7.16-7.49 (8H, m), 7.65-7.73 (2H, m), 7.84-7.86 (2H, m).

Example 41-2: {[4-((1E) -2- {4- [2- (dipropylamino) -ethyl] -phenyl} -vinyl) -phenyl] -methyl}-(imidazol-2-ylmethyl) Synthesis of)-[(1-methylimidazol-2-yl) -methyl] -amine [Compound No. 41] 113 mg of the compound obtained in Example 41-1 was dissolved in 5.0 ml of chloroform and 5.0 ml of methanol.
To the reaction solution, 0.5 ml of hydrazine monohydrate was added and heated to reflux for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Distilled water was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 5.0 ml of methanol, 41 mg of 2-imidazole carboxaldehyde and 0.065 ml of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 15.5 hours. After the reaction solution was cooled to 0 ° C., 22 mg of sodium borohydride was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate.
After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 37 ml of methanol and 9.5 mg of 1-methyl-2-imidazolecarboxaldehyde
Then, 0.051 ml of trimethyl orthoformate was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was cooled to 0 ° C., 18 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 65.4 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 511 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.92 (6H, t, J = 7.3 Hz), 1.71 (4H, sext., J = 7.3 Hz), 3.02-3.08 (6H, m), 3.20 -3.26 (2H, m), 3.64-3.72 (2H, m), 3.71 (3H, s), 4.09 (2H, s), 4.16 (2H, s), 7.21 (2H, s), 7.32 (2H, d , J = 8.2Hz), 7.40 (2H, d, J = 8.2Hz), 7.49 (2H, d, J = 8.4Hz), 7.52-7.56 (4H, m), 7.65 (2H, s), 10.45 (1H , br).

Production Example 42: {[4-((1E) -2- {4-[(dipropylamino) -methyl] -phenyl} -vinyl) -phenyl] -methyl} -bis- (imidazol-2-ylmethyl)- Synthesis of amine [Compound No. 42]

Example 42-1: {[4-((1E) -2- {4-[(dipropylamino) -methyl] -phenyl} -vinyl) -phenyl] -methyl} -bis- (imidazol-2-ylmethyl) Synthesis of) -amine [Compound No. 42] 311 mg of the compound obtained in Example 39-4 was dissolved in 5.0 ml of chloroform and 5.0 ml of methanol.
To the reaction solution, 0.5 ml of hydrazine monohydrate was added and heated to reflux for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Distilled water was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 8.0 ml of methanol. After cooling the reaction solution to 0 ° C., 128 mg of 2-imidazolecarboxaldehyde, 0.146 ml of trimethyl orthoformate and 107 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 38 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 50 mg of the title compound as a yellowish white solid.
MS (FAB, Pos.): M / z = 483 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.87 (6H, t, J = 7.3 Hz), 1.72 (4H, br), 2.93 (4H, br), 4.13 (2H, s), 4.30 ( 4H, br), 4.48 (2H, br), 7.28 (1H, d, J = 7.3Hz), 7.38 (1H, s), 7.43 (1H, d, J = 8.1Hz), 7.50 (1H, d, J = 8.2Hz), 7.59-7.71 (10H, m).

Production Example 43: [4- (6-{[(1H-imidazol-2-yl-methyl)-(1-methyl-imidazol-2-yl-methyl) -amino] -methyl} -benzothiazol-2-yl ) -Benzyl] -dipropyl-amine [Compound No. 43]

Example 43-1: Synthesis of N- (4-cyano-phenyl) -4-methyl-benzamide
4-Aminobenzonitrile (1.10 g) was dissolved in chloroform (30 ml). The reaction solution was cooled to 0 ° C., and 1.70 g of 4-dimethylaminopyridine and 1.95 g of p-toluic acid chloride were added. The reaction solution was returned to room temperature and stirred overnight. Distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate), then purified by recrystallization (hexane / ethanol), and 1.26 g of the title compound was obtained as a white solid. Got as.
MS (FAB, Pos.): M / z = 237 [M + H] ⁺

Example 43-2: Synthesis of N- (4-cyano-phenyl) -4-methyl-thiobenzamide 1.26 g of the compound obtained in Example 43-1 was dissolved in 20 ml of toluene, and 1.29 g of Lawesson's reagent was added. Heated to reflux for 2 hours. The reaction solution was cooled to room temperature, and the precipitated solid was filtered off. The obtained solid was recrystallized (methanol) to obtain 1.09 g of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 253 [M + H] ⁺

Example 43-3: Synthesis of 2-p-toluyl-benzothiazole-6-carbonitrile 5.78 g of potassium ferricyanide was dissolved in 40 ml of distilled water and heated to 90 ° C. A suspension of 1.09 g of the compound obtained in Example 43-2, 1.0 ml of ethanol and 3.2 ml of 30% aqueous sodium hydroxide solution was added to 5 suspensions.
It was added dropwise to the reaction solution over a period of minutes. After stirring at 90 ° C. for 3 hours, the mixture was cooled to room temperature. The precipitated solid was separated by filtration and purified by recrystallization (methanol) to obtain 0.53 g of the title compound as a white solid.
MS (FAB, Pos.): M / z = 251 [M + H] ⁺

Example 43-4: Synthesis of 2- (4-dipropyl-amino-methyl-phenyl) -benzothiazole-6-carbonitrile 0.53 g of the compound obtained in Example 43-3, 0.43 g of N-bromosuccinimide Weighed and added 15 ml of carbon tetrachloride. To the reaction solution, 13.2 mg of 2,2′-azobisisobutyronitrile was added and heated under reflux for 1.5 hours. The reaction solution was cooled to room temperature and then filtered through celite. The filtrate was concentrated under reduced pressure.
This was dissolved in dichloromethane (18 ml), 4-dimethylaminopyridine (0.55 g) and n-dipropylamine (0.5 ml) were added, and the mixture was stirred at room temperature for 2 hours. Distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 110.2 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 350 [M + H] ⁺

Example 43-5: Synthesis of [4- (6-amino-methyl-benzothiazol-2-yl) -benzyl] -dipropyl-amine 99.8 mg of the compound obtained in Example 43-4 was added to 1.0 ml of chloroform Dissolved in 10 ml.
To the reaction solution, 7.3 mg of platinum oxide was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (52.5 mg) as a pale yellow solid.
MS (FAB, Pos.): M / z = 354 [M + H] ⁺

Example 43-6: [4- (6-{[(1H-imidazol-2-yl-methyl) (1-methyl-imidazol-2-ylmethyl) -amino] -methyl} -benzothiazol-2-yl) Synthesis of -benzyl] -dipropyl-amine [Compound No. 43] 52.5 mg of the compound obtained in Example 43-5 was dissolved in 1.0 ml of methanol. To the reaction solution, 15.2 mg of 2-imidazole carboxaldehyde and 40 μl of trimethyl orthoformate were added and stirred at room temperature for 2 hours. Next, 15.3 mg of sodium borohydride was added and stirred at room temperature for 40 minutes. To the reaction solution, 2.0 ml of a saturated aqueous ammonium chloride solution was added and stirred at room temperature for 30 minutes. After extraction with chloroform, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure.
This was dissolved in 1.5 ml of methanol, and 37.0 mg of 1-methyl-2-imidazolecarboxaldehyde and 47.4 mg of sodium cyanoborohydride were added. Acetic acid was added to the reaction solution to adjust the pH to 5, followed by stirring at room temperature for 20 hours. A 1 mol / l aqueous sodium hydroxide solution was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 44.8 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 528 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.87 (6H, t, J = 7.3 Hz), 1.75 (4H, br), 2.96 (4H, br), 3.72 (3H, s), 3.86 ( 2H, s), 4.14 (2H, s), 4.21 (2H, s), 4.40 (2H, br), 7.51 (2H, s), 7.57 (1H, d, J = 8.3Hz), 7.63 (2H, s ), 7.83 (2H, d, J = 8.4Hz), 7.95 (1H, d, J = 8.3Hz), 8.16 (2H, d, J = 8.4Hz), 8.30 (1H, s).

Production Example 44: (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl- (4-piperidine-1 -Ilbutyl) amine [Compound No. 44]

Example 44-1: Synthesis of 4-[(4,4-diethoxybutylamino) methyl] -benzonitrile
4-Formylbenzonitrile (612.0 mg) was dissolved in methanol (18.4 ml), 4,4-diethoxybutylamine (752.5 mg) and trimethyl orthoformate (1.53 ml) were added, and the mixture was stirred at room temperature for 18 hours. Subsequently, 529.7 mg of sodium borohydride was added under ice cooling, and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was directly concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (1.16 g) as a yellow oily substance.
MS (FAB, Pos.): M / z = 277 [M + H] ⁺

Example 44-2: Synthesis of 4-{[(4,4-diethoxybutyl) methylamino] methyl} benzonitrile 1.16 g of the compound obtained in Example 44-1 was dissolved in 34.8 ml of methanol, and cyanohydrogen was added. 1.21 g of sodium borohydride and 0.648 ml of 36% formaldehyde aqueous solution were added, adjusted to pH = 4 with acetic acid, and stirred at room temperature for 18 hours. The reaction solution was directly concentrated under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.22 g of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 291 [M + H] ⁺

Example 44-3: Synthesis of 4-{[methyl- (4-oxobutyl) -amino] -methyl} -benzonitrile 1.22 g of the compound obtained in Example 44-2 was dissolved in 12.2 ml of THF, and 1 mol / l 12.2 ml of hydrochloric acid was added and stirred at room temperature for 19 hours. The reaction solution was directly concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (0.790 g) as a yellow oily substance.
MS (FAB, Pos.): M / z = 217 [M + H] ⁺

Example 44-4: Synthesis of 4- {methyl- (4-piperidin-1-ylbutyl) -amino] -methyl} -benzonitrile 0.790 g of the compound obtained in Example 44-3 was dissolved in 23.7 ml of methanol. , Piperidine (0.542 ml), sodium cyanoborohydride (459.3 mg), and adjusted to pH = 4 with acetic acid, and stirred at room temperature for 5 days. The reaction solution was directly concentrated under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 0.905 g of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 286 [M + H] ⁺

Example 44-5: Synthesis of (4-aminomethylbenzyl) -methyl- (4-piperidin-1-ylbutyl) -amine 360.8 mg of lithium aluminum hydride was suspended in 27 ml of THF and obtained in Example 44-4 A solution obtained by dissolving 904.6 mg of the compound in 27 ml of THF was slowly added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate, methanol, and 10% aqueous sodium potassium tartrate solution were added to the reaction mixture, and the mixture was stirred for 1 day. The mixture was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (247.5 mg) as a yellow oily substance.

Example 44-6: Synthesis of (4-{[(1H-imidazol-2-ylmethyl) -amino] -methyl) -benzyl} -methyl- (4-piperidin-1-ylbutyl) -amine Example 44-5 248.5 mg of the compound obtained in 1 above was dissolved in 12.4 ml of methanol, 123.7 mg of 2-imidazolecarboxaldehyde and 0.282 ml of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 2.5 hours. Subsequently, 97.4 mg of sodium borohydride was added under ice cooling, and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was directly concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (116.3 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 370 [M + H] +

Example 44-7: (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl- (4-piperidine Synthesis of 1-ylbutyl) amine [Compound No. 44] 116.3 mg of the compound obtained in Example 44-6 was dissolved in 5.81 ml of methanol, 52.0 mg of 1-methyl-2-imidazolecarboxaldehyde, cyanoborohydride 39.6 mg of sodium was added, the pH was adjusted to 4 with acetic acid, and the mixture was stirred at room temperature for 6 days. The reaction solution was directly concentrated under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l aqueous sodium hydroxide solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 163.4 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 464 [M + H] ^+
1 H-NMR (500 Mz, DMSO-d ₆ + D ₂ O): δ = 1.69-1.81 (10H, m), 2.58 (3H, m), 2.82-3.17 (6H, m), 3.71 (3H, s) , 3.74 (2H, s), 4.11 (2H, s), 4.19 (2H, s), 4.31 (2H, s), 7.41 (2H, d, J = 8.1Hz), 7.47 (2H, d, J = 8.1 Hz), 7.50 (2H, s), 7.62 (2H, s).

Production Example 45: 2- (2- (4-Dipropylamino-butyl) -6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino]- Synthesis of methyl} -benzimidazol-1-yl) -ethanol [Compound No. 45]

Example 45-1: Synthesis of 1-iodo-2-methoxymethoxy-ethane
0.637 g of 2-iodoethanol was dissolved in 5.0 ml of dimethoxymethane. To the reaction solution, 82 mg of p-toluenesulfonic acid monohydrate and 42 mg of lithium bromide were added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, distilled water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure to obtain the title compound (0.547 g) as a brown oil.
MS (FAB, Pos.): M / z = 217 [M + H] ⁺

Example 45-2: Synthesis of 3,4-diamino-benzonitrile
3-Nitro-4-amino-benzonitrile (4.38 g) was dissolved in ethanol (600 ml), stannous chloride dihydrate (34.6 g) was added thereto, and the mixture was heated to 60 ° C. To this was added 366 mg of sodium borohydride little by little, and the mixture was stirred at 60 ° C. overnight. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was recrystallized (
Hexane / ethyl acetate) gave 2.56 g of the title compound as brown crystals.
MS (EI): m / z = 133 [M] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 6.68 (1H, d, J = 8.1 Hz), 6.95 (1H, s), 7.05 (1H, d, J = 8.1 Hz).

Example 45-3: Synthesis of [4- (2 amino-5-cyano-phenylcarbamoyl) -butyl] -carbamic acid t-butyl ester
3.91 g of t-butoxycarbonylaminovaleric acid, 4.02 g of WSCI hydrochloride, and 2.82 g of HOBt were dissolved in chloroform 60 ml / DMF 30 ml and stirred for 1 hour. To this, 2.32 g of the compound obtained in Example 39-2 was added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4.06 g of the title compound as a white solid.
MS (FAB, Pos.): M / z = 333 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 1.34-1.46 (2H, m), 1.38 (9H, s), 1.56 (2H, quint., J = 7.3 Hz), 2.33 (2H, t, J = 7.3Hz), 2.93 (2H, dt, J = 6.1,6.8Hz), 5.93 (2H, br), 6.76 (1H, d, J = 8.4Hz), 6.83 (1H, t, J = 5.4Hz) , 7.28 (1H, d, J = 8.4Hz), 7.61 (1H, s), 9.10 (1H, s).

Example 45-4: Synthesis of 2- (4-dipropylamino-butyl) -3- (2-hydroxy-ethyl) -3H-benzimidazole-5-carbonitrile Compound 175.1 obtained in Example 45-3 mg was dissolved in 4.0 ml DMF. The reaction solution was cooled to 0 ° C., 45.2 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 40 minutes, then 179.9 mg of the compound obtained in Example 45-1 was added, and the mixture was stirred at room temperature for 2 hours. . Distilled water was added to the reaction solution and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 3.0 ml of methanol. 4ml / l hydrogen chloride / dioxane solution 2.0ml in reaction solution
And stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 1.5 ml of methanol. Add 76 μl of trimethyl orthoformate to the reaction solution and add 0
After cooling to ° C., a solution of propionaldehyde 40.1 mg in 1.0 ml of methanol was added dropwise and stirred at room temperature for 20 minutes. Next, 43.7 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 14.5 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (41.8 mg) as a purple solid.
MS (FAB, Pos.): M / z = 343 [M + H] ⁺

Example 45-5: 2- (2- (4-dipropylamino-butyl) -6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino Synthesis of] -methyl} -benzimidazol-1-yl) -ethanol [Compound No. 45] 41.8 mg of the compound obtained in Example 45-4 was dissolved in 1.5 ml of ethanol. 1mol / l in reaction solution
Add 0.3 ml of sodium hydroxide aqueous solution and 4.3 mg of Raney nickel and add 17 at room temperature under hydrogen atmosphere.
Stir for hours. Celite filtered. Distilled water was added and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 1.2 ml of methanol. To the reaction solution were added 2-imidazole carboxaldehyde (11.0 mg) and trimethyl orthoformate (30 μl), and the mixture was stirred at room temperature for 1.5 hours. After the reaction solution was cooled to 0 ° C., 2.7 mg of sodium borohydride was added and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 1.0 ml of methanol. 14.8 mg of 1-methyl-2-imidazolecarboxaldehyde and 15.4 mg of sodium cyanoborohydride were added to the reaction solution, adjusted to pH = 5 with acetic acid, and stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 32.4 mg of the hydrochloride of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 522 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.91 (6H, t, J = 7.3 Hz), 1.65-1.73 (4H, m), 1.83 (2H, m), 1.93 (2H, m), 2.99 (4H, br), 3.11 (2H, br), 3.29 (2H, br), 3.73 (3H, s), 3.88 (2H, s), 4.12 (2H, s), 4.20 (2H, s), 4.66 (2H, br), 7.53-7.55 (3H, m), 7.64 (2H, s), 7.70 (1H, d, J = 8.2Hz), 8.33 (1H, d, J = 8.2Hz), 10.27 (1H, br).

Production Example 46: [3- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazole Synthesis of 2-yl) -propyl] -dipropyl-amine [Compound No. 46]

Example 46-1 Synthesis of 3,4-diaminobenzonitrile
To a solution of 3.00 g of 4-amino-3-nitrobenzonitrile in 300 ml of ethanol was added 20.7 g of tin (II) chloride dihydrate, followed by 348 mg of sodium borohydride. After stirring overnight at 60 ° C., the solvent was distilled off to about 100 ml, and 100 ml of water was added to precipitate a large amount of solid.
42 ml of 5 mol / l sodium hydroxide aqueous solution was added to adjust to pH 7, the solvent was distilled off, the solid was filtered off through Celite, and washed successively with methanol and ethyl acetate. The filtrate was filtered again through Celite, and only the organic solvent was distilled off under reduced pressure. Got as.

Example 46-2: Synthesis of [3- (2-Amino-5-cyano-phenylcarbamoyl) -propyl] -carbamic acid t-butyl ester
To a solution of 4- (t-butoxycarbonylamino) butyric acid 1.53 g in DMF 30 ml, HOBt 1.07 g and WSCI hydrochloride 1.51 g were added and stirred for 0.5 hour, and this reaction solution was mixed with 1.00 g of the compound obtained in Example 46-1. The solution was added dropwise to 12 ml of DMF. After stirring at room temperature for 12 hours, the solvent was distilled off, dissolved in chloroform, washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a residue. Purification by chromatography (ethyl acetate / chloroform) gave 1.57 g of the title compound as a milky white solid.
MS (FAB, Pos.): M / z = 319 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.38 (9H, s), 1.68 (2H, quint., J = 7.1 Hz), 2.32 (2H, t, J = 7.6 Hz), 2.97 (2H, q , J = 6.6Hz), 5.95 (2H, s), 6.75 (1H, d, J = 8.5Hz), 6.86 (1H, t, J = 5.6Hz), 7.28 (1H, dd, J = 2.2,8.5Hz ), 7.59 (1H, d, J = 1.7Hz), 9.08 (1H, s).

Example 46-3: Synthesis of {3-[(2-amino-5-cyano-phenyl) -propyl-carbamoyl] -propyl} -carbamic acid t-butyl ester 0.501 g of the compound obtained in Example 46-2 60% sodium hydride (76.0 mg) was added to a DMF 4.0 ml solution, and the mixture was stirred at room temperature for 30 minutes. Evaporate the solvent, dissolve in chloroform, wash with saturated aqueous sodium bicarbonate, dry over anhydrous magnesium sulfate, and evaporate the residue to purify the residue by silica gel column chromatography (ethyl acetate / chloroform). This gave 0.378 g of the title compound as colorless crystals.
MS (FAB, Pos.): M / z = 343 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.99 (3H, t, J = 7.3Hz), 1.42 (9H, s), 1.85 (2H, sext., J = 7.3Hz), 2.14 (2H, quint ., J = 7.3Hz), 2.95 (2H, t, J = 7.3Hz), 3.30 (2H, q, J = 6.3Hz), 4.10 (2H, t, J = 7.3Hz), 4.86 (1H, br) 7.50 (1H, dd, J = 1.5,8.3Hz), 7.64 (1H, dd, J = 0.7,1.5Hz), 7.75 (1H, dd, J = 0.5,8.3Hz).

Example 46-4: Synthesis of 2- (3-aminopropyl) -3-propyl-3H-benzo [d] imidazole-5-carbonitrile 0.375 g of the compound obtained in Example 46-3 was added to 4.0 ml of ethyl acetate. Dissolved in. 1.09 ml of 4 mol / l hydrogen chloride / dioxane solution was added and stirred for 20 minutes, 8.0 ml of methanol was added and the solvent was distilled off.
Chloroform was added to the concentrate, washed with a 1 mol / l aqueous sodium hydroxide solution, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 0.314 g of a crude product containing the title compound as an amber liquid.

Example 46-5: Synthesis of 2- (3- (dipropylamino) propyl) -3-propyl-3H-benzo [d] imidazole-5-carbonitrile Crude compound obtained in Example 46-4 Acetic acid (100 μl) was added to 0.314 g of methanol (8.0 ml), sodium cyanoborohydride (0.275 g) was added, and propionaldehyde (0.237 ml) was slowly added dropwise. After stirring at room temperature for 13 hours, the solvent was distilled off, ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain a residue. Purification by chromatography (methanol / chloroform) gave 0.365 g of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 327 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.92 (6H, t, J = 7.3 Hz), 1.00 (3H, t, J = 7.3 Hz), 1.54 (4H, sext., J = 7.6 Hz), 1.86 (2H, sext., J = 7.3Hz), 2.17 (2H, quint., J = 6.3Hz), 2.58 (4H, br), 2.79 (2H, br), 3.01 (2H, t, J = 7.3Hz) ), 4.13 (2H, t, J = 7.3Hz), 7.50 (1H, dd, J = 1.5, 8.3Hz), 7.65 (1H, dd, J = 0.7, 1.5Hz), 7.73 (1H, dd, J = 0.7,8.3Hz).

Example 46-6: Synthesis of 3- [6- (aminomethyl) -1-propyl-1H-benzo [d] imidazol-2-yl] -N, N-dipropylpropan-1-amine Example 46- 3.6 ml of 1 mol / l sodium hydroxide aqueous solution was added to a solution of 0.363 g of the compound obtained in 5 in 12 ml of ethanol, 120 mg of Raney nickel was added, and the mixture was stirred for 6 hours in a hydrogen atmosphere. The catalyst is removed by Celite filtration, and after distilling off the solvent, it is partitioned between chloroform and water, separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent is subjected to silica gel column chromatography. Purification by chromatography (chloroform) gave 0.244 g of the title compound as a colorless liquid.
MS (FAB, Pos.): M / z = 331 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 0.99 (3H, t, J = 7.6 Hz), 1.44 (4H, sext., J = 7.3 Hz), 1.60 (2H, br), 1.84 (2H, sext., J = 7.6Hz), 2.04 (2H, quint., J = 7.8Hz), 2.39 (4H, t, J = 7.8Hz), 2.56 (2H, t , J = 6.8Hz), 2.88 (2H, t, J = 7.6Hz), 4.00 (2H, s), 4.08 (2H, t, J = 7.3Hz), 7.15 (1H, dd, J = 1.7,8.3Hz ), 7.28 (1H, d, J = 1.0Hz), 7.66 (1H, d, J = 8.3Hz).

Example 46-7: 3- (6-{[(1H-imidazol-2-yl) methylamino] methyl} -1-propyl-1H-benzo [d] imidazol-2-yl) -N, N-di Synthesis of Propylpropan-1-amine 0.244 g of the compound obtained in Example 46-6 and 2-imidazole carboxaldehyde 85.0 mg in anhydrous methanol 4.0 ml was added trimethyl orthoformate 0.242 ml and stirred at room temperature for 14 hours. Next, 0.140 g of sodium borohydride was added and stirred for 2 hours, and then the solvent was distilled off. Dissolve in chloroform, wash with saturated aqueous sodium bicarbonate, dry over anhydrous magnesium sulfate, and evaporate the residue to purify the residue by silica gel column chromatography (chloroform / methanol) to give 0.167 g of the title compound. Was obtained as a colorless oil.
MS (FAB, Pos.): M / z = 411 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3 Hz), 0.98 (3H, t, J = 7.6 Hz), 1.45 (4H, sext., J = 7.6 Hz), 1.6-2.0 (1H, br), 1.83 (2H, sext., J = 6.6Hz), 2.04 (2H, quint., J = 7.6Hz), 2.40 (4H, t, J = 7.3Hz), 2.57 (2H , t, J = 7.1Hz), 2.88 (2H, t, J = 7.6Hz), 3.93 (2H, s), 3.97 (2H, s), 4.07 (2H, t, J = 7.6Hz), 6.99 (2H , s), 7.17 (1H, d, J = 8.3Hz), 7.23 (1H, s), 7.65 (1H, d, J = 8.3Hz).

Example 46-8: [3- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-
Ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -propyl]-
Synthesis of dipropyl-amine [Compound No. 46] 10 drops of acetic acid was added to a solution of 0.166 g of the compound obtained in Example 46-7 and 53.0 mg of 1-methyl-2-imidazolecarboxaldehyde in 3.0 ml of anhydrous methanol, and cyanohydrogen was added. 76.0 mg of sodium borohydride was added and stirred for 21 hours. The reaction solution is distilled off, dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent is purified by silica gel column chromatography (chloroform). Gave 86.0 mg of the title compound as a pale yellow oil. This was treated with hydrochloric acid to obtain 87.0 mg of the hydrochloride of the title compound as a colorless solid.
MS (FAB, Pos.): M / z = 505 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3 Hz), 0.97 (3H, t, J = 7.3 Hz), 1.44 (4H, sext., J = 7.6 Hz), 1.81 (2H, sext., J = 7.6Hz), 2.03 (2H, quint., J = 7.6Hz), 2.38 (4H, t, J = 7.6Hz), 2.56 (2H, t, J = 6.8Hz), 2.88 (2H, t, J = 7.6Hz), 3.43 (2H, s), 3.50 (3H, s), 3.69 (2H, s), 3.82 (2H, s), 4.06 (2H, t, J = 7.3Hz ), 6.86 (1H, d, J = 1.5Hz), 7.00 (1H, d, J = 1.2Hz), 7.10 (1H, s), 7.15 (1H, s), 7.28 (1H, s), 7.33 (1H , d, J = 8.3Hz), 7.67 (1H, d, J = 8.1Hz), 12.4 (1H, br).

Production Example 47: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-isopropyl-1H-benzimidazole -2-yl) -butyl]-
Synthesis of dipropyl-amine [Compound No. 47]

Example 47-1 Synthesis of {4-[(2-amino-5-cyano-phenyl) -isopropyl-carbamoyl] -butyl} -carbamic acid t-butyl ester 242 mg of the compound obtained in Example 45-3 Dissolved in 5.0 ml of DMF, 29.1 mg of 60% sodium hydride and then 79.6 μl of 2-iodopropane in an ice bath were added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, distilled water was added and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 44.1 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 375 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.00 (3H, d, J = 6.6 Hz), 1.21 (3H, d, J = 6.6 Hz), 1.43 (9H, s), 1.53-1.65 (4H, m), 1.88-2.01 (2H, m), 3.00-3.07 (2H, m), 4.45 (2H, brs), 4.58 (1H, brs), 4.90 (1H, sept., J = 6.6Hz), 6.80 ( 1H, d, J = 8.3Hz), 7.23 (1H, d, J = 2.0Hz), 7.45 (1H, dd, J = 2.0,8.3Hz).

Example 47-2: Synthesis of 2- (4-amino-butyl) -3-isopropyl-3H-benzimidazole-5-carbonitrile 44.1 mg of the compound obtained in Example 47-1 was dissolved in 1.0 ml of anhydrous methanol. Then, 1.0 ml of 4 mol / l hydrogen chloride / dioxane solution was added and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off. To this was added a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 26.0 mg of the title compound as white crystals.
MS (FAB, Pos.): M / z = 257 [M + H] ⁺

Example 47-3: Synthesis of 2- (4-dipropylamino-butyl) -3-isopropyl-3H-benzimidazole-5-carbonitrile 26.0 mg of the compound obtained in Example 47-2 was added to 1.0 ml of anhydrous methanol. Then, 19.1 mg of sodium cyanoborohydride, 27.7 μl of trimethyl orthoformate and 18.3 μl of propionaldehyde were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 34.0 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 341 [M + H] ⁺

Example 47-4: Synthesis of [4- (6-Aminomethyl-1-isopropyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine 34.0 mg of the compound obtained in Example 47-3 Dissolved in 2.0 ml of ethanol, 340 μl of 1 mol / l sodium hydroxide aqueous solution and 4.0 mg of Raney nickel were added and stirred overnight at room temperature in a hydrogen atmosphere. After completion of the reaction, the mixture was filtered through Celite, the solvent was distilled off, this was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 31.3 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 345 [M + H] ⁺

Example 47-5: N- [4-({[(1H-imidazol-2-yl) methyl] amino} methyl) benzyl] -N- (1-cyanoethyl) -N ′, N′-dipropylbutane- Synthesis of 1,4-diamine 31.3 mg of the compound obtained in Example 47-4 was dissolved in 1.0 ml of anhydrous methanol. Stir. Next, 3.40 mg of sodium borohydride was added in an ice bath and stirred at room temperature for 2 hours.
After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 41.7 mg of the title compound as a colorless solid.
MS (FAB, Pos.): M / z = 425 [M + H] ⁺

Example 47-6: [4- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole-2-
Synthesis of (Ilmethyl) -amino] -methyl} -1-isopropyl-1H-benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 47] 41.7 mg of the compound obtained in Example 47-5 The product was dissolved in anhydrous methanol (1.0 ml), sodium cyanoborohydride (9.30 mg), acetic acid (100 μl) and 1-methyl-2-imidazolecarboxaldehyde (11.9 mg) were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform. A 1 mol / l sodium hydroxide aqueous solution was added and stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 26.4 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 519 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.43-1.45 (4H, m), 1.63 (6H, d, J = 6.8 Hz), 1.62-1.65 ( 2H, m), 1.80-1.87 (2H, m), 2.36 (4H, br), 2.48 (2H, br), 2.90 (3H, t, J = 7.8Hz), 3.43 (2H, s), 3.51 (3H , s), 3.70 (2H, s), 3.82 (2H, s), 4.67 (1H, sept., J = 6.8Hz), 6.86 (1H, d, J = 1.2Hz), 7.00 (1H, d, J = 1.2Hz), 7.13 (2H, d, J = 22.2Hz), 7.31 (1H, dd, J = 1.5,8.3Hz), 7.48 (1H, s), 7.66 (1H, dd, J = 3.9,8.3Hz ), 12.4 (1H, br).

Production Example 48: [5- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazole -2-yl) -pentyl] -dipropyl-amine [Compound No. 48]

Example 48-1: Synthesis of [5- (2-amino-5-cyano-phenylcarbamoyl) -pentyl] -carbamic acid benzyl ester 510 mg of the compound obtained in Example 46-1 was dissolved in 20 ml of DMF and prepared beforehand. 1.10 g of 6-benzyloxycarbonylamino-hexanoic acid previously prepared was dissolved in 10 ml of DMF, 1.08 g of WSCI hydrochloride and 762 mg of HOBt were added, and a solution stirred for 30 minutes was added dropwise and stirred for 20 hours. The residue obtained by evaporating the solvent was extracted with chloroform, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol) to obtain 961 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 381 [M + H] ^+
1 H-NMR (500 MHz, DMSO): δ = 1.30 (2H, m), 1.43 (2H, tt, J = 7.1,7.3 Hz), 1.58 (2H, m), 2.32 (2H, t, J = 7.4 Hz) ), 2.99 (2H, dt, J = 6.3,6.8Hz), 5.00 (2H, s), 5.93 (2H, s), 6.75 (1H, d, J = 8.3Hz), 7.26-7.38 (6H, m) , 7.62 (1H, d, J = 2.0Hz), 9.08 (1H, s).

Example 48-2: Synthesis of {5-[(2-amino-5-cyano-phenyl) -propyl-carbamoyl] -pentyl} -carbamic acid benzyl ester 961 mg of the compound obtained in Example 48-1 was added to 20 ml of DMF. After dissolving, this was cooled to 0 ° C., 72.9 mg of 60% sodium hydride was added, and the mixture was returned to room temperature and stirred for 30 minutes. To this solution, 0.30 ml of 1-iodopropane was added dropwise and further stirred for 3 hours. This was cooled to 0 ° C., water was added to stop the reaction, and the mixture was concentrated. The residue was extracted with chloroform, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (317 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 423 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.90 (3H, t, J = 7.3 Hz), 1.22-1.27 (2H, m), 1.40-1.46 (2H, m), 1.49-1.63 (2H, m ), 1.89-1.94 (1H, m), 2.01-2.07 (1H, m), 3.10-3.17 (3H, m), 3.86-3.92 (1H, m), 4.40 (2H, s), 4.79 (1H, s ), 5.08 (2H, d, J = 1.5Hz), 6.76 (1H, d, J = 8.5Hz), 7.25 (1H, d, J = 1.7Hz), 7.30-7.38 (5H, m), 7.41 (1H , dd, J = 1.7,8.5Hz).

Example 48-3: Synthesis of [5- (6-cyano-1-propyl-1H-benzimidazol-2-yl) -pentyl] -carbamic acid benzyl ester 317 mg of the compound obtained in Example 48-2 was dissolved in methanol. After dissolving in 5.0 ml, 2.0 ml of 4 mol / l hydrogen chloride / dioxane solution was added and stirred for 16 hours. The residue obtained by distilling off the solvent was dissolved in methanol and neutralized with an anion exchange resin (Amberlite IRA-410). The resin was filtered off and the solvent was distilled off to obtain 291 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 405 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.99 (3H, t, J = 7.3 Hz), 1.48-1.54 (2H, m), 1.58-1.62 (2H, m), 1.84 (2H, tq, J = 7.3,7.6Hz), 1.95 (2H, tt, J = 7.3,7.6Hz), 2.89 (2H, t, J = 7.6Hz), 3.27 (2H, d, J = 7.6H
z), 4.09 (2H, t, J = 7.4Hz), 5.09 (2H, s), 5.15 (1H, s), 7.32-7.50 (5H, m), 7.62 (1H, t, J = 0.7Hz), 7.72 (1H, d, J = 8.3Hz).

Example 48-4: Synthesis of 2- (5-amino-pentyl) -3-propyl-3H-benzimidazole-5-carbonitrile 107 mg of the compound obtained in Example 48-3 was dissolved in 10 ml of ethanol, and palladium was added. Carbon 20mg
And stirred for 20 hours under hydrogen atmosphere. After filtration through celite, the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 25.6 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 271 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.00 (3H, t, J = 7.4 Hz), 1.48-1.58 (4H, m), 1.82-1.89 (2H, m), 1.93-1.99 (2H, m ), 2.73 (2H, t, J = 6.7Hz), 2.90 (2H, t, J = 7.8Hz), 4.10 (2H, t, J = 7.4Hz), 7.49 (1H, dd, J = 1.7, 8.3Hz) ), 7.64 (1H, dd, J = 0.7,1.5Hz), 7.76 (1H, dd, J = 0.5,8.3Hz).

Example 48-5: 2- (5-dipropylamino-pentyl) -3-propyl-3H-benzimidazole-5-
Synthesis of carbonitrile 26.4 mg of the compound obtained in Example 48-4 was dissolved in 2.0 ml of methanol, and 15.8 mg of sodium cyanoborohydride was added. After adjusting the pH to 4 with acetic acid, 0.020 ml of propionaldehyde was added and stirred at room temperature for 20 hours. After the solvent was distilled off, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 29.4 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 355 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.4 Hz), 1.00 (3H, t, J = 7.3 Hz), 1.40-1.49 (6H, m), 1.51-1.56 ( 2H, m), 1.81-1.88 (2H, m), 1.91-1.97 (2H, m), 2.36 (4H, t, J = 7.7Hz), 2.41-2.44 (2H, m), 2.89 (2H, t, J = 7.9Hz), 4.10 (2H, t, J = 7.4Hz), 7.48 (1H, dd, J = 1.7,8.3Hz), 7.63 (1H, dd, J = 1.5Hz), 7.76 (1H, dd, (J = 0.5, 8.3Hz).

Example 48-6: [5- (6-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -pentyl] -dipropyl-amine Synthesis of 29.8 mg of the compound obtained in Example 48-5 was dissolved in 20 ml of ethanol, and 4.0 ml of 1 mol / l aqueous sodium hydroxide solution was added. Raney nickel in ethanol suspension was added thereto and stirred for 6 hours under hydrogen atmosphere. After filtration through Celite, the solvent was distilled off and extracted with chloroform.
The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off.
This was dissolved in 2.0 ml of methanol, 13.4 mg of 2-imidazole carboxaldehyde and 0.030 ml of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 3 hours. After cooling this to 0 ° C,
Sodium borohydride (10.5 mg) was added, and the mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to stop the reaction, and then the solvent was distilled off and extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (26.0 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 439 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (3H, t, J = 7.4 Hz), 1.01 (6H, t, J = 7.1 Hz), 1.40-1.49 (4H, m), 1.50-1.56 ( 4H, m), 1.78-1.86 (2H, m), 1.89-1.95 (2H, m), 2.25-2.38 (2H, m), 2.42 (2H, t, J = 7.4Hz), 2.52 (2H, q, J = 7.1Hz), 2.85 (2H, t, J = 7.8Hz), 3.92 (2H, s), 3.96 (2H, s), 4.04 (2H, t, J = 7.4Hz), 6.99 (2H, s) , 7.15 (1H, d, J = 8.3Hz), 7.22 (1H, s), 7.64 (1H, d, J = 8.1Hz).

Example 48-7: [5- (6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-
Ylmethyl) -amino] -methyl} -1-propyl-1H-benzimidazol-2-yl) -pentyl]-
Synthesis of dipropyl-amine [Compound No. 48] 8.8 mg of the compound obtained in Example 48-6 was dissolved in 2.0 ml of methanol, 2.6 mg of 1-methyl-2-imidazolecarboxaldehyde, 2.5 mg of sodium cyanoborohydride Was adjusted to pH 4 with acetic acid and stirred at room temperature for 18 hours. After the solvent was distilled off, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 9.3 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 533 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.90 (6H, t, J = 7.3 Hz), 0.99 (3H, t, J = 7.3 Hz), 1.41-1.44 (2H, m), 1.65-1.70 ( 4H, m), 1.76-1.80 (4H, m), 1.90 (2H, m), 2.96-3.06 (6H, m), 3.22 (2H, m), 3.73 (3H, s), 3.89 (2H, s) , 4.12 (2H, s), 4.19 (2H, s), 4.53 (2H, s), 7.53 (1H, s), 7.55 (2H, s), 7.64 (2H, s), 7.69 (1H, d, J = 8.4Hz), 8.41 (1H, s), 14.99 (1H, br).

Production Example 49: N- (4-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzyl) -N- Synthesis of methyl-N ', N'-dipropyl-butane-1,4-diamine [Compound No. 49]

Example 49-1: N- (4-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzyl)- Synthesis of N-methyl-N ′, N′-dipropyl-butane-1,4-diamine [Compound No. 49] 203.5 mg of the compound obtained in Example 9-2 was dissolved in 8.1 ml of anhydrous methanol. 117.7 mg of 6,7-dihydro-5H-quinolin-8-one synthesized by the method and 99.9 mg of sodium cyanoborohydride were added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 2 days. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 69.5 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 517 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.63-1.76 (6H, m), 1.78-1.84 (4H, m), 1.92 -1.98 (4H, m), 2.57 (3H, s), 2.98-3.07 (10H, m), 3.83 (2H, s), 4.10-4.16 (2H, m), 4.29-4.31 (2H, m), 4.50 (1H, m), 7.41 (2H, d, J = 7.8Hz), 7.49 (2H.s), 7.55 (2H, t, J = 7.0Hz) 8.39 (2H, d, J = 1.4Hz), 8.83 ( (1H, d, J = 5.6Hz).

Production Example 50: N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -Amino] -methyl} -benzyl) -methanesulfonamide [Compound No. 50]

Example 50-1: Synthesis of (4-{[(4-Dipropylamino-butyl) -methanesulfonyl-amino] -methyl} -benzyl) -carbamic acid t-butyl ester Obtained in Example 23-4 198.3 mg of compound was dissolved in 4.0 ml of anhydrous dichloromethane, 0.142 ml of triethylamine and 0.060 ml of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 1 hour. After the reaction, it was washed with water. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 192.0 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 469 [M + H] ⁺

Example 50-2: Synthesis of N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methanesulfonamide 192 mg of the compound obtained in Example 50-1 was dissolved in 2.0 ml of methanol, 2.0 ml of 4 mol / l hydrogen chloride / dioxane solution was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in anhydrous methanol 7.0 ml, 2-imidazole carboxaldehyde 59.6 mg,
0.135 ml of trimethyl orthoformate was added and stirred at room temperature for 14.5 hours. Thereto was added 46.5 mg of sodium borohydride, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (154 mg) as a colorless oil.
MS (FAB, Pos.): M / z = 450 [M + H] ⁺

Example 50-3: N- (4-dipropylamino-butyl) -N- (4-{[(1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinoline-8- Synthesis of yl) -amino] -methyl} -benzyl) -methanesulfonamide [Compound No. 50] 154 mg of the compound obtained in Example 50-2 was dissolved in 6.2 ml of anhydrous methanol and synthesized by a known method. , 7-dihydro-5H-quinolin-8-one 75.1 mg and sodium cyanoborohydride 64.1 mg were added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 2 days. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. Dried over magnesium sulfate,
The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 69 mg of the hydrochloride of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 581 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.87 (6H, t, J = 7.3 Hz), 1.40-1.52 (4H, m), 1.59-1.66 (4H, m), 2.10-2.15 (4H , m), 2.87-2.90 (6H, m), 2.96 (3H, s), 3.05-3.08 (4H, m), 4.11 (2H, d, J = 15.5Hz), 4.24 (2H, s), 4.29- 4.43 (1H, m), 4.92 (2H, brs), 7.21 (2H, d, J = 7.8Hz), 7.56 (2H, s), 7.90 (1H, t, J = 6.1Hz), 8.20 (2H, d , J = 7.6Hz), 8.36 (1H, t, J = 6.3Hz), 8.86 (1H, d, J = 5.3Hz).

Production Example 51: 3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl } -Benzyl) -amino] -propionic acid [Compound No. 51]

Example 51-1: 3-[(4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -methyl} -benzyl) -amino] -propionic acid [Compound No. 51] 129 mg of the compound obtained in Example 34-3 was dissolved in 1.0 ml of anhydrous methanol, 10.0 ml of concentrated hydrochloric acid was added, and the mixture was heated to reflux. After completion of the reaction, the solvent was distilled off to obtain 71.4 mg of hydrochloride of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 538 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.5 Hz), 1.63-1.69 (6H, m), 1.79 (2H, br), 2.85-3.08 (10H, m), 3.16-3.22 (2H, m), 3.64 (2H, s), 3.75 (3H, s), 4.11 (2H, s), 4.19 (2H, s), 4.27-4.37 (2H, m ), 7.31 (2H, d, J = 8.1Hz), 7.46-7.51 (3H, m), 7.60 (2H, s), 7.56-7.63 (1H, m).

Production Example 52: (4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl ) -Cyanamide [Compound No. 52]

Example 52-1: Synthesis of (4-cyano-benzyl)-(4-dipropylamino-butyl) -carbamic acid t-butyl ester 236 mg of the compound obtained in Example 1-2 was dissolved in 4.0 ml of methanol. Then, 380 μl of trimethyl orthoformate and 159 mg of 4-cyanobenzaldehyde were added at room temperature, and the mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere, and then 103 mg of sodium borohydride was added under ice cooling, followed by stirring at room temperature for 30 minutes.
After completion of the reaction, water was added, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, water was added, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 384 mg of a yellow oil. Of this, 293 mg was dissolved in 6.0 ml of chloroform, 334 mg of di-t-butyl dicarbonate was added, and the mixture was stirred at room temperature for 10 hours in a nitrogen atmosphere. After completion of the reaction, 3.0 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the aqueous layer was extracted with chloroform.
The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (331 mg) as a yellow oil. .
MS (FAB, Pos.): M / z = 388 [M + H] ⁺

Example 52-2: (4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-
Synthesis of methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -carbamic acid t-butyl ester 331 mg of the compound obtained in Example 52-1 was dissolved in 13 ml of ethanol, and 1 mol / l water An aqueous sodium oxide solution (3.0 ml) and an ethanol suspension of Raney nickel were added, and the mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. After completion of the reaction, the mixture was filtered through celite, and the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 283 mg of a colorless oil.
This was dissolved in 6.0 ml of methanol, and 240 μl of trimethyl orthoformate and 83.7 mg of 2-imidazole carboxaldehyde were added at room temperature. After stirring for 15 hours at room temperature under a nitrogen atmosphere, 59.0 mg of sodium borohydride was added under ice cooling. And stirred at room temperature for 30 minutes. After completion of the reaction, water was added, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, water was added, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off.
This was dissolved in 7.0 ml of ethanol, 117 mg of 1-methyl-2-imidazolecarboxaldehyde and 326 mg of sodium triacetoxyborohydride were added, and the mixture was stirred for 17 hours under a nitrogen atmosphere at room temperature. After completion of the reaction, the mixture was poured into 20 ml of a saturated aqueous sodium hydrogen carbonate solution, the solvent was distilled off, the residue was dissolved in chloroform, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (360 mg) as a yellow oil.
MS (FAB, Pos.): M / z = 566 [M + H] ⁺

Example 52-3: N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ′, N Synthesis of '-dipropyl-butane-1,4-diamine 360 mg of the compound obtained in Example 52-2 was dissolved in 3.6 ml of methanol, 3.6 ml of 4 mol / l hydrogen chloride / dioxane solution was added, and room temperature under nitrogen atmosphere Stir for 13 hours. After the reaction, the solvent was distilled off.
A 1 mol / l aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 306 mg of the title compound as a pale yellow oil. .
MS (FAB, Pos.): M / z = 465 [M + H] ⁺

Example 52-4: (4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-
[Compound No. 52] Synthesis of Methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -cyanamide 13.4 mg of the compound obtained in Example 52-3 was dissolved in 0.26 ml of THF, and triethylamine was dissolved. 10 μl and 3.65 mg of bromocyan were added and stirred for 2 hours under a nitrogen atmosphere at room temperature. After completion of the reaction, the mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol) and treated with tartaric acid to give the tartrate salt of the title compound. 12.5 mg was obtained as a white solid.
MS (FAB, Pos.): M / z = 491 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.4 Hz), 1.39-1.50 (6H, m), 1.67 (2H, quint., J = 7.5 Hz), 2.30-2.34 (4H, m), 2.39 (2H, t, J = 7.3Hz), 2.96 (2H, t, J = 7.3Hz), 3.48 (2H, s), 3.58 (3H, s), 3.60 (2H, s) , 3.69 (2H, s), 4.17 (2H, s), 6.89 (1H, d, J = 1.2Hz), 7.00 (1H, d, J = 1.2Hz), 7.08 (1H, brs), 7.13 (1H, brs), 7.31 (2H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1Hz), 12.37 (1H, brs).

Production Example 53: (4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl ) -Formamide [Compound No. 53]

Example 53-1: (4-Dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-
Synthesis of methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -formamide [Compound No. 53] 82.9 mg of the compound obtained in Example 52-3 was dissolved in 1.0 ml of ethanol, and formic acid was added. 50 μl and formamide 50 μl were added and stirred at an external temperature of 100 ° C. for 3 hours. 60 μl of formic acid was added and stirred for 15 hours. After the reaction, the solvent was distilled off. The residue was dissolved in chloroform, and 1 mol / l aqueous sodium hydroxide solution was added to adjust the pH to 11. The aqueous layer was extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (
Purification with chloroform / methanol) and treatment with hydrochloric acid gave 27.0 mg of the hydrochloride of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 494 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.85 (6H, t, J = 7.2 Hz), 1.23-1.56 (6H, m), 2.29-2.37 (6H, m), 3.14 (2H, t , J = 7.0Hz), 3.23 (2H, t, J = 7.3Hz), 3.46 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 3.59 (2H, s), 3.60 (3H , s), 3.67 (2H, s), 3.68 (2H, s), 4.38 (2H, s), 4.53 (2H, s), 6.88 (1H, d, J = 1.2Hz), 6.89 (1H, d, J = 1.4Hz), 7.00 (1H, d, J = 1.2Hz), 7.01 (2H, d, J = 1.2Hz), 7.08 (1H, s), 7.13 (1H, s), 7.18 (1H, d, J = 8.3Hz), 7.22 (1H, d, J = 8.0Hz), 7.37 (1H, d, J = 8.0Hz), 7.43 (1H, d, J = 8.3Hz), 8.20 (1H, s), 8.28 (1H, s), 12.38 (1H, brs).

Production Example 54: [(4-{[(1-carboxymethyl-1H-imidazol-2-ylmethyl)-(1-methyl-1H-
Synthesis of Imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) amino] -acetic acid [Compound No. 54]

Example 54-1: [(4-Dipropylamino-butyl)-(4-{[(1-methoxycarbonylmethyl-1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) Synthesis of) -amino] -methyl} -benzyl) -amino] -acetic acid methyl ester 81.9 mg of the compound obtained in Example 52-3 was dissolved in 2.0 ml of THF, and 76.0 μl of triethylamine and 46.0 μl of methyl bromoacetate were added. The mixture was stirred for 11 hours at room temperature under a nitrogen atmosphere. After completion of the reaction, methanol was added, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 23.7 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 610 [M + H] ⁺

Example 54-2: [(4-{[(1-carboxymethyl-1H-imidazol-2-ylmethyl)-(1-methyl-1H
Synthesis of -Imidazol-2-ylmethyl) -amino] -methyl} -benzyl)-(4-dipropylamino-butyl) amino] -acetic acid [Compound No. 54] 23.7 mg of the compound obtained in Example 54-1 Was dissolved in 1.0 ml of 1,4-dioxane, 1.0 ml of concentrated hydrochloric acid was added, and the mixture was heated to reflux for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 17.2 mg of hydrochloride of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 582 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.66-1.80 (8H, m), 2.94-3.17 (8H, m), 3.38-3.83 (5H , m), 3.90 (2H, brs), 4.13 (2H, brs), 4.17 (2H, brs), 4.35 (2H, brs), 5.16 (2H, brs), 7.44 (2H, d, J = 8.3Hz) , 7.47 (2H, d, J = 8.0Hz), 7.52 (1H, s), 7.55 (1H, s), 7.65 (1H, s), 7.66 (1H, s).

Production Example 55: [4- (1-Benzyl-6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1H-benzimidazole Synthesis of -2-yl) -butyl] -dipropyl-amine [Compound No. 55]

Example 55-1: Synthesis of 3-benzyl-2- (4-t-butoxycarbonylamino-butyl) -3H-benzimidazole-5-carboxylic acid methyl ester 965.3 mg of the compound obtained in Example 2-1 Dissolved in 20 ml of DMF. The reaction solution was cooled to 0 ° C., 221.8 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour, and then 0.35 ml of benzyl bromide.
And stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, distilled water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (0.469 g) as a white solid.
MS (FAB, Pos.): M / z = 438 [M + H] ⁺

Example 55-2: Synthesis of 3-benzyl-2- (4-dipropylamino-butyl) -3H-benzimidazole-5-carboxylic acid methyl ester 0.469 g of the compound obtained in Example 55-1 was added to 5.0 ml of methanol. Dissolved in. To the reaction solution was added 3.0 ml of 4 mol / l hydrogen chloride / dioxane solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure,
A 1 mol / l aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 8.0 ml of methanol. After adding 0.25 ml of trimethyl orthoformate to the reaction solution and cooling to 0 ° C., a solution of 134.4 mg of propionaldehyde dissolved in 1.0 ml of methanol was added dropwise and stirred at room temperature for 25 minutes. Subsequently, 214 mg of sodium cyanoborohydride was added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (267 mg) as a yellow oil.
MS (FAB, Pos.): M / z = 422 [M + H] ⁺

Example 55-3: Synthesis of 3-benzyl-2- (4-dipropylamino-butyl) -3H-benzimidazole-5-carbaldehyde 267 mg of the compound obtained in Example 55-2 was dissolved in 5.0 ml of THF. . The reaction solution was cooled to 0 ° C., 38.5 mg of lithium aluminum hydride was added, and the mixture was stirred at room temperature for 40 minutes, and then cooled again to 0 ° C. To the reaction solution were added 1.0 ml of acetone and 2.0 ml of ethyl acetate, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous sodium potassium tartrate solution was added, and the mixture was vigorously stirred at room temperature for 19 hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 5.0 ml of chloroform. 1.14 g of manganese dioxide was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure to obtain 25.5 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 392 [M + H] ⁺

Example 55-4: [4- (1-Benzyl-6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -1H- Synthesis of Benzimidazol-2-yl) -butyl] -dipropyl-amine [Compound No. 55] The compound 225 mg obtained in Example 55-3 was dissolved in methanol 4.0 ml. 64.5 mg of the compound obtained in Example 14-7 and 0.13 ml of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was cooled to 0 ° C., 20.8 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, distilled water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure.
This was dissolved in 6.0 ml of methanol. To the reaction solution, 83.3 mg of 2-imidazolecarboxaldehyde and 77.3 mg of sodium cyanoborohydride were added, adjusted to pH = 5 by adding acetic acid, and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) and treated with hydrochloric acid to obtain 174.3 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 567 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.64-1.86 (8H, m), 2.95 (4H, br), 3.05 (2H, br), 3.28 (2H, br), 3.67 (3H, s), 3.83 (2H, s), 4.10 (2H, s), 4.17 (2H, s), 5.94 (2H, s), 7.31-7.39 (5H, m) , 7.49-7.54 (3H, m), 7.60 (2H, s), 7.72 (1H, d, J = 8.4Hz), 8.17 (1H, s), 10.43 (1H, br), 14.94 (2H, br).

Production Example 56: 3-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of [-Benzyl) -amino] -propionic acid ethyl ester [Compound No. 56]

Example 56-1: 3-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -Methyl] -benzyl) -amino] -propionic acid ethyl ester [Compound No. 56] 135.4 mg of the compound obtained in Example 51-1 was suspended in 13.5 ml of ethanol and heated to reflux for 16 hours. After the reaction, the solvent was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying with magnesium sulfate, the solvent was distilled off to obtain 127.0 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 566 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.23 (3H, t, J = 7.3 Hz), 1.39-1.44 (8H, m), 2.18-2.37 ( 6H, m), 2.41-2.46 (4H, m), 2.78 (2H, t, J = 7.1Hz), 3.46 (2H, s), 3.55 (5H, s), 3.62 (2H, s), 3.67 (2H , s), 4.10 (2H, q, J = 7.3Hz), 6.87 (1H, d, J = 1.2Hz), 6.99 (1H, d, J = 1.2Hz), 7.10 (2H, d, J = 21.0Hz) ), 7.26 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.1Hz), 12.34 (1H, br).

Production Example 57: 3-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of [-Benzyl) -amino] -propionic acid isopropyl ester [Compound No. 57]

Example 57-1: 3-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -Methyl] -benzyl) -amino] -propionic acid isopropyl ester [Compound No. 57] 10 ml of 2-propanol was added to 88.0 mg of the hydrochloride of the compound obtained in Example 51-1, and the mixture was heated to reflux for 2 hours. . After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 32.8 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 580 [M + H] ⁺

Production Example 58: 3-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl ] -Benzyl) -amino] -propionic acid 1- (cyclohexyloxycarbonyloxy) -ethyl ester [Compound No. 62]

Example 58-1: 3-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -methyl] -benzyl) -amino] -propionic acid 1- (cyclohexyloxycarbonyloxy) -ethyl ester [Compound No. 62] 352.4 mg of the compound obtained in Example 51-1, 420.2 mg of potassium carbonate, iodine 41.5 mg of potassium halide and 7.0 ml of anhydrous DMF were suspended. Thereto, 3.5 ml of a DMF solution containing 152.9 mg of carboxylic acid 1-chloro-ethyl ester cyclohexyl ester was added. Stir at 60 ° C. for 15 hours. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate). The title compound (199.6 mg) was obtained as a colorless oil.
MS (FAB, Pos.): M / z = 566 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.22-1.43 (15H, m), 1.48 (3H, d, J = 5.4 Hz), 1.53-1.54 ( 1H, m), 1.73 (2H, m), 1.91 (2H, m), 2.18-2.34 (6H, m), 2.42 (2H, t, J = 6.8Hz), 2.48 (2H, t, J = 7.6Hz ), 2.79 (2H, t, J = 7.8Hz), 3.46 (2H, s), 3.55 (5H, s), 3.62 (2H, s), 3.67 (2H, s), 4.59-4.64 (1H, m) , 6.75 (1H, q, J = 5.4Hz), 6.87 (1H, d, J = 1.2Hz), 6.99 (1H, d, J = 1.2Hz), 7.10 (2H, d, J = 20.8Hz), 7.26 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.1Hz), 12.34 (1H, br).

Production Example 59 2,2-Dimethyl-propionic acid 3-[(4-dipropylamino-butyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole-2 -Ilmethyl) -amino] -methyl}-
Synthesis of [Benzyl] -amino] -propionyloxymethyl ester [Compound No. 65]

Example 59-1: 2,2-Dimethyl-propionic acid 3-[(4-dipropylamino-butyl)-(4-{[(1H-
Synthesis of Imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl] -amino] -propionyloxymethyl ester [Compound No. 65] Example 51-1 217.5 mg of the compound obtained by the above, potassium carbonate 257.1 mg, potassium iodide 24.9 mg, and anhydrous DMF 4.3 ml were suspended. Thereto was added 0.7 ml of a DMF solution containing 67.8 mg of 2,2-dimethyl-propionic acid 1-chloro-ethyl ester. Stir at 60 ° C. for 15 hours. After the reaction, the solvent was distilled off.
Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate). The title compound (13.8 mg) was obtained as a colorless oil.
MS (FAB, Pos.): M / z = 652 [M + H] ⁺

Production Example 60: 3-[(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid [compound No.72] synthesis

Example 60-1: 3-[(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid Synthesis of [Compound No. 72] 550 mg of the compound obtained in Example 34-1 was dissolved in 10 ml of anhydrous methanol, 239 μl of trimethyl orthoformate and 154 mg of 2-imidazolecarboxaldehyde were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. Next, 55.2 mg of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. 738 mg of this residue was dissolved in 15 ml of anhydrous methanol, 152 mg of sodium cyanoborohydride, 1.50 ml of acetic acid and 170 mg of 2-imidazolecarboxaldehyde were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent is distilled off,
It melt | dissolved in chloroform, saturated sodium hydrogencarbonate aqueous solution was added, and it stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate). To the obtained compound (232 mg) was added concentrated hydrochloric acid (20.0 ml), and the mixture was heated to reflux. After completion of the reaction, the solvent was distilled off to obtain 262 mg of hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.62-1.78 (8H, m), 2.85-2.86 (2H, m), 2.97 -3.08 (8H, m), 3.17 (2H, t, J = 7.6Hz), 3.73 (2H, s), 4.17 (4H, s), 4.27-4.30 (2H, m), 7.45 (2H, t, J = 8.4Hz), 7.50 (2H, t, J = 8.2Hz), 7.56 (4H, s).

Production Example 61: (1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-[2- (4-piperidin-1-yl-butyl) -3-propyl-3H-benz Synthesis of imidazol-5-ylmethyl] -amine [Compound No. 80]

Example 61-1: Synthesis of 5-piperidin-1-yl-pentanoic acid
1.22 g of 5-bromopentanoic acid methyl ester was dissolved in 24.4 ml of acetonitrile, 1.30 g of potassium carbonate, 0.104 g of potassium iodide and 0.928 ml of piperidine were added, and the mixture was stirred at 70 ° C. for 2.5 hours. Water was added to the reaction solution, followed by separation / extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was again dissolved in 20 ml of 18% hydrochloric acid and heated to reflux for 3 hours. The reaction solution was directly concentrated under reduced pressure and recrystallized from acetone / acetic acid to obtain 1.15 g of the hydrochloride of the title compound as colorless crystals.
MS (FAB, Pos.): M / z = 186 [M + H] ⁺

Example 61-2: Synthesis of 5-piperidin-1-yl-pentanoic acid (2-amino-5-cyano-phenyl) -amide 0.461 g of commercially available 3,4-diaminobenzonitrile was dissolved in 18.4 ml DMF, WSCI hydrochloride 0.996g
0.702 g of HOBt and 0.844 g of the compound obtained in Example 60-1 were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was directly concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.04 g of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 301 [M + H] ⁺

Example 61-3: Synthesis of 2- (4-piperidin-1-yl-butyl) -3-propyl-3H-benzimidazole-5-carbonitrile 1.04 g of the compound obtained in Example 61-2 was added to DMF31. The mixture was dissolved in 2 ml, and 0.166 g of 60% sodium hydride and 0.405 ml of 1-iodopropane were added with stirring under ice cooling, and the mixture was warmed to room temperature and stirred for 15 hours. The reaction solution was poured into ice water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved again in 10 ml of 4 mol / l hydrogen chloride / dioxane solution and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain 451.8 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 325 [M + H] ⁺

Example 61-4: Synthesis of (1H-imidazol-2-ylmethyl)-[2- (4-piperidin-1-yl-butyl) -3-propyl-3H-benzimidazol-5-ylmethyl] -amine 451.8 mg of the compound obtained in 61-3 was dissolved in 18.1 ml of ethanol, 4.52 ml of 1 mol / l sodium hydroxide aqueous solution and Raney nickel were added, and the mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere. The reaction solution was filtered using celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved again in 22.1 ml of methanol, 194.0 mg of 2-imidazole carboxaldehyde and 0.442 ml of trimethyl orthoformate were added, and the mixture was stirred at room temperature for 1.5 hours. Subsequently, 152.8 mg of sodium borohydride was added under ice cooling, and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was directly concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (429.5 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 409 [M + H] ⁺

Example 61-5: (1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-[2- (4-piperidin-1-yl-butyl) -3-propyl-3H Synthesis of -benzimidazol-5-ylmethyl] -amine [Compound No. 80] 429.5 mg of the compound obtained in Example 61-4 was dissolved in 21.5 ml of methanol, 173.6 mg of 1-methyl-2-imidazole carboxaldehyde, Sodium cyanoborohydride (132.1 mg) was added, the pH was adjusted to 4 with acetic acid, and the mixture was stirred at room temperature for 4 days. The reaction solution was directly concentrated under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l aqueous sodium hydroxide solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and treated with hydrochloric acid to obtain 559.2 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 503 [M + H] ^+
1 H-NMR (500 Mz, DMSO-d ₆ + D ₂ O): δ = 0.98 (3H, t, J = 7.3 Hz), 1.69-1.92 (12H, m), 2.84-2.88 (2H, m), 3.08 -3.11 (2H, m), 3.23-3.26 (2H, m), 3.41-3.46 (2H, m), 3.72 (3H, s), 3.91 (2H, s), 4.11 (2H, s), 4.20 (2H , s), 4.48 (2H, t, J = 7.5Hz), 7.50 (2H, s), 7.56 (1H, d, J = 8.5Hz), 7.61 (2H, s), 7.71 (1H, d, J = 8.5Hz), 8.23 (1H, s).

Production Example 62: 3-[(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-piperidine- Synthesis of 1-yl-butyl) -amino] -propionic acid [Compound No. 81]

Example 62-1: Synthesis of (4-[[(2-Cyano-ethyl)-(4-piperidin-1-yl-butyl) -amino] -methyl] -benzyl) -carbamic acid t-butyl ester 1.04 g of the compound obtained by 23-3 was dissolved in 40 ml of anhydrous methanol. There 4,4-
863 mg of diethoxy-butylamine and 1.44 ml of trimethyl orthoformate were added. Stir at room temperature for 3 hours. Thereto, 499 mg of sodium borohydride was added and stirred at room temperature for 30 minutes. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate).
This was dissolved in 25 ml of methanol and 4.8 ml of water. Acrylonitrile 0.43ml was added there. Stir at room temperature for 16.5 hours. After the reaction, the solvent was distilled off and extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 12 ml of THF, 12 ml of acetone and 12 ml of 1 mol / l hydrochloric acid, and stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform.
Dried over magnesium sulfate. The solvent was distilled off.
This was dissolved in 26 ml of anhydrous methanol. Thereto were added 0.49 ml of piperidine and 415 mg of sodium cyanoborohydride. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 3 days. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1.13 g of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 429 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.27-1.50 (6H, m), 1.47 (9H, s), 1.55-1.60 (4H, m), 2.25 (2H, t, J = 7.3Hz), 2.34 (4H, br), 2.40 (2H, t, J = 7.0Hz), 2.49 (2H, t, J = 6.9Hz), 2.77 (2H, t, J = 7.0Hz), 3.59 (2H, s), 4.31 (2H, d, J = 5.5Hz), 7.23 (2H, d, J = 7.9Hz), 7.29 (2H, d, J = 8.2Hz).

Example 62-2: 3-[(4-[[(1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-piperidin-1-yl-butyl) -amino] -propionic acid Synthesis of methyl ester 1.12 g of the compound obtained in Example 62-1 was dissolved in 11.2 ml of methanol. 6.7 ml of 4 mol / l hydrogen chloride / dioxane solution was added and stirred at room temperature for 2 hours. Further, 18 ml of 10% hydrogen chloride / methanol solution was added and stirred at 60 ° C. overnight. After the reaction, the solvent was distilled off. The pH was adjusted to 8 with a 1 mol / l aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogen carbonate solution. Extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off.
This was dissolved in 24.5 ml of anhydrous methanol. Thereto, 245 mg of 2-imidazole carboxaldehyde and 0.56 ml of trimethyl orthoformate were added and stirred at room temperature for 20 hours. Thereto was added 193 mg of sodium borohydride, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (403 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 442 [M + H] ⁺

Example 62-3: 3-[(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-
Synthesis of methyl methyl ylmethyl) -amino] -methyl] -benzyl)-(4-piperidin-1-yl-butyl) -amino] -propionic acid Dissolve 403 mg of the compound obtained in Example 62-2 in 16 ml of anhydrous methanol did. Thereto were added 151 mg of 1-methyl-2-imidazolecarboxaldehyde and 172 mg of sodium cyanoborohydride. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 18 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate). This gave 333 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 536 [M + H] ⁺

Example 62-4: 3-[(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-
Synthesis of (Ilmethyl) -amino] -methyl] -benzyl)-(4-piperidin-1-yl-butyl) -amino] -propionic acid [Compound No. 81] 333 mg of the compound obtained in Example 62-3 was dissolved in water. The mixture was dissolved in 0.5 ml and 6.0 ml of concentrated hydrochloric acid and heated to reflux for 2 hours. After the reaction, the solvent was distilled off. 336 mg of the hydrochloride salt of the title compound was obtained as a white solid.
MS (FAB, Pos.): M / z = 522 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 1.71-1.80 (10H, m), 2.80-2.99 (8H, m), 3.14 (2H, m), 3.37 (2H, d, J = 12.4Hz ), 3.71 (3H, s), 3.73 (2H, s), 4.11 (2H, s), 4.19 (2H, s), 4.26 (2H, s), 7.45 (2H, d, J = 8.2Hz), 7.51 -7.54 (4H, m), 7.63 (2H, s).

Production Example 63: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetonitrile [Compound No. 82]

Example 63-1: Synthesis of (4-[[Cyanomethyl- (4-dipropylamino-butyl) -amino] -methyl] -benzyl) -carbamic acid t-butyl ester Compound obtained in Example 23-4 522 mg was dissolved in 10 ml of DMF, 372 μl of triethylamine and 139 μl of bromoacetonitrile were added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (469 mg) as a colorless oil.
MS (FAB, Pos.): M / z = 431 [M + H] ⁺

Example 63-2: Synthesis of [4- (aminomethyl-benzyl)-(4-dipropylamino-butyl) -amino] -acetonitrile 147 mg of the compound obtained in Example 63-1 was dissolved in 1.5 ml of anhydrous THF. Then, 3.0 mol of 4 mol / l hydrogen chloride / dioxane solution was added and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. To this was added a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 103 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 331 [M + H] ⁺

Example 63-3: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of] -benzyl) -amino] -acetonitrile [Compound No. 82] 103 mg of the compound obtained in Example 63-2 was dissolved in 2.0 ml of anhydrous methanol, 51.1 μl of trimethyl orthoformate, and 32.9 mg of 2-imidazole carboxaldehyde. And stirred overnight at room temperature under a nitrogen atmosphere. Next, 11.8 mg of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. 127 mg of this residue was dissolved in 3.0 ml of anhydrous methanol, 29.2 mg of sodium cyanoborohydride, 300 μl of acetic acid, and 37.5 mg of 1-methyl-2-imidazolecarboxaldehyde were added, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with tartaric acid to obtain 191 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 505 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.89 (6H, t, J = 7.5 Hz), 1.46-1.52 (2H, m), 1.56-1.64 (6H, m), 2.49 -2.52 (2H, m), 2.94-3.00 (6H, m), 3.51 (3H, s), 3.54 (2H, s), 3.58 (2H, s), 3.60 (2H, s), 3.61 (2H, s ), 3.62 (2H, s), 4.21 (6H, s), 6.85 (1H, d, J = 1.2Hz), 7.04 (2H, s), 7.10 (1H, d, J = 1.2Hz), 7.25 (2H , d, J = 7.9Hz), 7.34 (2H, d, J = 8.2Hz).

Production Example 64: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetic acid methyl ester [Compound No. 83]

Example 64-1 Synthesis of [(4-aminomethyl-benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid methyl ester 265 mg of the compound obtained in Example 63-1 was added to 2.5 ml of anhydrous methanol. 4mol / l hydrogen chloride /
5.00 ml of dioxane solution was added and stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off. To this was added a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 161 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 364 [M + H] ⁺

Example 64-2: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of] -benzyl) -amino] -acetic acid methyl ester [Compound No. 83] 161 mg of the compound obtained in Example 64-1 was dissolved in 3.0 ml of anhydrous methanol, 72.5 μl of trimethyl orthoformate, 2-imidazole carboxaldehyde 46.7 mg was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Next, 16.7 mg of sodium borohydride was added in an ice bath and stirred at room temperature for 2 hours.
After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. This residue (167 mg) was dissolved in anhydrous methanol (3.0 ml), sodium cyanoborohydride (35.4 mg), acetic acid (300 μl) and 1-methyl-2-imidazolecarboxaldehyde (45.5 mg) were added, and the mixture was stirred at room temperature for 3 days in a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 88.6 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 538 [M + H] ⁺

Production Example 65: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetic acid [Compound No. 84]

Example 65-1: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of [-benzyl) -amino] -acetic acid [Compound No. 84] 3.00 ml of concentrated hydrochloric acid was added to 30.8 mg of hydrochloride of the compound obtained in Example 64-2, and the mixture was heated to reflux. After completion of the reaction, the solvent was distilled off to obtain 30.5 mg of hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.62-1.70 (6H, m), 1.74-1.82 (2H, m), 2.97 -3.01 (4H, m), 3.06 (2H, t, J = 7.6Hz), 3.14 (2H, t, J = 7.6Hz), 3.72 (3H, s), 3.75 (2H, s), 3.96 (2H, s), 4.09 (2H, s), 4.17 (2H, s), 4.35 (2H, s), 7.43-7.49 (6H, m), 7.60 (2H, s).

Production Example 66: 3-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of [-Benzyl) -amino] -propionic acid 1-isopropoxycarbonyloxy-ethyl ester [Compound No. 85]

Example 66-1: 3-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -Methyl] -benzyl) -amino] -propionic acid 1-isopropoxycarbonyloxy-ethyl ester [Compound No. 85] Compound 217.0 mg, potassium carbonate 257.1 mg, potassium iodide obtained in Example 51-1 24.9 mg and anhydrous DMF 4.3 ml were suspended. Thereto was added 0.7 ml of a DMF solution containing 74.9 mg of carboxylic acid 1-chloro-ethyl ester isopropyl ester. Stir at 60 ° C. for 15 hours. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate). The title compound (13.8 mg) was obtained as a colorless oil.
MS (FAB, Pos.): M / z = 668 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.29 (6H, dd, J = 2.9, 6.1 Hz), 1.40-1.44 (8H, m), 1.48 ( 3H, d, J = 5.4Hz), 2.32-2.35 (6H, m), 2.42 (2H, t, J = 6.8Hz), 2.48 (2H, t, J = 7.6Hz), 2.79 (2H, t, J = 7.1Hz), 3.46 (2H, s), 3.55 (5H, s), 3.62 (2H, s), 3.67 (2H, s), 4.87 (1H, quint., J = 6.3Hz), 6.74 (1H, q, J = 5.4Hz), 6.87 (1H, d, J = 1.2Hz), 6.99 (1H, d, J = 1.2Hz), 7.10 (2H, d, J = 20.7Hz), 7.26 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.1Hz), 7.47 (1H, br).

Production Example 67: 3-[(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid methyl ester Synthesis of [Compound No. 86]

Example 67-1: 3-[(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -propionic acid Synthesis of methyl ester [Compound No. 86] 550 mg of the compound obtained in Example 34-1 was dissolved in 10 ml of anhydrous methanol, 239 μl of trimethyl orthoformate and 154 mg of 2-imidazole carboxaldehyde were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. . Next, 55.2 mg of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. 738 mg of this residue was dissolved in 15 ml of anhydrous methanol, 152 mg of sodium cyanoborohydride, 1.50 ml of acetic acid and 170 mg of 2-imidazolecarboxaldehyde were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent is distilled off,
It melt | dissolved in chloroform, saturated sodium hydrogencarbonate aqueous solution was added, and it stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 225 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 538 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.2 Hz), 1.64-1.79 (8H, m), 2.92-3.07 (10H, m), 3.21 (2H, t, J = 7.6Hz), 3.64 (3H, s), 3.72 (2H, s), 4.16 (2H, s), 4.27-4.31 (2H, m), 7.45 (2H, d, J = 8.4 Hz), 7.50 (2H, d, J = 8.2Hz), 7.57 (4H, s).

Production Example 68: [(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid methyl ester [Compound No. .87]

Example 68-1: [(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid methyl ester [ Synthesis of Compound No. 87] 1.4928 g of the compound obtained in Example 64-1 was dissolved in 59.6 ml of anhydrous methanol. Thereto were added 1.1848 g of 2-imidazole carboxaldehyde and 1.0331 g of sodium cyanoborohydride. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 3 days. After the reaction, a 1 mol / l sodium hydroxide aqueous solution was added, followed by extraction with chloroform. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate). Hydrochloric acid treatment gave 705.7 mg of the title compound hydrochloride as a white solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.64-1.70 (6H, m), 1.77 (2H, m), 2.97-3.00 (4H, m), 3.03-3.06 (2H, m), 3.15 (2H, t, J = 7.9Hz), 3.67 (3H, s), 3.72 (2H, s), 4.06 (2H, s), 4.15 ( 4H, s), 4.35 (2H, s), 7.45-7.49 (4H, m), 7.58 (4H, s).

Production Example 69: [(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid [Compound No. 88 Synthesis

Example 69-1: [(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid [Compound No. Synthesis of .88] 533.4 mg of the compound obtained in Example 68-1 was dissolved in 0.5 ml of water, 2.5 ml of concentrated hydrochloric acid was added thereto, and the mixture was heated to reflux for 30 minutes. After the reaction, the solvent was distilled off to obtain 384.1 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 510 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.62-1.68 (6H, m), 1.77 (2H, m), 2.97-3.00 (4H, m), 3.05 (2H, t, J = 7.9Hz), 3.12 (2H, t, J = 7.5Hz), 3.72 (2H, s), 3.96 (2H, s), 4.14 (4H, s) , 4.34 (2H, s), 7.44-7.49 (4H, m), 7.56 (4H, s).

Production Example 70: [(4-Dipropylamino-butyl)-([[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -Amino] -acetic acid benzyl ester [Compound No. 89]

Example 70-1: [(4-Dipropylamino-butyl)-([[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetic acid benzyl ester [Compound No. 89] 145.0 mg of the compound obtained in Example 65-1 was dissolved in 3.0 ml of benzyl alcohol, and WSCI hydrochloride 58.9 mg and HOBt 41.5 mg were added thereto. In addition, the mixture was stirred at room temperature for 18 hours. After completion of the reaction, 1 mol / l hydrochloric acid was added and excess benzyl alcohol was removed with chloroform. The mixture was made alkaline by adding a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate). .
MS (FAB, Pos.): M / z = 614 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.89 (6H, t, J = 7.3 Hz), 1.60-1.70 (8H, m), 2.80-3.00 (4H, m), 2.98-3.04 (8H , m), 3.20-3.50 (5H, m), 3.68 (4H, s), 4.07 (2H, s), 4.14 (2H, s), 5.17 (2H, br), 7.30-7.31 (3H, m), 7.32-7.46 (6H, m), 7.50-7.51 (2H, m), 7.62 (2H, s).

Production Example 71: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetic acid 2-morpholin-4-yl-ethyl ester [Compound No. 90]

Example 71-1: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of [-benzyl) -amino] -acetic acid 2-morpholin-4-yl-ethyl ester [Compound No. 90] 185.8 mg of the compound obtained in Example 65-1 was dissolved in a small amount of water, and 1 mol of chloroform and / l Aqueous sodium hydroxide was added, and the organic layer and oil were collected and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off. To a solution of the obtained sodium salt 143.6 mg and N- (2-hydroxyethyl) morpholine 38 mg in anhydrous DMF 2 ml were added HOBt 37 mg and WSCI hydrochloride 63 mg, and the mixture was stirred overnight. After evaporation of the solvent, the residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, the aqueous phase was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a reaction mixture that was subjected to silica gel column chromatography (chloroform). And dissolved in dioxane, and a salt was precipitated with a 4 mol / l hydrogen chloride / dioxane solution. After distilling off the solvent, the solid was pulverized and dried under reduced pressure to obtain 143.9 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 637 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.38-1.56 (8H, m), 2.28-2.38 (6H, m), 2.46-2.58 (6H, m ), 2.60-2.65 (2H, m), 3.31 (2H, s), 3.47 (2H, s), 3.57 (3H, s), 3.61 (2H, s), 3.67-3.69 (4H, m), 3.73 ( 2H, t, J = 4.9Hz), 3.76 (2H, s), 4.23 (2H, t, J = 5.6Hz), 6.88 (1H, d, J = 1.2Hz), 7.00 (1H, d, J = 1.2) Hz), 7.08 (1H, bs), 7.12 (1H, bs), 7.31 (2H, d, J = 8.1Hz), 7.35 (2H, d, J = 7.8Hz), 12.32 (1H, bs).

Production Example 72: [[4- (Dipropyl-amino) -butyl]-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl ] -Benzyl) -amino] -acetic acid ethyl ester [Compound No. 91]

Example 72-1: Synthesis of [[4- (t-butoxycarbonylamino-methyl) -benzyl]-(4-dipropylamino-butyl) -amino] -acetic acid ethyl ester obtained by Example 23-4 Compound 28.58 g was dissolved in anhydrous DMF 560 ml. 20.35 ml of triethylamine and 12.14 ml of ethyl bromoacetate were added. Stir at room temperature for 2 hours. After the reaction, the solvent was distilled off. Dissolved in ethyl acetate and washed with water. Dried over magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 21.265 g of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 478 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.40-1.50 (8H, m), 1.46 (9H, s), 2.32-2.39 (6H, m), 2.62 (2H, t, J = 7.6Hz), 3.28 (2H, s), 3.75 (2H, s), 4.12-4.17 (2H, m), 4.82 (1H , br), 7.22 (2H, d, J = 8.1Hz), 7.30 (2H, d, J = 8.1Hz).

Example 72-2: Synthesis of [(4-aminomethyl-benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid ethyl ester 21.265 g of the compound obtained in Example 72-1 was added to 100 ml of ethanol Dissolved. Thereto was added 140 ml of 4 mol / l hydrogen chloride / dioxane solution, and the mixture was stirred at room temperature for 1 hour. Subsequently, it stirred at 40 degreeC for 1 hour. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added to adjust the pH to 12, followed by chloroform extraction. Dried over magnesium sulfate. The solvent was distilled off to obtain 16.46 g of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 378 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.41-1.52 (8H, m), 2.33-2.40 ( 6H, m), 2.63 (2H, t, J = 7.3Hz), 3.29 (2H, s), 3.76 (2H, s), 3.85 (2H, s), 4.15 (2H, t, J = 7.2Hz), 7.25 (2H, d, J = 8.2Hz), 7.31 (2H, d, J = 8.1Hz).

Example 72-3: [[4- (dipropyl-amino) -butyl]-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -methyl] -benzyl) -amino] -acetic acid ethyl ester [Compound No. 91] 16.46 g of the compound obtained in Example 72-2 was dissolved in 320 ml of absolute ethanol, and 6.285 g of 2-imidazole carboxaldehyde was added thereto. Then, 21.76 ml of triethyl orthoformate was added and stirred at room temperature for 3 hours. After ice cooling, 4.948 g of sodium borohydride was added thereto and stirred at room temperature for 30 minutes. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 400 ml of absolute ethanol. Thereto were added 7.02 g of 1-methyl-2-imidazolecarboxaldehyde and 18.48 g of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for 5 hours. After the reaction, a saturated aqueous sodium hydrogen carbonate solution was added. The solvent was distilled off and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate).
16.165 g (107.7 mmol) of L-tartaric acid was dissolved in 162 ml of ethanol. Thereto was added dropwise 99 ml of an ethanol solution of the above compound 19.782 g. Stir at room temperature for 15 minutes. Decanted the supernatant. Washed with ethanol (40 ml). This was dried to obtain 30.8 g of the title compound tartrate salt as a white solid.
MS (FAB, Pos.): M / z = 552 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 1.07 (6H, t, J = 7.0 Hz), 1.18 (3H, t, J = 7.1 Hz), 1.46-1.48 (2H, m ), 1.57-1.62 (6H, m), 2.56 (2H, t, J = 7.2Hz), 2.93-3.00 (6H, m), 3.26 (2H, s), 3.50 (3H, s), 3.52 (2H, s), 3.58 (2H, s) .3.59 (2H, s), 3.66 (2H, s), 4.07 (2H, q, J = 7.2Hz), 4.20 (6H, s), 7.03 (1H, s), 7.09 (2H, s), 7.09 (1H, s), 7.24 (2H, d, J = 7.9Hz), 7.30 (2H, d, J = 8.1Hz).

Production Example 73: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetic acid 2-methoxy-ethyl ester [Compound No. 92]

Example 73-1: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of] -benzyl) -amino] -acetic acid 2-methoxy-ethyl ester [Compound No. 92] 190.7 mg of the compound obtained in Example 65-1 was dissolved in 4.0 ml of 2-methoxyethanol, Stir for hours. After the reaction, the solvent was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate). Hydrochloric acid treatment gave 37.9 mg of the hydrochloride salt of the title compound as a white solid.
MS (FAB, Pos.): M / z = 582 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.63-1.67 (6H, m), 1.70-1.80 (2H, m), 2.97 -3.01 (4H, m), 3.05-3.06 (4H, m), 3.54-3.56 (2H, m), 3.69 (3H, s), 3.71 (3H, s), 3.73 (2H, s), 3.90-4.00 (2H, m), 4.07 (2H, s), 4.15 (2H, s), 4.24-4.25 (4H, m), 7.41 (4H, s), 7.48 (2H, s), 7.60 (2H, s).

Production Example 74: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetic acid cinnamyl ester [Compound No. 93]

Example 74-1: [(4-dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of] -benzyl) -amino] -acetic acid cinnamyl ester [Compound No. 93] Dissolve 203 mg of the hydrochloride of the compound obtained in Example 65-1 in 3.0 ml of DMF, add 73.9 μl of cinnamyl alcohol and heat overnight. Refluxed. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 19.1 mg of the hydrochloride of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 640 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.91 (6H, t, J = 7.2 Hz), 1.61-1.73 (8H, m), 2.96-3.06 (8H, m), 3.66 (2H, s), 3.69 (3H, s), 3.75 (4H, s), 4.05 (2H, s), 4.13 (2H, s), 4.80 (2H, d, J = 6.3Hz), 6.36 (1H, td, J = 6.3,15.7Hz), 6.73 (1H, d, J = 15.7Hz), 7.20-7.51 (11H, m), 7.59 (2H, s).

Production Example 75: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetic acid 2- (2-hydroxy-ethoxy) -ethyl ester [Compound No. 94]

Example 75-1: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of [-benzyl) -amino] -acetic acid 2- (2-hydroxy-ethoxy) -ethyl ester [Compound No. 94] 424.0 mg of the compound obtained in Example 65-1 was dissolved in 8.0 ml of diethylene glycol, Stir for 3 days at ° C. After the reaction, chloroform was added and washed with water. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol). Hydrochloric acid treatment gave 280.2 mg of the title compound hydrochloride as a white solid.
MS (FAB, Pos.): M / z = 612 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.2 Hz), 1.63-1.69 (6H, m), 1.80 (2H, m), 2.98-3.01 (4H, m), 3.06 (2H, t, J = 8.2Hz), 3.17 (2H, t, J = 7.9Hz), 3.43-3.51 (4H, m), 3.65 (2H, t, J = 3.8Hz) , 3.73 (3H, s), 3.78 (2H, s), 4.06 (2H, s), 4.12 (2H, s), 4.20 (2H, s), 4.27 (2H, t, J = 4.0Hz), 4.37 ( 2H, s), 7.43-7.49 (6H, m), 7.60 (2H, s).

Production Example 76: (4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl ) -Carbamic acid t-butyl ester [Compound No. 95]

Example 76-1: Synthesis of 2- [4-[(4-dipropylaminobutylamino) methyl] benzyl] isoindole-1,3-dione 103 mg of the compound obtained in Example 1-1 was added to 10 ml of anhydrous methanol. 114 mg of the hydrochloride of the compound obtained in Example 1-2 was added. Triethylamine 0.108ml and anhydrous magnesium sulfate 3g were added there, and it stirred at room temperature for 1 hour. The anhydrous magnesium sulfate was removed by Celite filtration, methanol was distilled off, and the residue was dried with a vacuum pump. This was dissolved in 10 ml of anhydrous methanol, and 22.0 mg of sodium borohydride was gradually added under ice cooling. This was returned to room temperature and stirred for 1 hour. After completion of the reaction, methanol was distilled off, and water and chloroform were added to extract the organic layer. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol / water) to obtain 60.3 mg of the title compound as a pale yellow viscous liquid.
MS (FAB, Pos.): M / z = 420 [M + H] ⁺

Example 76-2: [4- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -benzyl]-(4-dipropylamino-butyl) -carbamic acid t-butyl ester Synthesis 60.3 mg of the compound obtained in Example 76-1 was dissolved in chloroform, and 47.0 mg of di-t-butoxy dicarbonate was added thereto. After stirring at room temperature for 30 minutes, the mixture was concentrated and purified by silica gel column chromatography (chloroform / methanol) to obtain 70.0 mg of the title compound as a colorless viscous liquid.
MS (FAB, Pos.): M / z = 522 [M + H] ⁺

Example 76-3: (4-Aminomethyl-benzyl)-(4-dipropylamino-butyl) -carbamic acid t-
Synthesis of Butyl Ester 3.0 ml of 40% methylamine / methanol solution was added to 70.0 mg of the compound obtained in Example 76-2 and stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off, 1 mol / l aqueous sodium hydroxide solution and chloroform were added, and the aqueous layer was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 65.5 mg of the title compound as a colorless viscous liquid.

Example 76-4: Synthesis of (4-dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -carbamic acid-t-butyl ester 0.78 g of the compound obtained in Example 76-3 was dissolved in 20 ml of methanol, 214.6 mg of 2-imidazole carboxaldehyde was added, and the mixture was stirred at room temperature for 17 hours. After the solvent was distilled off, vacuum-dried, dissolved in 15 ml of methanol, added with 217.8 mg of sodium borohydride, 45
Stir for minutes. 10 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. Saturated saline was added to the reaction solution, extracted with chloroform, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 1.01 g of the title compound as a yellow solid.
MS (FAB, Pos.): M / z = 472 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3Hz), 1.26-1.49 (17H, m), 2.32-2.35 (6H, m), 3.12 (1H, brs), 3.21 (1H, brs), 3.79 (2H, brs), 3.92 (2H, brs), 4.12 (1H, brs), 4.13 (1H, brs), 6.99 (2H, s), 7.20 (2H, brs), 7.25 (2H, d, J = 7.5Hz).

Example 76-5: (4-dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-
Synthesis of methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -carbamic acid t-butyl ester [Compound No. 95] 231 mg of the compound obtained in Example 76-4 was added to anhydrous methanol 5.0 ml Then, 61.6 mg of sodium cyanoborohydride, 2.00 ml of acetic acid, and 80.9 mg of 1-methyl-2-imidazolecarboxaldehyde were added, and the mixture was stirred at room temperature for 6 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / methanol / water) to obtain 197 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 566 [M + H] ⁺

Production Example 77: N- (2-chloro-4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -N- Synthesis of methyl-N ', N'-dipropyl-butane-1,4-diamine [Compound No. 96]

Example 77-1 Synthesis of N-methyl-N ′, N′-dipropyl-butane-1,4-diamine 0.26 ml of formic acid was added to 0.60 ml of acetic anhydride, and the mixture was heated to reflux for 1.5 hours. After the reaction, the temperature was returned to room temperature, 2.0 ml of THF and 8.0 ml of a THF solution of 400 mg of the compound obtained in Example 1-2 were added, and the mixture was stirred at room temperature for about 4 hours. After the reaction, the solvent was distilled off.
429 mg of lithium aluminum hydride was suspended in 10 ml of anhydrous THF. Thereto was added dropwise 8.0 ml of an anhydrous THF solution of the compound obtained above. Stir at room temperature for 4 hours. Sodium sulfate decahydrate was added. 20% aqueous sodium hydroxide solution was added. The suspension was filtered through celite, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 61.8 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 187 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3 Hz), 1.41-1.50 (8H, m), 2.35-2.42 (6H, m), 2.43 (3H, s), 2.58 (2H, t, J = 6.8Hz).

Example 77-2: Synthesis of 3-chloro-4-methyl-benzoic acid methyl ester
1.09 g of 3-chloro-4-methyl-benzonitrile was dissolved in 12 ml of methanol. To the reaction solution was added 10 ml of a 1 mol / l aqueous sodium hydroxide solution, and the mixture was heated to reflux for 1 hour. The reaction solution was cooled to room temperature. 1 mol / l hydrochloric acid was added to the reaction solution to adjust the pH to 3, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure, and the resulting residue was dissolved in 15 ml of methanol. 1 ml of concentrated sulfuric acid was added to the reaction solution, and the mixture was heated to reflux for 6 hours. The reaction solution was cooled to room temperature, adjusted to pH 9 by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure to give 1.125 g of the title compound as a white solid.
MS (FAB, Pos.): M / z = 185 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 2.43 (3H, s), 3.91 (3H, s), 7.29 (1H, d, J = 8.1 Hz), 7.82 (2H, d, J = 8.1 Hz) , 8.01 (1H, s).

Example 77-3: Synthesis of 3-chloro-4-[[(4-dipropylamino-butyl) -methyl-amino] -methyl] -benzoic acid methyl ester 0.98 g of the compound obtained in Example 77-2 Was dissolved in 21.4 ml of carbon tetrachloride. NBS1.033g and AIBN68.0mg were added to the reaction solution, and it heated and refluxed for 30 minutes. After the reaction solution was cooled to room temperature, the precipitated solid was filtered off through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in 27 ml of DMF. To the reaction solution were added 1.0929 g of the compound obtained in Example 77-1 and 1.323 g of potassium carbonate, and the mixture was stirred at room temperature for 2 hours. Distilled water was added to the reaction solution, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The resulting residue was purified by column chromatography (chloroform / ethyl acetate to chloroform / methanol) to obtain 526.4 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 369 [M + H] ⁺

Example 77-4: Synthesis of (3-chloro-4-[[(4-dipropylamino-butyl) -methyl-amino] -methyl] -phenyl) -methanol Compound 526.4 obtained in Example 77-3 mg was dissolved in 10 ml of THF and cooled to 0 ° C. Under a nitrogen atmosphere, 3 ml of a 0.94 mol / l DIBALn-hexane solution was added dropwise to the reaction solution, followed by stirring at room temperature for 1 hour. The reaction solution was cooled to 0 ° C., 10 ml of ethyl acetate and 10 ml of acetone were added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 30 ml of saturated aqueous sodium potassium tartrate solution, and the mixture was vigorously stirred at room temperature for 2 hours, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The resulting residue was purified by column chromatography (n-hexane / ethyl acetate) to obtain the title compound (290.8 mg) as a yellow oil.
MS (FAB, Pos.): M / z = 341 [M + H] ⁺

Example 77-5: Synthesis of 3-chloro-4-[[(4-dipropylamino-butyl) -methyl-amino] -methyl] -benzaldehyde 290.8 mg of the compound obtained in Example 77-4 was added to 6 ml of chloroform. Dissolved in. To the reaction solution was added 1.4331 g of manganese dioxide, and the mixture was stirred at room temperature for 22 hours. The catalyst was filtered off through celite. The filtrate was concentrated under reduced pressure to obtain 256.4 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 339 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.89 (6H, t, J = 7.3 Hz), 1.53-1.73 (10H, m), 2.24 (3H, s), 2.48 (6H.br), 3.64 ( 2H, s), 7.71 (1H, d, J = 8.5Hz), 7.75 (1H, d, J = 8.5Hz), 7.86 (1H, s), 9.96 (1H, s).

Example 77-6: N- (2-chloro-4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)- Synthesis of N-methyl-N ′, N′-dipropyl-butane-1,4-diamine [Compound No. 96] 124.0 mg of the compound obtained in Example 77-5 was dissolved in 1.5 ml of methanol. To the reaction solution were added 45.2 mg of the compound obtained in Example 14-7 and 0.2 ml of trimethyl orthoformate, and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0 ° C., 27.8 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. Distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure, and the resulting residue was dissolved in 2 ml of methanol. To the reaction solution, 53.9 mg of 2-imidazolecarboxaldehyde and 59.3 mg of sodium cyanoborohydride were added, adjusted to pH 5 with acetic acid, and stirred at room temperature for 15 hours. To the reaction solution was added 1 mol.l sodium hydroxide aqueous solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate).
Hydrochloric acid treatment gave 42.3 mg of the hydrochloride salt of the title compound as a pale pink solid.
MS (FAB, Pos.): M / z = 514 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.91 (6H, t, J = 7.3 Hz), 1.64-1.73 (8H, m), 2.64 (3H, s), 2.95-3.16 (8H.m ), 3.73 (3H, s), 3.77 (2H, s), 4.12 (2H, s), 4.20 (2H, s), 4.27 (1H, br), 4.44 (1H, br), 7.47 (1H, d, J = 7.9Hz), 7.54 (1H, d, J = 1.9Hz), 7.55 (1H, d, J = 1.9Hz), 7.60 (1H, s), 7.65 (2H, s), 7.77 (1H, d, J = 7.9Hz), 10.33 (1H, br), 10.84 (1H, br).

Production Example 78: [(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid ethyl ester [Compound No. .97]

Example 78-1: [(4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid ethyl ester [ Synthesis of Compound No. 97] 275.6 mg of the compound obtained in Example 69-1 was dissolved in 11 ml of ethanol and heated to reflux for 21 hours.
After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off. Treatment with hydrochloric acid gave 181.4 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 538 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.18 (3H, t, J = 7.2 Hz), 1.63-1.68 (6H, m ), 1.76 (2H, br), 2.97-3.00 (4H, m), 3.05 (2H, t, J = 7.8Hz), 3.13 (2H, br), 3.71 (2H, s), 4.03 (2H, s) 4.10-4.15 (6H, m), 4.32 (2H, s), 7.46 (4H, dd, J = 8.4,15.4Hz), 7.58 (4H, d, J = 4.4Hz).

Production Example 79: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetic acid 3,7,11-trimethyl-dodeca-2,6,10-trienyl ester [Compound No. 98]

Example 79-1: [(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl ] -Benzyl) -amino] -acetic acid 3,7,11-trimethyl-dodeca-2,6,10-trienyl ester [Compound No. 98] 182 mg of the compound obtained in Example 65-1 in chloroform The suspension was suspended, a 1 mol / l aqueous sodium hydroxide solution was added, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain 122 mg of the sodium salt as a pale yellow solid. This was dissolved in chloroform, WSCI hydrochloride 58.2 mg, HOBt 34.7 mg, farnesol 290 μl and N-methylmorpholine 33.4 μl were added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 3 and a half hours. The reaction solution was concentrated under reduced pressure, and the residue was allowed to stand at room temperature for 14 hours. After completion of the reaction, the reaction mixture was diluted with chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 191 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 728 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.24-1.60 (8H, m), 1.68 (9H, d, J = 1.2 Hz), 2.32-2.39 ( 6H, m), 2.63 (2H, t, J = 7.0Hz), 3.30 (2H, s), 3.45 (2H, s), 3.53 (3H, s), 3.63 (2H, s), 3.67 (2H, s ), 3.76 (2H, s), 4.16 (2H, d, J = 7.0Hz), 5.08-5.12 (2H, m), 5.42-5.44 (1H, m), 6.86 (1H, d, J = 1.2Hz) , 6.99 (1H, d, J = 1.2Hz), 7.07 (1H, s), 7.11 (1H, s), 7.30 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.1Hz) .

Production Example 80: 2-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of] -Benzyl) -amino] -N, N-dimethyl-acetamide [Compound No. 99]

Example 80-1: 2-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -methyl] -benzyl) -amino] -N, N-dimethyl-acetamide [Compound No. 99] 190 mg of the hydrochloride of the compound obtained in Example 65-1 was dissolved in 5.0 ml of DMF and N- (2 -Hydroxyethyl) -succinimide (57.8 mg) was added, and the mixture was heated to reflux for 4 hours. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / methanol)
Hydrochloric acid treatment gave 82.5 mg of the title compound hydrochloride as a pale yellow solid.
MS (FAB, Pos.): M / z = 551 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.3 Hz), 1.64-1.68 (8H, m), 2.84 (3H, s), 2.90 (3H , s), 2.97-3.01 (4H, m), 3.06 (4H, t, J = 7.2Hz), 3.72 (3H, s), 4.08 (2H, s), 4.16 (2H, s), 4.15-4.39 ( 4H, m), 7.43 (2H, d, J = 8.2Hz), 7.47-7.49 (4H, m), 7.60 (2H, s).

Production Example 81: [(4-[[Bis- (1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid [ Synthesis of Compound No. 100]

Example 81-1: [(4-[[Bis- (1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]-
Synthesis of (benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid methyl ester 1.78 g of the compound obtained in Example 64-1 was dissolved in 30 ml of methanol, 1.8 ml of trimethyl orthoformate, 1.0 ml of acetic acid, 0.324 g of sodium cyanoborohydride was added. To this, 5.0 ml of a methanol solution of 0.550 g of 1-methyl-2-imidazolecarboxaldehyde was added little by little. Thereafter, the mixture was stirred at room temperature for 1 hour. Further, 6.086 ml of a methanol solution of 0.486 g of sodium cyanoborohydride and 0.660 g of 1-methyl-2-imidazolecarboxaldehyde was added, and the mixture was stirred at room temperature for 63 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (1.18 g) as a colorless oily substance.
MS (FAB, Pos.): M / z = 552 [M + H] ⁺

Example 81-2: [(4-[[Bis- (1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]-
Synthesis of (benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid [Compound No. 100] 36.8 mg of the compound obtained in Example 81-1 was dissolved in 1.0 ml of concentrated hydrochloric acid and dissolved at 100 ° C. for 1 hour. Stir. After completion of the reaction, the reaction mixture was concentrated and vacuum dried to obtain 46.8 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 538 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.65-1.73 (6H, m), 1.82 (2H, br), 2.93-2.98 (4H, m ), 3.00-3.04 (2H, m), 3.13 (2H, br), 3.76 (6H, s), 3.79 (2H, s), 3.84-4.35 (6H, m), 4.37 (2H, s), 7.44 ( 2H, d, J = 8.2Hz), 7.49 (2H, d, J = 8.2Hz), 7.53 (2H, s), 7.59 (2H, s), 10.83 (1H, br).

Production Example 82: [(4-[[Bis- (1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)-(4-dipropylamino-butyl) -amino] -ethyl acetate Synthesis of ester [Compound No. 101]

Example 82-1: [(4-[[Bis- (1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]-
Synthesis of (benzyl)-(4-dipropylamino-butyl) -amino] -acetic acid ethyl ester [Compound No. 101] 1.02 g of the compound obtained in Example 81-2 was dissolved in 15 ml of ethanol, and 1.0 ml of concentrated hydrochloric acid was obtained. Then, 3.2 g of molecular sieve 3A was added and refluxed for 2 hours. After the reaction, it was filtered and the filtrate was concentrated. The residue was dissolved in chloroform, washed with 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 121.8 mg of the title compound as a colorless oil. Of these, 50.5 mg was converted to hydrochloride to give 61.9 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 566 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.79 (6H, t, J = 7.3 Hz), 1.18 (3H, t, J = 7.1 Hz), 1.32 (4H, sext., J = 7.3 Hz) ), 1.28-1.41 (4H, m), 2.22-2.27 (6H, m), 3.24 (2H, s), 3.30 (6H, s), 3.31-3.40 (2H, br), 3.52 (2H, s), 3.56 (4H, s), 3.66 (2H, s), 4.06 (2H, q, J = 7.1Hz), 6.78 (2H, s), 7.05 (2H, s), 7.18 (2H, d, J = 8.1Hz ), 7.23 (2H, d, J = 8.1Hz).

Production Example 83: [(4-Dipropylamino-butyl)-([[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -Amino] -acetic acid- (R)-(-)-tetrahydrofuran-2-ylmethyl ester [Compound No. 102]

Example 83-1: [(4-Dipropylamino-butyl)-([[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -acetic acid- (R)-(-)-tetrahydrofuran-2-ylmethyl ester [Compound No. 102] 145.0 mg of the compound obtained in Example 65-1 was dissolved in 2.0 ml of chloroform. WSCI hydrochloride 74.5 mg, HOBt 53.0 mg and N-methylmorpholine 142 μl were added thereto, and the mixture was stirred at room temperature for 30 minutes. To this was added 270 mg of (R)-(−)-tetrahydrofurfuryl alcohol, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate), which was converted to hydrochloride to give 62.5 mg of the title compound as a white solid. It was.
MS (FAB, Pos.): M / z = 608 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.53-1.59 (2H, m), 1.64-1.73 (6H, m), 1.73-1.86 (6H , m), 1.92-1.95 (1H, m), 2.91-2.98 (4H, m), 2.98-3.04 (2H, m), 3.12 (2H, br), 3.29-3.36 (2H, m), 3.60 (4H , s), 4.12 (2H, s), 4.20 (2H, s), 4.36 (2H, br), 7.48 (4H, br), 7.53 (2H, d, J = 7.9Hz), 7.63 (2H, s) .

Production Example 84: ([4-[(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-
Synthesis of (Ilmethyl) -amino] -methyl] -benzyl) -methyl-amino] -butyl] -propyl-amino) -acetic acid [Compound No. 103]

Example 84-1: Synthesis of (4-propylamino-butyl) -carbamic acid-t-butyl ester
400.0 mg of (4-amino-butyl) -carbamic acid-t-butyl ester is dissolved in 6.0 ml of methanol, 0.12 ml of acetic acid and 172.5 mg of sodium cyanoborohydride are added, and then 0.155 ml of propionaldehyde is added dropwise at room temperature. For 2 hours. After completion of the reaction, the solvent was distilled off, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 339.6 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 231 [M + H] ⁺

Example 84-2: Synthesis of [(4-t-butoxycarbonylamino-butyl) -propyl-amino] -acetic acid ethyl ester 339.0 mg of the compound obtained in Example 84-1 was dissolved in 5.1 ml of chloroform to obtain triethylamine. 0.41 ml was added. To this, 0.20 ml of ethyl bromoacetate was added dropwise and stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 273.9 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 317 [M + H] ⁺

Example 84-3: Synthesis of 4-[[((1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzoic acid methyl ester Aminomethyl-methyl benzoate hydrochloride was desalted to give a free form. 1.04 g of the obtained free form was dissolved in 15.0 ml of methanol, 0.529 g of 2-imidazolecarboxaldehyde was added, and the mixture was stirred at room temperature for 14 hours. After cooling to 0 ° C., 0.249 g of sodium borohydride was added and stirred at 0 ° C. for 30 minutes and then at room temperature for 30 minutes. After the reaction, the solvent was distilled off, and the residue was dissolved in chloroform and washed with a 1 mol / l aqueous sodium hydroxide solution. The mixture was extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off to give 4-[[(1H-imidazole-2-
1.47 g of a crude product of ylmethyl) -amino] -methyl] -benzoic acid methyl ester was obtained. 1.47 g of the resulting crude product was dissolved in 15.0 ml of methanol, 0.844 g of 1-methyl-2-imidazolecarboxaldehyde was added, and the mixture was stirred at room temperature for 1 hour. After cooling to 0 ° C. and adding 2.18 g of sodium triacetoxyborohydride, the mixture was stirred at room temperature for 22 hours. After the reaction, the solvent was distilled off, and the residue was dissolved in chloroform and washed with a 1 mol / l aqueous sodium hydroxide solution. After extraction with chloroform, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (1.44 g) as a white foam.
MS (FAB, Pos.): M / z = 340 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 3.46 (2H, s), 3.57 (3H, s), 3.61 (2H, s), 3.74 (2H, s), 3.92 (3H, s), 6.89 ( 1H, s), 7.01 (1H, s), 7.08-7.13 (2H, br), 7.50 (2H, d, J = 8.5Hz), 8.02 (2H, d, J = 8.5Hz).

Example 84-4: Synthesis of (4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -phenyl) -methanol Example 84 1.43 g of the compound obtained in -3 was dissolved in 32.0 ml of THF and cooled to -20 ° C. To this, 2.0 ml of 65% sodium bis (2-methoxyethoxy) aluminum hydride / toluene solution was added little by little and stirred for 2 days. After the reaction, 2.0 ml of methanol and 10% aqueous potassium potassium tartrate solution were added and stirred for a while. After THF was distilled off under reduced pressure, the mixture was extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.10 g of the title compound as a pale yellow foam.
MS (FAB, Pos.): M / z = 312 [M + H] +
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 3.50 (4H, s), 3.52 (3H, s), 3.56 (2H, s), 4.48 (2H, d, J = 4.9 Hz), 5.18 (1H, t, J = 5.5Hz), 6.81 (1H, s), 6.87 (1H, s), 7.10 (2H, d, J = 10.0Hz), 7.27 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.1Hz).

Example 84-5: Synthesis of (4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzaldehyde In Example 84-4 1.10 g of the obtained compound was dissolved in 20.0 ml of dichloromethane, 3.07 g of manganese dioxide (chemically treated product) was added, and the mixture was stirred at room temperature for 16 hours, filtered through Celite, and the filtrate was concentrated. Purification by chromatography (chloroform / methanol) gave 0.79 g of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 310 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 3.50 (2H, s), 3.60 (5H, s), 3.76 (2H, s), 6.90 (1H, s), 7.02 (1H, s), 7.04- 7.15 (2H, br), 7.61 (2H, d, J = 8.1Hz), 7.87 (2H, d, J = 8.1Hz), 10.01 (1H, s).

Example 84-6: [[4- (4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzylamino) -butyl Synthesis of] -propyl-amino] -acetic acid ethyl ester Dissolve 273.0 mg of the compound obtained in Example 84-2 in 2.7 ml of ethanol, add 2.7 ml of 4 mol / l hydrogen chloride / dioxane solution, and stir at room temperature for 1 hour. did. Further, 1.0 ml of 4 mol / l hydrogen chloride / dioxane solution was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off to obtain 350.0 mg of a crude product of [(4-amino-butyl) -propyl-amino] -acetic acid ethyl ester as a colorless oil. 350.0 mg of the resulting crude product was dissolved in 4.5 ml of ethanol, and 2.6 ml of an ethanol solution of the compound 258 mg obtained in Example 84-5, 0.10 ml of acetic acid, and 267.0 mg of sodium triacetoxyborohydride were added, and 2 at room temperature was added. Stir for hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform, washed with 1 mol / l aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (238.0 mg) as a pale yellow oily substance.
MS (FAB, Pos.): M / z = 510 [M + H] ⁺

Example 84-7: ([4-[(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -methyl -Amino] -butyl] -propyl-amino)-
Synthesis of Ethyl Acetate 169.0 mg of the compound obtained in Example 84-6 was dissolved in 5.1 ml of ethanol, and 0.08 ml of 36% formaldehyde aqueous solution and 0.08 ml of formic acid were added and refluxed for 1 hour. After completion of the reaction, the solvent was distilled off, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform / methanol), thereby obtaining the subject compound (71.0 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 524 [M + H] ⁺

Example 84-8: ([4-[(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) -methyl -Amino] -butyl] -propyl-amino)-
Synthesis of Acetic Acid [Compound No. 103] 71.0 mg of the compound obtained in Example 84-7 was dissolved in concentrated hydrochloric acid and refluxed for 2 hours. After completion of the reaction, the solvent was distilled off and the residue was dried under vacuum to obtain 87.9 mg of hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 496 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + H ₂ O): δ = 0.91 (3H, t, J = 7.3 Hz), 1.63-1.83 (6H, m), 2.58 (3H, s), 2.81-3.14 (4H, m), 3.18 (2H, t, J = 7.8Hz), 3.66-3.89 (2H, m), 3.72 (3H, s), 4.10 (2H, s), 4.12 (3H, s), 4.18 ( 2H, s), 4.29-4.37 (1H, m), 7.40 (2H, d, J = 8.3Hz), 7.43-7.49 (4H, m), 7.59 (2H, s).

Production Example 85: ([4- [Carboxymethyl- (4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl)- Amino] -butyl] -propyl-
Synthesis of amino) -acetic acid [Compound No. 104]

Example 85-1: ([4- [ethoxycarbonylmethyl- (4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- Synthesis of (benzyl) -amino] -butyl] -propyl-amino) -acetic acid ethyl ester 169.0 mg of the compound obtained in Example 84-6 was dissolved in 2.5 ml of chloroform, 0.055 ml of triethylamine was added and then 0.045 ethyl bromoacetate was added. ml was added dropwise and stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain the title compound (31.5 mg) as a colorless oil.
MS (FAB, Pos.): M / z = 596 [M + H] ⁺

Example 85-2: ([4- [carboxymethyl- (4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -benzyl) Synthesis of) -amino] -butyl] -propyl-amino) -acetic acid [Compound No. 104] 10.1 mg of the compound obtained in Example 85-1 was dissolved in concentrated hydrochloric acid and refluxed for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was dried under vacuum to obtain 13.8 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 540 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.90 (3H, t, J = 7.3 Hz), 1.63-1.80 (6H, m), 3.06-3.20 (6H, m), 3.71 (3H, s), 3.95 (2H, s), 4.09 (2H, s), 4.13 (2H, s), 4.17 (2H, s), 4.35 (2H, s), 7.43-7.49 (6H, m), 7.59 (2H, s).

Production example 86: (2-[[(1-carboxymethyl-1H-imidazol-2-ylmethyl)-(4-[[(4-dipropylamino-butyl) -methyl-amino] -methyl] -benzyl)- Synthesis of [amino] -methyl] -imidazol-1-yl) -acetic acid [Compound No. 105]

Example 86-1: (2-[[(4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -benzyl)-(1-ethoxycarbonylmethyl-1H-imidazole-2- Synthesis of (Ilmethyl) -amino] -methyl] -imidazol 1-yl) -ethyl acetate N- (4-[[Bis- (1H-imidazol-2-ylmethyl) -amino] -methyl]-obtained by known methods (Benzyl) -N-methyl-N ', N',-dipropyl-butane-1,4-diamine (533 mg) is dissolved in THF (10 ml), and t-butoxy sodium (290 mg) is added under an ice-cooled nitrogen atmosphere. Half stirred. Under ice cooling, 280 μl of ethyl bromoacetate was slowly added, and the mixture was stirred for 1 hour and a half with ice cooling.
After completion of the reaction, the mixture was neutralized by adding 30 μl of acetic acid under ice cooling. The solvent was distilled off under reduced pressure, the residue was diluted with chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the pH of the aqueous layer was adjusted to 8. The aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethanol) to obtain 280 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 638 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.23 (3H, t, J = 7.1 Hz), 1.41-1.47 (8H, m),
2.14 (3H, s), 2.14-2.41 (8H, m), 3.44 (2H, s), 3.61 (2H, s), 3.64 (2H, s), 3.66 (2H, s), 4.10 (2H, q, J = 7.1Hz), 4.51 (4H, s), 6.84 (2H, d, J = 1.2Hz), 6.97 (2H, d, J = 1.5Hz), 7.16 (2H, d, J = 8.3Hz), 7.24 (2H, d, J = 8.3Hz).

Example 86-2: (2-[[(1-carboxymethyl-1H-imidazol-2-ylmethyl)-(4-[[(4-dipropylamino-butyl) -methyl-amino] -methyl] -benzyl ) -Amino] -methyl] -imidazol-1-yl) -acetic acid [Compound No. 105] 34.1 mg of the compound obtained in Example 86-1 was dissolved in 1.0 ml of dioxane, and 500 μl of concentrated hydrochloric acid at room temperature. And stirred for 4 hours at an external temperature of 100 ° C. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to obtain 43.4 mg of hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 583 [M + H] +
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.63-1.91 (8H, m), 2.57 (3H, s), 3.16-3.50 (8H, m ), 3.63-3.90 (8H, m), 5.10 (4H, brs), 7.44 (2H, d, J = 8.1Hz), 7.49 (2H, d, J = 8.1Hz), 10.49 (2H, brs).

Production Example 87: (2-[[(4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino ] -Methyl] -imidazol-1-yl) -acetic acid [Compound No. 106]

Example 87-1: (2-[[(4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) Synthesis of -amino] -methyl] -imidazol-1-yl) -ethyl acetate N- (4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole-) obtained by a known method 2-ylmethyl) -amino] -methyl] -benzyl) -N-methyl-N ', N'-dipropyl-butane-1,4-diamine (835 mg) was dissolved in 10 ml of THF and t-butoxy was dissolved in an ice-cooled nitrogen atmosphere. Sodium 200 mg was added, and the mixture was returned to room temperature and stirred for 1.5 hours. Under ice cooling, 230 μl of ethyl bromoacetate was slowly added, and the mixture was stirred for 1 hour and a half with ice cooling. After completion of the reaction, the mixture was neutralized by adding 30 μl of acetic acid under ice cooling. The solvent was distilled off under reduced pressure, the residue was diluted with chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the pH of the aqueous layer was adjusted to 8. The aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethanol) to obtain 522 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 566 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.6 Hz), 1.23 (3H, t, J = 8.1 Hz), 1.41-1.51 (8H, m), 2.14 (3H, s), 2.33-2.41 (8H, m), 3.28 (3H, s), 3.44 (2H, s), 3.61 (2H, s), 3.62 (2H, s), 3.71 (2H, s), 4.11 (2H , q, J = 7.1Hz), 4.56 (2H, s), 6.78 (1H, d, J = 1.2Hz), 6.85 (1H, d, J = 1.5Hz), 6.92 (1H, d, J = 1.5Hz) ), 6.97 (1H, d, J = 1.5Hz), 7.16 (2H, d, J = 8.1Hz), 7.23 (2H, d, J = 8.1Hz).

Example 87-2: (2-[[(4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) Synthesis of -amino] -methyl] -imidazol-1-yl) -acetic acid [Compound No. 106] 41.6 mg of the compound obtained in Example 87-1 was dissolved in 0.80 ml of dioxane and concentrated hydrochloric acid 800 at room temperature.
μl was added and stirred at an external temperature of 100 ° C. for 5 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to obtain 78.7 mg of hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 538 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.64-1.91 (8H, m), 2.52 (3H, s), 3.44-3.54 (8H, m ), 3.66-3.91 (9H, m), 4.11 (2H, s), 5.12 (2H, s), 7.41 (2H, d, J = 7.6Hz), 7.49 (2H, d, J = 8.0Hz), 7.51 (1H, s), 7.53 (1H, s), 7.62 (1H, s), 7.63 (1H, s), 10.37 (1H, brs), 11.05 (1H, brs).

Production Example 88: 4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -N- (1H-imidazol-2-ylmethyl) -N- (1-methyl-1H-imidazole-2 Synthesis of -Ilmethyl) -benzamide [Compound No. 107]

Example 88-1: Synthesis of 4-[(4-Dipropylamino-butylamino) -methyl] -benzoic acid methyl ester 153 mg of commercially available methyl 4-aminomethyl-benzoate was dissolved in 4.0 ml of methanol. 17-5
209 mg of the compound obtained in 1 above and 200 μl of trimethyl orthoformate were added and stirred at room temperature for 2 hours. After cooling to 0 ° C., 100 mg of sodium borohydride was added and stirred at 0 ° C. for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with water, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 310 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 321 [M + H] ⁺

Example 88-2: Synthesis of 4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -benzoic acid methyl ester 310 mg of the compound obtained in Example 88-1 in 4.5 ml of ethanol After dissolution, 150 μl of 36% aqueous formaldehyde solution and 175 μl of formic acid were added and refluxed for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 234 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 335 [M + H] ⁺

Example 88-3: Synthesis of 4-[[(4-dipropylamino-butyl) -methyl-amino] -methyl] -benzoic acid 234 mg of the compound obtained in Example 88-2 was dissolved in 2.5 ml of methanol. Then, 2.5 ml of 1 mol / l sodium hydroxide aqueous solution was added and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was neutralized with 1 mol / l hydrochloric acid, and the solvent was distilled off under reduced pressure. The residue was suspended in ethanol and the white precipitate was filtered off. The organic layer was distilled off under reduced pressure, and the residue was dried in vacuo to give 204 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 321 [M + H] ⁺

Example 88-4: Synthesis of (1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amine 201 mg of the compound obtained in Example 14-7 was dissolved in 4.0 ml of methanol. Then, 200 μl of trimethyl orthoformate and 115 mg of 2-imidazole carboxaldehyde were added and stirred at room temperature for 30 minutes. After cooling to 0 ° C., 89.6 mg of sodium borohydride was added, followed by stirring at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with water, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol).
To give 137 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 192 [M + H] ⁺

Example 88-5: 4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -N- (1H-imidazol-2-ylmethyl) -N- (1-methyl-1H-imidazole Synthesis of 2-ylmethyl) -benzamide [Compound No. 107] 204 mg of the compound obtained in Example 88-3, 184 mg of WSCI hydrochloride and 129 mg of HOBt were dissolved in 4.0 ml of chloroform, and the mixture was stirred at room temperature for 30 minutes. This was added dropwise to 2.0 ml of a chloroform solution of the compound 137 mg obtained in Example 88-4 and stirred at room temperature for 15 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with saturated brine, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 31.5 mg of the title compound as a pale yellow oil. This was treated with hydrochloric acid to obtain 43.5 mg of the hydrochloride of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 494 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.60-1.84 (8H, m), 2.62 (3H, s), 2.88-3.12 (8H, m ), 3.28-3.60 (3H, m), 3.84-3.96 (2H, m), 4.20-4.28 (1H, m), 4.32-4.40 (1H, m), 4.92-5.16 (2H, m), 7.56-7.72 (8H, m).

Production Example 89: 2-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of [-Benzyl) -amino] -malonic acid diethyl ester [Compound No. 108]

Example 89-1 Synthesis of 2-[[4- (t-Butoxycarbonylamino-methyl) -benzyl]-(4-dipropylamino-butyl) -amino] -malonic acid diethyl ester In Example 23-4 520 mg of the obtained compound was dissolved in 10 ml of anhydrous DMF, 463 μl of diisopropylethylamine and 340 μl of diethyl bromomalonate were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified through silica gel column chromatography (hexane / ethyl acetate), thereby obtaining the subject compound (421 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 550 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3Hz), 1.29 (6H, t, J = 7.1Hz), 1.37-1.44 (8H, m), 1.46 (9H, s), 2.30-2.35 (6H, m), 2.68 (2H, t, J = 6.8Hz), 3.84 (2H, s), 4.21 (1H, s), 4.23 (4H, q, J = 7.1Hz), 4.30 (2H, d, J = 5.8Hz), 4.81 (1H, br), 7.21 (2H, d, J = 8.1Hz), 7.35 (2H, d, J = 8.1Hz).

Example 89-2: Synthesis of 2-[(4-aminomethyl-benzyl)-(4-dipropylamino-butyl) -amino] -malonic acid diethyl ester 421 mg of the compound obtained in Example 89-1 was anhydrous Dissolve in 4.0 ml of ethanol, 4 mol / l hydrogen chloride /
The dioxane solution 4.00ml was added and it stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off. To this was added a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 338 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 450 [M + H] ⁺

Example 89-3: 2-[(4-Dipropylamino-butyl)-(4-[[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -Methyl] -benzyl) -amino] -malonic acid diethyl ester [Compound No. 108] 338 mg of the compound obtained in Example 89-2 was dissolved in 6 ml of absolute ethanol, 375 μl of triethyl orthoformate, 2-imidazolecarboxyl 86.7 mg of aldehyde was added and stirred overnight at room temperature under a nitrogen atmosphere. Next, 56.9 mg of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, distilled water was added and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. 463 mg of this residue was dissolved in 10 ml of absolute ethanol, 556 mg of sodium triacetoxyborohydride and 116 mg of 1-methyl-2-imidazolecarboxaldehyde were added, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 262 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 624 [M + H] ^{+
1 H-NMR (500MHz, DMSO} -d 6 + D 2 O): δ = 0.90 (6H, t, J = 7.3Hz), 1.21 (6H, t, J = 7.2Hz), 1.43-1.46 (2H, m ), 1.55-1.66 (6H, m), 2.63 (2H, t, J = 6.9Hz), 2.92-2.98 (6H, m), 3.69 (2H, s), 3.70 (3H, s), 3.72 (2H, s), 4.10 (2H, s), 4.15-4.21 (7H, m), 7.23 (2H, d, J = 8.1Hz), 7.31 (2H, d, J = 8.2Hz), 7.46 (1H, d, J = 2.0Hz), 7.47 (1H, d, J = 2.0Hz), 7.58 (2H, s).

Production Example 90: (2- {2-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl -Amino] -ethoxy} -ethyl) -dipropyl-amine [Compound No. 109]

Example 90-1: Synthesis of [2- (2-amino-ethoxy) -ethyl] -carbamic acid t-butyl ester
2,2′-Oxybisethylamine 459 mg was dissolved in anhydrous DMF 90 ml, triethylamine 1.16 ml and di-t-butoxydicarbonate 339 mg were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, added with distilled water, and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 450 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 205 [M + H] ⁺

Example 90-2: Synthesis of [2- (2-dipropylamino-ethoxy) -ethyl] -carbamic acid t-butyl ester 279 mg of the compound obtained in Example 90-1 was dissolved in 5.5 ml of anhydrous methanol. 374 μl of trimethyl acid and 257 mg of sodium cyanoborohydride were added, and 246 μl of propionaldehyde was added in an ice bath and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, added with distilled water, and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 130 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 289 [M + H] ⁺

Example 90-3: Synthesis of [2- (2-amino-ethoxy) -ethyl] -dipropyl-amine 128 mg of the compound obtained in Example 90-2 was dissolved in 2.0 ml of anhydrous methanol to obtain 4 mol / l hydrogen chloride. /
2.00 ml of dioxane solution was added and stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. To this was added a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 81.0 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 189 [M + H] +

Example 90-4: Synthesis of (4-{[2- (2-dipropylamino-ethoxy) -ethylamino] -methyl} -benzyl) -carbamic acid t-butyl ester obtained in Example 90-3 81.0 mg of the compound was dissolved in 2.0 ml of anhydrous methanol, 94.1 μl of trimethyl orthoformate and 101 mg of the compound obtained in Example 23-3 were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Next, 32.6 mg of sodium borohydride was added in an ice bath and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, added with distilled water, and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 158 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 408 [M + H] ⁺

Example 90-5: Synthesis of (4-{[(4-Dipropylaminomethyl-benzyl) -methyl-amino] -methyl} -benzyl) -carbamic acid t-butyl ester obtained in Example 90-4 67.2 mg of the compound was dissolved in 1.5 ml of methanol, 31.1 mg of sodium cyanoborohydride, 150 μl of acetic acid and 18.6 μl of 36% formaldehyde aqueous solution were added, and the mixture was stirred overnight at room temperature in a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 102 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 422 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.41-1.49 (4H, m), 1.46 (9H, s), 2.25 (3H, s), 2.41 ( 4H, t, J = 7.3Hz), 2.59 (2H, t, J = 6.1Hz), 2.64 (2H, t, J = 6.3Hz), 3.49 (2H, t, J = 6.3Hz), 3.53 (3H, s), 3.57 (2H, t, J = 6.1Hz), 4.30 (2H, d, J = 6.6Hz), 7.22 (2H, d, J = 8.3Hz), 7.28 (2H, d, J = 8.1Hz) .

Example 90-6: Synthesis of (2- {2-[(4-aminomethyl-benzyl) -methyl-amino] -ethoxy} -ethyl) -dipropyl-amine 102 mg of the compound obtained in Example 90-5 Dissolved in 1.0 ml of anhydrous methanol, 4 mol / l hydrogen chloride /
1.00 ml of dioxane solution was added and stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. To this was added a 1 mol / l aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 78.5 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 322 [M + H] ⁺

Example 90-7: (2- {2-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) Synthesis of -methyl-amino] -ethoxy} -ethyl) -dipropyl-amine [Compound No. 109] 78.5 mg of the compound obtained in Example 90-6 was dissolved in 1.6 ml of anhydrous methanol, and 40.1 μl of trimethyl orthoformate was obtained. 2-Imidazolecarboxaldehyde (25.8 mg) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Next, 18.5 mg of sodium borohydride was added in an ice bath, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, added with distilled water, and stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. 97.0 mg of this residue was dissolved in 2.0 ml of ethanol, 154 mg of sodium triacetoxyborohydride and 29.3 mg of 1-methyl-2-imidazolecarboxaldehyde were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, dissolved in chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. This was extracted with chloroform, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 106 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 496 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.91 (6H, t, J = 7.3 Hz), 1.68-1.73 (4H, m), 2.68 (3H, s), 3.02-3.07 (4H, m), 3.17-3.19 (2H, m), 3.20-3.31 (2H, m), 3.71 (3H, s), 3.74 (2H, s), 3.75-3.78 (2H, m), 3.80-3.83 (2H, m), 4.10 (2H, s), 4.18 (2H, s), 4.28 (2H, dd, J = 31.4, 12.8Hz), 7.39 (2H, d, J = 8.1Hz), 7.47 (1H, d, J = 2.0Hz), 7.48 (1H, d, J = 2.0Hz), 7.50 (2H, d, J = 8.2Hz), 7.60 (2H, s).

Production Example 91: N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ′, N′- Synthesis of dipropyl-N- (1H-tetrazol-5-ylmethyl) -butane-1,4-diamine [Compound No. 110]

Example 91-1: Synthesis of 4-{[(1-Methyl-1H-imidazol-2-ylmethyl)-(1-trityl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzaldehyde Example 84 281 mg of the compound obtained in -5 was dissolved in 6.0 ml of dichloromethane, 310 μl of diisopropylethylamine was added in a nitrogen atmosphere at room temperature, 310 mg of trityl chloride was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, methanol was added. The solvent was distilled off under reduced pressure, the residue was diluted with chloroform, water was added, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 217 mg of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 552 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 2.84 (2H, s), 3.33 (2H, s), 3.47 (2H, s), 3.77 (3H, s), 6.73 (1H, d, J = 1.2 Hz), 6.78 (1H, d, J = 1.5Hz), 6.83 (1H, d, J = 1.2Hz), 7.03 (1H, d, J = 1.5Hz), 7.05-7.28 (17H, m), 7.67 ( 2H, d, J = 8.3Hz), 9.95 (1H, s).

Example 91-2: N- (4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(1-trityl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)- Synthesis of N ′, N′-dipropyl-butane-1,4-diamine 47.2 mg of the compound obtained in Example 91-1 was dissolved in 1.0 ml of methanol, and 28.0 μl of trimethyl orthoformate was carried out under a nitrogen atmosphere at room temperature. A methanol solution of 14.7 mg of the compound obtained in Example 1-2 was added dropwise and stirred for 12 hours. Under ice-cooling, 10.0 mg of sodium borohydride was added, and the mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, water was added. The solvent was distilled off under reduced pressure, the residue was diluted with chloroform, water was added, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 51.6 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 708 [M + H] ^{+
1 H-NMR (500MHz, CDCl} 3): δ = 0.86 (6H, t, J = 7.3Hz), 1.25-1.64 (8H, m), 2.33-2.37 (4H, m), 2.41 (2H, t, J = 6.7Hz), 2.61 (2H, t, J = 6.7Hz), 2.83 (2H, s), 3.19 (2H, s), 3.39 (2H, s), 3.72 (2H, s), 3.77 (3H, s ), 6.74 (1H, d, J = 1.2Hz), 6.77 (1H, d, J = 1.5Hz), 6.83 (1H, d, J = 1.2Hz), 7.02 (1H, d, J = 1.5Hz), 7.02-7.29 (19H, m).

Example 91-3: Synthesis of 5-chloromethyl-1- (tetrahydro-pyran-2-yl) -1H-tetrazole
5-Chloromethyl-1 (2) H-tetrazole 52.8 mg was dissolved in anhydrous dichloromethane 3.0 ml and anhydrous DMF 0.50 ml, and 50.0 μl of 2,4-dihydro-2H-pyran was added at room temperature under a nitrogen atmosphere. 11.9 mg of p-toluenesulfonate was added and the mixture was returned to room temperature and stirred for 2 hours. Further, 75.0 μl of 2,4-dihydro-2H-pyran was added, and 22.0 mg of pyridinium-p-toluenesulfonate was added under ice cooling, followed by returning to room temperature and stirring for 22 hours. After completion of the reaction, the reaction solution was poured into 10 ml of a saturated aqueous solution of sodium bicarbonate under ice cooling to adjust the pH of the aqueous layer to 8. The aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (toluene / acetone) to obtain 4.6 mg of the title compound as a colorless oil.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 1.64-1.82 (3H, m), 2.14-2.48 (3H, m), 3.74-3.90 (2H, m), 4.88 (1H, d, J = 12.7Hz ), 4.97 (1H, d, J = 12.7Hz), 5.86 (1H, dd, J = 3.4Hz, 7.5Hz).

Example 91-4: N- (4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(1-trityl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl)- Synthesis of N ′, N′-dipropyl-N- [1- (tetrahydro-pyran-2-yl) -1H-tetrazol-5-ylmethyl] -butane-1,4-diamine obtained in Example 91-2 57.7 mg of compound was dissolved in 1.2 ml of anhydrous DMF, and 34.0 μl of diisopropylmethylethylamine, 15.2 mg of potassium iodide and 28.0 mg of the compound (chloro compound) obtained in Example 91-3 were added at room temperature under a nitrogen atmosphere at room temperature. Stir overnight. After completion of the reaction, methanol was added. Concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 35.6 mg of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 874 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.30-1.62 (11H, m), 2.28-2.53 (11H, m), 2.84 (2H, s), 3.20 (2H, s) 3.40 (2H, s), 3.41 (1H, d, J = 13.2Hz), 3.64 (1H, d, J = 13.4Hz), 3.76 (3H, s) 3.81 (1H, d, J = 14.1Hz), 3.93 (1H, d, J = 13.9Hz), 5.64 (1H, dd, J = 3.2,8.5Hz), 6.74 (1H, d, J = 1.2Hz), 6.77 (1H, d, J = 1.5Hz), 6.83 (1H, d, J = 1.2Hz), 7.01 (1H, d, J = 1.2Hz), 7.06-7.30 (19H, m).

Example 91-5: N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -N ′, N Synthesis of '-dipropyl-N- (1H-tetrazol-5-ylmethyl) -butane-1,4-diamine [Compound No. 110] 35.6 mg of the compound obtained in Example 91-4 was dissolved in 0.80 ml of methanol. 0.80 ml of 10% hydrogen chloride / methanol solution was added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate and water were added to the residue, and the aqueous layer was washed with ethyl acetate. The aqueous layer was concentrated to dryness under reduced pressure to obtain 23.9 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 548 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.64-2.00 (8H, m), 2.93-3.17 (8H, m), 3.72 (4H, s ), 3.74 (2H, s), 4.13 (3H, s), 4.22 (2H, s), 4.34 (2H, s), 7.44 (1H, s), 7.46 (1H, s), 7.53 (1H, s) 7.54 (1H, s), 7.54 (2H, d, J = 8.7Hz), 7.58 (2H, d, J = 8.1Hz), 10.6 (1H, brs), 15.0 (1H, brs).

Production Example 92: 5-dipropylamino- (2S)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of (benzyl) -methyl-amino] -pentanoic acid ethyl ester [Compound No. 111]

Example 92-1: Synthesis of 5-t-butoxycarbonylamino- (2S)-(9H-fluoren-9-ylmethoxycarbonylamino) -pentanoic acid ethyl ester
Dissolve 2.50 g of 5-t-butoxycarbonylamino- (2S)-(9H-fluoren-9-ylmethoxycarbonylamino) -pentanoic acid in 50.0 ml of DMF, add 1.21 g of WSCI hydrochloride and 0.84 g of HOBt to room temperature. For 1.5 hours. Ethanol 1.0ml was added to this, and also it stirred at room temperature for 17 hours. After completion of the reaction, the solvent was distilled off, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane /
Purification by ethyl acetate) gave 1.22 g of the title compound as a white solid.
MS (FAB, Pos.): M / z = 483 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.29 (3H, t, J = 7.1 Hz), 1.45 (9H, s), 1.49-1.57 (2H, m), 1.64-1.71 (1H, m), 1.84-1.94 (1H, m), 3.11-3.20 (2H, br), 4.19-4.26 (3H, m), 4.33-4.40 (1H, m), 4.41 (2H, d, J = 7.1Hz), 4.54- 4.60 (1H, br), 5.40-5.47 (1H, br), 7.32 (2H, t, J = 7.6Hz), 7.40 (2H, t, J = 7.6Hz), 7.57-7.63 (2H, m), 7.77 (2H, d, J = 7.6Hz).

Example 92-2: Synthesis of 5-amino- (2S)-(9H-fluoren-9-ylmethoxycarbonylamino) -pentanoic acid ethyl ester After dissolution, 8.7 ml of 4 mol / l hydrogen chloride / dioxane solution was added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off, and the residue was vacuum-dried to obtain 817.9 mg of a crude product of (2S) -amino-5-dipropylamino-pentanoic acid ethyl ester as hydrochloride.
MS (FAB, Pos.): M / z = 483 [M + H] ⁺

Example 92-3: Synthesis of (2S) -amino-5-dipropylamino-pentanoic acid ethyl ester 300.0 mg of the crude product obtained in Example 92-2 was dissolved in 6.0 ml of ethanol to obtain 1 mol / l. After adding 0.72 ml of an aqueous sodium hydroxide solution, acetic acid was added to adjust the pH to around 5. To this was added 144.5 mg of sodium cyanoborohydride, 0.155 ml of propionaldehyde was added dropwise, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off. The obtained crude product was dissolved in 6.4 ml of DMF, 0.32 ml of diethylamine was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform) to obtain 54.2 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 245 [M + H] ⁺

Example 92-4: 5-dipropylamino- (2S)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl } -Benzyl) -methyl-amino] -pentanoic acid ethyl ester [Compound No. 111] 54.2 mg of the compound obtained in Example 92-3 and 76.8 mg of the compound obtained in Example 84-5 And 80 μl of acetic acid was added. To this was added 49.6 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 1.5 hours. To this, 0.10 ml of 36% formaldehyde solution was added and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform) to obtain 94.9 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 552 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.31 (3H, t, J = 7.1 Hz), 1.39-1.48 (5H, m), 1.53-1.63 ( 1H, m), 1.67-1.73 (2H, m), 2.25 (3H, s), 2.33-2.37 (4H, m), 2.41 (2H, t, J = 7.3Hz), 3.30 (1H, t, J = 7.6Hz), 3.47 (2H, s), 3.56 (3H, s), 3.59-3.62 (3H, m), 3.68 (2H, s), 3.76-3.79 (1H, m), 4.16-4.24 (2H, m ), 6.87 (1H, s), 7.00 (1H, s), 7.10 (2H, d, J = 21.7Hz), 7.29 (2H, d, J = 8.3Hz), 7.34 (2H, d, J = 8.3Hz) ).

Production Example 93: 5-dipropylamino- (2S)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of (benzyl) -methyl-amino] -pentanoic acid [Compound No. 112]

Example 93-1: 5-dipropylamino- (2S)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of} -benzyl) -methyl-amino] -pentanoic acid [Compound No. 112] 42.9 mg of the compound obtained in Example 92-4 was dissolved in 1.0 ml of concentrated hydrochloric acid and stirred at 100 ° C. for 5 hours.
After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was vacuum-dried to obtain 52.3 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.91 (6H, t, J = 7.3 Hz), 1.64-1.72 (4H, m), 1.76-1.92 (2H, br), 1.93-2.04 (1H , br), 2.12-2.24 (1H, br), 2.60-2.72 (3H, br), 2.92-3.04 (4H, m), 3.06-3.14 (2H, m), 3.40-3.80 (7H, m), 3.84 -3.94 (1H, br), 4.12 (2H, s), 4.19 (2H, s), 7.48 (4H, s), 7.52-7.54 (2H, m), 7.61-7.63 (2H, m), 10.48-10.60 (1H, br).

Production Example 94: (2S) -Dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of (benzyl) -methyl-amino] -pentanoic acid ethyl ester [Compound No. 113]

Example 94-1: (S) -2- (9H-fluoren-9-ylmethoxycarbonylamino) -5-[(4-{[(1H
-Imidazole-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino]
-Methyl} -benzyl) -methyl-amino] -pentanoic acid ethyl ester 268.0 mg of the crude product obtained in Example 92-2 and 180.0 mg of the compound obtained in Example 84-5 in 7.0 ml of ethanol Dissolve and add 180 μl acetic acid. To this was added 98.0 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 1.5 hours. To this, 0.242 ml of 36% formaldehyde solution was added and stirred at room temperature for 15 hours. Further, 39.0 mg of sodium cyanoborohydride was added and stirred at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off and the residue was dried under vacuum to obtain 382.4 mg of the title compound as a pale yellow solid.
MS (FAB, Pos.): M / z = 690 [M + H] ⁺

Example 94-2: (2S) -dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl } -Benzyl) -methyl-amino] -pentanoic acid ethyl ester [Compound No. 113] 382.0 mg of the compound obtained in Example 94-1 was dissolved in 7.6 ml of DMF, 0.40 ml of diethylamine was added, and the solution was stirred at room temperature. Stir for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dried in vacuo to give (2S) -amino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl- A crude product of 1H-imidazol-2-ylmethyl) -amino] -methyl} -benzyl) -methyl-amino] -pentanoic acid ethyl ester was obtained. This crude product was dissolved in 7.0 ml of ethanol, and 0.20 ml of acetic acid and 117.0 mg of sodium cyanoborohydride were added. To this was added dropwise 0.127 ml of propionaldehyde and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off, the residue was dissolved in chloroform, washed with 1 mol / l sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform) to obtain 109.1 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 552 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.85 (6H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.34-1.53 (5H, m), 1.57-1.75 ( 3H, m), 2.17 (3H, s), 2.36-2.43 (4H, m), 2.51-2.57 (2H, m), 3.28 (1H, t, J = 7.2Hz), 3.46 (4H, s), 3.55 (3H, s), 3.62 (2H, s), 3.68 (2H, s), 4.10-4.18 (2H, m), 6.87 (1H, s), 7.00 (1H, s), 7.07-7.15 (2H, br ), 7.27 (2H, d, J = 8.1Hz), 7.34 (2H, d, J = 8.1Hz).

Production Example 95: (2S) -Dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of (benzyl) -methyl-amino] -pentanoic acid [Compound No. 114]

Example 95-1: (2S) -Dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of} -benzyl) -methyl-amino] -pentanoic acid [Compound No. 114] 33.0 mg of the compound obtained in Example 94-2 was dissolved in 1.0 ml of concentrated hydrochloric acid and stirred at 100 ° C. for 5 hours.
After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was vacuum-dried to obtain 32.8 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.90 (6H, t, J = 7.3 Hz), 1.68-1.80 (4H, br), 1.84-2.16 (4H, m), 1.56-2.64 (3H , m), 2.90-3.16 (6H, m), 3.70-3.76 (4H, m), 4.00-4.50 (7H, m), 7.44-7.56 (6H, m), 7.64-7.68 (2H, m), 10.43 -10.52 (1H, m), 11.10-11.24 (1H, br).

Production Example 96: 5-dipropylamino- (2R)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of (benzyl) -methyl-amino] -pentanoic acid ethyl ester [Compound No. 115]

Example 96-1: Synthesis of 5-t-butoxycarbonylamino- (2R)-(9H-fluoren-9-ylmethoxycarbonylamino) -pentanoic acid ethyl ester
Dissolve 1.9914 g of 5-t-butoxycarbonylamino- (2R)-(9H-fluoren-9-ylmethoxycarbonylamino) -pentanoic acid in 60 ml of ethanol and add HOBt770.2 mg and WSCI hydrochloride 1.0927 g to it. Stir at room temperature for 2 hours. After the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with 1 mol / l hydrochloric acid, 1 mol / l aqueous sodium hydroxide solution and saturated brine. Dried over magnesium sulfate. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.9846 g) as a white solid.
MS (FAB, Pos.): M / z = 483 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.29 (3H, t, J = 7.1 Hz), 1.45 (9H.s), 1.48-1.57 (2H, m), 1.65-1.69 (1H, m), 1.85-1.91 (1H, m), 3.15 (2H, br), 4.12-4.24 (3H, m), 4.34-4.38 (1H, m), 4.41 (2H, d, J = 6.8Hz), 4.58 (1H, br), 5.45 (1H, d, J = 7.8Hz), 7.31-7.34 (2H, m), 7.39-7.42 (2H, m), 7.60-7.62 (2H, m), 7.77 (2H, d, J = 7.6Hz).

Example 96-2: Synthesis of (2R) -amino-5-t-butoxycarbonylamino-pentanoic acid ethyl ester 1.9846 g of the compound obtained in Example 96-1 was dissolved in 19 ml of DMF, and 14 ml of diethylamine was added thereto. And stirred at room temperature for 30 minutes. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1.2212 g of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 261 [M + H] ⁺

Example 96-3: 5-t-butoxycarbonylamino- (2R)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] Synthesis of -methyl} -benzyl) -methyl-amino] -pentanoic acid ethyl ester 694.2 mg of the compound obtained in Example 96-2 was dissolved in 20.8 ml of anhydrous methanol. Thereto were added 909.5 mg of the compound obtained in Example 84-5 and 0.876 ml of trimethyl orthoformate, and the mixture was stirred at room temperature for 17 hours. This was ice-cooled, and 303 mg of sodium borohydride was added thereto. Stir at room temperature for 1 hour. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Washed with saturated brine. Dried over magnesium sulfate. The solvent was distilled off.
This was dissolved in 44 ml of anhydrous methanol, and 0.31 ml of 36% formaldehyde aqueous solution and 503.3 mg of sodium cyanoborohydride were added thereto. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 17 hours. After the reaction, the solvent was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 805.8 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 568 [M + H] ⁺

Example 96-4: 5-dipropylamino- (2R)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl } -Benzyl) -methyl-amino] -pentanoic acid ethyl ester [Compound No. 115] 805.8 mg of the compound obtained in Example 96-3 was dissolved in 8.0 ml of ethanol, and 4 mol / l hydrogen chloride / The dioxane solution 8.0ml was added and it stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. Dried over magnesium sulfate,
The solvent was distilled off.
This was dissolved in 26.5 ml of ethanol, to which 0.246 ml of propionaldehyde, 0.709 ml of triethyl orthoformate and 267.7 mg of sodium cyanoborohydride were added and stirred at room temperature for 21 hours. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (205.2 mg) as a yellow oily substance.
MS (FAB, Pos.): M / z = 552 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.3 Hz), 1.31 (3H, t, J = 7.1 Hz), 1.39-1.50 (4H, m), 1.66-1.75 ( 4H, m), 2.26 (3H, s), 2.32-2.36 (4H, m), 2.39-2.42 (2H, m), 3.27-3.31 (1H, m), 3.46 (2H, s), 3.56 (3H, s), 3.62 (2H, s), 3.68 (2H, s), 4.16-4.25 (2H, m), 6.88 (1H, s), 7.00 (1H, s), 7.08 (1H, s), 7.13 (1H) , s), 7.28 (2H, d, J = 8.1Hz), 7.34 (2H, d, J = 8.1Hz), 12.35 (1H, br).

Production Example 97: 5-dipropylamino- (2R)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of (benzyl) -methyl-amino] -pentanoic acid [Compound No. 116]

Example 97-1: 5-dipropylamino- (2R)-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of} -benzyl) -methyl-amino] -pentanoic acid [Compound No. 116] 200 mg of the hydrochloride of the compound obtained in Example 96-4 was dissolved in 3 ml of concentrated hydrochloric acid and 0.2 ml of water. Heated to reflux for 4 hours. After the reaction, the solvent was distilled off to obtain 175.1 mg of the hydrochloride of the title compound as a white solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.92 (6H, t, J = 7.2 Hz), 1.62-1.70 (4H, m), 1.71-1.93 (2H, m), 1.99 -2.01 (1H, m), 2.15 (1H, m), 2.67 (3H, s), 2.99-3.02 (4H, m), 3.11-3.15 (2H, m), 3.72 (3H, s), 3.75 (2H , s), 3.96-4.00 (1H, m), 4.10 (2H, s), 4.19 (2H, s), 4.27 (1H, m), 4.33 (1H, m), 7.44 (4H, d, J = 4.3 Hz), 7.48 (2H, d, J = 1.5Hz), 7.61 (2H, s).

Production Example 98: (2R) -dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of (benzyl) -methyl-amino] -pentanoic acid ethyl ester [Compound No. 117]

Example 98-1: Synthesis of 5-t-butoxycarbonylamino- (2R) -dipropylamino-pentanoic acid ethyl ester 333.2 mg of the compound obtained in Example 96-2 was dissolved in 13.2 ml of anhydrous methanol to give propion. 0.221 ml of aldehyde, 0.42 ml of trimethyl orthoformate and 241.3 mg of sodium cyanoborohydride were added. Stir at room temperature for 3 days. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dried over magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 156.5 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 345 [M + H] ⁺

Example 98-2: (2R) -dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl } -Benzyl) -methyl-amino] -pentanoic acid ethyl ester [Compound No. 117] 156.5 mg of the compound obtained in Example 98-1 was dissolved in 1.5 ml of methanol. Thereto was added 1.5 ml of a 4 mol / l hydrogen chloride / dioxane solution, and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 6 ml of anhydrous methanol. Thereto were added 167.1 mg of the compound obtained in Example 84-5 and 0.148 ml of trimethyl orthoformate, and the mixture was stirred at room temperature for 16 hours. Thereto was added 51.1 mg of sodium borohydride. Stir at room temperature for 1 hour. After the reaction, water was added. The solvent was distilled off and extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off.
This was dissolved in 9.7 ml of anhydrous methanol, and 0.053 ml of 36% formaldehyde aqueous solution and 84.4 mg of sodium cyanoborohydride were added. The pH was adjusted to 5 with acetic acid. Stir at room temperature for 18 hours. After the reaction, the solvent was distilled off. A 1 mol / l aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and treated with hydrochloric acid to obtain 120 mg of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 552 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.79 (6H, t, J = 7.1 Hz), 1.18 (3H, t, J = 7.1 Hz), 1.24-1.40 (6H, m), 1.47- 1.62 (2H, m), 2.31-2.37 (4H, m), 2.43-2.49 (2H, m), 2.51 (3H, s), 3.22 (1H, t, J = 8.1Hz), 3.34-3.42 (2H, br), 3.49-3.52 (4H, m), 3.50 (3H, s), 3.56 (2H, s), 4.00-4.10 (2H, m), 6.80 (1H, d, J = 1.22Hz), 6.98-7.06 (2H, br), 7.07 (1H, d, J = 1.2Hz), 7.22 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.1Hz).

Production Example 99: (2R) -dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl}- Synthesis of (benzyl) -methyl-amino] -pentanoic acid [Compound No. 118]

Example 99-1: (2R) -dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl Synthesis of} -benzyl) -methyl-amino] -pentanoic acid [Compound No. 118] 93.1 mg of the compound obtained in Example 98-2 was dissolved in 2 ml of concentrated hydrochloric acid and 0.1 ml of water. Heated to reflux for 4 hours. After the reaction, the solvent was distilled off to obtain 90.3 mg of hydrochloride of the title compound as a brown solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ + D ₂ O): δ = 0.91 (6H, t, J = 7.1 Hz), 1.67-1.73 (4H, m), 1.92 (4H, m), 2.59 (3H , s), 3.06-3.17 (6H, m), 3.72 (3H, s), 3.80 (2H, s), 4.11-4.13 (1H, m), 4.11 (2H, s), 4.19 (2H, s), 4.31-4.34 (2H, m), 7.41 (2H, d, J = 7.9Hz), 7.45-7.47 (2H, m), 7.48 (2H, s), 7.60 (2H, s).

Production Example 100: [(4-Dipropylamino-butyl) -methyl-amino]-(4-{[(1H-imidazole-2-
Synthesis of (Ilmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl) -acetic acid ethyl ester [Compound No. 119]

Example 100-1: N- (4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-
Synthesis of (Ilmethyl) -amino] -methyl} -benzylidene) -N ′, N′-dipropyl-butane-1,4-diamine 210 mg of the compound obtained in Example 84-5 was dissolved in 6.3 ml of anhydrous methanol. Example 1-2
117 mg of the compound obtained by 297 μl of trimethyl orthoformate was added and stirred at room temperature for 6 and a half hours. After the reaction, the solvent was distilled off to obtain 325 mg of the title compound as a brown oil.
MS (FAB, Pos.): M / z = 464 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3Hz), 1.40-1.82 (8H.m), 2.34-2.46 (6H, m), 2.55-2.70 (2H, m ), 3.45 (2H, s), 3.55 (3H, s), 3.63 (2H, s), 3.72 (2H, s), 6.88 (1H, d, J = 1.2Hz), 6.99 (1H, d, J = 1.2Hz), 7.05-7.13 (2H, m), 7.46 (2H, d, J = 8.3Hz), 7.69 (2H, d, J = 8.3Hz), 8.27 (1H, s), 12.39 (1H, br) .

Example 100-2: [(4-Dipropylamino-butyl) -methyl-amino]-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -Amino] -methyl} -phenyl)-
Synthesis of ethyl acetate [Compound No. 119] 147 mg of the compound obtained in Example 100-1 was dissolved in 4.41 ml of anhydrous methylene chloride, and 59.2 mg of ytterbium trifluoromethanesulfonate was added. The solution was cooled to 0 ° C., 130 μl of trimethylsilylcyanide was added, the temperature was returned to room temperature, and the mixture was stirred for 24 hours. Then again the solution is 0
The mixture was cooled to 0 ° C., 130 μl of trimethylsilylcyanide was added, and the mixture was returned to room temperature, and further stirred for 30 hours. After the reaction, the solvent was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off to obtain 156 mg of the title compound as a pale yellow oil.
This was dissolved in 4.7 ml of ethanol, 780 μl of concentrated hydrochloric acid was added, and the mixture was refluxed at 95 ° C. for 16 hours.
After cooling to room temperature, the solvent was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off.
This was dissolved in 2.7 ml of absolute ethanol and 71 μl of 36% formaldehyde aqueous solution was added. 27.9 mg of sodium cyanoborohydride was added. The pH was adjusted to 5 with acetic acid and stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 13.2 mg of the title compound as a colorless oil.
MS (FAB, Pos.): M / z = 552 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.87 (6H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.34-1.51 (8H.m), 2.27-2.40 ( 6H, m), 2.62-2.65 (2H, m), 3.29 (3H, s), 3.46 (2H, s), 3.57 (3H, s), 3.61 (2H, s), 3.69 (2H, s), 3.85 (1H, s), 6.88 (1H, d, J = 1.2Hz), 7.00 (1H, d, J = 1.2Hz), 7.05-7.11 (2H, m), 7.30-7.36 (4H, m), 8.27 ( 1H, s), 12.35 (1H, br).

Production Example 101: [(4-Dipropylamino-butyl) -methyl-amino]-(4-{[(1H-imidazole-2-
Synthesis of (Ilmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl} -phenyl) -acetic acid [Compound No. 120]

Example 101-1: [(4-Dipropylamino-butyl) -methyl-amino]-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl) -Amino] -methyl} -phenyl)-
Synthesis of Acetic Acid [Compound No. 120] 5.1 mg of the compound obtained in Example 100-2 was dissolved in 204 μl of concentrated hydrochloric acid and refluxed at 100 ° C. for 20 hours. After the reaction, the solvent was distilled off to obtain 6.0 mg of the title compound as a white solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.91 (6H, t, J = 7.3 Hz), 1.63-1.69 (8H.m), 2.95-2.98 (6H, m), 3.00-3.11 (2H , m), 3.24-3.51 (5H, m), 3.70 (3H, s), 3.72 (2H, s), 4.08 (2H, s), 4.14 (1H, s), 7.45-7.55 (6H, m), 7.63-7.66 (2H, m).

Production Example 102: 2-{[(4-Dipropylamino-butyl) -methyl-amino] -methyl} -5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole-2 -Ilmethyl) -amino] -methyl} -benzoic acid ethyl ester [Compound No. 121]

Example 102-1: Synthesis of 2,5-dimethylbenzoic acid methyl ester
1.772 g of 2,5-dimethylbenzoic acid was dissolved in 30 ml of methanol. To the reaction solution, 0.7 ml of concentrated sulfuric acid was added, and the mixture was refluxed for 17 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue to adjust the pH to 9, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1.9353 g of the title compound as a pale yellow oil.
MS (FAB, Pos.): M / z = 165 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 2.34 (3H, s), 2.55 (3H, s), 3.89 (3H, s), 7.13 (1H, d, J = 7.6 Hz), 7.
20 (1H, d, J = 7.6Hz), 7.72 (1H, s).

Example 102-2: Synthesis of 6-hydroxymethyl-3H-isobenzofuran-1-one 1.1274 g of the compound obtained in Example 102-1 was dissolved in 19.2 ml of carbon tetrachloride. To the reaction solution, 2.417 g of N-bromosuccinimide and 147.2 mg of benzoyl peroxide were added, and the mixture was heated to reflux for 6.5 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2.4003 g of a mixture containing 2,5-bis-bromomethyl-benzoic acid methyl ester. The resulting mixture was dissolved in 48 ml of 50% 1,4-dioxane aqueous solution. To the reaction solution, 3.4823 g of calcium carbonate was added and stirred at 100 ° C. for 16.5 hours. The reaction solution was cooled to room temperature, then cooled to 0 ° C., concentrated hydrochloric acid was gradually added to adjust to pH 2, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 372.0 mg of the title compound as white crystals.
MS (FAB, Pos.): M / z = 165 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 1.91 (1H, t, J = 5.9 Hz), 4.83 (2H, d, J = 5.9 Hz), 5.33 (2H, s), 7.50 (1H, d, J = 7.8Hz), 7.72 (1H, d, J = 7.8Hz), 7.93 (1H, s).

Example 102-3: Synthesis of 2-{[(4-Dipropylamino-butyl) -methyl-amino] -methyl} -5- (2-methoxy-methoxyethoxymethyl) -benzoic acid In Example 102-2 160.7 mg of the obtained compound was dissolved in 5 ml of chloroform. To the reaction solution, 485.2 mg of 2-methoxyethoxymethyl chloride and 540.2 mg of diisopropylethylamine were added, and the mixture was stirred at room temperature for 16.5 hours. 1 mol / l hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 3 ml of methanol. To the reaction solution was added 3 ml of a 1 mol / l aqueous sodium hydroxide solution, and the mixture was heated to reflux for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and extracted with chloroform. The aqueous layer was adjusted to pH 3 by adding 1 mol / l hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 4 ml of chloroform. To the reaction solution, 421.3 mg of manganese dioxide was added and stirred at room temperature for 5.5 hours. The catalyst was filtered off through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in 3 ml of methanol. To the reaction solution were added 187.7 mg of N′-methyl-N, N-dipropyl-butane-1,4-diamine and 178.7 mg of sodium cyanoborohydride obtained by the method described in the patent (WO 2004/024697). The pH was adjusted to 5 and the mixture was stirred at room temperature for 15.5 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to obtain 263.3 mg of a crude product of the title compound as a yellow oil.
MS (FAB, Pos.): M / z = 439 [M + H] ⁺

Example 102-4: Synthesis of 2-{[(4-Dipropylamino-butyl) -methyl-amino] -methyl} -5-hydroxymethyl-benzoic acid ethyl ester Compound 263.3 obtained in Example 102-3 mg was dissolved in 6 ml of ethanol. WSCI hydrochloride 147.5 mg and HOBt 104.9 mg were added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 6 ml of 2-methyl-2-propanol. To the reaction solution was added 35.2 mg of pyridinium p-toluenesulfonate, heated to reflux for 2 days, 4 ml of 1 mol / l hydrochloric acid was added, and the mixture was stirred at 90 ° C. for 30 minutes. The reaction solution was cooled to room temperature and extracted with chloroform. A 1 mol / l aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to 13, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (83.5 mg) as a colorless oil.
MS (FAB, Pos.): M / z = 379 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.4Hz), 1.37-1.64 (13H, m), 2.15 (3H, s), 2.32-2.38 (6H, m), 3.78 (2H, s), 4.34 (2H, q, J = 7.1Hz), 4.71 (2H, s), 7.43 (1H, d, J = 7.8Hz), 7.51 (1H, d, J = 7.8Hz), 7.74 (1H, s).

Example 102-5: 2-{[(4-Dipropylamino-butyl) -methyl-amino] -methyl} -5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole -2-ylmethyl) -amino] -methyl}-
Synthesis of ethyl benzoate [Compound No. 121] 83.5 mg of the compound obtained in Example 102-4 was dissolved in 3 ml of chloroform. To the reaction solution, 423.5 mg of manganese dioxide was added and stirred at room temperature for 2 hours. The catalyst was filtered off through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in 1.5 ml of methanol. To the reaction solution, 45.2 mg of the compound obtained in Example 88-4 and 21.1 mg of sodium cyanoborohydride were added, adjusted to pH 5 with acetic acid, and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, 1 mol / l aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate), thereby obtaining the subject compound (5.7 mg) as a colorless oily substance.
MS (FAB, Pos.): M / z = 552 [M + H] ^+
1 H-NMR (500 MHz, CDCl ₃ ): δ = 0.86 (6H, t, J = 7.6 Hz), 1.37-1.43 (9H, m), 1.69 (4H, br), 2.15 (3H, s), 2.35 2.37 (6H, m), 3.44 (2H, s), 3.57 (3H, s), 3.64 (2H, s), 3.71 (2H, s), 3.75 (2H, s), 4.34 (2H, q, J = 7.1Hz), 6.88 (1H, d, J = 1.5Hz), 7.00 (1H, d, J = 1.5Hz), 7.08 (1H, br), 7.13 (1H, br), 7.45-7.50 (2H, m) , 7.80 (1H, s), 12.34 (1H, br).

Production Example 103: 2-{[(4-Dipropylamino-butyl) -methyl-amino] -methyl} -5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole-2 -Ilmethyl) -amino] -methyl} -benzoic acid [Compound No. 122]

Example 103-1: 2-{[(4-Dipropylamino-butyl) -methyl-amino] -methyl} -5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazole) -2-ylmethyl) -amino] -methyl}-
Synthesis of Benzoic Acid [Compound No. 122] 5.7 mg of the compound obtained in Example 102-5 was suspended in 30 μl of distilled water. 100 μl of concentrated hydrochloric acid was added to the reaction solution, and the mixture was stirred at 80 ° C. for 19 hours. The reaction solution is cooled to room temperature and then concentrated under reduced pressure.
6.9 mg of the title compound was obtained as a white solid.
MS (FAB, Pos.): M / z = 524 [M + H] ^+
1 H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.92 (6H, t, J = 7.3 Hz), 1.66-1.82 (8H, m), 2.61 (3H, s), 2.98 (4H, br), 3.05 (2H, br), 3.17 (2H, br), 3.71 (3H, s), 3.83 (2H, s), 4.12 (2H, s), 4.21 (2H, s), 4.35 (1H, br), 4.60 (1H, br), 7.49 (1H, d, J = 2.0Hz), 7.51 (1H, d, J = 2.0Hz), 7.59 (1H, d, J = 7.8Hz), 7.63 (2H, s), 7.74 (1H, dd, J = 7.8,1.7Hz), 7.93 (1H, d, J = 1.7Hz), 9.37 (1H, br), 10.35 (1H, br).

  Next, structural formulas of the compounds of the present invention, such as the compounds produced in the above production examples, are shown in Table 1-1 to Table 1-11.

  Next, the results of the activity test etc. of the compound of the present invention are shown.

Test example 1

HIV-1IIIB-infected MT-4 cells (3.0 × 10 ⁴ / well, MOI (Multiplicity of infection): 0.01) were added to a 96-well microtiter plate together with various concentrations of test compounds immediately after infection. After culturing at 37 ° C for 5 days in a carbon dioxide incubator, the MTT (tetrazolium) method (Pawels, e
t al, Journal of Virology Method (J. of Virol. Method.), 20, 309-321 (1988)). The antiviral activity is expressed in μM at a concentration that inhibits cell damage caused by HIV infection by 50% (EC50: 50% Effective Concentration). Table 2 shows the results.

Test example 2

MT-4 cells (5 × 10 ⁶ /0.2 ml / well) were cultured on a 24-well microtiter plate. After culturing at 37 ° C. for 24 hours in a carbon dioxide incubator, the culture solution was replaced with a buffer solution (RPMI-1640 containing 0.1% BSA). Various concentrations of the test substance were combined with the ligand ¹²⁵ I-SDF-1α (specific activity 2,200 Ci / mmol; manufactured by Daiichi Chemicals (Tokyo)) for 2 hours under ice cooling. After washing the unbound ligand with cold PBS, the radioactivity of the bound ligand is measured with a liquid scintillation counter (manufactured by Japan Packard (Tokyo)), and the rate at which the test substance inhibits the binding between the radioactive ligand and the receptor CXCR4 (0.01 μM %).
The results are shown in Table 3.

Test example 3

The acute toxicity of the compound was examined. That is, 6-week-old SD rats (male) were divided into 2 to 3 rats in each group, and the compound of the example was dissolved in physiological saline and administered once intravenously (dosage 2.5 mg / kg). The number of deaths was examined. The results are shown in Table 4.
As shown in Table 4, it was confirmed that any compound administered did not die and had no acute toxicity.

Test example 4

34.6% of compound No. 4 compound, 34.6% of JP lactose, 17.3 JP corn starch
%, JP hydroxypropylcellulose 7.3%, JP low substituted hydroxypropylcellulose 6.2%, and mixed well in a plastic bag. To this was added the same amount of JP purified water as the compound, and kneaded with a twin screw kneader for 20 minutes to form a wet mass. This was granulated using an extrusion granulator (cylindrical hole diameter 1 mm), and the granulated product was dried using a fluidized bed dryer (40 ° C., 30 minutes). The dried granules were sieved, mixed well at a ratio of 1% magnesium stearate to 99% of the sieved product, and tableted using a tableting machine to obtain tablets with an average weight of 292 mg.
Separately, 8% of JP hydroxypropyl methylcellulose, 1.6% of JP Macrogol 6000, 5% of the tablet weight of the tablet that was first tableted with 100% of these dissolved in JP purified water. It sprayed using the high coater in the ratio of%. After spraying, it was dried for 20 minutes to prepare an undercoat tablet.
Next, 10% of the pharmaceutical additive standard hydroxypropyl cellulose acetate succinate, 3% of JP JP triethyl citrate, 2% JP JP titanium dioxide, 0.05% JP JP hydroxypropyl cellulose were dissolved in JP purified water 100 An enteric coating solution having a concentration of% was prepared. This enteric coating solution was sprayed using a high coater at a ratio of 10% with respect to the tablet weight. After spraying, it was dried for 30 minutes to prepare an enteric solvent. This enteric solvent did not elute the main drug for 2 hours in JP 1 liquid, and had the property of eluting more than 80% of the main drug in 30 minutes in JP 2 liquid.

Test Example 5

Collected blood from human serum pool (Cosmo Bio) or Crj: CD (SD) IGS male rat (Charles River Japan) in a tube, and pooled by centrifugation (3500 rpm) for 10 minutes Serum was dispensed in 147 μl. 147 μl of physiological saline (manufactured by Hikari Pharmaceutical Co., Ltd.) was dispensed thereto. It was then preincubated for 3 minutes. Thereto, a 25 mmol / l DMSO solution of Compound No. 91 was diluted with physiological saline, and 3 μl of a solution adjusted to 500 μmol / l was added and mixed. The reaction was started with a thermomixer, and after 30 minutes, 600 μl of a 0.1% formic acid / methanol solution was added and mixed. This was centrifuged (15000 rpm) for 5 minutes, and LCMS (liquid chromatography mass spectrometry) measurement was performed on the supernatant to confirm that compound 91 was changed to compound 84. The results are shown in Table 5.

The novel amine compound according to the present invention or a pharmacologically acceptable salt thereof, or a prodrug thereof can provide a novel CXCR4 antagonist. The novel CXCR4 antagonist of the present invention has a CXCR4 antagonistic action, and exhibits an excellent effect as a therapeutic or preventive drug for diseases such as viral infections such as HIV, rheumatism, or cancer metastasis based on the CXCR4 antagonistic action.

Claims (9)

A compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof.
In formula (1)
n _1, n _2, n ₃ is an integer of 1-3.
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ represent a hydrogen atom.
A ₁ and A ₂ each independently represent an optionally substituted imidazole group, and at least one of them represents N- (carboxylmethyl) imidazole or N- (ethoxycarbonylmethyl) imidazole.
W represents an optionally substituted benzene ring.
X represents CH ₂ .
D represents a group represented by the following formula (6).
In formula (6)
Q is CH ₂ , NR ₁₂
R ₁₂ represents a hydrogen atom or a methyl group.
Y represents a group represented by the following formula (7).
In formula (7)
m ₃ represents an integer of 0-6.
R ₁₈ and R ₁₉ represent a hydrogen atom.
B represents a group represented by the following formula (8).
In formula (8)
R ₂₅ and R ₂₆ represent an optionally substituted alkyl group having 1 to 15 carbon atoms.
In addition, in the case where one or two or more asymmetric carbons that may be present in the compound represented by the general formula (1) are one, a pure optically active substance represented by an absolute configuration R or S, Mixtures, racemates, and optically pure diastereomers, racemates, or combinations of these in any ratio, if any, are present. Good. _2. The compound according to claim ₁ , wherein n ₁ , n ₂ , and n ₃ are represented by an integer of 1, or a pharmacologically acceptable salt thereof. W is represented by a benzene ring, X is represented by -CH _2- , D is a group represented by the formula (6),
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q in the formula (6) is a group represented by NR ₁₂ and R ₁₂ is as described above. (2-[[(1-Carboxymethyl-1H-imidazol-2-ylmethyl)-(4-[[(4-dipropylamino-butyl) -methyl-amino] -methyl] -benzyl) -amino] -methyl ] -Imidazol-1-yl) -acetic acid,
(2-[[(4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl] -Imidazol-1-yl) -acetic acid,
(2-[[(4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -benzyl)-(1-ethoxycarbonylmethyl-1H-imidazol-2-ylmethyl) -amino]- Methyl] -imidazole 1-
Yl) -ethyl acetate,
2-[[(4-[[(4-Dipropylamino-butyl) -methyl-amino] -methyl] -benzyl)-(1-methyl-1H-imidazol-2-ylmethyl) -amino] -methyl]- A compound selected from imidazol-1-yl) -ethyl acetate or a pharmacologically acceptable salt thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.   A CXCR4 antagonist comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.   The antiviral agent which contains the compound in any one of Claim 1 thru | or 4, or its pharmacologically acceptable salt as an active ingredient.   A rheumatic disease ameliorating agent based on CXCR4 antagonism, comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.   A cancer metastatic disease ameliorating agent based on CXCR4 antagonism comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.