CA2488785C

CA2488785C - Amine compound and use thereof

Info

Publication number: CA2488785C
Application number: CA2488785A
Authority: CA
Inventors: Toru Yamazaki; Shigeyuki Kikumoto; Masahiro Ono; Atsushi Saitou; Haruka Takahashi; Sei Kumakura; Kunitaka Hirose; Mikiro Yanaka; Yoshiyuki Takemura; Shigeru Suzuki; Ryo Matsui
Original assignee: Kureha Corp
Current assignee: Kureha Corp
Priority date: 2002-09-11
Filing date: 2003-09-05
Publication date: 2012-07-03
Anticipated expiration: 2023-09-05
Also published as: CN1646495A; WO2004024697A1; US7833991B2; US7176227B2; KR20050035873A; AU2003261974A1; CA2488785A1; US20070208033A1; KR100863667B1; EP1550657A4; JP3714948B2; CN100528846C; US20050165063A1; US20110046113A1; EP1550657A1; JPWO2004024697A1

Abstract

It is intended to provide novel amine compounds which are efficacious against diseases such as infection with HIV virus, rheumatism and cancer metastasis. Namely, amine compounds represented by the following general formula (1): (see formula 1) In a typical case, A1 and A2 represent each an optionally substituted monocyclic or polycyclic aromatic heterocycle; W represents cyclic C3-10 alkylene, an optionally substituted monocyclic or polycyclic aromatic heterocycle, a monocyclic or polycyclic aromatic ring or a partly saturated polycyclic aromatic ring; X represents O, CH2, C(=O) or NR11; and D is a group represented by the following general formula (4) or (6). (see formula 4) (see formula 6) In the formula (6), Q represents a single bond, S, O or NR12; and Y is a group represented by the following general formula (7). (see formula 7) z represents an optionally substituted monocyclic or polycyclic aromatic ring. In the formula (6), B represents NR25R26. In the above formulae, R1 to R26 each represents hydrogen, alkyl, alkenyl or alkynyl.

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
CECI EST LE TOME DE _2 NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.

JUMBO APPLICATIONS / PATENTS

THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE: For additional volumes please contact the Canadian Patent Office.

Description AMINE COMPOUND AND USE THEREOF
Technical Field The present invention relates to an amine compound or a pharmacologically acceptable salt thereof, or a prodrug thereof, in particular, an amine compound having anti-virus activity based on antagonism to chemokine receptor CXCR4.
Furthermore, the present invention relates to a pharmaceutical drug for associated diseases such as rheumatic diseases and cancer metastatic diseases, based on antagonism against a chemokine receptor CXCR4.

Background Art While examples of therapeutic drugs against the acquired immunodeficiency syndrome (AIDS) caused by an infection with the human immunodeficiency virus (HIV) include a reverse transcriptase inhibitor and a protease inhibitor, therapeutic effectiveness of those drugs has been lost due to the emergence of drug resistant HIV mutants (see, for example, Saishin Igaku, Vol. 53, No. 9, p. 2031 (1998)).
Also, the polypharmacy using the combination of such drugs has such disadvantages that it requires many conditions to be observed in administration, that it is complex, that it needs many kinds of drugs to be administered, and that it causes various side effects (see, for example, Nikkei Science, Oct., p. 29 (1998)). Moreover, particularly in case of using the protease inhibitor, it is known that the probability of causing emergence and screening of the resistant strain will increase unless the administration of approximately 100% of the drugs is kept, in spite of the complex administration method and many side effects thereof (see, for example, Molecular Medicine, Vol. 36, No. 9, p.
1012 (1999)).

Alternatively, development of vaccine has been attempted because many viral diseases were destroyed or remarkably weakened by vaccines in the past. However, this is considered to be extremely difficult since mutations are occurred frequently in HIV (see, for example, Nikkei Science, Oct., p. 42 (1998)).

Although several kinds of compounds having an anti-HIV
effect have been reported as described above, it is now strongly desired to develop a novel antiviral drug which has excellent anti-retrovirus effect, is capable of opposing to the expression of the resistance, and which has little toxicity and causes little side effect, thereby allowing long term administration.

Chemokines is one kind of cytokine which renders chemotaxis to leukocytes, and is a secretory protein.
Chemokine is classified into CXC-chemokine, CC-chemokine, C-chemokine, CX3C-chemokine according to the cysteine (Cys) sequence at N-terminal, and the total number thereof is said to be about 30. The chemokine receptor includes several sub types. Among them, it is known that the CXCR4 which is a ligand for CXC-chemokine SDF-1 is utilized as a coreceptor on infection to a host cell of T cell-directive HIV (see,

2 for example, Science, 272, 872 (1996) and Nature, 382, 829 (1996)). The HIV invades through binding to the CXCR4 on the surface of a host cell of an envelope protein gp120.
That is, the drug having antagonism against the CXCR4 is expected as an anti-HIV drug based on a novel mechanism of invasion inhibition, and there have been reported three low molecular compounds as such drugs: AMD3100 (see, for example, J. Exp. Med, 186, 1383 (1997), T22 (see, for example, J. Exp.
Med, 186, 1389 (1997)), and ALX40-4C (see, for example, J.
Exp. Med, 186, 1395 (1997)).

On the other hand, it has been elucidated that the CXCR4 associates with various diseases besides HIV infection.
For example, there has been reported its association with rheumatic disease (see, for example, WO 00/06086), cancer metastatic disease (see, for example, Nature, 410, 50 (2001)), etc.

As a therapeutic drug for such diseases, it is strongly desired to develop a novel low-molecular drug which has CXCR4 antagonism, and which has little toxicity and causes little side effect, thereby allowing long term administration.

Disclosure of the Invention An object of the present invention is to provide a drug and a prodrug thereof having an excellent anti-retrovirus effect, and also a novel chemical structure having an excellent CXCR4 antagonism against SDF-la, and high safety.

As a result of studies to develop a compound

3 having an excellent anti-retrovirus effect, and also having a novel chemical structure useful as an excellent CXCR4 antagonist against SDF-la, the present inventors have found a group of amine compounds which exhibit protection characteristics in a cell vaccinated with HIV-1 and therefore are regarded as having a potentiality for treatments of AIDS, AIDS-associated complication, and the like, and which also exhibit a powerful CXCR4 antagonism and therefore are regarded as having a potentiality for treatments of rheumatic disease, cancer metastatic diseases, and the like. Thus, another object of the present invention is to provide a compound represented by the general formula (1) defined below, which has an anti-virus activity for mainly HIV and a CXCR4 antagonism, and still another object of the invention is to provide a drug comprising the compound represented by the general formula (1), for treating virus-infected patients and patients suffering from rheumatism, cancer, or the like.

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

Ai (CR R2)nl N (CR5R6)n3 W X D = = (1 ) A2-(CR3R4)n2 wherein each of n1, n2, and n3 is an integer of 0 to 3;

4 each of R1, R2, R3, R4, Rõ and R6 is independently a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, or a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms; and each of Al and A2 is independently a substitutable monocyclic or polycyclic heteroaromatic ring, a partly saturated substitutable polycyclic heteroaromatic ring, a substitutable monocyclic or polycyclic aromatic ring, a partly saturated substitutable polycyclic aromatic ring, a substitutable heterocycle, or a group represented by the following formula (2):

N -C .....(2) R8 Rio wherein each of R7, R8, R9, and R10 is independently a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, or a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms;

W is a substitutable alkylene group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenylene group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynylene group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable cyclic alkylene group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms, a substitutable monocyclic or polycyclic heteroaromatic ring, a partly saturated substitutable polycyclic heteroaromatic ring, a substitutable monocyclic or polycyclic aromatic ring, a partly saturated substitutable polycyclic aromatic ring, or a substitutable heterocycle;

X is 0, CH2r NR11r or a group represented by the following formula (3);

R11 is a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, or a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms;

or S .... (3) II II
O (O)m1 wherein m1 is an integer of 1 or 2;

D is a group represented by the following formula (4) or (6) :

N\ N R13 or -N (4) wherein R13 is a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, or a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms, or a group represented by the following formula (5):

(CR14R15)m2 N /\ ..... (5) wherein m2 is an integer of 2 to 4;

each of R14, R15, R16, and R17 is independently a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, or a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms;

Q -Y B .....(6) wherein Q is a single bond when X is 0, a single bond or a group represented by the formula (3) when X is NR11, or a single bond, S, 0, or NR12 when X is CH2 or represented by the formula (3);

R12 is a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, or a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms; and Y is a group represented by the following formula (7):
(CR18R19)m3 or .....(7) (CR20R21)m4 z (CR22R23)m5 wherein m3 is an integer of 0 to 6;

each of R18 and R19 is independently a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms, or a substitutable aromatic ring, and R12 and R18 may form a ring;

each of m4 and m5 is an integer of 0 to 2;

each of R20, R21, R22, and R23 is independently a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, or a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms;

z is a substitutable cyclic alkylene group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms, a substitutable monocyclic or polycyclic heteroaromatic ring, a partly saturated substitutable polycyclic heteroaromatic ring, a substitutable monocyclic or polycyclic aromatic ring, a partly saturated substitutable polycyclic aromatic ring, or a substitutable heterocycle;

B is a group represented by the following formula (8):
01 Q2 or .... 8 wherein Q1 is S, 0, or NH and Q2 is S, 0, or NR27;

each of R24 and R27 is independently a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms, or a substitutable aromatic ring, and R24 and R27 may form a ring;

each of R25 and R26 is, when above X is CH2, independently a hydrogen atom, a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms and 1 to 3 double bonds, or a substitutable alkynyl group having 2 to 15 carbon atoms, preferably 2 to carbon atoms, and more preferably 2 to 7 carbon atoms and having 1 to 3 triple bonds, where R25 and R26 may form a ring and, depending on circumstances, the ring may be formed by binding through a heteroatom, a cyclic alkyl group, an aromatic ring, a heteroaromatic ring, or a heterocycle;

each of R25 and R26 is, when above X is not CH2, independently a hydrogen atom, a substituent represented by the following formula (9), a substitutable alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms, a substitutable cyclic alkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms, a substitutable alkenyl group having 1 to 3 double bonds and 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, or a substitutable alkynyl group having 1 to 3 triple bonds and 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, and R25 and R26 may form a ring and, depending on circumstances, the ring may be formed by binding through a heteroatom, a cyclic alkyl group, an aromatic ring, a heteroaromatic ring, or a heterocycle:

R28 \/Q3 G
o .... (9) /--I Oms R29 ~4 wherein m6 is 0 or 1, where when m6 = 0, Q3 is CH or N and Qq is N, S, or 0, and when m6 = 1, each of Q3 and Qq is independently CH or N;

G is a substitutable alkylene group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms or a substitutable alkenylene group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms;

R28 is an alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms to be substituted at any position except a nitrogen atom which may be present on the ring, a substitutable alkenyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, a substitutable alkynyl group, alkoxy group, a haloalkyl group, a 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 heterocycle, or a heteroaromatic ring having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms, or may be a hydrogen atom when m6 = 1 and Q3 and Q4 are both CH; and R29 is a hydrogen atom or the same group as R24, which may be coupled with G to form. a ring.

one or two or more asymmetric carbon atoms may exist in the compound represented by the general formula (1), where when one asymmetric carbon atom exists, the compound may be in the form of any one of a pure optically active substance represented by the absolute configuration R or S, a mixture thereof in a predetermined ratio, and a racemic mixture thereof or when two or more asymmetric carbon atoms exist, the compound may be in the form of any one of an optically pure diastereomer, a racemic mixture thereof, and a combination thereof in a predetermined ratio.

The terms as used in this specification are defined as described below, and they may be used singly or in combination.

An alkyl group represents a saturated hydrocarbon group with any structure of a linear chain, a branched chain, or a ring. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a pentyl group, and a neopentyl group.

An alkenyl group represents a hydrocarbon group with any structure of a linear chain, a branched chain, or a ring having a double bond. Examples of the alkenyl group include an allyl group, a 1-butenyl group, a 2-butenyl group, an isobutenyl group, and a cyclohexenyl group.

An alkynyl group represents a hydrocarbon group with any structure of a linear chain, a branched chain, or a ring having a triple bond. Examples of the alkynyl group include a propynyl group and a 1-butynyl group.

A cyclic alkyl group represents a cyclic hydrocarbon group. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

An aromatic ring represents an aromatic ring formed of a hydrocarbon. Examples of a monocyclic aromatic ring include a benzene ring; and examples of a polycyclic aromatic ring include a naphthalene ring and an anthracene ring. Examples of a partly saturated polycyclic aromatic ring include a dihydronaphthalene ring, a tetralin ring, an indan ring and the like. A heteroaromatic ring represents an aromatic ring having one or two or more nitrogen atoms, oxygen atoms, or sulfur atoms in the ring. Examples of a monocyclic heteroaromatic ring include a pyrrole ring, a furan ring, a thiophene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, an imidazole ring, a pyrazole ring, an oxazole ring, a thiazole ring, a thiadiazole ring, an oxadiazole ring, and a triazole ring.
Examples of a polycyclic heteroaromatic ring include a quinoline ring, an isoquinoline ring, a benzimidazole ring, an indazole ring, a benzothiazole ring, a benzoxazole ring, an indole ring, a benzofuran ring, and a benzothiophene ring.

Examples of a partly saturated polycyclic aromatic ring include a tetrahydroisoquinoline ring and a tetrahydroquinoline ring. A heterocycle represents a saturated ring that may have one or two or more nitrogen atoms, oxygen atoms, or sulfur atoms in the ring. Examples of the heterocycle include pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine.

An alkylene group represents a hydrocarbon group that can be bonded two groups at the terminals. Examples of the alkylene group include an ethylene group, a propylene group, an isopropylene group, a butylene group, an isobutylene group, and a 2,2-dimethylethylene group.

An alkenylene group represents an alkylene group having a double bond. Examples of the alkenylene group include a propenylene group, a 2-butenylene group, and a 1,3-butadienylene group.

An alkynylene group represents an alkylene group having a triple bond. Examples of the alkynylene group include a propyny-'iene group and a butynylene group.

The cyclic alkylene group in W represents a cyclic hydrocarbon group that can be bonded two groups at any positions. Examples of the cyclic alkylene group include a cyclopropylene group, a cyclopentylene group, a cyclohexylene group, and a tetralinylene group. An aromatic ring also represents an aromatic ring that can be bonded two groups at any positions. Examples of the aromatic ring group include a phenylene group and a napthalene group.

A heteroaromatic ring also represents a heteroaromatic ring that can be bonded two groups at any positions.
Examples of the heteroaromatic ring to be used include a pyrrole ring, a furan ring, a thiophene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, an imidazole ring, a thiazole ring, an oxazole ring, a triazole ring, a quinoline ring, an isoquinoline ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, an indole ring, a benzofuran ring, and a benzothiophene ring.

B represents R25(R26)N-, where R25 and R26 may form a ring. Examples of a ring formed by binding R25 and R26 directly together with a nitrogen atom to which they are bound include a pyrrolidine ring, a piperidine ring, a hexamethyleneimine ring, and a heptamethyleneimine ring.

Examples of a ring formed by binding R25 and R26 through a heteroatom together with a nitrogen atom to which they are bound include a morpholine ring and a piperazine ring.
Examples of a ring formed by binding R25 and R26 through an aromatic ring together with a nitrogen atom to which they are bound include a tetrahydroisoquinoline ring and a tetrahydroindole ring.

When R25 and/or R26 is a group represented by the formula (8) and R29 and G form a ring, examples of R25 and R26 include a tetralinyl group, an indanyl group, a tetrahydroquinolyl group, and a tetrahydroisoquinolyl group.

Examples of the "substitutable" groups in the expressions for each substituent include a hydroxyl group, a thiol group, a formyl group, a carboxyl group, a sulfonyl group, an amino group, an amide group, a carbamoyl group, a cyano group, an alkoxy group, an alkoxycarbonyl group, an alkylamino group, an acylamino group, an alkoxycarbonylamino group, alkylthio group, an aminosulfonyl group, a dialkylaminosulfonyl group, a methanesulfonyl group, a p-toluenesulfonyl group, and a phenyl group. The alkoxy group represents a group in which an alkyl group binds through an oxygen atom, and the acylamino group represents a group in which an alkyl group or a phenyl group binds to an amino group through a carbonyl group. Further, examples of the "substitutable" groups in Al and A2 include an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, and an aminoalkyl group other than the group described above.

The prodrug is a precursor substance that becomes an effective drug through biochemical metabolism after administration to the living body. Specifically, the prodrug is a compound which is obtained by binding one or more appropriate groups, that is eliminated by metabolism in the living body, such as alkoxycarbonyl group or dialkylaminosulfone group with N in the ring or chain of a heterocycle or the like contained in the compound represented by the general formula (1). Alternatively, the prodrug is a compound coupled with one or more ester groups or the like that utilize alcohol or carboxylic acid, which may be contained in the compound represented by the general formula (1).

In addition, pharmacologically acceptable salts include trifluoroacetates, hydrochlorides, acetates, sulfates, nitrates, lactates, maleates, methane sulfonates, toluene sulfonates, tartrates, citrates, oxalates, malonates, succinates, fumarates, propionates, butyrates,phosphorates, terephthalates, and glucuronates.

BRIEF DESCRIPTION OF THE DRAWINGS

Figs. 1 - 24 illustrate process steps of production methods described below for several compounds of the present invention. In other words, Figs. 1 to 24 show reaction process steps of Production Method Examples 1 - 24, respectively.

BEST MODE FOR CARRYING OUT THE INVENTION

Compounds of the present invention can be produced by organic chemical reactions generally employed in the art.
Hereinafter, production methods therefor will be exemplified with reference to the accompanying drawings, Figs. 1 - 24.
However, the synthesis of the compounds of the present invention is not limited to these methods.

Production Method Example 1 The reaction process steps of Production Method Example 1 are shown in Fig. 1.

Step 1-1 An easily obtainable compound (I-1) is reacted with commercially available 2-imidazole carboxaldehyde and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to obtain a compound (1-2).

Step 1-2 The compound (1-2) is reacted with commercially available di-t-butyl dicarbonate and an appropriate base such as triethylamine in an appropriate solvent such as chloroform to thereby obtain a compound (I-3).

Step 1-3 The compound (1-3) is reacted with an appropriate base such as a sodium hydroxide aqueous solution in an appropriate solvent such as methanol to thereby obtain a compound (I-4).

Step 1-4 An easily obtainable compound (1-5) is reacted with commercially available propionaldehyde, an appropriate 1') dehydrating agent such as trimethyl orthoformate, and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (I-6).

Step 1-5 The compound (1-6) is deprotected by reaction with an appropriate acid such as a hydrogen chloride/dioxane solution in an appropriate solvent such as methanol. Then, the resultant is reacted with the compound (1-4) and an appropriate condensing agent such as commercially available 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimide (hereinafter, referred to as WSCI)/1-hydroxy benzotriazole (hereinafter, referred to as HOBt) in an appropriate solvent such as chloroform to thereby obtain a compound (I-7).

Step 1-6 The compound (1-7) is deprotected by reaction with an appropriate acid such as a hydrogen chloride/dioxane solution in an appropriate solvent such as methanol to thereby obtain a compound (I-8).

Step 1-7 Easily obtainable aldehyde A2-CHO (A2 is as described above) is reacted with the compound (1-8), an appropriate dehydrating agent such as trimethyl orthoformate, and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (1-9) represented by the general formula (1).

Step 1-8 A commercially available compound (I-10) is reacted with commercially available propionaldehyde and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain the compound (I-il).

Step 1-9 The compound (I-11) is reacted with an appropriate reductant such as hydrazine monohydrate in an appropriate solvent such as methanol/tetrahydrofuran (hereinafter, referred to as THF) to thereby obtain a compound (I-12).
Step 1-10 The compound (1-12) is reacted with the compound (1-4) and an appropriate condensing agent such as commercially available PS-carbodiimide/HOBt in an appropriate solvent such as DMF to thereby obtain a compound (I-13).

Step 1-11 An easily obtainable aldehyde A2-CHO (A2 is as described above) is reacted with the compound (1-13) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (1-14) represented by the general formula (1).
Step 1-12 A commercially available compound (1-10) is reacted with commercially available cyclohexanone, an appropriate dehydrating agent such as trimethyl orthoformate, and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (1-15).

Step 1-13 The compound (1-15) is reacted with commercially available benzyloxycarbonyl chloride and an appropriate base such as a sodium hydroxide aqueous solution in an appropriate solvent such as dioxane to obtain a benzyloxycarbonyl (hereinafter, referred to as Cbz) protecting substance, followed by the reaction with an appropriate reductant such as hydrazine monohydrate in an appropriate solvent such as methanol/THF to thereby obtain a compound (1-16).

Step 1-14 The compound (1-16) is reacted with the compound (1-4) and an appropriate condensing agent such as commercially available WSCI/HOBt in an appropriate solvent such as chloroform and then deprotected by reaction with an appropriate acid such as a hydrogen chloride/dioxane solution in an appropriate solvent such as methanol to thereby obtain a compound (I-17).

Step 1-15 An easily obtainable aldehyde A2-CHO (A2 is as described above) is reacted with the compound (1-17) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol and then deprotected by reaction with an appropriate reductant such as 10%

palladium-carbon under hydrogen atmosphere in an appropriate solvent such as ethanol to thereby obtain a compound (1-18), which is a compound represented by the general formula (1).
Production Method Example 2 The reaction process steps of Production Method Example 2 are shown in Fig. 2..

Step 2-1 The compound (1-4) is deprotected and esterified by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol to thereby obtain a compound (I-2).

Step 2-2 The compound (1-2) is reacted with 2-imidazole carboxaldehyde and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol and then reacted with an appropriate base such as a sodium hydroxide aqueous solution in an appropriate solvent such as methanol to thereby obtain a compound (II-1).

Step 2-3 An easily obtainable compound (11-2) is reacted with commercially available isobutylaldehyde and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (II-3).
Step 2-4 The compound (11-3) is deprotected by reaction with an appropriate reduct.ant such as 10% palladium-carbon under hydrogen atmosphere in an appropriate solvent such as ethanol. Then, the resultant is reacted with the compound (II-1) and an appropriate condensing agent such as commercially available dicyclohexylcarbodiimide (hereinafter, referred to as DCC')/HOBt in an appropriate solvent such as DMF to thereby obtain a compound (11-4) which is a compound represented by the, general formula (1).

Step 2-5 An easily obtainable compound (11-5) is reacted with commercially available propionaldehyde and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (II-6).
Step 2-6 The compound (11-6) is deprotected by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol and then reacted with the compound (II-1) and an appropriate condensing agent such as DCC/HOBt in an appropriate solvent such as DMF to thereby obtain a compound (11-7) which is a compound represented by the general formulation (1).

Step 2-7 The compound (1-12) is reacted with formic acid in an appropriate solvent such as acetic anhydride/THF and then reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THF to thereby obtain a compound (II--8).

Step 2-8 The compound. (11-8) is reacted with the compound (II-1) and an appropriate condensing agent such as DCC/HOBt in an appropriate solvent such as DMF to thereby obtain a compound (11-9) which is a compound represented by the general formula (1).

Step 2-9 A commercially available compound (II-10) is reacted with commercially available propionaldehyde, an appropriate dehydrating agent such as trirnethyl orthoformate, and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (II-11).

Step 2-10 The compound (II-11) is deprotected by reaction with an appropriate reluctant such as 10% palladium-carbon under hydrogen atmosphere in an appropriate solvent such as ethanol. Then, the resultant is reacted with the compound (II-1) and an appropriate condensing agent such as DCC/HOBt in an appropriate solvent such as DMF to thereby obtain a compound (11-12) which is a compound represented by the general formula (1).

Production Method Example 3 The reaction process steps of Production Method Example 3 are shown in Fig. 3.

Step 3-1 The compound (II-1) is reacted with the compound (1-5) and an appropriate condensing agent such as DCC/HOBt in an appropriate solvent such as DMF and then deprotected by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol to thereby obtain a compound (III-1).

Step 3-2 The compound (III-1) is reacted with easily obtainable aldehyde or ketone corresponding to R25 and R26 (R25 and R26 are as described above), an appropriate dehydrating agent such as trimethyl orthoformate, and an appropriate reductant such as sodium cya.noborohydride in an appropriate solvent such as DMF to thereby obtain a compound (111-2) which is a compound represented by the general formula (1).

Step 3-3 The compound (II-1) is reacted with commercially available 1-t-butoxycarbonyl-piperazine and an appropriate condensing agent such as WSCI/HOBt in an appropriate solvent such as DMF, and then deprotected by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol to thereby obtain a compound (III-3).

Step 3-4 The compound (111-3) is reacted with easily obtainable aldehyde or ketone corresponding to R13 (R13 is as described above), an appropriate dehydrating agent such as trimethyl orthoformate, and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as DMF to thereby obtain a compound (111-4) which is a compound represented by the general formula (1).

Production Method Example 4 The reaction process steps of Production Method Example 4 are shown in Fig. 4.

Step 4-1 The compound (I-1) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (IV-1).
Step 4-2 The compound (IV-1) is reacted with commercially available N-carbethoxyphthalimide and an appropriate base such as sodium carbonate in an appropriate solvent such as THE/water to thereby obtain a compound (IV-2).

Step 4-3 The compound (IV-2) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as chloroform to thereby obtain a compound (IV-3).
Step 4-4 The compound (1-12) is reacted with the compound (IV-3) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol and then t-butoxycarbonylated (hereinafter, butoxycarbonyl is referred to as Boc) by reaction with commercially available di-t-butyl dicarbonate, and an appropriate base such as triethylamine in an appropriate solvent such as DMF, and further reacted with an appropriate base such as an aqueous methylamine solution in an appropriate solvent such as methanol to thereby obtain a compound (IV-4).

Step 4-5 Easily obtainable aldehyde Al-CHO when Al and A2 are identical or easily obtainable Al-CHO and A2-CHO when Al and A2 are not identical (Al and A2 are as described above) is/are separately one after another reacted with the compound (IV-4) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol, and then deprotected by react-Lon with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol to thereby obtain a compound (IV-5) which is a compound represented by the general formula (1).

Step 4-6 A compound (IV-6), which is obtained by deprotecting the compound (1-6) with acid, is reacted with the compound (IV-3) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol, then t-butoxycarbonylated by reaction with commercially available di-t-butyl dicarbonate and an appropriate base such as triethylamine in an appropriate solvent such as DMF, and further reacted with an appropriate base such as an aqueous methylamine solution in an appropriate solvent such as methanol to thereby obtain a compound (IV-7).

Step 4-7 Easily obtainable aldehyde Al-CHO when Al and A2 are identical or easily obtainable Al-CHO and A2-CHO when Al and A2 are not identical (Al and A2 are as described above) is/are separately one after another reacted with the compound (IV-7) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol, and then deprotected by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol to thereby obtain a compound (IV-8) which is a compound represented by the general formula (1).

Step 4-8 A commercially available compound (IV-9) is reacted with commercially available N--carbethoxyphthalimide and an appropriate base such as sodium carbonate in an appropriate solvent such as water to thereby obtain a compound (IV-10).
Step 4-9 The compound (IV-10) is reacted with chlorosulfonic acid in an appropriate solvent: such as chloroform to thereby obtain a compound (IV-11).

Step 4-10 The compound (IV-11) is reacted with phosphorous pentachloride, to thereby obtain a compound (IV-12).
Step 4-11 The compound (IV-12) is reacted with the compound (IV-6) and an appropriate base such as triethylamine in an appropriate solvent such as chloroform, and then reacted with an appropriate reductant such as an aqueous methylamine solution in an appropriate solvent such as methanol to thereby obtain a compound (IV--13).

Step 4-12 Easily obtainable aldehyde Al-CHO when Al and A2 are identical or easily obtainable Al-CHO and A2-CHO when Al and A2 are not identical (A1 and A,, are as described above) is/are separately one after another reacted with the compound (IV-13) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (IV-14) which is a compound represented by the general formula (1).

Production Method Example 5 The reaction process steps of Production Method Example 5 are shown in Fig. 5.

Step 5-1 The compound (1-4) is esterified and then reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (V-1).

Step 5-2 The compound (V-1) is reacted with commercially available methanesulfonyl chloride and an appropriate base such as diisopropylethylamine in an appropriate solvent such as dichloromethane to thereby obtain a compound (V-2).

Step 5-3 A commercially available compound (V-3) is reacted with commercially available propionaldehyde and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (V-4).

Step 5-4 The compound (V-4) is reacted with the compound (V-1) and an appropriate Mitsunobu reagent such as triphenylphosphine/diethylazodicarboxylate in an appropriate solvent such as THE to thereby obtain a compound (V-5).

Step 5-5 The compound. (V-5) is deprotected by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol. Then, the resultant is reacted with an easily obtainable aldehyde A2-CHO (A2 is as described above) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (V-6) which is a compound represented by the general formula (1).

Step 5-6 A compound (V-7), which is obtained such that commercially available 4-aminomethylbenzoic acid is esterified and subjected to reductive condensation reaction with propionaldehyde, is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (V-8).

Step 5-7 The compound (V-8) is reacted with the compound (V-2) and an appropriate base such as potassium carbonate in an appropriate solvent such as DMF, then deprotected by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol, and further reacted with easily obtainable aldehyde A2-CHO (A2 is as described above) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (V-9) which is a compound represented by the general formula (1).

Step 5-8 A commercially available compound (V-10) is reacted with commercially available propionaldehyde and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (V-11).

Step 5-9 The compound (V-11) is reacted with the compound (V-2) and an appropriate base such as potassium carbonate in an appropriate solvent such as DMF, then deprotected by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol, and further reacted with easily obtainable aldehyde A2-CHO (A2 is as described above) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (V-12) which is a compound represented by the general formula (1).

Step 5-10 A commercially available compound (V-13) is reacted with commercially available propionaldehyde and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (V-14).

Step 5-11 The compound (V-14) is reacted with the compound (V-2) and an appropriate base such as potassium bicarbonate in an appropriate solvent such as dichloromethane, then deprotected by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol, and further reacted with easily obtainable aldehyde A2-CHO
(A2 is as described above) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (V-15) which is a compound represented by the general formula (1).

Production Method Example 6 The reaction process steps of Production Method Example 6 are shown in Fig. 6.

Step 6-1 The commercially available compound (VI-1) is reacted with commercially available di-t-butyl dicarbonate and an appropriate base such as triethylamine in an appropriate solvent such as dichloromethane to thereby obtain a compound (VI-2).

Step 6-2 A commercially available compound (VI-3) is reacted with commercially available propionaldehyde, an appropriate dehydrating agent such as trimethyl orthoformate, and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (VI-4).

Step 6-3 The compound (VI-2) is reacted with the compound (VI-4) and an appropriate condensing agent such as WSCI/HOBt in an appropriate solvent such as DMF to thereby obtain a compound (VI-5).

Step 6-4 A compound (VI-5) is deprotected by reaction with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol, and then easily obtainable aldehyde Al-CHO when Al and A2 are identical or easily obtainable Al-CHO and A2-CHO when Al and A2 are not identical (Al and A2 are as described above) is/are separately one after another reacted with an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (VI-6) which is a compound represented by the general formula (1).

Production Method Example 7 The reaction. process steps of Production Method Example 7 are shown in Fig. 7.

Step 7-1 A commercially available compound (VII-1) is reacted with an appropriate oxidant such as m-chloroperbenzoic acid in an appropriate solvent such as dichloromethane to thereby obtain a compound (VII-2).

Step 7-2 The compound (VII-2) is reacted with trifluoroacetic anhydride in an appropriate solvent such as dichloromethane to thereby obtain a compound (VII-3).

Step 7-3 The compound (VII-3) is reacted with an appropriate base such as sodium methoxide in an appropriate solvent such as methanol to thereby obtain a compound (VII-4).

Step 7-4 The compound (VII-4) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as chloroform to thereby obtain a compound (VII-5) which is raw material aldehyde A2-CHO (A2 is as described above).

Step 7-5 A commercially available compound (VII-6) is esterified to thereby obtain a compound (VII-7).
Step 7-6 The compound (VII-7) is reacted with an appropriate reductant such as sodium borohydride in an appropriate solvent such as ethanol/THF to thereby obtain a compound (VII-8).

Step 7-7 The compound (VII-8) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as chloroform to thereby obtain a compound (VII-9) which is raw material aldehyde Al-CHO (A1 is as described above).

Production Method Example 8 The reaction process steps of Production Method Example 8 are shown in Fig. 8.

Step 8-1 A compound (VIII-1) is reacted with a prodrug reagent such as ethyl chloroformate and an appropriate base such as triethylamine in an appropriate solvent such as chloroform to thereby obtain a compound (VIII-2) and a compound (VIII-3), which are the compounds represented by the general formula (1) and prodrugs.
Production Method Example 9 The reaction process steps of Production Method Example 9 are shown in Fig. 9.

Step 9-1 A compound (IV-8) is reacted with easily obtainable aldehyde R11-CHO (R11 is as described above) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (IX-1) which is a compound represented by the general formula (1).

Production Method Example 10 The reaction process steps of Production Method Example 10 are shown in Fig. 10.

Step 10-1 A commercially available compound (1-5) is reacted with commercially available cyclohexane and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (X-2).
Step 10-2 The compound (X-2) is reacted with a commercially available aqueous formaldehyde solution and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (X-3).
Step 10-3 The compound (X-3) is deprotected by reaction with an appropriate acid such as a hydrogen chloride/dioxane solution in an appropriate solvent such as methanol, and then reacted with the compound (II-1) and an appropriate condensing agent such as WSCI/HOBt in an appropriate solvent such as DMF to thereby obtain a compound (X-4).

Step 10-4 The compound. (X-3) is deprotected by reaction with an appropriate acid such as a hydrogen chloride/dioxane solution in an appropriate solvent such as methanol, and then reacted with the compound (1-4) and an appropriate condensing agent such as WSCI/HOBt in an appropriate solvent such as chloroform. to thereby obtain a compound (X-5).

Step 10-5 The compound (X-5) is reacted with an appropriate acid such as a hydrogen chloride/dioxane solution in an appropriate solvent such as methanol to thereby obtain a compound (X-6).

Step 10-6 The compound (X-6) is reacted with easily obtainable aldehyde A2-CHO (A2 is as described above) and an appropriate reduct.ant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (X-7) which is a compound represented by the general formula (1).

Production Method Example 11 The reaction process steps of Production Method Example 11 are shown in Fig. 11.

Step 11-1 The compound (IV-12) is reacted with the compound (I-

5) and an appropriate base such as triethylamine in an appropriate solvent such as chloroform, and then further reacted with an appropriate base such as methylamine in an appropriate solvent such as methanol to thereby obtain a compound (XI-1).

Step 11-2 Easily obtainable aldehyde Al-CHO when Al and A2 are identical or easily obtainable aldehydes Al-CHO and A2-CHO
when Al and A2 are not identical (Al and A2 are as described above) is/are separately one after another reacted with the compound (XI-1) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XI-2) which is a compound represented by the general formula (1).

Step 11-3 The compound (XI-2), which is a compound represented by the general formula (1), is reacted with an appropriate acid such as a hydrogen chloride/dioxane solution in an appropriate solvent such as methanol to thereby obtain a compound (XI-3) which is a compound represented by the general formula (1).

Step 11-4 The compound. (XI-3) which is a compound represented by the general formula (1) is reacted with an easily obtainable aldehyde or ketone corresponding to R25 and R26 (R25 and R26 are as described above), and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XI-4) which is a compound represented by the general formula (1).

Step 11-5 A compound (IV-6), which is prepared by deprotecting the compound (1-6) with acid, is reacted with a formylating agent such as a mixture of formic acid and acetic anhydride in an appropriate solvent such as THE to thereby obtain a compound (XI-5).

Step 11-6 The compound (XI-5) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (XI-6).
Step 11-7 The compound (XI-6) is reacted with the compound (IV-12) and an appropriate base such as triethylamine in an appropriate solvent such as chloroform, and then reacted with an appropriate reductant such as an aqueous methylamine solution in an appropriate solvent such as methanol to thereby obtain a compound (XI'-7).

Step 11-8 Easily obtainable aldehyde Al-CHO when Al and A2 are identical or easily obtainable aldehydes Al-CHO and A2-CHO
when Al and A2 are not identical (Al and A2 are as described above) is/are separately one after another reacted with the compound (XI-7) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XI-8) which is a compound represented by the general formula (1).

Production Method Example 12 The reaction process steps of Production Method Example 12 are shown in Fig. 12.

Step 12-1 The easily obtainable compound (I-1) is reacted with commercially available di-t-butyl dicarbonate and an appropriate base such as triethylamine in an appropriate solvent such as chloroform to thereby obtain a compound (XII-1).

Step 12-2 The compound (XII-1) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (XII-2).
Step 12-3 The compound (XII-2) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as chloroform to thereby obtain a compound (XII-3).

Step 12-4 The compound. (XII-3) is reacted with the compound (II-2), an appropriate dehydrating agent such as trimethyl orthoformate, and an appropriate reductant such as sodium borohydride in an appropriate solvent such as methanol to thereby obtain a compound (XII-4).

Step 12-5 The compound (XII-4) is reacted with an aqueous formaldehyde solution and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XII-5).

Step 12-6 The compound (XII-5) is reacted with an appropriate acid such as a hydrogen chloride/dioxane solution in an appropriate solvent such as methanol, to thereby obtain a compound (XII-6).

Step 12-7 Easily obtainable aldehyde Al-CHO when Al and A2 are identical or easily obtainable aldehydes Al-CHO and A2-CHO
when Al and A2 are not identical (A1 and A2 are as described above) is/are separately one after another reacted with the compound (XII-6) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XII-7) which is a the compound represented by the general formula (1).

Step 12-8 The compound (XII-7) which is a compound represented by the general formula (1) is reacted with an appropriate reductant such as 10% palladium-carbon under a hydrogen atmosphere in an appropriate solvent such as ethanol to thereby obtain a compound (XII-8) which is a compound represented by the general formula (1).

Step 12-9 The compound (XII-8) which is a compound represented by the general formula (1) is reacted with an easily obtainable aldehyde or ketone corresponding to R25 and R26 (R25 and R26 are as described above), and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XII-9) which is a compound represented by the general formula (1).

Step 12-10 The compound. (XI-6) is reacted with the compound (1-4) and an appropriate condensing agent such as WSCI/HOBt in an appropriate solvent such as chloroform to thereby obtain a compound (XII-10).

Step 12-11 The compound (XII-10) is reacted with an appropriate acid such as a hydrogen chloride/dioxane solution in an appropriate solvent such as methanol to thereby obtain a compound (XII-11).

Step 12-12 The compound (XII-11) is reacted with an easily obtainable aldehyde A2-CHO (A2 is as described above) and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XII-12) which is a compound represented by the general formula (1).

Production Method Example 13 The reaction. process steps of Production Method Example 13 are shown in Fig. 13.

Step 13-1 The compound. (VI-1) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as dichloromethane, to thereby obtain a compound (XIII-1).

Step 13-2 The compound. (1-5) is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate dehydrating agent such as trirnethyl orthoformate, and an appropriate reductant such as sodium borohydride in an appropriate solvent such as methanol to thereby obtain a compound (XIII-2).

Step 13-3 The compound (XIII-2) is reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate acid such as acetic acid, and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XIII-3).

Step 13-4 The compound (XIII-3) is reacted with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol to thereby obtain a compound (XIII-4).
Step 13-5 The compound (XIII-4) is reacted with the compound (XIII-1), an appropriate dehydrating agent such as trimethyl orthoformate and an appropriate reductant such as sodium borohydride in an appropriate solvent such as methanol to thereby obtain a compound (XIII-5).

Step 13-6 The compound (XIII-5) is reacted with a commercially available aqueous formaldehyde solution, an appropriate dehydrating agent such as trimethyl orthoformate, and an appropriate reductant such as sodium borohydride in an appropriate solvent such as methanol to thereby obtain a compound (XIII-6) which is a compound represented by the general formula (1).

Production Method Example 14 The reaction. process steps of Production Method Example 14 are shown in Fig. 14.

Step 14-1 The compound (IV-6), which is prepared by deprotecting the compound (1-6) with acid, is reacted with the compound (XII-3), an appropriate dehydrating agent such as trimethyl orthoformate and an appropriate reductant such as sodium borohydride in an appropriate solvent such as methanol to thereby obtain a compound (XIV-1).

Step 14-2 The compound(XIV-1) is reacted with an aqueous formaldehyde solution and an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XIV-2).

Step 14-3 The compound. (XIV-2) is deprotected by a reaction with an appropriate acid such as a hydrogen chloride/dioxane solution, and then easily obtainable aldehyde Al-CHO when Al and A2 are identical or easily obtainable Al-CHO and A2-CHO
when Al and A2 are not identical (A2 and A2 are as described above) is/are separately one after another reacted with an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XIV-3) which is a compound represented by the general formula (1).

Production Method Example 15 The reaction process steps of Production Method Example 15 are shown in Fig. 15.

Step 15-1 The commercially available compound (VI-3) is reacted with di-t-butyl dicarbonate and an appropriate base such as a sodium hydroxide aqueous solution in an appropriate solvent such as dioxane to thereby obtain a compound (XV-1).
Step 15-2 The compound (XV-1) is reacted with the compound (I-12) and an appropriate condensing agent such as WSCI in an appropriate solvent such as chloroform, to thereby obtain a compound (XV-2).

Step 15-3 The compound (XV-2) is deprotected by a reaction with an appropriate acid such as a hydrogen chloride/dioxane solution, and then easily obtainable aldehyde Al-CHO when Al and A2 are identical or easily obtainable Al-CHO and A2-CHO
when Al and A2 are not identical (A1 and A2 are as described above) is/are separately one after another reacted with an appropriate reductant such as sodium cyanoborohydride in an appropriate solvent such as methanol to thereby obtain a compound (XV-3) which is a compound represented by the general formula (1).

Production Method Example 16 The reaction process steps of Production Method Example 16 are shown in Fig. 16.

Step 16-1 A commercially available compound (XVI-1) is reacted with an appropriate oxidant such as meta-chloroperbenzoic acid in an appropriate solvent such as dichloromethane to thereby obtain a compound (XVI-2).

Step 16-2 The compound. (XVI-2) is reacted with trifluoroacetic anhydride in an appropriate solvent such as dichloromethane to thereby obtain a compound (XVI-3).

Step 16-3 The compound (XVI-3) is reacted with an appropriate base such as sodium methoxide in an appropriate solvent such as methanol to thereby obtain a compound (XVI-4).

Step 16-4 The compound. (XVI-4) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as chloroform to thereby obtain a compound (XVI-5) which is raw material aldehyde A2-CHO (A2 is as described above).

Step 16-5 A commercially available compound (XVI-6) is reacted with an appropriate oxidant such as meta-chloroperbenzoic acid in an appropriate solvent such as dichloromethane to thereby obtain a compound (XVI-7).

Step 16-6 The compound. (XVI-7) is reacted with trifluoroacetic anhydride in an appropriate solvent such as dichloromethane to thereby obtain a compound (XVI-8).

Step 16-7 The compound. (XVI-8) is reacted with an appropriate base such as sodium methoxide in an appropriate solvent such as methanol to thereby obtain a compound (XVI-9).

Step 16-8 The compound (XVI-9) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as chloroform to thereby obtain a compound (XVI-10) which is raw material aldehyde Al-CHO (A1 is as described above).

Production Method Example 17 The reaction process steps of Production Method Example 17 are shown in Fig. 17.

Step 17-1 An easily obtainable compound (XVII-1) is reacted with 5-t-butoxycarbonylaminovaleric acid, an appropriate condensing agent and catalyst such as WSCI or HOBt in an appropriate solvent such as DMF to thereby obtain a compound (XVII-2).

Step 17-2 The compound (XVII-2) is reacted in an appropriate solvent such as methanol in the presence of an appropriate acid such as hydrochloric acid. Then, the resultant is reacted with propionaldehyde, an appropriate reductant such as sodium cyanoborohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XVII-3).

Step 17-3 The compound (XVII-3) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as TEF, and then reacted with p-toluenesulfonyl chloride and an appropriate base such as triethylamine in an appropriate solvent such as dichloromethane to thereby obtain a compound (XVII-4).
Step 17-4 The compound (XVII-4) is reacted with potassium phthalimide in an appropriate solvent such as DMF, and then reacted with an appropriate base such as methylamine in an appropriate solvent such as methanol to thereby obtain a compound (XVII-5).

Step 17-5 The compound (XVII-5) is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol, and then reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate or an appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XVII-6) which is a compound represented by the general formula (1).

Production Method Example 18 The reaction. process steps of Production Method Example 18 are shown in Fig. 18.

Step 18-1 A commercially available compound (XVIII-1) is reacted with N-bromosuccinimide and an appropriate radical generator such as azobisisobutyronitrile in an appropriate solvent such as carbon tetrachloride to thereby obtain a compound (XVIII-2).

Step 18-2 The compound (XVIII-2) is reacted with potassium phthalimide in an appropriate solvent such as DMF to thereby obtain a compound (XVIII-3).

Step 18-3 The compound (XVIII-3) is reacted with an appropriate oxidant such as meta-chloroperbenzoic acid in an appropriate solvent such as chloroform, resulting in a compound (XVIII-4).

Step 18-4 The compound (XVIII-4) is reacted with appropriate acid anhydride such as trifluoroacetic anhydride in an appropriate solvent such as dichloromethane, and then reacted with an appropriate base such as sodium hydrogen carbonate in an appropriate solvent such as methanol to thereby obtain a compound (XVIII-5).

Step 18-5 The compound (XVIII-5) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as chloroform to thereby obtain a compound (XVIII-6).
Step 18-6 The compound (XVIII-6) is reacted with triphenyl phosphonylideneacetonitrile in an appropriate solvent such as THE to thereby obtain a compound (XVIII-7).

Step 18-7 The compound (XVIII-7) is reacted, under hydrogen atmosphere, with an appropriate catalyst such as palladium hydroxide-carbon in an appropriate solvent such as ethanol to thereby obtain a compound (XVIII-8).

Step 18-8 The compound (XVIII-8) is reacted with an appropriate base such as methylamine in an appropriate solvent such as methanol, and then reacted with di-t-butyl dicarbonate and an appropriate base such as triethylamine to thereby obtain a compound (XVIII--9).

Step 18-9 The compound (XVIII-9) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THF, and then reacted with propionaldehyde, an appropriate reductant such as sodium cyanoborohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XVIII-10).

Step 18-10 The compound (XVIII-10) is reacted in an appropriate solvent such as methanol in the presence of an appropriate acid such as hydrochloric acid. Then, it is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol. Subsequently, the resultant was reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, an appropriate dehydrating agent, and appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XVIII-11) which is a compound represented by the general formula (1).

Step 18-11 A commercially available compound, 4-bromobutyronitrile is reacted with triphenylphosphine in an appropriate solvent such as toluene to thereby obtain a compound (XVIII-12).

Step 18-12 The above compound (XVIII-6) is reacted with the compound (XVIII-12) and an appropriate base such as lithium diisopropylamide in an appropriate solvent such as THE to thereby obtain a compound (XVIII-13).

CO

Step 18-13 The compound (XVIII-13) is reacted with an appropriate base such as methylamine in an appropriate solvent such as methanol, and then. reacted with di-t-butyl dicarbonate and an appropriate base such as triethylamine. Subsequently, under hydrogen atmosphere, the resultant is reacted with an appropriate catalyst such as palladium hydroxide in an appropriate solvent such as ethanol to thereby obtain a compound (XVIII-14).

Step 18-14 The compound (XVIII-14) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THF, and then reacted with propionaldehyde, an appropriate reductant such as sodium cyanoborohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an. appropriate solvent such as methanol to thereby obtain a compound (XVIII-15).

Step 18-15 The compound (XVIII-15) is reacted in an appropriate solvent such as methanol in the presence of an appropriate acid such as hydrochloric acid.

Then, the resultant is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol.

Subsequently, the resultant was reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, an appropriate dehydrating agent, and appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XVIII-16) which is a compound represented by the general formula (1).

Production Method Example 19 The reaction process steps of Production Method Example 19 are shown in Fig. 19.

Step 19-1 A known compound (XIX-1) is reacted with N-bromosuccinimide, an appropriate radical generator such as azobisisobutyronitrile in an appropriate solvent such as carbon tetrachloride, and then reacted with potassium phthalimide in an appropriate solvent such as DMF to thereby obtain a compound (XIX-2).

Step 19-2 The compound. (XIX-2) is reacted with an appropriate base such as methylamine in an appropriate solvent such as methanol, then reacted with di-t-butyl dicarbonate and an appropriate base such as triethylamine. Subsequently, the resultant is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (XIX-3).

Step 19-3 The compound. (XIX-3) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as chloroform, and then reacted with methyl triphenylphosphora.nylideneacetate in an appropriate solvent such as THE to thereby obtain a compound (XIX-4).

Step 19-4 The compound (XIX-4) is reacted under a hydrogen atmosphere with an appropriate catalyst such as palladium-carbon in an appropriate solvent such as a chloroform -methanol mixture solvent, and then reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (XIX-5).

Step 19-5 The compound (XIX-5) is reacted with an appropriate oxidant such as Dess-Martin periodinane in an appropriate solvent such as dichloromethane. Then, the resultant is reacted with dipropylamine, an appropriate reductant such as sodium cyanoborohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XIX-

6).
Step 19-6 The compound (XIX-6) is reacted with an appropriate acid catalyst such as hydrochloric acid in an appropriate solvent such as dioxane, and then reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XIX-7).

Step 19-7 The compound (XIX-7) is reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, an appropriate dehydrating agent, and an appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XIX-8) which is a compound represented by the general formula (1).

Production Method Example 20 The reaction process steps of Production Method Example 20 are shown in Fig. 20.

Step 20-1 A commercially available compound (XX-1) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (XX-2).

Step 20-2 The compound. (XX-2) is reacted with t-butyldimethylsilyl chloride and an appropriate base such as imidazole in an appropriate solvent such as DMF to thereby obtain a compound (XX-3).

Step 20-3 The compound (XX-3) is reacted with an appropriate oxidant such as manganese dioxide in an appropriate solvent such as chloroform to thereby obtain a compound (XX-4).
Step 20-4 The compound (XX-4) is reacted with methyl triphenylphosphoranylideneacetate in an appropriate solvent such as THF, to thereby obtain a compound (XX-5).

Step 20-5 The compound (XX-5) is reacted, under hydrogen atmosphere, with an appropriate catalyst such as palladium black in an appropriate solvent such as benzene to thereby obtain a compound (XX-6).

Step 20-6 The compound (XX-6) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (XX-7).
Step 20-7 The compound (XX-7) is reacted with an appropriate oxidant such as Dess-Martin periodinane in an appropriate solvent such as dichloromethane, to thereby obtain a compound (XX-8).
Step 20-8 The compound (XX-8) is reacted with dipropylamine, an appropriate reductant such as sodium cyanoborohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XX--9).

Step 20-9 The compound (XX-9) is reacted with an appropriate deprotecting agent such as tetrabutylammonium fluoride (hereinafter, referred to as TBAF) in an appropriate solvent such as THE to thereby obtain a compound (XX-10).

Step 20-10 The compound (XX-10) is reacted with phthalimide, an appropriate dehydrating agent such as triphenylphosphine and diethyl azodicarboxylate in an appropriate solvent to thereby obtain a compound (XX-11).

Step 20-11 The compound (XX-11) is reacted with an appropriate base such as methylamine in an appropriate solvent such as methanol to thereby obtain a compound (XX-12).

Step 20-12 The compound (XX-12) is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol. Then, the resultant is reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate acid catalyst such as acetic acid in an appropriate solvent: such as methanol to thereby obtain a compound (XX-13) which is a compound represented by the general formula (1).

Step 20-13 Methoxymethyltriphenylphosphonium chloride is reacted with an appropriate base such as lithium diisopropylamide in an appropriate solvent such as THF. Then, the resulting reaction mixture is added and reacted with the above compound (XX-8) to thereby obtain a compound (XX-14).

Step 20-14 The compound (XX-14) is reacted with an appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol, and then reacted with dipropylamine, an appropriate reductant such as sodium cyanoborohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XX--15).

Step 20-15 The compound (XX-15) is reacted with phthalimide and an appropriate dehydrating agent such as triphenylphosphine and diethyl azodicarboxylate in an appropriate solvent to thereby obtain a compound (XX--16).

Step 20-16 The compound (XX-16) is reacted with an appropriate base such as methylamine in an appropriate solvent such as methanol to thereby obtain a compound (XX-17).

Step 20-17 The compound (XX-17) is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol. Then, the resultant is reacted with commercially available 1-methyl-2-imidazole carboxaldehyde and an appropriate reductant such as sodium borohydride, an appropriate dehydrating agent such as trimethyl orthoformate or an appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XX-18) which is a compound represented by the general formula (1).

Production Method Example 21 The reaction process steps of Production Method Example 21 are shown in Fig. 21.

Step 21-1 The above compound (XVII-1) is reacted with iodopropane in an appropriate solvent such as DMF in the presence of an appropriate base such as potassium carbonate to thereby obtain a compound (XXI-1).

Step 21-2 The compound (XXI-1) is reacted with 5-t-butoxycarbonylaminovaleric acid, an appropriate condensing agent and catalyst such as WSCI and HOBt in an appropriate solvent such as DMF to thereby obtain a compound (XXI-2).
Step 21-3 The compound (XXI-2) is reacted in an appropriate solvent such as methanol in the presence of an appropriate acid such as hydrochloric acid, and then reacted with propionaldehyde, an appropriate reductant such as sodium cyanoborohydride, and optionally an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XXI-3).

Step 21-4 The compound (XXI-3) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE to thereby obtain a compound (XXI-4).
Step 21-5 The compound (XXI-4) is reacted with phthalimide and an appropriate dehydrating agent such as triphenylphosphine and diethyl azodicarboxylate in an appropriate solvent to thereby obtain a compound (XXI-5).

Step 21-6 The compound (XXI-5) is reacted with an appropriate base such as methylamine in an appropriate solvent such as methanol to thereby obtain a compound (XXI-6).

Step 21-7 The compound (XXI-6) is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XXI-7) which is a compound represented by the general formula (1).

Step 21-8 The compound (XXI-6) is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol. Then, the resultant is reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate or an appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XXI-8) which is a compound represented by the general formula (1).

Production Method Example 22 The reaction process steps of Production Method Example 22 are shown in Fig. 22.

Step 22-1 A commercially available compound (XXII-1) is reacted with t-butyldiphenylsilyl chloride and an appropriate base such as imidazole in an appropriate solvent such as DMF to thereby obtain a compound (XXII-2).

Step 22-2 The compound (XXII-2) is reacted with an appropriate oxidant such as N-methyl-morpholine-N-oxide and tetrapropylammonium perruthenate in an appropriate solvent such as dichloromethane to thereby obtain a compound (XXII-3).

Step 22-3 The compound (XXII-3) is reacted with the compound (XXII-4) and an appropriate base such as lithium bistrimethylsilyl amide in an appropriate solvent such as THF. Then, the resultant is reacted with methanesulfonyl chloride and an appropriate base such as triethylamine in an appropriate solvent such as DMF, and further reacted with an appropriate strong base such as DBU to thereby obtain a compound (XXII-5).

Step 22-4 The compound (XXII-5) is reacted with an appropriate reductant such as K-Selectride in an appropriate solvent such as THF to thereby obtain a compound (XXII-6).

Step 22-5 The compound (XXII-6) is reacted with an appropriate reductant such as sodium borohydride in an appropriate solvent such as methanol to thereby obtain a compound (XXII-

7).

Step 22-6 The compound (XXII-7) is reacted with methoxymethyl chloride and an appropriate base such as sodium hydride in an appropriate solvent such as DMF to thereby obtain a compound (XXII-8).

Step 22-7 The compound (XXII-8) is reacted with an appropriate deprotecting agent such as TBAF in an appropriate solvent such as THF. Then, the resultant is reacted with an appropriate oxidant such as N--methyl-morpholine-N-oxide and tetrapropylammonium perruthenate in an appropriate solvent such as dichloromethane to thereby obtain a compound (XXII-9).

Step 22-8 The compound (XXII-9) is reacted with dipropylamine and an appropriate reductant such as sodium triacetoxy borohydride in an appropriate solvent such as dichloroethane to thereby obtain a compound (XXII-10).

Step 22-9 The compound (XXII-10) is reacted with an appropriate cyanide reagent such as zinc cyanide and an appropriate catalyst such as tetrakistriphenylphosphine palladium in an appropriate solvent such as DNIF to thereby obtain a compound (XXII-11).

Step 22-10 The compound (XXII-11) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THF to thereby obtain a compound (XXII-12).
Step 22-11 The compound (XXII-12) is reacted with carbethoxyphthalimide and an appropriate base such as potassium carbonate in an appropriate solvent such as DMF to thereby obtain a compound (XXII-13).

Step 22-12 The compound (XXII-13) is reacted with an appropriate acid catalyst such as hydrochloric acid in an appropriate solvent such as a methanol/dioxane mixture to thereby obtain a compound (XXII-14).

Step 22-13 The compound (XXII-14) is reacted with an appropriate base such as hydrazine monohydrate in an appropriate solvent such as methanol to thereby obtain a compound (XXII-15).
Step 22-14 The compound (XXII-15) is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XXII-16).

Step 22-15 The compound (XXII-26) is reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, an appropriate dehydrating agent, and an appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XXII-17) which is a compound represented by the general formula (1).

Production Method Example 23 The reaction process steps of Production Method Example 23 are shown in Fig. 23.

Step 23-1 A commercially available compound (XXIII-1) is reacted with 1-iodopropane and an appropriate base such as sodium hydride in an appropriate solvent such as DMF to thereby obtain a compound (XXIII-2).

Step 23-2 The compound (XXIII-2) is reacted with an appropriate reductant such as tin(II) chloride and sodium borohydride in an appropriate solvent such as ethanol to thereby obtain a compound (XXIII-3).

Step 23-3 The compound. (XXIII-3) is reacted with 5-t-butoxy carbonylaminovaleric acid and an appropriate condensing agent and catalyst such as WSCI and HOBt in an appropriate solvent such as DMF to thereby obtain a compound (XXIII-4).
Step 23-4 The compound (XXIII-4) is reacted in an appropriate solvent such as methanol in the presence of an appropriate acid such as hydrochloric acid. Then, the resultant is reacted with propionaldehyde, an appropriate reductant such as sodium cyanoborohydride, and an appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XXIII-5).

Step 23-5 The compound (XXIII-5) is reacted with an appropriate reductant such as lithium aluminum hydride in an appropriate solvent such as THE. Then, the resultant is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol. Subsequently, the resultant is reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate or an appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XXIII-6) which is a compound represented by the general formula (1).
Production Method Example 24 The reaction process steps of Production Method Example 24 are shown in Fig. 24.

Step 24-1 A commercially available compound (XXIV-1) is reacted with an appropriate condensing agent and catalyst such as WSCI and HOBt in methanol to thereby obtain a compound (XXIV-2).

Step 24-2 The compound (XXIV-2) is reacted with N-bromosuccinimide (hereinafter, referred to as NBS) and an appropriate radical generator such as azobisisobutyronitrile in an appropriate solvent such as carbon tetrachloride to thereby obtain a compound (XXIV-3).

Step 24-3 The compound (XXIV-3) is reacted with potassium phthalimide in an appropriate solvent such as DMF to thereby obtain a compound (XXIV-4).

Step 24-4 The compound (XXIV-4) is reacted with an appropriate base such as hydrazine monohydrate in an appropriate solvent such as methanol, and then reacted with di-t-butyl dicarbonate and an appropriate base such as triethylamine to thereby obtain a compound (XXIV-5).

Step 24-5 The compound (XXIV-5) is reacted with an appropriate base such as sodium hydroxide and water in an appropriate solvent such as methanol to thereby obtain a compound (XXIV-6).

Step 24-6 The compound. (XXIV-6) is reacted with the above compound (IV-6) in an appropriate solvent such as xylene to thereby obtain a compound (XX=IV-7).

Step 24-7 The compound. (XXIV-7) is reacted in an appropriate solvent such as methanol in the presence of an appropriate acid such as hydrochloric acid. Then, the resultant is reacted with commercially available 2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, and an appropriate dehydrating agent such as trimethyl orthoformate in an appropriate solvent such as methanol to thereby obtain a compound (XXIV-8).

Step 24-8 The compound (XXIV-8) is reacted with commercially available 1-methyl-2-imidazole carboxaldehyde, an appropriate reductant such as sodium borohydride, an appropriate dehydrating agent, and an appropriate acid catalyst such as acetic acid in an appropriate solvent such as methanol to thereby obtain a compound (XXIV-9) which is a compound represented by the general formula (1).

The following compounds can be exemplified as the amine compounds of the present invention:
4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylamino-butyl)-benzamide [Compound No.1], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-diisobutylamino-butyl)-benzamide [Compound No.2], 4-{[bis(lH-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-aminobutyl)-benzamide [Compound No.3], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylamino-butyl)-benzamide [Compound No.4], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-benzyloxycarbonylaminobutyl)-benzamide [Compound No.5], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-methoxy-benzylamino)-butyl]-benzamide [Compound No.6], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-dipropylamino-ethyl)-benzamide [Compound No.7], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-cyclohexylaminoethyl)-benzamide [Compound No.8], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexylmethyl-amino)-butyl]-benzamide [Compound No.9], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-t-butyl-benzylamino)-butyl]-benzamide [Compound No.10], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethyl)-benzylamino-butyl]-benzamide [Compound No.11], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethoxy)-benzylamino--butyl]-benzamide [Compound No.12], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-methylsulfanyl-benzylamino)-butyl]-benzamide [Compound No.13], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzamide [Compound No.14], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminophenyl)-benzamide [Compound No.15], 4-{[bis(1H-imidazol-2-ylmethy-)-amino]-methyl}-N-{4-[bis(3-methyl-butyl)-amino]butyl}-benzamide [Compound No.16], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dimethylamino-butyl)-benzamide [Compound No.17], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cycloheptylaminobutyl)-benzam_Lde [Compound No.18], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-berizamide [Compound No.19], N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.20], N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(thiazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.21], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminopropyl)-benzamide [Compound No.22], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylamino-2,2-dimethylpropyl)-benzamide [Compound No.23], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzenesulfonamide [Compound No.24], N-(4-{[bis(1H-imi(dazol-2-ylmethyl)-amino]-methyl}-benzyl)-N',N'-dipropylbutane-1,4-diamine [Compound No.25]
N-(4-dipropylamin(Dbutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl.)-amino]-methyl}-benzamide [Compound No.26], N-(4-dipropylamin(Dbutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-pyrazol-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.27], N-(4-dipropylamin(Dbutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2R)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.28], N-(4-dipropylamin(Dbutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2S)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.29], N-(4-dipropylamin(Dbutyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methyl-1H-imidazol-5-ylmethyl)-amino]-methyl}-benzamide [Compound No.30], (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-dipropylaminopiperidin-1-yl)-methanone [Compound No.31], (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-propylpiperazin-1-yl)-methanone [Compound No.32], 4-{[bis(1H-imidaz(Dl-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminometh_ylphenyl)-benzamide [Compound No.33], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-benzamide [Compound No.34], [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-benzyl]-dipropylamine [Compound No.35], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-naphtalene-l-carboxylic acid (4-dipropylaminomethylphenyl)-amide [Compound No.36], (4-{[bis(1H-imidazol-2-ylmeth)7l)-amino]-methyl}-phenyl)-[4-(1-propylbutyl)-piperazin-1-yl]-methanone_[Compound No.37], (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-cyclohexylpiperazin-1-yl)-methanone [Compound No.38], (4-{[bis(1-methyl-1H-imidazol--2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine [Compound No.39], 4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzamide [Compound No.40], 4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.41], [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzylamino)-butyl]-carbamic acid benzyl ester [Compound No.42], (4-{[bis(1H-imidazol-2-ylmeth)7l)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine [Compound No.43], (4-dipropylaminomethylphenyl)--(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amine [Compound No.44], (4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(2H-pyrazol-3-ylmethyl)-amino:,-methyl}-benzyl)-amine [Compound No.45], N-(4-dipropylamino.butyl)-4-{[(1H-imidazol-2ylmethyl)-(6-methylpyridin-2-yl-methyl)-amino]-methyl}-benzamide [Compound No.46], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.47], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.48], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(l-methyl-lH-imidazc)1-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.49], N-(4-{[bis(1H-imidazol-2-ylmet:hyl)-amino]-methyl}-benzyl)-N-methyl-N',N'-dipropylbutane-l,4-diamine [Compound No.50], N-(4-dipropylaminomethylphenyl.)-4-{[(1H-imidazol-2-ylmethyl)-(6-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.51], N-(4-dipropylaminomethylphenyl.)-4-{[(1H-imidazol-2-ylmethyl)-(6-bromopyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.52], N-(4-dipropylaminomethylphenyl.)-4-{[(1H-imidazol-2-ylmethyl)-(3-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.53], N-(4-dipropylaminomethylphenyl.)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-4-ylmethyl.)-amino]-methyl}-benzamide [Compound No.54], N-(4-dipropylaminomethylphenyl.)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-2-ylmethyl.)-amino]-methyl}-benzamide [Compound No.55], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.56], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.57], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.58], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-ethoxypyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.59], [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-butyl]-dipropylamirle [Compound No.60], N-(4-dipropylaminomethylphenyi)-4-{[(1H-imidazol-2-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.61], N-(4-dipropylaminomethylphen y_)-4-{[(1H-imidazol-2-ylmethyl)-(2-methylthiazol-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.62], N-(4-dipropylaminomethylpheny=_)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-l-ylmethyl)-amino]-methyl}-benzamide [Compound No.63], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.64], 4-({bis[1-(toluene-4-sulfonyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.65], 4-{[bis(1-methanesulfonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.66], 2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-l-carboxylic acid ethyl ester [Compound No.67], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-N-methylbenzamide [Compound No.68], N,N-bis(1H-imidazol-2-ylmethyl)-N',N'-dipropylnonane-l,9-diamine [Compound No.69], N-(4-dipropylamino:methylphenyl)-{[(1H-imidazol-2-ylmethyl)-(quinolin-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.70], N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-4-dipropylaminomethylbenzamide [Compound No.71], N-(4-dipropylamino:methylphenyl)-4-{[(8-hydroxyquinolin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.72], N-(4-dipropylamino:methylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyrazine-2--ylmethyl)-amino]-methyl}-benzamide [Compound No.73], N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.74], N-(4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridine-2-ylmethyl)-amino]-methyl}-benzyl)-N',N'-dipropylbutane-1,4-diamine [Compound No.75], N-(4-dipropylamino:methylphenyl)-4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5-methy.lpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.76], 4-{[bis(5-methylpyridin-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-bennzamide [Compound No.77], N-(4-dipropylaminomethylphenyl)-4-{[N-(1H-imidazol-2-ylmethyl)-(4-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.78], {2-[4-(4-{[bis(1H-:imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-phenyl]-ethyl}-dipropylamine [Compound No.79], [4-(4-{[bis(1H-imi(Jazol-2-ylmethyl)-amino]-methyl}-benzyloxymethyl)-benzyl]-dipropylamine [Compound No.80], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-([1,2,3]--thiadiazole-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.81], 4-{[(1-dimethylsulfamoyl-lH-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.82], 2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-1H-imidazol--2-ylmethyl)-amino}-methyl)-imidazol-l-carboxylic acid dirnethylamide [Compound No.83], 4-{[bis(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.84], N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyrazine-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.85], N-(4-dipropylaminornethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylLisoxazol-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.86], 4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzoyl)-(2-dipropylaminoethyl)-piperazine [Compound No.87], N-(4-cyclohexylaminomethylpheriyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.88], 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylaminomethylphenyl)-benzamide [Compound No.89], N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N',N'-dipropylbutane-1,4-diamine [Compound No.90], N-(4-dipropylaminomethylphenyl.)-4-{[(1-ethyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.91], N-(4-dipropylaminomethylphenyl.)-4-{[(1H-imidazol-2-ylmethyl)-(1-propy.l-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.92], N-(4-dipropylaminomethylphenyl.)-4-({(1H-imidazol-2-ylmethyl)-[1-(2-methoxymethoxyethyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-benzamide [Compound No.93], N-(4-dipropylaminomethylphenyl.)-4-({[1-(2-hydroxyethyl)-1H-imidazol-2-ylmethyl]-(1H-imida.zol-2-ylmethyl)-amino}-methyl)-benzamide [Compound No.94], 4-{[bis(1-hexyloxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminometh.ylphenyl)-benzamide [Compound No.95], 4-{[bis(1-heptyloxycarbonyl-1H.-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No. 96] , 4-{[bis(1-butoxycarbonyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.97], N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N',N'-dipropylbutane-1,4-diamine [Compound No.98], 4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexyl-methyl-amino)-butyl]-benzamide [Compound No.99], N-[4-(cyclohexyl-methyl-amino)-butyl]-4-{[(1H-imidazol-2-ylmethyl)-(l-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.100], 4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4--dipropylaminomethyl-phenyl)-benzamide [Compound No.101], N-(4-dipropylaminomethyl-phenyl)-4-{[(5-ethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.102], N-(4-cyclohexylamino-butyl)-4--{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide [Compound No.103], N-cyclohexyl-N'-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N'-methyl-butane-1,4-diamine [Compound No.104], N-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide [Compound No.105], N-(4-diisobutylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide [Compound No.106], 4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-isobutylamino-butyl)-benzenesulfonamide [Compound No.107], 4-{[bis-(1H-imidazol-2-ylmethvl)-amino]-methyl}-N-(4-dipropylamino-butyl)-N-methylbenzamide [Compound No.108], N-[4-(cyclohexyl-methyl-amino)-butyl]-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzenesulfonamide [Compound No.109], 2- [ (4-dipropylamino-butyl) - (4--{ [ (1H-imidazol-2-ylmethyl) - (1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amino]-ethanol [Compound No.110], 4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4--[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzenesulfonamide [Compound No.111], N-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-methylbenzamide [Compound No.:112], N-(4-dipropylamino-butyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-N-methyl-benzenesulfonamide [Compound No.113], N-(4-di-n-propylaminomethyl-phenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.114], [4-(6-{[(1H-imidaz;ol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzimidazol-2-yl)-butyl]-dipropylamine [Compound No.115], N-(4-{[(imidazol-2-ylmethyl)-([1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-berizyl)-N-methyl-N',N'-dipropylbutane-1,4-diamine [Compound No.116], N-methyl-N-(4-{[(1-methyl-imidazol-2-ylmethyl)-([1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzyl)-N',N'-dipropyl-butane-1,4-diamine [Compound No.117], N-(4-dipropylaminomethylbenzyl)-N'-(1H-imidazol-2-ylmethyl)-N'-(1-methyl-1H-imidazol-2-ylmethyl)-1,4-butanediamine [Compound No.118], N-(4-dipropylaminomethylbenzyl)-N'-(1H-imidazol-2-ylmethyl)-N-methyl-N'-(1-methyl-1H-imidazol-2-ylmethyl)-butane-l,4-diamine [Compound No.119], [3-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-propyl]-dipropylamine [Compound No.120], [3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzo[b]-thiophen-2-yl)-propyl]-dipropyl-amine [Compound No.121], 2-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-6-(3--dipropylaminopropyl)-naphtalene [Compound No.122], N-(4-di-n-propylaminomethyl-phenyl)-4-{[(1-methyl-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.123], [5-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-pentyl]-dipropylamine [Compound No.124], 2-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-6-(4--dipropylaminobutyl)-naphtalene [Compound No.125], [4-(6-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine [Compound No.126], [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylamine [Compound No.127], [4-(5-{[(imidazol-2-ylmethyl)-(1-methylimidazol-2-ylmethyl)-amino]-methyl}-1-methoxy-indan-2-yl)-butyl]-dipropylamine [Compound No.128], [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropylaminne [Compound No.129], 2-(4-di-n-propylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-isoindole-1,3-dione [Compound No.130], N-(4-{[(1H-imidazol-2-ylmethyl.)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-imidazol-2-ylmethyl)-N-methyl-N',N'-dipropyl-butane-1,4-diamine [Compound No.131], N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-thiazol-2-ylmethyl)-N-methyl-N',N'-dipropyl-butane-1,4-diamine [Compound No.132], 5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-pyridin-2-carboxylic acid (4-dipropylamino-butyl)-amide [Compound No.1331, 5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-pyrazine-2-carboxylic acid (4-dipropylamino-butyl)-amide [Compound No.134], [3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-iridol-2-yl)-propyl]-dipropyl-amine [Compound No.135]

2-(4-dipropylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-indan-l-one [Compound No.136], 2-(4-dipropylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-inden-l-one [Compound No.137], 3-amino-2-(4-dipropylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-inden-l-one [Compound No.138], [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzc>thiazol-2-yl)-butyl]-dipropyl-amine [Compound No.139], [3-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-benzimidazol-2-ylsulfanyl)-propyl]-dipropyl-amine [Compound No.140], [3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-inden-2-yl)-propyl]-dipropyl-amine [Compound No.141]

[3-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzc>furan-2-yl)-propyl]-dipropyl-amine [Compound No.142], 2-(4-dipropylamino-butyl)-5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-2,3-dihydro-isoindol-l-one [Compound No.14:3], 2-(4-dipropylamino-butyl)-6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1,1-dioxo-1,2-dihydro-1X6-benzo[d]-isothiazol-3-one [Compound No.144], [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1,1-clioxo-lH-1(6-benzo[e]-[1,2]-thiazin-2-yl)-butyl]-dipropyl-amine [Compound No.145], 2-(4-dipropylamino-butyl)-6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1,2-dihydro-indazol-3-one [Compound No.146], [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.147], [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-butyl]-dipropyl-amine [Compound No.148], [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinoxalin-2-yl)-butyl]-dipropyl-amine [Compound No.149], 3-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-chromen-2-one [Compound No.150], (3-dipropylaminomethyl-phenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-methanone [Compound No.151], 3-(4-dipropylamino-butyl)-8-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-3,4-dihydro-1H-benzo[e]-[1,4]-diazepin-2,`i-dione [Compound No.152], 3-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-3,4-dihydro-1H-benzo[e]-[1,4]-diazepin-2,`i-dione [Compound No.153], 2-(4-dipropylamino-butyl)-6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-3,4-dihydro-2H-isoquinolin-l-one [Compound No.154], N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-thiophen-2-ylmethyl)-N-methyl-N',N'-dipropyl-butane-1,4-diamine [Compound No.155], [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinazolin-2-yl)-butyl]-dipropyl-amine [Compound No.156], [4-(6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-chroman-2-yl)-butyl]-dipropyl-amine [Compound No.157], [4-(7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-chroman-3-yl)-butyl]-dipropyl-amine [Compound No.158], 3-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-chromen-4-one [Compound No.159], 2-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-2,3-dihydro-1H-isoquinolin-4-one [Compound No.160], 2-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-2,3,4,5-tetrahydro-benzo[c]-azepin-l-one [Compound No.161], 2-(4-dipropylamino-butyl)-7-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-2,5-dihydro-benzo[c]-azepin-l-one [Compound No.162], 6-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-4-oxo-3,4-dihydro-quinazolin-2-carboxylic acid (2-dipropylamino-ethyl)-amide [Compound No.163], 2-dipropylamino-5-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-methyl-amino]-valeric acid [Compound No.164], 5-dipropylamino-2-[(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-methyl-amino]-valeric acid [Compound No.165], [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-iriden-2-yl)-butyl]-dipropylamine [Compound No.166], [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-indol-2-yl)-butyl]-dipropylamine [Compound No.167], [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-methyl-lH-indol-2-yl)-butyl]-dipropylamine [Compound No.168], [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzofuran-2-yl)-butyl]-dipropylamine [Compound No.169], [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzoxazol-2-yl)-butyl]-dipropylamine [Compound No.170], [4-(5-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzothiazol-2-yl)-butyl]-dipropylamine [Compound No.171], The present invention relates to a CXCR4 antagonist including the above-described compounds or a pharmacologically acceptable salt thereof as an active ingredient.

The CXCR4 antagonist or salt thereof according to the present invention may be used in treatment or prevention of viral disease such as AIDS, cancer treatment, or treatment or prevention of rheumatism, etc.

The pharmacologically acceptable salt is a salt which may be formed by the amine compound represented by the above described formula (1), and may be any salt that is pharmacologically acceptable. For example, trifluoroacetates, hydrochloric acid saltshydrochlorides, acetates, sulfuric acid salts, nitric acid salts, lactic acid salts, maleic acid salts, methanesulfonic acid salts, toluenesulfonic acid salts, tartaric acid salts, citric acid salts, oxalic acid salts, malonic acid salts, fumaric acid salts, propionic acid salts, butanoic acid saltssulfates, nitrates, lactates, maleates, methane sulfonates, toluene sulfonates, tartrates, citrates, oxalates, malonates, succinates, fumarates, propionates, butyrates, glucuronates, terephthalates, phosphorates, and the like can be given.
Those compounds may form a hydrate or a solvate.

One or two or more asymmetric carbon atoms may exist in the compound represented by the general formula (1); when one asymmetric carbon atoms exists, the compound may be in any form of a pure optically-active substance represented as absolute configuration of R or S, a mixture thereof in an arbitrary ratio, and a racemic mixture thereof, and when two or more asymmetric carbon atoms exist in the compound, the compound may be in any form of an optically pure diastereomer, a racemic mixture thereof, and a combination thereof in an arbitrary ratio.

The medical preparation including the compound of the present invention represented by the general formula (1) or pharmacologically acceptable salt thereof as an active ingredient may be administered orally or parenterally in a form of tablet, powder, granule, capsule, pill, suppository, injection, eye-drops, solution, troche, aerosol, suspension, emulsion, syrup, or the like, mixed with a well-known pharmacologically acceptable carrier, excipient, diluent, extender, decaying agent, stabilizer, preservative, buffer, emulsifier, perfuming agent, colorant, sweetener, thickening agent, flavor, solubilizing agent, and other additives, specific examples thereof including: water; vegetable oil;
alcohol such as ethanol or benzyl alcohol; carbohydrate such as glycol, glycerol triacetate, gelatin, lactose, or starch;
magnesium stearate; potassium stearate; tarc; lanoline;
vaseline; macrogol; crystalline cellulose; hydroxypropyl cellulose, and the like. While the dose may vary depending on the kind and degree of disease, the kind of the compound to be administered, the administration path, and the age, sex, and weight of the patient:, in general, 0.1 to 5,000 mg), particularly 1 to 3,000 mg) per one adult is preferably administered. In the case of a prodrug, it is preferable to administer 1 to 5,000 mg) per adult.

Examples A production method of CXCR4 antagonist of the present invention will now be described in more detail with reference to Examples. Hereinafter, unless particularly described, reagents used are commercially available products (e.g., Tokyo Kasei Kogyo Co. Ltd. (Tokyo), KANTO KAGAKU

(Tokyo), etc.) readily available to a person skilled in the art.

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

Example 1-1: Synthesis of 4-[N-Boc-N-(1H-imidazol-2-ylmethyl) aminomethyl]-benzoic acid Commercially available methyl bromomethylbenzoate (manufactured by Aldrich Corporation) (10.0 g) was dissolved in DMF (100 ml), and the solution was added with potassium phthalimide potassium salt (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (9.70 g) and stirred at room temperature for 1.5 hours. After completion of the reaction, the solution was concentrated, and water was added to the concentrate. Then, extraction was performed with chloroform.
The resultant solution was washed with saturated saline solution and dried with anhydrous sodium sulfate, and the solvent was distilled off, thereby obtaining a white solid (12.9 g). Subsequently, 7.56 g of the solid was dissolved in methanol (100 ml), and the solution was added with hydrazine monohydrate (manufactured by Nacalai Tesque, Inc.) (6.25 ml) and stirred at 60(C for 1.5 hours. After completion of the reaction, the precipitated solid was separated by filtration, and the solvent was distilled off.
Water was added to the residue, and extraction was performed with chloroform. The resultant solution was washed with a 0.3 mol/1 sodium hydroxide aqueous solution and saturated saline solution and dried with anhydrous sodium sulfate, and the solvent was distilled off. Methanol (120 ml) and 2-imidazole carboxaldehyde (manufactured by Aldrich Corporation) (2.35 g) were added to the residue, followed by stirring at room temperature for 2 days. After completion of the reaction, the precipitated solid was separated by filtration. The liquid layer was evaporated to dryness, and washing was performed by adding anhydrous methanol (30 ml).
Then, the solid was separated by filtration. The resultant solid and the solid that had been previously separated by filtration were suspended in methanol (86 ml), and sodium borohydride (1.42 g) was added under ice-cooling. The solution was stirred at room temperature for 1 hour, and the solvent was distilled off. After addition of water, extraction was performed with chloroform, and the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure and drying, thereby obtaining a colorless viscous liquid (4.32 g). 4.28 g of the liquid was dissolved in DMF (65 ml), and the solution was added with di-t-butyl dicarbonate (8.90 ml) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform, followed by washing with saturated saline solution. After drying with anhydrous sodium sulfate, the solvent was distilled off, and THE (43 ml), methanol (43 ml), and a 1 mol/l sodium hydroxide aqueous solution (43 ml) were added to the residue, followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off, and water (5 ml) was added to the residue. Further, a 1 mol/1 hydrochloric acid aqueous solution was carefully added to the solution, and the acid-precipitate was separated by filtration and dried, thereby obtaining the subject compound (4.87 g) as a white solid.
MS(FAB,Pos.):m/z=332[M+H]+

Example 1-2: Synthesis of N,N--dipropylbutane-1,4-diamine N-(4-aminobutyl)carbamic acid t-butyl ester (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (500 ml) was dissolved in methanol (10 ml) and then added with propionaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.418 ml), sodium cyanoborohydride (404 mg), and trimethyl orthoformate (1.60 g), followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was added with chloroform, washed with distilled water and saturated saline solution, and then dried with anhydrous sodium sulfate. After concentration and evaporation to dryness, methanol (4.0 ml) and a 4 mol/1 hydrogen chloride/dioxane solution (4.0 ml) were added to the dried product and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off and then dioxane was added to wash the residue, thereby obtaining hydrochloride (654 mg) of the subject compound.

MS (FAB, Pos.) :m/z=173 [M+H]+

Example 1-3: Synthesis of 4-{[N-Boc-N-(1H-imidazol-2-ylmethyl)amino]methyl}-N-(4-di_propylaminobutyl)benzamide The compound (203 mg) obtained in Example 1-2 was dissolved in DMF (5.0 ml) and chloroform (5.0 ml), and then added with triethylamine (0.374 ml), WSCI hydrochloride (382 mg), HOBt (200 mg), and the compound (463 mg) obtained in Example 1-1 and the whole was stirred at room temperature for 23 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was added with chloroform and washed with water and saturated saline solution. The solution was dried with anhydrous sodium sulfate and then the solvent was distilled off.
Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (168 mg) as colorless foam.
MS(FAB,Pos.):m/z=486[M+H]+

Example 1-4: Synthesis of 4-{[N-(1H-imidazol-2-ylmethyl)amino]methyl-N-(4-dipropylaminobutyl)benzamide The compound. (117 mg) obtained in Example 1-3 was dissolved in methanol (1.2 ml.) and then added with a 4 mol/1 hydrogen chloride/dioxane solution (1.2 ml), followed by stirring at room temperature for 5 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in water and then purified through solid-phase extraction column (Sep-Pak , tCl8, manufactured by Waters Corporation), thereby obtaining hydrochloride (118 mg) of the subject: compound as a white solid.
MS(FAB,Pos.):m/z=386[M+H]+

H-NMR (500MHz, DMSO--d6) :6=0.89 (6H, t, J=7. 3Hz) , 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 . lHz) , 8.71 (1H, d, J=4 . 4Hz) .

Example 1-5: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylarnino-butyl)-benzamide [Compound No.1]

The compound. (24.0 mg) obtained in Example 1-4 was suspended in chloroform and extracted by the addition of a 1 mol/l sodium hydroxide aqueous solution. The organic layer was dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue was dissolved in methanol (0.5 ml) and added with 2-imidazole carboxaldehyde (4.60 mg) and sodium cyanoborohydride (4.60 mg). Then, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 19 hours. After completion of the reaction, the solvent was distilled off and the residue was then suspended in chloroform, followed by washing with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. Subsequently, the residue was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was dissolved in chloroform and added with methanesulfonic acid (12.6 l). The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining methanesulfonate (21.9 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=486[M+H]+

1H-NMR(500MHz,DMSO-d6):5=0.89(6H,t,J=7.3Hz),1.50-1.69(8H,m),2.94-3.01(4H,m),3.04-3.13(2H,m),3.24-3.32 (2H,m) , 3.75 (2H, s) , 4 .08 (4H, s) , 7 .43 (2H, d, J=8.4Hz) , 7.62 (4H, s),7.77(2H,d,J=8.4Hz),8.51(1H,t,J=5.8Hz),8.99(1H,brs).
Production Example 2: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4--diisobutylamino-butyl)-benzamide [Compound No.2]

Example 2-1: Synthesis of 4-(1H-imidazol-2-ylmethylaminomethyl) benzoic acid methyl ester The compound (2.01 g) obtained in Example 1-1 was dissolved in a solution (20 ml) of 10% hydrogen chloride/methanol and the solution was then stirred at room temperature for 23 hours. After completion of the reaction, the solution was concentrated and suspended in chloroform.
Then, the suspension was added with a 1 mol/l sodium hydroxide aqueous solution to separate the solution into layers. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was dried under reduced pressure, thereby obtaining the subject compound (0.80 g) as a white solid.
MS(FAB,Pos.):m/z=246[M+H]+

Example 2-2: Synthesis of 4-[N,N-bis-(imidazol-2-ylmethyl) aminomethyl]-benzoic acid The compound (800 mg) synthesized in Example 2-1 was dissolved in methanol (32 ml) and then the solution was added with 2-imidazole carboxaldehyde (345 mg) and sodium cyanoborohydride (307 mg). Then, the solution was adjusted to approximately pH 5 with acetic acid and stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off and the residue was then suspended in chloroform, followed by washing with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. Subsequently, the resultant was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was dissolved in methanol (10 ml) and a 1 mol/l sodium hydroxide aqueous solution (10 ml), followed by stirring at room temperature for 2.5 hours. After completion of the reaction, the organic solvent portion was distilled off. Then, the residue was adjusted to pH 6 by the addition of 1 mol/l hydrochloric acid. The aqueous layer was washed with chloroform. The solution was concentrated to remove water and the residue was then added with methanol. After the insoluble matter had been removed through filtration, the methanol was distilled off and the residue was then concentrated under reduced pressure, thereby obtaining the subject compound (1.05 g).
MS(FAB,Pos.):m/z=312[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=3.70 (2H, s) , 3.90 (4H, s) , 7.32 (4H, s) , 7.52 (2H, d, J=8 .2Hz) , 7.86 (2H, d, J=8.2Hz) .

Example 2-3: Synthesis of N-benzyloxycarbonyl-N',N'-1,4-diaminobutane N-benzyloxycarbonyl-1,4-diaminobutane (200 mg) synthesized by the method described in Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull) vol. 32, page cyanoborohydride (136 mg). Then, the solution was adjusted to approximately pH 5 with acetic acid and stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off and the residue was then suspended in chloroform, followed by washing with a 1 mol/1 sodium hydroxide aqueous solution and saturated saline solution. The resultant was dried with anhydrous sodium sulfate and the solvent was then distilled off.
Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (125 mg) as a colorless liquid.

MS (FAB, Pos.) :m/z=335 [M+H] +

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

The compound (125 mg) obtained in Example 2-3 was dissolved in ethanol (7.5 ml). Then, the solution was added with 10% palladium-carbon (63.0 mg), followed by stirring under a hydrogen atmosphere at room temperature for 1 hour.
After completion of the reaction, the catalyst was removed by Celite'" filtration and the solvent was then distilled off, followed by distilling azeotropically with dichloromethane to obtain a deprotected product. Subsequently, the product was dissolved in DMF (3.5 ml) and added with DCC (84.9 mg), HOBt (55.6 mg), and the compound (128 mg) obtained in Example 2-2, followed by stirring at room temperature for 17 hours. After completion of the reaction, insoluble matter Example 2-2, followed by stirring at room temperature for 17 hours. After completion of the reaction, insoluble matter was removed by decantation and the solvent was then distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution.
After the organic layer was added with hydrochloric acid, the solution was separated into layers. Then, the aqueous layer was adjusted to pH 11 by the addition of a sodium hydroxide aqueous solution, followed by extraction with chloroform. Subsequently, the organic layer was dried and concentrated with anhydrous sodium sulfate. The residue was purified through silica gel column chromatography (chloroform/methanol/water) and treated with hydrochloric acid, thereby obtaining hydrochloride (54.5 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=494[M+H]+

1H-NMR (500MHz, DMSO--d6) : b=0.96 (6H, d, J=6.8Hz) , 0.98 (6H, d, J=6.8Hz) , 1.51-1 . 69 (2H, m) , 1.67-1.75 (2H, m) , 2 . C)5 (2H, sept. , J=6. 8Hz) , 2 . 82-2.96(4H,m),3.08-3.13(2H,m),3.25-3.33(2H,m),3.71(2H,s),4.13(4H,s),7.54 (2H,d,J=8.lHz),7.61(4H, s) , 7.78 (2H,d,J=8.1Hz) , 8.59 (1H,brs) , 8.97 (1H,br) .

Production Example 3: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4--aminobutyl)-benzamide [Compound No.3]

Example 3-1: Synthesis of 4-{N,N-bis-(imidazol-2-ylmethyl)amino]methyl}-N-(Boc--aminobutyl)-benzamide The compound (406 mg) obtained in Example 2-2 and N-(4-aminobutyl)carbamic acid t-butyl ester (Tokyo Kasei Kogyo Co., Ltd.) (206 mg) were dissolved in DMF (12 ml) and added with WSCI hydrochloride (410 mg), followed by stirring for 6.5 hours. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. After that, the solution was washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution and then concentrated. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (23.0 mg) as colorless foam.
MS(FAB,Pos.):m/z=482[M+H]+

Example 3-2: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-aminobutyl)-benzamide [Compound No.3]
The compound (22.0 mg) obtained in Example 3-1 was dissolved in methanol (0.2 ml) and added with a 4 mol/1 hydrogen chloride/dioxane solution (0.22 ml), followed by stirring at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off.
The residue was dried under reduced pressure and then suspended in chloroform. The suspension was washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution and dried with anhydrous sodium sulfate.
Subsequently, the solvent was distilled off and the residue was then dried under reduced pressure, thereby obtaining the subject compound (32.5 mg).

MS(FAB,Pos.):m/z=382[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=2.73-2.81 (2H, m) , 3 . 24-3. 30 (2H,m) , 3.71 (2H,, s) , 4.14 (4H, s) , 7 .53 (2H, d, J=8.2Hz) , 7.60 (4H, s),7.67 (2H,d,J=8.2Hz),7.93(3H,brs),8.59(1H,t,J=5.6Hz),14.8(3 H, brs) .

Production Example 4: 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylamino-butyl)-benzamide [Compound No.4]

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

The compound (28.8 mg) obtained in Example 3-2 was dissolved in methanol (0.5 ml). The solution was added with cyclohexanone (8.80 l) and sodium cyanoborohydride (4.40 mg) and then adjusted to approximately pH 5 with acetic acid, followed by stirring at room temperature for 16 hours.

After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by the addition of 1 mol/l hydrochloric acid to extract the objective substance.
Subsequently, the aqueous layer was concentrated under reduced pressure and then the residue was purified through a solid-phase extraction column (Bond Elut C18 (manufactured by Varian Inc.), 200 mg), thereby obtaining hydrochloride (17.6 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=463[M+H]+

iH-NMR (500MHz, DMSO-d6) :5=1.03-1..14 (1H, m) , 1 . 16-1.33(4H,m),1.54-1.69(5H,m),1.70-1.80(2H,m),1.98-2.06(2H,m),2.85-2.97(3H,m),3.23-3.31 (2H,m) , 3.69 (2H, s) , 4.11 (4H, s) , 7.45 (2H, d, J=8 . 4Hz) , 7.58 (4H, s) , 7.76 (2H, d, J=8.4Hz) , 8.48 (1H,brs) , 8.72 (1H,br) .

Production Example 5: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-benzyloxycarbonylaminobutyl)-benzamide [Compound No.5]

Example 5-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-benzyloxyc:arbonylaminobutyl)-benzamide [Compound No.5] The compound (413 mg) obtained in Example 2-2 and N-benzyloxycarbonyl-1,4-diaminobutane (247 mg) were dissolved in anhydrous DMF (8.0 ml) and added with WSCI

hydrochloride (234 mg) and HOBt (165 mg), followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform, washed with 1 mol/l hydrochloric acid, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution, and dried with anhydrous magnesium sulfate, followed by distilling the solvent off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and treated with hydrochloric acid, thereby obtaining hydrochloride (23.0 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=516[M+H]+

1H-NMR(500MHz,DMSO-d6):6=1.40-1.50(4H,m),2.99(2H,dd,J=6.3, 12.4Hz),3.22(2H,dd,J=6.1,12.6Hz) ,3.71(2H,s),4.12(4H,s),4.99(2H,s),7.27-7.37 (6H,m) , 7.50 (2H,d, J=8.3Hz) , 7.61 (4H, s) , 7.76 (2H,dd, J=8.3Hz) ,8.44(1H,t,J=5.6Hz).

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

Example 6-1: Synthesis of4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-methoxy-benzylamino)-butyl]-benzamide [Compound No.6]

The compound (63.9 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (1.3 ml) and then added with 2-methoxybenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0350 ml) and trimethyl orthoformate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0560 ml), followed by stirring at room temperature for 30 minutes. The solution was added with sodium borohydride (19.3 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off.
Then, the residue was added with water and extracted with chloroform, and the extract was washed with saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and treated with hydrochloric acid. The residue was purified through a solid-phase extraction column (Sep-Pack , tC18, manufactured by Waters Corporation), thereby obtaining hydrochloride (6.80 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=502[M+H]+
1H-NMR (500MHz, DMSO--d6) :8=1.53-1.57 (2H, m) , 1 . 64-1. 69 (2H,m) , 2.92 (2H,br) , 3.25 (2H, dd, J=6. 7, 12.5Hz) , 3.71 (2H, s) , 3 .83(2H,s),4.06-4.08 (2H,m) , 4.10 (4H, s) , 6.99 (1H,dt, J=1. 1, 7.5Hz) , 7.09 (1H, d, J=7.
6Hz),7.40-7.46(2H,m),7.52(2H,d,J=8.4Hz),7.60(4H,s),7.77(2H,d,J=8.4Hz),

8. 53 (1H, t, J=5 . 5Hz) , 8.81 (2H, br) .

Production Example 7: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2--dipropylamino-ethyl)-benzamide [Compound No.7]

Example 7-1: Synthesis of mono-N-Boc-ethylenediamine Ethylenediamine (manufactured by Kanto Kagaku) (5.01 g) was dissolved in chloroform (100 ml) and added with triethylamine (13.9 ml), followed by dropping a chloroform solution (5.0 ml) of di-t-butyl dicarbonate (2.27 g) therein.
After the mixture had been stirred at room temperature for 4 hours, the solvent was distilled off under reduced pressure and the residue was then dissolved in ethyl acetate. Then, the residue was washed with a 1 mol/l sodium hydroxide aqueous solution and water and extracted with ethyl acetate, and the extract was washed with saturated saline solution, followed by drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (1.09 g) as a pale-yellow liquid.

MS(FAB,Pos.) :m/z=161[M+H]'' 1H-NMR (500MHz, DMSO-d6) :6=1.37 (9H, s) , 2 . 4 9-2.54 (2H,m) , 2.90 (2H,q, J=6.lHz) , 6.74 (1H,brs) .
Example 7-2: Synthesis of 4-{[bis-(1H-imidazol-2-ylmethyl)amino]methyl}-N-(2-N-Boc-aminoethyl)-benzamide The compound (342 mg) obtained in Example 2-2, DCC
(227 mg), and HOBt (149 mg) were dissolved in DMF (3.0 ml), followed by stirring for 10 minutes. A DMF solution (2.0 ml) of the compound (160 mg) obtained in Example 7-1 was dropped in this solution, and the whole was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 0.2 mol/l hydrochloric acid and washed with chloroform. The aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. The organic layer was washed with saturated saline solution, followed by drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (334 mg) as a pale-yellow solid.
MS(FAB,Pos.):m/z=454[M+H]+

1H-NMR (500MHz, DMSO--d6) :6=1.37 (9H, s) , 3 .. 09 (2H, q, J=6.3Hz) , 3.28 (2H, q, J=6.3Hz) , 3.56 2H, s) , 3.58 (4H, s) , 6. 90-6. 92 (2H,m) , 7.06 (2H,br) , 7.48 (2H, d, J=8 .2Hz) , 7.78 (2H, d, J=8 . 1Hz) ,8.41(1H,t,J=5.4Hz).

Example 7-3: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-dipropylamino-ethyl)-benzamide [Compound No.7]

The compound (165 mg) obtained in Example 7-2 was dissolved in methanol (1.7 ml). A 4 mol/l hydrogen chloride/dioxane solution (0.83 ml) was added in this solution, and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was dried under vacuum. The dried product was dissolved in methanol (4.0 ml) and then added with trimethyl orthoformate (165 l), acetic acid (200 l), propionaldehyde (78.0 l), and sodium cyanoborohydride (68.6 mg) and stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, and added with 1 mol/l hydrochloric acid to transfer the objective substance to the aqueous layer, followed by washing with chloroform. The 1 mol/l sodium hydroxide aqueous solution was added again to alkalinize the solution. The solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution and dried with anhydrous sodium sulfate.
After filtration, the solvent was distilled off under reduced pressure. Then, the residue was dried under vacuum and treated with hydrochloric acid, thereby obtaining hydrochloride (110 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=438[M+H]+
1H-NMR(500MHz,DMSO-d6) :6=0.89 (6H, t, J=7 . 3Hz) , 1.69 (4H, sext . , J=7 . 3Hz) , 3. 04-3.08(4H,m),3.23(2H,m),3.49-3. 66 (2H,m) , 3.72 (2H, s) , 4.14 (4H, s) , 7.54 (2H, d, J=8. 4Hz) , 7.60 (4H, s) , 7.83 (2H, d, J=8.2Hz) , 8.97 (1H,brs) , 10.40 (1H,br) .

Production Example 8: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2--cyclohexylaminoethyl)-benzamide [Compound No.8]

Example 8-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(2-cyclohexylaminoethyl)-benzamide [Compound No.8]

The compound (165 mg) obtained in Example 7-2 was dissolved in methanol (1.7 ml). A 4 mol/1 hydrogen chloride/dioxane solution (0.83 ml) was added in this solution, and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was dried under vacuum, thereby obtaining a crude product. The product was dissolved in methanol (4.0 ml) and then added with trimethyl orthoformate (165 l), acetic acid (200 l), cyclohexanone (75.0 l), and sodium cyanoborohydride (68.6 mg) and stirred for 23 hours at room temperature. The solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, and added with 1 mol/l hydrochloric acid to transfer the objective substance to the aqueous layer, followed by washing with chloroform.
The 1 mol/1 sodium hydroxide aqueous solution was added again to alkalinize the solution. The solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was dried under vacuum and treated with hydrochloric acid, thereby obtaining hydrochloride (116.0 mg) of the subject compound as a white solid.

MS(FAB,Pos.)m/z=436[M+H]+
1H-NMR (500MHz, DMSO--d6) :8=1 . 08-1.35 (6H,m) , 1.59 (2H,d,J=12.7Hz) , 1.75 (2H,d,J=12.7Hz) ,2.04 (2H,d ,J=10.2Hz),3.00-3.09 (3H,m) , 3.59 (2H, q, J=5. 9Hz) , 3.72 (2H, s) , 4.14 (4H, s) , 7 .53 (2H, d,J=8.2Hz),7.61(4H,s),7.86(2H,d,J=8.4Hz),8.90(lH,t,J=5.9Hz),

9.07(1H,brs).

Production Example 9: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexylmethyl-amino)-butyl]-benzamide [Compound No.9]

Example 9-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(cyclohexylmethyl-amino)-butyl]-benzamide [Compound No.9]

The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with cyclohexane carboxaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0240 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and. saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methan(Dl/water), thereby obtaining hydrochloride (42.0 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=478[M+H]+

1H-NMR (500MHz, DMSO--d6) :6=0.88-0. 95 (2H, m) , 1. 04-1.23(3H,m),1.51-1.57(2H,m),1.60-1.69(6H,m),1.75(2H,d,J=12.4Hz),2.69-2.73(2H,m),2.88(2H,br),3.24-3.28 (2H,m) , 3.71 (2H, s) , 4 .12 (4H, s) , 7 .53 (2H, d, J=8.2Hz) , 7.61 (4H, s),7.78(2H,d,J=8.4Hz),8.55(2H,t,J=5.5Hz),8.59(2H,br).
Production Example 10: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-t-butyl-benzylamino)-butyl]-benzamide [Compound No.10]

Example 10-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-t-butyl-benzylamino)-butyl]-benzamide [Compound No.10]

The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 4-t-butyl-benzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0330 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes.
Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes.
After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid.
Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (42.0 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=528[M+H]+
1H-NMR(500MHz,DMSO-d6):5=1. 28(9H,s),1.53-1.56 (2H,m) , 1.67 (2H,m) , 2.91 (2H,br) , 3.25 (2H, d, J=6.3Hz) , 3.71 (2H
,s),4.07(2H,t,J=5.5Hz),4.11(4H,s),7.45(4H,d,J=2.lHz),7.52(8.
2Hz),7.60(4H,s),7.77(2H,d,J=8.2Hz),8.53(1H,t,J=5.6Hz),9.08(1 H,br).

Production Example 11: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethyl)-benzylamino-butyl]-benzamide [Compound No.11]

Example 11-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethyl)-benzylamino-butyl]-benzamide [Compound No.11]

The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 2-trifluoromethylbenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0260 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (57.1 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=540[M+H]+

1H-NMR(500MHz, DMSO-d6+D20) :6=1.57-1.60 (2H,m) , 1. 69-1 . 70 (2H,m) , 3.07 (2H, t, J=7 . 6Hz) , 3.28 (2H, t, J=6. 8Hz) , 3.74 (2H, s) , 4.10(4H,s),4.30(2H,s),7.45(2H,d,J=8.3Hz),7.57 (4H,s),7.67-7.85(6H,m).

Production Example 12: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethoxy)-benzylamino-butyl]--benzamide [Compound No.12]

Example 12-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethoxy)-benzylamino-butyl]-benzamide [Compound No.12]

The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 2-trifluoromethoxybenzaldehyde (manufactured by Avocado Co., Ltd.) (0.0290 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes.
Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes.
After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid.
Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (39.7 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=556[M+H]+
1H-NMR (500MHz, DMSO-d6) :6=1.55-'-.57 (2H, m) , 1. 68-1 . 70 (2H,m) , 2.99 (2H,br) , 3.26 (2H, d, J=6. OHz) , 3.71 (2H, s) , 4.10 (4H

,s),4.20(2H,s),7.4`>-7.53(4H,m),7.56-7.59(1H,m),7.77-7.82 (3H,m) , 8.53 (1H, t, J=5.5Hz) , 9.24 (2H,br) .

Production Example 13: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-methylsulfanyl-benzylamino)-butyl]-benzamide [Compound No.13]

Example 13-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(4-methylsulfanyl-benzylamino)-butyl]-benzamide [Compound No.13]

The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 4-methylthiobenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0270 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes.
Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes.
After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid.
Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (64.0 mg) of the subject compound as a white solid.

MS (FAB, Pos .) :m/z=518 [M+H] +

1H-NMR(500MHz,DMSO-d6): 6=1.50-1.59(2H,m),1.61-1.70 (2H,m) , 2.48 (3H, s) , 2.88 (2H,br) , 3.24 (2H, d, J=5. 8Hz) , 3.71 (2H, s) , 4.07 (2H, m) , 4.11 (4H
,s),7.29(2H,d,J=8.4Hz),7.46(2H,d,J=8.4Hz),7.52 (2h,d,J=8.2Hz) ,7.60(4H,s),7.77(2H,d,J=8.4Hz),8.52(1H,t,J=5.5Hz),9.09(2H,br Production Example 14: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzamide [Compound No.14]

Example 14-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-benzamide [Compound No.14]

The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 3-methylpyridine-2-carboxaldehyde (24.2 mg) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (59.3 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=487[M+H]+

1H-NMR(500MHz,DMSO-d6):5=1.56-1.61(2H,m),1.73-1.75(2H,m),2.29(3H,s),3.03-3.06(2H,m),3.27(2H,dd,J=6.3,12.4Hz),3.71(2H,s),4.12(4H,s),4.
33(2H,t,J=5.8Hz),7.34-7.36(1H,m),7.54(2H,d,J=8.2Hz),7.61(4H,s),7.70(1H,d,J=7.8Hz), 7.78 (2H,d, J=8.2Hz) , 8.45 (1H,d, J=3.7Hz) , 8.55 (1H, t, J=5.5Hz) , 9.1 3 (2H,br) , 12.68 (3H,br) .

Production Example 15: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminophenyl)-benzamide [Compound No.15]

Example 15-1: Synthesis of N,N-dipropyl-N'-Boc-1,4-phenylenediamine N-Boc-1,4-phenylenediamine (manufactured by Furka Co., Ltd.)(589 mg) was dissolved in anhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride (533 mg), trimethyl orthoformate (774 l), and propionaldehyde (510 l), followed by stirring overnight under a nitrogen atmosphere at room temperature. After completion of the reaction, the solvent was distilled off. Then, the residue was then dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring.
This solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution.

The organic layer was dried with anhydrous sodium sulfate.
The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform), thereby obtaining the subject compound (863 mg) as an auburn liquid.

MS(FAB,Pos.):m/z=292[M+H]+
'H-NMR(500MHz,CDC13):8=0.90(6H,t,J=7.6Hz),1.50(9H,s),1.57(4H,se xt. , J=7.6Hz) , 3.18 (4H, t, J=7.6Hz) , 6.22 (1H,brs) , 6.58 (2H,d, J=9.0 Hz),7.15(2H,br).

Production Example 15-2: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminophenyl)-benzamide [Compound No.15]

The compound (300 mg) obtained in Example 2-2 was dissolved in DMF (10 ml) and added with DCC (298 mg), HOBt (195 mg), and the compound (185 mg) obtained in Example 15-1, followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by separating the solution into layers by the addition of 1 mol/l hydrochloric acid. The aqueous layer was made basic by the addition of a 1 mol/1 sodium hydroxide aqueous solution. Then, the solution was subjected to extraction with chloroform. The extract was washed with saturated saline solution and the organic layer was then dried with anhydrous sodium sulfate. The solvent was distilled off.
Subsequently, the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (96.4 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=486[M+H]+

1H-NMR (500MHz, DMSO-d6) :8=0.83 (6H, t, J=6. 9Hz) , 1 . 12-1.30(2H,m),1.66(2H,brs),3.44(4H,m),3.76(2H,s),4.16(4H,s),7.6 2(6H,brs),7.79(2H,brs),7.94(2H,d,J=7.6Hz),7.99(2H,brs),10.6( 1H, brs) , 12.7 (1H,brs) , 14.8 (1H,brs) .

Production Example 16: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[bis(3-methyl-butyl)-amino]butyl]}-benzamide [Compound No.16]

Example 16-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-{4-[bis(3-methyl-butyl)-amino]butyl}-benzamide [Compound No.16]

The compound (30.0 mg) obtained in Example 3-2 was dissolved in methanol (0.6 ml). Then, the solution was added with trimethyl orthoformate (30.0 l), acetic acid (30.0 l), isovaleraldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (25.3 l), and sodium cyanoborohydride (14.9 mg), followed by stirring at room temperature for 3 hours.

After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After the residue had been washed with a 1 mol/1 sodium hydroxide aqueous solution, the objective substance was transferred to the aqueous layer by the addition of 1 mol/1 hydrochloric acid, followed by washing with chloroform. The 1 mol/l sodium hydroxide aqueous solution was added again to alkalinize the solution, followed by extraction with chloroform. Then, the extract was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was dried under vacuum. Subsequently, the residue was treated with hydrochloric acid, thereby obtaining hydrochloride (21.8 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=522[M+H]+
1H-NMR (500MHz, DMSO-d6) :6=0.87 (12H, d, J=6. 1Hz) , 1 . 46-1.60(8H,m),1.67(2H,br),2.98-3.04 (6H,m) , 3.28 (2H, d, J=5.8Hz) , 3.71 (2H, s) , 4.13 (4H, s) , 7 .54 (2H, d, J=8.1Hz) ,7.61 (4H, s) ,7.79 (2H,d,J=8.2Hz) , 8.57 (1H,t,J=5.8Hz) ,

10.23(1H,brs).

Production Example 17: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dimethylamino-butyl)-benzamide [Compound No.17]

Example 17-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dimethylamino-butyl)-benzamide [Compound No.17]

The compound (27.7 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (1.1 ml). Then, the solution was added with a 36% formaldehyde aqueous solution (manufactured by Kanto Kagaku) (0.0160 ml) and sodium cyanoborohydride (13.2 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 22 hours.

After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by washing with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution and drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid.
Subsequently, the residue was purified through a solid-phase extraction column (Sep-Pack , tC18, manufactured by Waters Corporation), thereby obtaining hydrochloride (16.4 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=410[M+H]+

1H-NMR (500MHz, DMSO--d6) :6=1 . 51-1 . 54 (2H,m) , 1.65 (2H,m) , 2.73 (6H, d, J=4. 9Hz) , 3. 03-3. 04 (2H,m) , 3.26 (2H, d, J=5. 6Hz) , 3.72 (2H, s) , 4.08 (4H, s) , 7.51 (2H, d, J=8 . 5Hz) , 7.59 (4H, s) , 7.77 (2H, d, J=8.3Hz) , 8.52 (1H, t, J=5. 5Hz) .
Production Example 18: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cycloheptylaminobutyl)-benzamide [Compound No.18]

Example 18-1: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cycloheptylaminobutyl)-benzamide [Compound No.18]

The compound (30.0 mg) obtained in Example 3-2 was dissolved in methanol (0.6 ml). This solution was added with trimethyl orthoformate (30.0 l), acetic acid (30.0 l), cycloheptanone (manufactured by Merck, Inc.) (18.7 l), and sodium cyanoborohydride (14.9 mg), followed by stirring for 3 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform, washed with a 1 mol/l sodium hydroxide aqueous solution, and added with 1 mol/l hydrochloric acid to transfer the objective substance to the aqueous layer, followed by washing with chloroform. The 1 mol/l sodium hydroxide aqueous solution was added again to alkalinize the solution.
The solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was dried under vacuum and treated with hydrochloric acid, thereby obtaining hydrochloride (32.2 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=478[M+H]+

1H-NMR(500MHz,DMSO-d6):5=1.29-1.66(14H,m),2.00-2 . 03 (2H,m) , 2.88 (2H,br) , 3. 06-3.12(1H,m),3.26(2H,d,J=6.1Hz),3.71(2H,s),4.13(4H,s),7.53(2H, d, J=8.2Hz) , 7.61 (4H, s) , 7.78 (2H, d, J=8. 4Hz) , 8.57 (1H, t, J=6. lHz) , 8.69(1H,brs).

Production Example 19: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.19]

Example 19-1: Synthesis of (4-nitrobenzyl) dipropylamine Commercially available 4-nitrobenzylamine hydrochloride (manufactured by Tokyo Kasei Kogyo., Ltd.) (1.82 g) was suspended in chloroform (15 ml). Then, a 1 Subsequently, the solution was added with propionaldehyde (1.66 ml) and sodium cyanoborohydride (1.81 g) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 21 hours. After completion of the reaction, the solvent was distilled off. The residue was added with 1 mol/l sodium hydroxide and then subjected to chloroform extraction. The extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off.
The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.67 g) as a yellow oily substance.

NMR(500MHz,CDC13):5=0.87(6H,t,J=7.3Hz),1.47(4H,sext.,J=7.3Hz) , 2.38 (4H, t, J=7 . lHz) , 3.63 (2H, s) , 7.52 (2H, d, J=9 . OHz) , 8 .16 (2H, d, J=8.8Hz).

Example 19-2: Synthesis of 4-dipropylaminomethyl phenylamine The compound (492 mg) obtained in Example 19-1 was dissolved in methanol (5.0 ml) and THE (2.5 ml). Then, the solution was added with activated carbon (49.0 mg) and iron trichloride hexahydrate (manufactured by Kanto Kagaku) (4.90 mg), followed by refluxing under heating for 30 minutes.
After the solution was cooled to room temperature, hydrazine monohydrate (0.35 ml) was added to the solution and then the whole was refluxed for 3 hours under heat. After completion of the reaction, the reaction product was filtrated through Celite' and the solvent was then distilled off. After the addition of water, chloroform extraction was performed. The extract was dried with anhydrous magnesium sulfate. The whole was refluxed for 3 hours under heat. After completion of the reaction, the reaction product was filtrated through Celite and the solvent was then distilled off. After the addition of water, chloroform extraction was performed. The extract was dried with anhydrous magnesium sulfate. The solvent was distilled off, thereby obtaining the subject compound (437 mg) as a yellow oily substance.
MS(FAB,Pos.):m/z=207[M+H]+

Example 19-3: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropyla.minomethylphenyl)-benzamide [Compound No.19]

The compound (57.2 mg) obtained in Example 19-2, the compound (106 mg) obtained in Example 2-2, and HOBt (162 mg) were dissolved in anhydrous DMF (2.5 ml) and then added with PS-carbodiimide (manufactured by Argonaut Technologies, Inc.) (419 mg), followed by stirring at room temperature for 12 hours. After completion of the reaction, the solution was filtrated and the solvent was then distilled off. The residue was dissolved in chloroform and then washed with 1 mol/l sodium hydroxide and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (18.3 mg) of the subject compound as a yellow solid.
MS(FAB,Pos.):m/z=500[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=0.87 (6H, t, J=7 . 3Hz) , 1. 67-1.77(4H,m),2.88-2.93(4H,m),3.76(2H,s),4.14(4H,s),4.26(2H,d,J=5.2Hz),7.56(2H, d,J=8.5Hz),7.62(4H,s),7.88(2F[,d,J=8.7Hz),7.91(2H,d,J=8.2Hz), 10. 18 (1H,br),10.39(1H,s) .

Production Example 20: Synthesis of N-(4-dipropylaminobuty.l)-4-{[(1H-i.midazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.20]

Example 20-1: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.20]

The compound (39.8 mg) obtained in Example 1-3 and pyridine-2-aldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (16.1 mg) were dissolved in anhydrous methanol (2.0 ml). The solution was added with sodium cyanoborohydride (18.9 mg) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 39.5 hours.
After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and then washed with a 1 mol/l sodium hydroxide and saturated saline solution, followed by drying with anhydrous magnesium sulfate. Subsequently, the residue was distilled off and the residue was then treated with hydrochloric acid. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (7.00 mg) of the subject compound as a yellow solid.

MS(FAB,Pos.):m/z=478[M+H]+

1H-NMR(500MHz,DMSO-d6):6=0.89(6H,t,J=7.3Hz),1.53-1.56(2H,m),1.61-1.69(4H,m),2.94-3.01(4H,m),3.04(2.H,br),3.28(2H,d,J=6.OHz),3.76(2H,s),3.95(2H
,br),4.10(2H,s),7.50(2H,d,J=8.4Hz),7.60(2H,s),7.79(2H,d,J=8.
2Hz) , 8.54 (1H, t, J=5 . 5Hz) , 8.63--8.67 (2H, m) , 9.83 (1H, br) .
Production Example 21: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(thiazol-2-ylmethyl)-amino]-methyl}-benz:amide [Compound No.21]

Example 21-1: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(thiazol.-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.21]

The compound (39.8 mg) obtained in Example 1-3 and 2-formylthiazole (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (16.9 mg) were dissolved in anhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride (18.9 mg). The solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 39.5 hours. After completion of the reaction, the solvent was distilled off.
The residue was dissolved in chloroform and then washed with 1 mol/l sodium hydroxide and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (9.20 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=483[M+H]+

1H-NMR(500MHz,DMS(D-d6):6=0.89(6H,t,J=7.3Hz),1.61-1.75(8H,m),3.00-3.05(6H,m),3.30-3.37(2H,m),3.81(2H,s),4.03(2H,s),4.12(2H,s),7.50-7.52(3H,m),7.59(2H,s),7.71(1H,d,J=3.4Hz),7.77(1H,d,J=3.4Hz), 7.83 (2H,d, J=8.4Hz) , 8.56 (1H, t, J=5. 6Hz) , 9.74 (1H,br) .
Production Example 22: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminopropyl)-benzamide [Compound No.22]

Example 22-1: Synthesis of N-Boc-1,3-propanediamine 1,3-propanediamine (manufactured by Kanto Kagaku)(2.57 g) was dissolved in anhydrous dichloromethane (75 ml) and then added with triethylamine (4.80 ml) and di-t-butoxydicarbonate (3.78 g), followed by stirring overnight under a nitrogen atmosphere at room temperature. After completion of the reaction, the solution was added with water and then stirred, followed by extraction with dichloromethane. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (3.15 g) as a colorless liquid.

MS(FAB,Pos.):m/z=175[M+H]+
Example 22-2: Synthesis of N,N-dipropyl-N'-Boc-1,3-propanediamine The compound (1.50 g) obtained in Example 22-1 was dissolved in anhydrous methanol (20 ml) and added with sodium cyanoborohydride (1.62 g), trimethyl orthoformate (2.35 ml), and propionaldehyde (1.55 ml), followed by stirring under a nitrogen atmosphere at room temperature for 3 days. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The solution was subjected to extraction with chloroform and then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby the subject compound (2.67 g) as a colorless liquid.

MS(FAB,Pos.):m/z=259[M+H]+
Example 22-3: Synthesis of N,N-dipropyl-1,3-propanediamine The compound (2.67 g) obtained in Example 22-2 was dissolved in anhydrous methanol (2.0 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (20.0 ml), followed by stirring at room temperature for 1.5 hours.
After completion of the reaction, the solvent was distilled off. Then, the residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with dichloromethane. The extract was washed with distilled water and saturated saline solution, and then the organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off, thereby obtaining the subject compound (726 mg) as a pale-yellow liquid.

MS(FAB,Pos.):m/z=159[M+H]+

Example 22-4: Synthesis of 4--{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminopropyl)-benzamide [Compound No.22]

The compound (190 mg) obtained in Example 2-2 was dissolved in DMF (3.0 ml) and added with DCC (189 mg), HOBt (124 mg), and the compound (96.9 mg) obtained in Example 22-3, followed by stirring overnight at room temperature.

After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by separating the solution into layers by the addition of 1 mol/l hydrochloric acid. The aqueous layer was made basic with a 1 mol/l sodium hydroxide aqueous solution. Then, the solution was subjected to extraction with chloroform. The extract was washed with saturated saline solution and the organic layer was then dried with anhydrous sodium sulfate. The solvent was distilled off.
Subsequently, the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (84.8 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=452[M+H]+

1H-NMR(500MHz,DMSO-d6):5=0.89(6H,t,J=7.3Hz),1.65(4H,sext.,J=7.3Hz),1.86-1.94(2H,m),2.95-2.99(4H,m),3.04-3. 09 (2H,m) , 3.32 (2H,m) , 3.72 (2H, s) , 4.13 (4H, s) , 7 .54 (2H, d, J=8.

z) , 7.60 (4H, s) , 7.78 (2H, d, J=8. 4Hz) , 8.68 (1H, t, J=5. 8Hz) , 10.2 (1H, brs).

Production Example 23: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylamino-2,2-dimethylpropyl)-benzamide [Compound No.23]

Example 23-1: Synthesis of N--Boc-2,2-dimethyl-l,3-propanediamine 2,2-dimetyl-1,3-propanediamine (manufactured by Aldrich Corporation) (2.00 g) was dissolved in anhydrous dichloromethane (100 ml) and then added with triethylamine (2.70 ml) and di-t-butoxydicarbonate (2.14 g), followed by stirring overnight under a nitrogen atmosphere at room temperature. After completion of the reaction, the solution was added with water and stirred, followed by extraction with dichloromethane. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (1.76 g) as a white solid.
MS(FAB,Pos.):m/z=203[M+H]+

Example 23-2: Synthesis of (N,N-dipropyl-N'-Boc)-2,2-dimethyl-1,3-propanediamine The compound (501 mg) obtained in Example 23-1 was dissolved in anhydrous methanol (5.0 ml) and then added with sodium cyanoborohydride (467 mg), trimethyl orthoformate (677 l), and propionaldehyde (447 l), followed by stirring at room temperature under a nitrogen atmosphere for 3 days.
After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The solution was extracted with chloroform and the extract was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (740 mg) as a pale-yellow liquid.
MS(FAB,Pos.):m/z=287[M+H]+

Example 23-3: Synthesis of N,N-dipropyl-2,2-dimethyl-1,3-propanediamine The compound (740 mg) obtained in Example 23-2 was dissolved in anhydrous methanol (3.0 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (15.0 ml), followed by stirring at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off and the residue was then added with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with dichloromethane. After the extract had been washed with distilled water and saturated saline solution, the organic layer was dried with anhydrous sodium sulfate. The solvent was then distilled off, thereby obtaining the subject compound (351 mg) as a colorless liquid.
MS(FAB,Pos.):m/z=187[M+H]+

Example 23-4: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylamino-2,2-dimethylpropyl)-benzamide [Compound No.23]

The compound (100 mg) obtained in Example 2-2 was dissolved in DMF (2.0 ml) and then added with DCC (55.4 mg), HOBt (36.3 mg), and the compound (50.0 mg) obtained in Example 23-3, followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. Then, the solution was added with 1 mol/l hydrochloric acid to separate the solution into layers.
After the aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution to make the solution basic, the solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution.
Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. After that, the residue was subjected to purification through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (17.5 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=480[M+H]+
1H-NMR(500MHz,DMS(D-d6):6=0.89(6H,t,J=7.3Hz),1.09(6H,s),1.61-1.78(4H,m),3.02-3.03(6H,m),3.26-3.27 (2H,m) , 3.72 (2H, s) , 4.12 (4H, s) , 7.58 (2H, d, J=8.2Hz) , 7.61 (4H, s) , 7.82 (2H, d, J=8.2Hz) , 8.61-8.63 (1H, m) , 9.18 (1H, brs) .
Production Example 24: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzenesulfonamide [Compound No.24]

Example 24-1: Synthesis of 2-benzylisoindole-l,3-dione Benzylamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.00 g) was dissolved in purified water (20 ml) and then added with N-carbethoxyphthalimide (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (3.06 g) and sodium carbonate (2.47 g), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solution was filtered and the residue was washed with purified water and then dried under vacuum at 60 C, thereby obtaining the subject compound (1.82 g) as a white solid.
MS(FAB,Pos.):m/z=238[M+H]+

Example 24-2: Synthesis of 4--(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)benzenesulfonylchloride The compound (330 mg) obtained in Example 24-1 was dissolved in chloroform and then added with chlorosulfuric acid (manufactured by Kishida Chemical Co., Ltd.) (0.177 ml) under ice-cooling. The solution was stirred at room temperature for 2 days, and then concentrated and dried.
The resultant was gradually added with phosphorus pentachloride (300 mg) and then heated to 80 C, followed by stirring for 4 hours.

After completion of the reaction, the reacted solution was stood to cool and then dropped into ice cold water. The product was extracted with chloroform and then washed with a 5% aqueous sodium bicarbonate solution and saturated saline solution. Subsequently, the product was dried with anhydrous sodium sulfate and then concentrated, thereby obtaining the subject compound (440 mg) as a yellowish white solid.

MS(FAB,Pos.):m/z=336[M+H]+
1H-NMR (500MHz, DMSO-d6) :6=4.95 (2H, s) , 7.66-7.68 (2H, m) , 7 . 74-7 . 77 (2H,m) , 7.87-7.90 (2H,m) , 7.99-8.01 (2H,m) .

Example 24-3: Synthesis of 4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-N-(4-(Jipropylaminobutyl)benzenesulfonamide The compound (150 mg) obtained in Example 24-2 was dissolved in chloroform (10 ml) and then added with the compound (131 mg) obtained in Example 1-2 and triethylamine (0.224 ml), followed by stirring at room temperature for 15 minutes. The solution was added with water and subjected to extraction. The organic layer was washed with saturated saline solution and then dried and concentrated with anhydrous sodium sulfate, thereby obtaining the subject compound (160 mg) as a colorless viscous liquid.
MS(FAB,Pos.):m/z=472[M+H]+

Example 24-4: Synthesis of 4-aminomethyl-N-(4-dipropylaminobutyl) benzenesulfonamide The compound (160 mg) obtained in Example 24-3 was added with 2.0 ml of a 40% methylamine/methanol solution (manufactured by Tokyo Kasei Kogyo Co., Ltd.), followed by stirring at room temperature for 40 hours. After completion of the reaction, the solvent was distilled off and the residue was subjected to extraction by the addition of a 1 mol/l sodium hydroxide aqueous solution and chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off, thereby obtaining the subject compound (114 mg) as a colorless viscous liquid.
MS(FAB,Pos.):m/z=342[M+H]+

Example 24-5: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropyla.minobutyl)-benzenesulfonamide [Compound No.24]

The compound (114 mg) obtained in Example 24-4 was dissolved in anhydrous methanol (7.0 ml), and then the solution was added with 2-imidazole carboxaldehyde (73.0 mg), sodium cyanoborohydride (42.0 mg), and acetic acid (0.1 ml) in that order, followed by stirring at room temperature for 2 days. The methanol was distilled off and a 1 mol/1 sodium hydroxide aqueous solution (1.8 ml) was then added to the residue. The solution was extracted with chloroform and the extract was then dried with anhydrous sodium sulfate, followed by distilling the solvent off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and then treated with hydrochloric acid, thereby obtaining hydrochloride (160 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=502[M+H]+

1H-NMR(500MHz,DMSC)-d6):6=0.89(6H,t,J=7.4Hz),1.40-1.44(2H,m),1.60-1.70(6H,m),2.67-2.72(2H,m),2.93-3.01(6H,m),3.76-3.80(2H,m),4.14-4.16(4H,m),7.48-7.84 (8H,m) , 9.94 (1H,brs) .

Methyl 4-(aminomethyl)-benzoate hydrochloride (manufactured by Aldrich Corporation) (773 mg) was dissolved in THE (50 ml) and then gradually added with lithium aluminum hydride (300 mg) under ice-cooling. The solution was stirred at room temperature for 3 hours and then cooled with ice, followed by gradual addition of a concentrated sodium hydroxide aqueous solution until foam was not observed. CeliteTM filtration was carried out on the solution using chloroform as a solvent and then the filtrate was concentrated and dried. The dried product was dissolved in purified water (10 ml) and THE (10 ml). After having been cooled with ice, the solution was added with N-carbethoxyphthalimide (1.26 g) and sodium carbonate (900 mg).
After the mixture had been stirred at room temperature for 4 hours, THE was distilled off and chloroform was then added to the residue to carry out extraction. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. Subsequently, the residue was further dried under vacuum. Next, this compound was dissolved in chloroform (20 ml) and then added with manganese dioxide (5.0 g), followed by stirring at room temperature for 3 hours. After the solution had been subjected to Celite filtration, the filtrate was concentrated and then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (259 mg) as a white solid.
MS(FAB,Pos.):m/z=266[M+H]+

1H-NMR(500MHz,CDC13):8=4.92(2H,s),7.58(2H,d,J=8.3Hz),7.72-7. 76 (2H,m) , 7.83-7.89 (4H,m) 9.98 (lH, s) .

Example 25-2: Synthesis of 2-{4-[(4-dipropylaminobutyl amino)-methyl]benzyl}isoindole-l,3-dione The compound (103 mg) obtained in Example 25-1 was dissolved in anhydrous methanol (10 ml) and then added with the hydrochloride (114 mg) of the compound obtained in Example 1-2. Then, the solution was added with triethylamine (0.108 ml) and anhydrous magnesium sulfate (3 g), followed by stirring at room temperature for 1 hour.
Anhydrous magnesium sulfate was removed from the solution by CeliteTM filtration. Then, methanol was distilled off and the residue was dried using a vacuum pump. The residue was dissolved in anhydrous methanol (10 ml) and sodium borohydride (22.0 mg) was then gradually added under ice-cooling. The solution was warmed to room temperature and then stirred for 1 hour. After completion of the reaction, methanol was distilled off and the residue was then added with water and chloroform to extract the organic layer.
After the organic layer had been dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (60.3 mg) as a pale-yellow viscous liquid.

MS (FAB, Pos .) :m/z=420 [M+H] +

Example 25-3: Synthesis of [4-(1,3-dioxo-l,3-dihydroisoindol-2-ylmethyl)benzyl]-(4-dipropylaminobutyl) carbamic acid t-butyl ester The compound (60.3 mg) obtained in Example 25-2 was MS(FAB,Pos.):m/z=420[M+H]+

Example 25-3: Synthesis of [4-(1,3-dioxo-1,3-dihydroisoindol-2--ylmethyl)benzyl]-(4-dipropylaminobutyl) carbamic acid t-butyl ester The compound (60.3 mg) obtained in Example 25-2 was dissolved in chloroform and then added with di-t-butoxydicarbonate (47.0 mg). After having been stirred at room temperature for 30 minutes, the solution was subjected to concentration and then purification through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (70.0 mg) as a colorless viscous liquid.

MS(FAB,Pos.):m/z=522[M+H]+
Example 25-4: Synthesis of (4-aminomethylbenzyl)-(4-dipropylaminobutyl) carbamic acid t-butyl ester The compound (70.0 mg) obtained in Example 25-3 was added with a 40% methylamine/methanol solution (3.0 ml) and then stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off.
Then, the residue was then added with a 1 mol/l sodium hydroxide aqueous solution and chloroform to extract the aqueous layer therefrom with chloroform. The extract was dried with anhydrous sodium sulfate, and the solvent was distilled off, thereby obtaining the subject compound (65.5 mg) as a colorless viscous liquid.

Example 25-5: Synthesis of N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-rnethyl}-benzyl)-N',N'-dipropylbutane-1,4-diamine [Compound No.25]

The compound (45.5 mg) obtained in Example 25-4 was dissolved in anhydrous methanol (3.0 ml), and then the solution was added with 2-imidazole carboxaldehyde (25.0 mg), sodium cyanoborohydride (15.0 mg), and acetic acid (0.1 ml) in that order, followed by stirring at room temperature for 15 hours. The methanol was distilled off and a 1 mol/l sodium hydroxide aqueous solution (1.0 ml) was then added to the residue. The solution was extracted with chloroform and the extract was then dried with anhydrous sodium sulfate, followed by distilling the solvent off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and then treated with hydrochloric acid, thereby obtaining hydrochloride (28.0 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=452[M+H]+

1H-NMR(500MHz,DMSC-d6):6=0.90(6H,t,J=7.3Hz),1.62-1 . 78 (8H,m) , 2.83 (2H,brs) , 2.93-3.04 (8H,m) , 3.67 (2H, s) , 4 . 05-4. 10 (2H,m) , 4.11 (4H, s) , 7.46-7.50 (4H,m) , 7. 60-7. 64 (4H,m) , 9.40 (2H,brs) , 10.24 (1H,brs) , 14.68 (1H,brs) .
Production Example 26: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.26]

1.31 Example 26-1: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmeth_yl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.26]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol (0.8 ml) and then added with trimethyl orthoformate (50 l), acetic acid (50 l), and 1-methyl-2-imidazolecarboxylaldehyde (manufactured by Aldrich Corporation) (28.5 mg). After the solution had been stirred at room temperature for 10 minutes, sodium cyanoborohydride (24.4 mg) was added and then the whole was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with 1 mol/l sodium hydroxide and saturated saline solution and drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (10.0 mg) of the subject compound as a pale-yellow solid.
MS(FAB,Pos.)m/z=480[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=0.89 (6H, t, J=7. 3Hz) , 1. 50-1 . 56 (2H,m) , 1.62-1.74 (6H,m) , 2.94 (4H, dt, J=4 . 6, 2 . 6Hz) , 3. 02-3. 06 (2H,m) , 3.27 (2H, q, J=6. 4Hz) , 3.71 (3H, s) , 3.75 (2H, s) , 4.09 (2H, s),4.17(2H,s),7.50(2H,d,J=8.2Hz),7.54(2H,d,J=8.2Hz),7.64(2H, s) , 7 .79 (1H, d, J=8.4Hz) , 8.59 (1H, t, J=5.5Hz) , 10.32 (1H,brs) .
Production Example 27: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-1.32 pyrazol-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.27]

Example 27-1: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-pyra.zol-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.27]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol (0.8 ml). Then, the solution was added with trimethyl orthoformate (50 l), acetic acid (50 l), and pyrazol-3-carboxaldehyde (manufactured by Merck, Inc.) (24.9 mg) and stirred at room temperature for 10 minutes. Subsequently, sodium cyanoborohydride (24.4 mg) was added, followed by stirring overnight at room temperature. The solvent was distilled off under reduced pressure and then the residue was dissolved in chloroform, followed by washing with 1 mol/1 sodium hydroxide and saturated saline solution and drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (26.1 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=466[M+H]+
1H-NMR (500MHz, DMSO-d6) :5=0.88 (6H, t, J=7. 3Hz) , 1 . 53-1.69(8H,m),2.95(4H,brs),3.05(2H,brs),3.25-3.40(2H,m),3.55(2H,s),3.58(2H,s),3.62(2H,s),6.27(1H,s),7.04( 2H,s),7.50(2H,d,J=8.2Hz),7.81(2H,d,J=8.2Hz),8.51(1H,t,J=5.5H
Z).

Production Example 28: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2R)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.28]

Example 28-1: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2R)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.28]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol (0.8 ml). Then, the solution was added with trimethyl orthoformate (50 l), acetic acid (50 l), N-Boc-D-prolinal (manufactured by Aldrich Corporation) (25.7 mg) and stirred at room temperature for 10 minutes.
Subsequently, sodium cyanoborohydride (24.4 mg) was added, followed by stirring overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with 1 mol/l sodium hydroxide and saturated saline solution and drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol). Then, the purified product was dissolved in methanol (500 l) and added with a 4 mol/1 hydrogen chloride/dioxane solution (500 pl), followed by stirring at room temperature for 2 hours.
After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining hydrochloride (33.9 mg) of the subject compound as a white solid.
MS(FAB,Pos.)m/z=469[M+H]+

1H-NMR(500MHz,DMSO-d6):6=0.89(6H,t,J=7.3Hz),1.45-1.58(3H,m),1.63-1.73(6H,m),1.83-1.94(2H,m),2.00-2 .05 (1H, m) , 2 .77 (1H, dd, J=3.8, 9. 9Hz) , 2.90-2.98 (5H, m) , 3.03-3.07 (2H,m) , 3.09-3.23 (1H,m) , 3.28 (2H,m) , 3. 60-3. 86 (4H,m) , 3.95 (1H, d, J=15. 6Hz) , 4.15 (1H, d, J=15. 6Hz) , 7.45 (2H, d , J=8.2Hz) , 7.49 (2H, s) , 7.78 (2H, d, J=8.2Hz) , 8.58 (1H, t, J=5. 6Hz) , 8 .94(1H,brs),9.82(1H,brs),10.21(1H,brs).
Production Example 29: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2S)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.29]

Example 29-1: Synthesis of N--(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-((2S)-pyrrolidin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.29]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol (0.8 ml). Then, the solution was added with trimethyl orthoformate (50 l), acetic acid (50 l), N-Boc-L-prolinal (manufactured by Aldrich Corporation) (25.7 mg) and stirred at room temperature for 10 minutes.
Subsequently, sodium cyanoborohydride (24.4 mg) was added, followed by stirring overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with 1 mol/l sodium hydroxide and saturated saline solution and drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol). Then, the purified product was dissolved in methanol (500 l) and added with a 4 mol/1 hydrogen. chloride/dioxane solution, followed by stirring at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining hydrochloride (20.5 mg) of the subject compound as a pale brown solid.
MS(FAB,Pos.)m/z=469[M+H]+

1H-NMR (500MHz, DMSC)-d6) :6=0.89 (6H, t, J=7. 3Hz) , 1. 47-1.58(3H,m),1.63-1.73(6H,m),1.83-1.91(2H,m),2.02-2.05(1H,m),2.78(1H,dd,J=3.8,9.9Hz),2.91-2.98(5H,m),3.03-3.07(2H,m),3.09-3.23(1H,m),3.26-3.30(2H,m),3.57-3 . 71 (2H, m) , 3.81 (2H, d, J=14 . OHz) , 3.96 (1H, d, J=15 . 6Hz) , 4.15 (1H, d , J=15. 6Hz) , 7.45 (2H, d, J=8.2Hz) , 7.49 (2H, s) , 7.78 (2H, d, J=8.2Hz) , 8.59(1H,t,J=5.6Hz),8.97(1H,brs),9.85(1H,brs),10.25(1H,brs).
Production Example 30: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methyl-1H-imidazol-5-ylmethyl)-amino]-methyl}-benzamide [Compound No.30]

Example 30-1: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methyl-1H-imidazol-5-ylmethyl)-amino]-methyl}-benzamide [Compound No.30]

The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol (0.8 ml). Then, the solution was added with trimethyl orthoformate (50 l), acetic acid (50 l), and 4-methyl-5-imidazole carboxaldehyde (manufactured by Aldrich Corporation) (28.5 mg) and stirred at room temperature for 10 minutes. Subsequently, sodium cyanoborohydride (24.4 mg) was added, followed by stirring overnight at room temperature. The solvent was distilled off under reduced pressure and then the residue was dissolved in chloroform, followed by washing with 1 mol/l sodium hydroxide and saturated saline solution and drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (33.5 mg) of the subject compound as a white solid.
MS(FAB,Pos.)m/z=480[M+H]+

1H-NMR (500MHz, DMSO-d6) : S=0.81 (6H, t, J=7 . 3Hz) , 1 . 32-1.43(6H,m),1.51(2H,quint.,J=7.lHz),2.04(3H,br),2.28(4H,t,J=7 . lHz) , 2.35 (2H, t, J=7 . lHz) , 3.24 (2H, dd, J=6. 8, 5. 9Hz) , 3. 31-3. 47 (2H,m) , 3.56 (4H,br) , 6.85 (1H,br) , 7.10 (1H,br) , 7 .47 (2H, d, J=7 .8Hz),7.51(1H,s),'7.78(2H,d,J==8.3Hz),8.40(1H,t,J=5.9Hz) .
Production Example 31: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-dipropylaminopiperidin-1-yl)-methanone [Compound No.31]

residue was then dissolved in chloroform. After having been washed with 1 mol/l sodium hydroxide, the solution was extracted with chloroform. The resulting organic layer was washed with saturated saline solution, followed by drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol). The purified product was dissolved in ethanol (50 ml) and then added with 10%
palladium-carbon (50.0 mg). Subsequently, 3 cycles of deaeration and replacement with nitrogen and then 3 cycles of deaeration and replacement with hydrogen were carried out, followed by stirring overnight at room temperature. Once the palladium catalyst was removed through CeliteTM
filtration, 10% palladium-carbon (50.0 mg) was added again.
Then, the mixture was subjected to 3 cycles of deaeration and replacement with nitrogen and 3 cycles of deaeration and replacement with hydrogen, followed by stirring overnight at room temperature. After completion of the reaction, the reaction mixture was filtrated through Celite filtration and the filtrate was then subjected to solvent distillation under reduced pressure. Subsequently, the residue was dried under vacuum, thereby obtaining the subject compound (145.9 mg) as a yellow liquid.

MS(FAB,Pos.)m/z=185[M+H]+
Example 31-2: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-dipropylaminopiperidin-1-yl)-methanone [Compound No.31]

under vacuum, thereby obtaining the subject compound (145.9 mg) as a yellow liquid.

MS(FAB,Pos.)m/z=185[M+H]+
Example 31-2: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-dipropylaminopiperidin-1-yl)-methanone [Compound No.31]

The compound (31.2 mg) obtained in Example 2-2, DCC
(30.0 mg), and HOBt (20.5 mg) were dissolved in DMF (0.5 ml) and stirred for 15 minutes. Then, the compound (25.6 mg) obtained in Example 31-1 was added, followed by stirring at room temperature for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in 1 mol/l hydrochloric acid, followed by removing impurities with chloroform. The resulting aqueous layer was added with chloroform and then added with 1 mol/l sodium hydroxide to make the layer alkaline, followed by extraction with chloroform. The extract was washed with saturated saline solution and then dried with anhydrous sodium sulfate.

After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol).
Subsequently, the purified product was treated with hydrochloric acid, thereby obtaining hydrochloride (9.9 mg) of the subject compound as a white solid.

MS (FAB, Pos. )m/z=478 [M+H]+

1H-NMR (500MHz, DMSO-d6+D2O) :6=0. 93 (6H, t, J=7 . 3Hz) , 1. 63-1.74(6H,m),1.94-2.14(2H,br),2.74-2.86(1H,br),2.91-3.00(2H,br),3.09-3.17(3H,m),3.49-3.60(2H,m),3.73(2H,s),4.18(4H,s),4.54-4 . 63 (1H,br) , 7 .28 (2H, d, J=8.2Hz) , 7.40 (2H, d, J=8.2Hz) , 7.56 (2H, s) .
Production Example 32: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-propylpiperazin-l-yl)-methanone [Compound No.32]

Example 32-1: Synthesis of 4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzoyl)-piperazin-l-carboxylic acid t-butyl ester The compound (500 mg) obtained in Example 2-2 was dissolved in DMF (10 ml) and added with WSCI hydrochloride (257 mg), HOBt (181 mg), and 1-Boc piperazine (manufactured by Aldrich Corporation) (249 mg), followed by stirring at room temperature for 3 days. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform for extraction, followed by washing with distilled water, a 1 mol/1 sodium hydroxide aqueous solution, and saturated saline solution. The resulting organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (111 mg) as a yellow oily substance.
MS(FAB,Pos.):m/z=480[M+H]+

1H-NMR (500MHz, DMSO-d6+D20) :6=1.40 (9H, s) , 3.25-3.44(8H,m),3.54(2H,s),3.63(4H,s),7.02(4H,s),7.34(2H, d,J=8.2H
( 2 H , 140 Example 32-2: Synthesis of (4-{[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-piperazin-l-yl-methanone The compound (111 mg) obtained in Example 32-1 was dissolved in anhydrous methanol (1.0 ml) and then added with a 4 mol/1 hydrogen chloride/dioxane solution (3.0 ml) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off and the residue was added with a 1 mol/l sodium hydroxide aqueous solution, followed by washing with dichloromethane. The aqueous layer was evaporated to dryness, followed by distilling azeotropically with chloroform. Consequently, the subject compound (48.5 mg) was obtained as a yellow oily substance.
MS (FAB, Pos .) :m/z=380 [M+H] +

Example 32-3: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-propylpiperazin-l-yl)-methanone [Compound No.32]

The compound (48.8 mg) obtained in Example 32-2 was dissolved in anhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride (16.2 mg), trimethyl orthoformate (21.1 l), propionaldehyde (13.9 l), followed by stirring overnight at room temperature under a nitrogen atmosphere.
After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. A
saturated aqueous sodium bicarbonate solution was added to the solution, followed by stirring. The resultant solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution, and then the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the treated product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (33.2 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=422[M+H]+

1H-NMR (500MHz, DMS0-d6+D20) :5=0. 93 (3H, s) , 1.68-1.74 (2H,m) , 3. 03-3.08(4H,m),3.39-3. 62 (6H,m) , 3.74 (2H, s) , 4.17 (4H, s) , 7.32 (2H, d, J=8.2Hz) , 7.42 (2H, d,J=8.2Hz),7.56(4H,s) .

Production Example 33: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminomethylphenyl)-benzamide [Compound No.33]

Example 33-1: Synthesis of (3-nitro-benzyl)dipropylamine Commercially available 3-nitrobenzylamine hydrochloride (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.62 g) was suspended in chloroform (15 ml) and then added with a 1 mol/l sodium hydroxide aqueous solution (15 ml).
The aqueous layer was extracted with chloroform and the extract was then dried with anhydrous magnesium sulfate, followed by distilling the solvent off. Subsequently, the residue was dissolved in anhydrous methanol (25 ml) and then added with propionaldehyde (1.49 ml), trimethyl orthoformate (2.82 ml), and sodium cyanoborohydride (1.62 g), followed by stirring at room temperature for 2 hours. After completion 1H-NMR(500MHz,DMSO-d6):5=0.87(6H,t,J=7.3Hz),1.48(4H,sext.,J=7.3Hz),2.39(4H,t,J=7 .lHz),3.63(2H,s),7.46(1H,t,J=8.lHz),7.69(1H,d,J=7.6Hz),8.08( 1H, d, J=5 . 9Hz) , 8.22 (1H, s) .

Example 33-2: Synthesis of 3-dipropylaminomethylaniline The compound (595 mg) obtained in Example 33-1 was dissolved in methanol (6.0 ml) and THE (3.0 ml). The solution was added with activated carbon (59.0 mg) and iron trichloride hexahydrate (manufactured by Kanto Kagaku) (5.90 mg), followed by thermal ref lux for 30 minutes. After having been cooled to room temperature, the mixture was added with hydrazine monohydrate (0.43 ml) and then subjected to thermal ref lux for 24 hours. After completion of the reaction, the mixture was subjected to CeliteTM
filtration and the solvent was then distilled off. The residue was added with water and then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and then solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (343.9 mg) as a yellow oily substance.

MS (FAB, Pos .) :m/z=207 [M+H] +
1H-NMR(500MHz,DMSO-d6):5=0.90(6H,t,J=7.3Hz),1.92-1 . 94 (4H,m) , 2.89 (4H, t, J=8 .2Hz) , 3.72 (2H,br) , 3.78 (2H, br) , 6.63 (1 H,dd,J=1.7,8.OHz),6.72(1H,d,J=7.3Hz),6.90(lH,brs),7.11(lH,t, J=7.8Hz).

chromatography (chloroform/methanol), thereby obtaining the subject compound (343.9 mg) as a yellow oily substance.
MS(FAB,Pos.):m/z=207[M+H]+

1H-NMR (500MHz, DMSC)-d6) :6=0. 90 (6H, t, J=7 .3Hz) , 1. 92-1. 94 (4H,m) , 2.89 (4H, t, J=8.2Hz) , 3.72 (2H,br) , 3.78 (2H,br) , 6.63 (1 H, dd, J=1. 7 , 8 . 0Hz) ,, 6.72 (1H, d, J=7 . 3Hz) , 6.90 (1H, brs) , 7.11 (1H, t, J=7.8Hz).

Example 33-3: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminomethylphenyl)-benzamide [Compound No.33]

The compound (51.6 mg) obtained in Example 33-2, the compound (117 mg) obtained in Example 2-2, and HOBt (50.0 mg) were dissolved in anhydrous DMF (2.5 ml). Then, the solution was added with PS-carbodiimide (manufactured by Argonaut Technologies, Inc.) (373.1 mg), followed by stirring at room temperature for 17 hours. After completion of the reaction, the mixture was filtrated and the solvent was then distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. The residue was dried with anhydrous magnesium sulfate and the solvent was distilled off, followed by treatment with hydrochloric acid. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (18.5 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=500[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=0.88 (6H, t, J==7 . 3Hz) , 1.73 (4H, sept. , J=7 .2Hz) , 2 . 94-2. 96 (4H,br) , 3.76 (2H, s) , 4.14 (4H, s) , 4.30 (2H,brs) , 7.36 (1H, d, J=7 .8Hz),7.45(1H,t,J==7.9Hz),7.60(2H,d,J=2.7Hz),7.62(4H,s),7.75( 1H, d, J=9. 0Hz) , 7.92 (2H, d, J=8 . 4Hz) , 8.05 (1H, s) , 10.16 (1H, br) , 10 .
40 (1H, s) .

Production Example 34: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-benzamide [Compound No.34]

Example 34-1: Synthesis of (1H-imidazol-2-ylmethyl)-(4-nitrobenzyl) amine Commercially available 4-nitrobenzylamine hydrochloride (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (647 mg) was suspended in chloroform (15 ml). Then, the suspension was added with a 1 mol/l sodium hydroxide aqueous solution (10 ml). The aqueous layer was extracted with chloroform and the extract was then dried with anhydrous magnesium sulfate, followed by distilling the solvent off.
Subsequently, the residue was dissolved in anhydrous methanol (20 ml). The solution was added with 2-imidazole carboxaldehyde (495 mg) and trimethyl orthoformate (1.13 ml), followed by stirring at room temperature for 15 hours.

After that, the solution was cooled with ice and added with sodium borohydride (389 mg), followed by stirring for 1 hour under ice-cooling. The solvent was distilled off under reduced pressure and the residue was added with water, followed by extraction with chloroform. The extract was The compound (733 mg) obtained in Example 34-1 was dissolved in chloroform (15 ml) and then added with di-t-butyl dicarbonate (1.51 g). After having been stirred at room temperature for 1 hour, the solution was concentrated and purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (993 mg) as a pale-yellow viscous liquid.
MS (FAB, Pos .) :m/z=333 [M+H] +

Example 34-3: Synthesis of (4-aminobenzyl)-(1H-imidazol-2-ylmethyl) carbamic acid t-butyl ester The compound (325 mg) obtained in Example 34-2 was dissolved in ethanol (15 ml) and then cooled with ice. The solution was carefully added with 101i palladium-carbon (Mitsuwa Chemicals Co., Ltd.) (300 mg), followed by stirring under a hydrogen atmosphere for 30 minutes. The solution was subjected to CeliteTM filtration and the filtrate was then concentrated, thereby obtaining the subject compound (233 mg) as a pale-red white solid.

MS (FAB, Pos .) :m/z=303 [M+H] +

Example 34-4: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzoylamino)benzyl]-(1H-imidazol-2-ylmethyl) carbamic acid t-butyl ester The compound (150 mg) obtained in Example 34-3 was dissolved in DMF (3.0 ml) and then added with the compound (140 mg) synthesized in Example 2-2. To the mixture solution, HOBt (79.0 mg) and PS-carbodiimide (manufactured by Argonaut Technologies, Inc.) (681 mg) were added, Example 34-4: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzoylamino)benzyl]-(1H-imidazol-2-ylmethyl) carbamic acid t-butyl ester The compound (150 mg) obtained in Example 34-3 was dissolved in DMF (3.0 ml) and then added with the compound (140 mg) synthesized in Example 2-2. To the mixture solution, HOBt (79.0 mg) and PS-carbodiimide (manufactured by Argonaut Technologies, Inc.) (681 mg) were added, followed by stirring at room temperature for 18 hours.
After completion of the reaction, PS-carbodiimide was filtrated and DMF in the filtrate was then distilled off.
The residue was added with chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. The residue was brought into an anhydrous state using anhydrous sodium sulfate and then concentrated.
Subsequently, the concentrated product was purified through column chromatography (chloroform/methanol), thereby obtaining the sub_~ect compound (105 mg) as a white solid.
MS(FAB,Pos.):m/z=596[M+H]+

Example 34-5: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-benzamide [Compound No.34]

The compound (105 mg) obtained in Example 34-4 was dissolved in methanol (10 ml) and then added with 1 mol/l hydrochloric acid (2.0 ml), followed by stirring at room temperature for 5 minutes. The solution was concentrated and dried, and then purified through column chromatography (chloroform/methanol), thereby obtaining hydrochloride (64 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=496[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=3.78(2H,s),4.15(4H,s),4.29(2H,s),4.53(2H,s),7.56(2H,d, J=8.7Hz),7.62(2H,(i,J=8.2Hz),7.62(4H,s),7.73(2H,s),7.85(2H,d, J=8.7Hz),7.92(2H,(I,J=8.2Hz),10.3(3H,s),14.6-14.9(4H,brs).
Production Example 35: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-benzyl]-dipropylamine [Compound No.35]

Example 35-1: Synthesis of 4-{[N-Boc(N-1H-imidazol-2-ylmethyl)amino]methyl} benzoic acid methyl ester The compound (2.00 g) obtained in Example 1-1 was dissolved in methanol (40 ml) and then added with WSCI
hydrochloride (1.74 g) and HOBt (1.22 g), followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. The solution was added with a saturated aqueous sodium bicarbonate solution and stirred, followed by extraction with chloroform. The extract was washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (2.42 g) as a colorless solid.

MS(FAB,Pos.):m/z=346[M+H]+

Example 35-2: Synthesis of 4-{[N-Boc(N-1H-imidazol-2-ylmethyl)amino]methyl} benzyl. alcohol The compound (2.42 g) obtained in Example 35-1 was dissolved in anhydrous THE (5.0 ml) and then added with lithium aluminum hydride (799 mg) in an ice bath, followed by stirring at room temperature for 2 hours. After completion of the reaction, the solution was added with methanol and then with an aqueous potassium sodium tartrate solution, followed by stirring. The solution was extracted with chloroform, followed by washing with saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.76 g) as a colorless solid.
MS(FAB,Pos.):m/z=318[M+H]+

Example 35-3: Synthesis of 4-(N,N-dipropylamino) methylphenol In methanol, 4-hydroxybenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.00 g) was dissolved. Then, the solution was added with dipropylamine (1.24 ml), trimethyl orthoformate (1.0 ml), and acetic acid (500 l) and stirred at room temperature for 15 minutes. The solution was cooled to 0 C and added with sodium cyanoborohydride (773 mg), followed by stirring for 6 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by the addition of water. The solution was adjusted to about pH 7 with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The resulting organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (76.8 mg) as a pale-yellow solid.
MS(FAB,Pos.):m/z=208[M+l]+

Example 35-4: Synthesis of [4-(4-{[N-Boc(N-1H-imidazol-2-ylmethyl)amino]methyl}benzyloxy)benzyl]dipropylamine The compound (107 mg) obtained in Example 35-2 was dissolved in THE (2.0 ml) and then added with the compound (76.8 mg) obtained in Example 35-3, triphenylphosphine (177 mg) and diethylazodicarboxylate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (305 l), followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform to extract. The extract was washed with saturated saline solution and the organic layer was then dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (28.4 mg) as a yellow oily substance.

MS(FAB,Pos.):m/z=507[M+H]+

Example 35-5: Synthesis of [4-(4-{[N-(1H-imidazol-2-ylmethl)amino]methyl}benzyloxy)benzyl]dipropylamine The compound (28.4 mg) obtained in Example 35-4 was dissolved in anhydrous methanol (1.0 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (1.00 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off.
Then, the residue was added with a 1 mol/l sodium hydroxide aqueous solution and subjected to extraction with chloroform.
The extract was washed with distilled water and saturated saline solution and the organic layer was then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off, thereby obtaining the subjected compound (20.4 mg) as a yellow oily substance.
MS(FAB,Pos.):m/z=407[M+H]+
Example 35-6: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-benzyl]-dipropylamine [Compound No.35]

The compound (20.4 mg) obtained in Example 35-5 was dissolved in anhydrous methanol (2.0 ml) and added with sodium cyanoborohydride (9.50 mg), acetic acid (2.0 ml), and 2-imidazole carboxaldehyde (9.60 mg), followed by stirring at room temperature under a nitrogen atmosphere for 6.5 hours and a half. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, and the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (4.50 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=487[M+H]+
Production Example 36: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-rnethyl}-naphtalene-l-carboxylic acid (4-dipropylaminometh_ylphenyl)-amide [Compound No.36]

Example 36-1: Synthesis of methyl 4-bromomethyl-l-naphthalene carboxylic acid Commercially available 4-methyl-l-naphthalene carboxylic acid (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (251 mg) was dissolved in methanol (7.5 ml) and then aerated under ice--cooling with hydrogen chloride gas for 5 minutes. After that, the solution was stirred at room temperature for 19 hours and the solvent was then distilled off. The residue was dissolved in chloroform and then washed with a 1 mol/l sodium hydroxide aqueous solution.
After the solution had been dried with anhydrous sodium sulfate, the solvent was then distilled off. The residue was dissolved in carbon tetrachloride (8.0 ml) and then added with N-bromo succinimide (253 mg) and azobisisobutyronitrile (22.1 mg), followed by stirring at 700C for 6 hours. After completion of the reaction, the solid was removed through glass filter, followed by concentration. The residue was dissolved in chloroform and then washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. The solution was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was dried under reduced pressure, thereby obtaining the subject compound (364 mg) as a pale-yellow oily substance.

MS(FAB,Pos.):m/z=279,281[M+H]+
1H-NMR(60MHz,CDC13) :6=3.94 (3H, s) , 4.86 (3H, s) , 7.35-7.68(3H,m),7.88-8.21(2H,m), 8. 66-8.89(1H,m).
Example 36-2: Synthesis of methyl-4-aminomethyl-l-naphthalene carboxylic acid The compound (328 mg) obtained in Example 36-1 was dissolved in DMF (7.2 ml), added with potassium phthalimide (359 mg), and stirred at room, temperature for 12 hours.
After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by washing with distilled water, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution.
The solution was dried with anhydrous sodium sulfate, and the solvent was distilled off, and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining a white solid (281 mg). Subsequently, the solid. (1.50 g) was dissolved in methanol (30 ml) and then added with hydrazine monohydrate (7.5 ml), followed by heating up to 60 C. Methanol (30 ml) was added further to the solution and the whole was stirred continuously for one hour at 60 C. After completion of the reaction, the solvent was distilled off and the residue was dissolved in chloroform. The solution was washed with distilled water and saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then dried under vacuum, thereby obtaining the subject compound (789 mg) as a pale-yellow solid.
MS(FAB,Pos.):m/z=216[M+H]+

'H-NMR (500MHz, CDCl3) :8=4.00 (3H, s) , 4.39 (2H, s) , 7.55 (1H, d, J=7 . 6Hz) ,7.57-7 . 65 (2H, m) , 8.11 (1H, d, J=8 . 3Hz) , 8.15 (1H, d, J=7 . 3Hz) , 8.97 (1H, d, J
=8.5Hz).

Example 36-3: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}naphthalene-l-carboxylic acid methyl ester The compound (390 mg) obtained in Example 36-2 was dissolved by the addition of anhydrous methanol (20 ml), and the solution was added with imidazole-2-carboxaldehyde (453 mg) and sodium cyanoborohydride (341 mg), and adjusted to pH
by the addition of acetic acid (0.5 ml), followed by stirring for 18 hours. After completion of the reaction, the methanol was distilled off and the residue was then added with 1 mol/l sodium hydroxide (20 ml), followed by extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous magnesium sulfate. After that, the solvent was distilled off and the residue was then dried, thereby obtaining the subject compound (680 mg) as a white solid.
MS(FAB,Pos.):m/z=376[M+H]+

NMR(500MHz,CDC13)::6=3.49(4H,s),4.00(3H,s),4.14 (2H,s),7.06(4H
,s),7.51-7.64(3H,m),8.06(1H,d,J=7.6Hz),8.30(1H,d,J=7.8Hz), 8.90(1H,d,J=7.8Hz).

Example 36-4: Synthesis of 4--{[bis(1H-imidazol-2-ylmethyl)amino]methyl}naphthalene-1-carboxylic acid The compound (675 mg) obtained in Example 36-3 was added with methanol (7.0 ml) and a 1 mol/l sodium hydroxide (7.0 ml), followed by stirring for 1 hour. After completion of the reaction, 1 mol/l hydrochloric acid (8.0 ml) was added to adjust the solution to pH 4. Then, the solvent was distilled off and the residue was washed with methanol, followed by drying. Consequently, the subject compound (677 mg) was obtained as a white solid.
MS(FAB,Pos.):m/z=362[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=4.12 (4H,s),4.17 (2H,s),7.30 (4H,s),7.58-7.66 (3H,m) , 8.02 (1:H,d, J=7.5Hz) , 8.07 (1H,d, J=7.3Hz) , 8.78 (1H,d, J
=8.1Hz).

Example 36-5: Synthesis of 4--{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-naphtalene-l-carboxylic acid (4-dipropylaminomethylphenyl)-amide [Compound No.36]

The compound (130 mg) obtained in Example 36-4 was dissolved in DMF (3.0 ml) and then added with DCC (60.0 mg) and HOBt (40.0 mg), followed by stirring at room temperature for 2 hours. The compound (50.0 mg) obtained in Example 19-2 was added to the solution at room temperature, and the whole was stirred overnight. After completion of the reaction, insoluble matter was removed from the solution through a G4 glass filter and the solvent was distilled off.
The residue was dissolved in chloroform and then washed with 1 mol/l hydrochloric acid. The organic layer was added with hydrochloric acid to separate the solution into layers.
Then, the aqueous layer was added with a sodium hydroxide aqueous solution to adjust it. to pH 12. The aqueous layer was subjected to extraction with chloroform, and the organic layer was dried with anhydrous sodium sulfate. Then, the solvent was distilled off. Subsequently, the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (17.4 mg) of the subject compound as a white foamed compound.
MS(FAB,Pos.):m/z=550[M+H]+

1H-NMR (500MHz, : 6 = 0 . 8 8 ,4.27 (2H,br) , 7.47 (4H, s) , 7.59 (4H,m) 7.67 (1H, d, J=7 .2Hz) , 7.80 (1H
,d,J=7.3Hz),7.89(2H,d,J=8.5Hz),8.13(2H,m),10.44(1H,br),10.74 (1H,br).

Production Example 37: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-[4-(1-propylbutyl)-piperazin-l-yl]-methanone [Compound No.37]

Example 37-1: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-[4-(1--propylbutyl)-piperazin-l-yl]-methanone [Compound No.37]

The compound (57.7 mg) obtained in Example 32-2 was dissolved in methanol (1.73 ml) and then added with 4-heptanone (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (30.7 l), sodium cyanoborohydride (13.8 mg), and triethylamine (76.5 pl). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 7 days.
The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then the whole was separated and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (27.7 mg) of the subject compound as a pale-yellow solid.
MS(FAB,Pos.):m/z=478[M+H]+

1H-NMR (500MHz, DMSC)-d6) :8=0.86 (6H, t, J=7 . 1Hz) , 1 .21-1.82(12H,m),3.04-3. 55 (5H,m) , 3.74 (2H, s) , 4.16 (4H, s) , 7.35 (2H, d, J=8. 3Hz) , 7.41 (2H, d,J=8.3Hz) ,7.57 (4H,s) .

Production Example 38: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-cyclohexylpiperazin-l-yl)-methanone [Compound No.38]

Example 38-1: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-(4-cyclohexylpiperazin-l-yl)-methanone [Compound No.38]

The compound (57.7 mg) obtained in Example 32-3 was dissolved in methanol (1.73 ml) and then added with cyclohexanone (21.6 mg), sodium cyanoborohydride (13.8 mg), and triethylamine (76.5 l). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 7 days. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then the whole was separated and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (7.9 mg) of the subject compound as a pale-yellow solid.
MS(FAB,Pos.):m/z=462[M+H]+

1H-NMR (500MHz, DMSC)-d6) :6=1.00-2.18 (15H,m) , 3. 02-3. 16 (4H,m) , 3.71 (2H, s) , 4.13 (4H, s) , 7.33 (2H, d, J=8. 1Hz) , 7.45 (2H, d,J=8.1Hz),7.56(4H,s).

Production Example 39: Synthesis of (4-{[bis(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine [Compound No.39]

Example 39-1: Synthesis of 2-{4-[(4-dipropylaminomethylphenylamino)methyl]benzyl}isoindole-1,3-dione The compound (17.6 mg) obtained in Example 25-1, the compound (13.2 mg) obtained in Example 19-2, and sodium cyanoborohydride (8.7 mg) were dissolved in anhydrous methanol (1.0 ml). The solution was then adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 4 hours. The reaction solution was added with distilled water and then subjected to extraction with chloroform. After that, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel preparative thin-layer chromatography (chloroform/methanol), thereby obtaining the subject compound (72.9 mg) as a yellow solid.
MS(FAB,Pos.):m/z=456[M+H]+

'H-NMR(500MHz,CDC13):6=0.84(6H,t,J=7.6Hz),1.47(4H,tq,J=7.1,7.6H
z),2.35(4H,t,J=7.1Hz),3.46(2H,brs),4.27 (2H,s),4.84 (2H,s),6.5 6 (2H, d, J=8 . 5Hz) , 7.09 (2H, d, J=8 . 3Hz) , 7.32 (2H, d, J=8 . lHz) , 7.41 (2 H, d, J=8. 1Hz) , 7.69--7.73 (2H,m) , 7.83-7.86 (2H,m) .

Example 39-2: Synthesis of (4-aminomethylbenzyl)-(4-dipropylaminometh_ylphenyl)-amine The compound (521.6 mg) obtained in Example 39-1 was dissolved in methanol (15 ml) and added with hydrazine monohydrate (0.11 ml), followed by stirring at 60 C for 1.5 hours. The reaction solution was added with a 1 mol/1 sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent had been distilled off, the subject compound (372 mg) was obtained as a yellow solid.

MS(FAB,Pos.):m/z=326[M+H]+
Example 39-3: Synthesis of (4-{[bis(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine [Compound No.39]

The compound (57.3 mg) obtained in Example 39-2 was dissolved in methanol (2.5 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (158 mg) and then added with sodium cyanoborohydride (68.4 mg). The reaction solution was adjusted to pH 5 by the addition of acetic acid, followed by stirring for 17 hours at room temperature. Then, the reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. After that, the organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent had been distilled off, a 10% hydrogen chloride/methanol solution was added to the residue, and the solvent was then distilled off. The residue obtained was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (55.2 mg) as a yellow solid.
MS(FAB,Pos.):m/z=514[M+H]+

1H-NMR(500MHz,DMSO-d6) :6=0.85 (6H, t, J=7 .3Hz) , 1.65 (4H,m) , 2.87 (4H,m) , 3.68 (2H,brs) , 3.70 (6H, s) , 4.09 (2H,brs) , 4.10 (4H,brs) , 4.22 (2H,brs) , 6.58 (2H, d, J=8. 7Hz) , 7 .21 (2H, d, J=8. 7Hz) , 7 .24 (4H, s) , 7.47-7.51 (4H,m) .

Production Example 40: Synthesis of 4-{[bis(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzamide [Compound No.40]

Example 40-1: Synthesis of 4-{[bis(1-methyl-lH-imidazol-2-ylmethyl) amino]methyl}-benzoic acid Commercially available amino methylbenzoic acid methyl ester (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (278 mg) was dissolved in methanol (9 ml). Then, the solution was added with 1-methyl-2-imidazole carboxaldehyde (manufactured by Aldrich Corporation) (407 mg) and sodium cyanoborohydride (317 mg), and then adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 3 days. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by washing with a 1 mol/l sodium hydroxide solution. The solution was dried with anhydrous sodium sulfate, and the solvent was distilled off. Subsequently, the residue was dissolved in methanol (6.0 ml) and then added with 1 mol/l sodium hydroxide, followed by stirring at room temperature for 6 hours. After completion of the reaction, 1 mol/l hydrochloric acid (6.0 ml) was added and the solvent was distilled off. After that, ethanol was added to remove insoluble matter, the solvent was distilled off, and the residue was then dried, thereby obtaining the subject compound (519 mg) as a pale-yellow foamy substance.
MS(FAB,Pos.):m/z=340[M+H]+

Example 40-2: Synthesis of 4-{[bis(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzamide [Compound No.40]

The compound (75.0 mg) obtained in Example 40-1 was dissolved in DMF (2.0 ml) and then added with DCC (46.0 mg) and HOBt (36.0 mg), followed by stirring for 6 hours. A
solution of the compound (76.0 mg) obtained in Example 1-2 in DMF was added to the reaction system and then the whole was stirred for 15 hours. After completion of the reaction, DMF was distilled off and the residue was then dissolved in chloroform, followed by extraction with 1 mol/l hydrochloric acid. The aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off, followed by treating with hydrochloric acid. Subsequently, the treated product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (23.9 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=494[M+H]+
1H-NMR (500MHz, DMSO-d6+D2O) :6=0.89 (6H, t, J=7 . 4Hz) , 1 . 22-1.70(8H,m),2.99(4H,t,J=8.2Hz),3.07(2H,t,J=7.OHz),3.72(6H,s), 3.78(2H,s),4.09(4H,s),7.39(2H,d,J=8.4Hz),7.49(4H,d,J=8.lHz), 7.76(2H,d,J=8.4Hz) .

Production Example 41: Synthesis of 4-{[bis(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.41]

Example 41-1: Synthesis of 4-{[bis(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.41]

The compound (100 mg) obtained in Example 2-2 was dissolved in DMF (2.0 ml) and then added with DCC (73.0 mg) and HOBt (36.0 mg), followed by stirring for 15 hours. A
solution (2.0 ml) of the compound (73.0 mg) obtained in Example 19-2 in DMF was added to the reaction system and then the whole was stirred for 24 hours. After completion of the reaction, DMF was distilled off and the residue was then dissolved in chloroform, followed by extraction with 1 mol/l hydrochloric acid. The aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off, followed by treating with hydrochloric acid. Subsequently, the treated product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (14.2 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=528[M+H]+
1H-NMR (500MHz, DMSO-d6+D2O) :6=0.88 (6H, t, J=7 . 3Hz) , 1. 63-1.75(4H,m),2.96(4H,t,J=7.5Hz),3.72(6H,s),3.82(2H,s),4.09(4H, s) , 4 .29 (2H, s) , 7.45-7.53 (8H,m) , 7.85-7.91 (4H,m) , 10.43 (1H, s) .
Production Example 42: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino:-methyl}-benzylamino)-butyl]-carbamic acid benzyl ester [Compound No.42]

Example 42-1: Synthesis of {4-[4-(1,3-dioxo-l,3-dihydroisoindol-2--ylmethyl)benzylamino]butyl} carbamic acid benzyl ester In ethanol (40 ml), 1,4-diaminobutane (1.28 g) was dissolved and then the solution was cooled to 0 C, followed by the addition of a 2 mol/l aqueous sodium acetate solution (10 ml) prepared in advance. Benzyloxylcarbonyl chloride (manufactured by Wako Pure Chemical Industries, Ltd.) (1.13 ml) and a 4 mol/l sodium hydroxide aqueous solution (1.2 ml) were added in this order. After having been heated to room temperature, the solution was stirred for 3 hours. Then, the solution was concentrated and ethanol was then distilled off, followed by the addition of chloroform to carry out extraction. The extract was dried with anhydrous sodium sulfate, and the solvent was distilled off. Then, the residue was added with the compound (151 mg) obtained in Example 25-1 and methanol (5.0 ml).
Subsequently, the mixture was added with sodium cyanoborohydride (36 mg) and acetic acid (0.1 ml), followed by stirring at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off, a 1 mol/l sodium hydroxide aqueous solution was added to the residue, and then the whole was extracted with chloroform.
The extract was dried with anhydrous sodium sulfate and the solvent was then distilled off. After that, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (153 mg) as a colorless viscous liquid.

MS(FAB,Pos.):m/z=472[M+H]+

Example 42-2: Synthesis of (4-benzyloxycarbonylaminobutyl)-[4-(1,3-dioxo-1,3-dihydroisoi.ndol-2-ylmethyl)benzyl]-carbamic acid t-butyl ester The compound (153 mg) obtained in Example 42-1 was dissolved in chloroform (15 ml) and then added with di-t-butyl dicarbonate (106 mg). After having been stirred at room temperature for 1 hour, the solution was concentrated and purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (173 mg) as a colorless viscous liquid.
MS(FAB,Pos.):m/z=572[M+H]+

Example 42-3: Synthesis of (4-aminomethylbenzyl)-(4-benzyloxycarbonylaminobutyl)-carbamic acid t-butyl ester The compound (173 mg) obtained in Example 42-2 was added with a 40% rnethylamine/methanol solution (3.0 ml), followed by stirring at room temperature for 14 hours.
After completion of the reaction, the solvent was distilled off and the residue was then added with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The extract was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off, thereby obtaining the subject compound (98.9 mg) as a colorless viscous liquid.

MS(FAB,Pos.):m/z=442[M+H]+

Example 42-4: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzylamino)-butyl]-carbamic acid benzyl ester [Compound No.42]

The compound (98.9 mg) obtained in Example 42-3 was dissolved in anhydrous methanol (5.0 ml) and then added with 2-imidazole carboxaldehyde (49.0 mg), sodium cyanoborohydride (28.0 mg), and acetic acid (0.1 ml) in this order. The solution was stirred at room temperature for 15 hours and methanol was then distilled off, followed by the addition of a 1 mol/l sodium hydroxide aqueous solution.

The solution was subjected to extraction with chloroform and the extract was then dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol/water) and then treated with hydrochloric acid, thereby obtaining hydrochloride (82.0 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=`i02[M+H]+

iH-NMR(500MHz,DMSO-d6):6=1.41-1.44(2H,m),1.59-1. 64 (2H,m) , 2.80 (2H,brs) , 2.97-3.01 (2H,m) , 3.67 (2H, s) , 4 . 02-4.05(2H,m),4.11(4H,s),5.00(2H,s),7.29-7.38(5H,m),7.44(2H,d,J=8.2Hz),7.49(2H,d,J=8.2Hz),7.61(4H,s), 9.18(2H,brs),14.69(3H,brs).

Production Example 43: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-Diethyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine [Compound No.43]

Example 43-1: Synthesis of (4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-amine The compound (63.1 mg) obtained in Example 39-2 was dissolved in methanol (2.0 ml) and then added with 2-imidazole carboxaldehyde (17.9 mg), followed by stirring at room temperature for 17 hours. After the solvent had been distilled off, the residue was dried under vacuum and then dissolved in methanol (2.5 ml). Subsequently, the solution was added with sodium borohydride (14.5 mg) and stirred at room temperature for 1 hour. The reaction solution was added with a saturated aqueous ammonium chloride solution (4.0 ml) and stirred at room temperature for 30 minutes.
Then, the reaction solution was added with saturated saline solution and subjected to extraction with chloroform, followed by drying with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/acetone), thereby obtaining the subject compound (45.2 mg) as a yellow solid.

MS(FAB,Pos.):m/z=4.06[M+H]+

NMR(500MHz,CDC13):6=0.85(6H,t,J=7. 3Hz), 1. 46(4H,tq,J=6.9,7.3H
z),2.34(4H,t,J=6.9Hz),3.44(2H,s),3.80(2H,s),3.93(2H,s),4.30( 2H,brs),6.58(2H,d,J=8.5Hz),6.99(2H,s),7.11(2H,d,J=8.5Hz),7.2 8 (2H, d, J=8 . 3Hz) , 7 .34 (2H, d, J=8 . 3Hz) .

Example 43-2: Synthesis of (4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-(4-dipropylaminomethylphenyl)-amine [Compound No.43]

The compound (199 mg) obtained in Example 43-1 was dissolved in methanol (6 ml) and then added with 2-imidazole carboxaldehyde (57.1 mg) and sodium cyanoborohydride (65.4 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (231 mg) of the subject compound as a yellow solid.

MS(FAB,Pos.):m/z=486[M+H]+
1H-NMR (500MHz, : 6 = 0 . , 3.70 (2H,brs) , 4.09 (4H,brs) , 4 .23 (2H,brs) , 6.59 (2H, d, J=8. 5Hz) , 7 .
19 (2H, d, J=8 . 5Hz) , 7 .24 (2H, d, J=8. 3Hz) , 7 .29 (2H, d, J=8 . 3Hz) , 7.55 ( 4H,s).

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

Example 44-1: Synthesis of (4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(l-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amine [Compound No.44]

The compound (72.7 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (28.6 mg) and sodium cyanoborohydride (22.8 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (71.3 mg) of the subject compound as a yellow solid.

MS(FAB,Pos.):m/z=500[M+H]+
1H-NMR (50 0MHz, DMSO-d6) :6=0.84 (6H, t, J=7 . 4Hz) , 1.69 (4H,m) , 2.84 (4H,m) , 3.57 (2H, s) , 3.
65 (3H, s) , 4.07 (2H, s;) , 4.08 (2H, s) , 4.16 (2H, s) , 6.62 (2H, d, J=8 .
1Hz) , 7 .24 (2H, d, J=8. 1Hz;) , 7.28 (2H, d, J=8.3Hz) , 7.34 (2H, d, J=8. 3Hz) , 7.
48(1H,d,J=1.9Hz),7.49(1H,d,J=1.9Hz),7.61(2H,s) .

Production Example 45: Synthesis of (4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(2H-pyrazol-3-ylmethyl)-amino]-methyl}-benzyl)-amine [Compound No.45]

Example 45-1: Synthesis of (4-dipropylaminomethylphenyl)-(4-{[(1H-imidazol-2-ylmethyl)-(2H-pyrazol-3-ylmethyl)-amino]-methyl}-benzyl)-amine [Compound No.45]

The compound (72.0 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with pyrazole-3-carboxaldehyde (24.5 mg) and sodium cyanoborohydride (35.9 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/1 sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (52.3 mg) of the subject compound as a yellow solid.

MS(FAB,Pos.):m/z=486[M+H]+
1H-NMR (500MHz, DMSO-d6) :8=0.85(6H,t,J=7.5Hz),1.65(4H,m),2.88(4H,m),3.70(2H,brs), 3.78 (2H,brs) , 4.00 (2H,brs) , 4.10 (2H,brs) , 4.28 (2H,brs) , 6.34 (1H, d, J=2 . 1Hz) , 6.65 (2H, d, J=8.5Hz) , 7 .21 (2H, d, J=8 . 5Hz) , 7.32 (2H, d, J
=8.3Hz),7.38(2H,d,J=8.3Hz),7.51(2H,s),7.69(1H,d,J=2.lHz) .
Production Example 46: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2ylmethyl)-(6-methylpyridin-2-yl-methyl)-amino]-methyl}-benzamide [Compound No. 4 6 ]

Example 46-1: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2ylmethyl)-(6-methylpyridin-2-yl-methyl)-amino]-methyl}-benzamide [Compound No.46]

The compound (44.3 mg) obtained in Example 1-4 was dissolved in methanol (1.0 ml.) and then added with 6-methylpyridine-2-carboxaldehyde (20.7 mg) and sodium cyanoborohydride (10.7 mg). The solution was adjusted to about pH 5 with acetic acid and then stirred at room temperature for 15 hours. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by washing with a 1 mol/1 sodium hydroxide aqueous solution and saturated saline solution and drying with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (9.9 mg) as a white solid.
MS(FAB,Pos.):m/z=491[M+H]+

1H-NMR (500MHz, DMSO-d6+D2O) :6=0. 90 (6H, t, J=7 . 3Hz) , 1. 51-1.73(8H,m),2.66(3H,s),2.95-3.03(4H,m),3.03-3.09(2H,m),3.24-3.32(2H,m),3.79(2H,s),4.00(2H,s),4.10(2H,s),7.33(1H,dd,J=7.5 , 2 . 9Hz) , 7.45 (2H, d, J=8. 3Hz) , 7.59 (1H, d, J=7. 5Hz) , 7.76 (2H, d, J=8.
3Hz) , 7.78-7.81 (1H, m) .

Production Example 47: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.47]

aqueous solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off to obtain an alcohol product. The alcohol product was redissolved again in chloroform (16.5 ml) and then added with manganese dioxide (chemically processed product:
manufactured by Wako Pure Chemical Industries, Ltd., the same shall apply hereinafter) (2.33 g), followed by stirring at room temperature for 0.5 hour. The reaction solution was filtrated through CeliteTM and the solvent was then distilled off. Then the residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (20.2 mg) as an orange-color solid.

1H-NMR(500MHz,CDC13) :8=7.78-7.84(2H,m),8.04(lH,d,J=8.lHz),8.09(1H,d,J=7.8Hz),8.41(1H,s), 9.39(1H,s),10.3(1H,s).

Example 47-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[N-Boc-N-(1H-imidazol-2-ylmethyl)amino]methyl}-benzamide The compound (1.34 g) obtained in Example 19-2 was dissolved in DMF (68 ml). The solution was added with WSCI
hydrochloride (4.73 g), HOBt (2.45 g), and the compound (5.74 g) obtained in Example 1-1, followed by stirring at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off and the residue was then redissolved in chloroform, followed by washing with distilled water, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution. The solution was dried with Example 47-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[N-Boc-N-(1H-imidazol-2-ylmethyl)amino]methyl}-benzamide The compound (1.34 g) obtained in Example 19-2 was dissolved in DMF (68 ml). The solution was added with WSCI
hydrochloride (4.73 g), HOBt (2.45 g), and the compound (5.74 g) obtained in Example 1-1, followed by stirring at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off and the residue was then redissolved in chloroform, followed by washing with distilled water, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution. The solution was dried with anhydrous sodium sulfate, and the solvent was distilled off.
The residue was recrystallized from ethyl acetate/chloroform, thereby obtaining the subject compound (5.04 g) as a white solid.

MS(FAB,Pos.):m/z=520[M+H]+
1H-NMR(500MHz,DMSO-d6) : S=0.82 (6H, t, J=7 .3Hz) , 1.36 (9H, brs) , 1.37-1 . 43 (4H, sext. , J=7 . 3Hz) , 2.32 (4H, t, J=7 .3Hz) , 3.47 (2H, s) , 4 .

4.55(4H,br),6.85(1H,s),7.05(1H,s),7.26(2H,d,J=8.5Hz),7.32 (2H
,br) , 7.70 (2H, d, J=B. 5Hz) , 7.91 (2H, d, J=8. 5Hz) , 10.18 (1H, s) , 11 .

12 . 0 (1H, br) .

Example 47-3: Synthesis of N-(4-dipropylamino-phenyl)-4-{[(1H-imidazol-2-ylmethyl)amino]methyl}-benzamide The compound (2.50 g) obtained in Example 47-2 was dissolved in methanol (25.0 ml) and then added with a 4 mol/l hydrogen chl.oride/dioxane solution (50.0 ml), followed by stirring at room temperature for 1 hour. The reaction solvent was distilled off and the residue was then added with a 1 mol/l sodium hydroxide aqueous solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate, and the solvent was then distilled off. The residue was dried under vacuum, thereby obtaining the subject compound (1.89 g) as a white solid.

Example 47-4: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.47]

The compound (53.9 mg) obtained in Example 47-3 was dissolved in methanol (2.0 ml) and then added with the compound (20.2 mg) obtained in Example 47-1 and sodium cyanoborohydride (12.8 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution,, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (10.1 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=561[M+H]+

1H-NMR (500MHz, DMSC-d6) :6=0. 88 (6H, t, J=7. 3Hz) , 1. 60-1.80(4H,m),2.96(4H,t,J=7.3Hz),3.86(2H,s),4.14(2H,s),4.17(2H, s),4.28(2H,s),7.48-7.60(6H,m),7.80-7.94(5H,m),8.04(1H,t,J=8.3Hz),8.14(1H,d,J=8.3Hz),8.25(1H,s), 8.39(1H,d,J=8.1Hz),9.64(1H,s).

Production Example 48: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.48]

Example 48-1: Synthesis of N--(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.48]

The compound (52.0 mg) obtained in Example 47-3 was dissolved in methanol (1.6 ml) and then added with pyridine-2-aldehyde (15.9 mg) and sodium cyanoborohydride (15.6 mg).
The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was added with a 1 mol/1 sodium hydroxide aqueous solution and then separated and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (15.2 mg) of the subject compound as a pale-yellow solid.
MS(FAB,Pos.):m/z=511[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=0.88 (6H, t, J=7 . 3Hz) , 1. 60-1 . 80 (4H,m) , 2.96 (4H, t, J=7. 3Hz) , 3.81 (2H, s) , 4.04 (2H, s) , 4.12 (2H, s) , 4.28 (2H, s) , 7.48-7.59(5H,m),8.18(1H,t,J=8.3Hz),8.69(1H,d,J=4.4Hz).

Production Example 49: Synthesis of N-(4-dipropylaminomethylphenyl)-4--{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.49]

Example 49-1: Synthesis of N--(4-dipropylaminomethylphenyl)-4-([(1H-imidazol-2-ylmethyl)-.(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.49]

The compound (52.0 mg) obtained in Example 47-3 was dissolved in methanol (1.6 ml) and then added with 1-methylimidazol-2-aldehyde (16.4 mg), and sodium cyanoborohydride (15.6 mg). The solution was adjusted to pH
with acetic acid and stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was added with a 1 mol/1 sodium hydroxide aqueous solution and then separated and extracted with chloroform.
The organic layer was dried with anhydrous sodium sulfate.
The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (15.2 mg) of the subject compound as a pale-yellow solid.

MS(FAB,Pos.):m/z=514[M+H]+
1H-NMR(500MHz,DMSO-d6):6=0.88(6H, t,J=7.3Hz),1.60-1 . 80 (4H,m) , 2.96 (4H, t, J=7 . lHz) , 3.72 (3H, s) , 3.81 (2H, s) , 4.08 (2H, s),4.16(2H,s),4.28(2H,s),7.42-7.58(6H,m),7.60(2H,s),7.82-7. 92 (4H,m) .

Production Example 50: Synthesis of N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N',N'-dipropylbutane-l, 4-diamine [Compound No.50]

Example 50-1: Synthesis of N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N',N'-dipropylbutane-l,4-diamine [Compound No.50]

The compound (150.7 mg) obtained in Example 25-5 was dissolved in methanol (3.0 ml). Then, a 36% formaldehyde aqueous solution (manufactured by Kanto Kagaku) (50 l) and sodium cyanoborohydride (36.2 mg) were added to the solution in this order. After the reaction solution was adjusted to pH 5 with acetic acid, the solution was stirred at room temperature for 17 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Subsequently, the organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (126.2 mg) of the subjected compound as a white solid.

MS(FAB,Pos.):m/z=466[M+H]+
1H-NMR (500MHz, DMSO-d6) :6=0.92 (6H, t, J=7 . 6Hz) , 1. 63-1.68(6H,m),1.69-1.93(2H,m),2.58(3H,brs),2.98-3.01(6H,m),3.06(2H,t,J=B.lHz),3.62(2H,s),3.72(2H,s),4.14(4H, s),7.45(4H,s),7.58(4H,s).

Production Example 51: Synthesis of N-(4-dipropylaminomethylphenyl)-4--{[(1H-imidazol-2-ylmethyl)-(6-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.51]

Example 51-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.51]

The compound (104.9 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with 6-methylpyridine-2-carboxaldehyde (36.3 mg) and sodium cyanoborohydride (31.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (75.9 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=525[M+H]+

1H-NMR (500MHz, DMSO--d6) :6=0.88 (6H, t, J=7 .3Hz) , 1. 60-1 . 80 (4H,m) , 2 .74 (3H, s) , 2 . 88-3.00(4H,m),3.84(2H,s),4.12(2H,s),4.17(2H,s),4.28(2H,s),7.48-7 . 60 (6H, m) , 7.72 (1H, d, J=8 . 1Hz) , 7 . 82-7 . 92 (4H, m) , 7.96 (1H, d, J=7 . 8Hz) , 8.34 (1H, t, J=8 . lHz) .

Production Example 52: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-bromopyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.52]

Example 52-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-bromopyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.52]

The compound (104.9 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with 6-bromopyridine-2-aldehyde (55.8 mg) and sodium cyanoborohydride (31.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (91.9 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=590[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=0.88 (6H, t, J=7 . 3Hz) , 1. 60-1.80(4H,m),2.88-3.00(4H,m),3.81(2H:,s),3.81(2H,s),4.09(2H,s),4.28(2H,s),7.50-7.62 (8H,m) , 7.75 (1H, t, J=7. 6Hz) , 7.88 (2H, d, J=8. 5Hz) , 7.95 (2H, d, J
=8 .5Hz) .

a 1 mol/1 sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous sodium sulfate. Then, the solvent was distilled off, thereby obtaining crude 2,3-lutidin-N-oxide (3.16 g). A 2.00 g part thereof was dissolved in dichloromethane (40 ml) and then the solution was cooled to 0 C. Subsequently, the solution was added with trifluoroacetic anhydride (4.49 ml), followed by stirring at room temperature for 4 hours and then at 45 C
for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in methanol (30 ml), followed by the addition of a sodium methoxide/methanol solution until the pH of the solution would reach pH = 10. After the solution had been stirred at room temperature for 1 hour, the solvent was distilled off and extraction was then carried out with dichloromethane.
The extract was dried with anhydrous sodium sulfate and the solvent was then distilled off, thereby obtaining 3-methyl-2-hydroxymethylpyridine (1.30 g). A 605.3 mg part thereof was dissolved in chloroform (30 ml) and then added with manganese dioxide (chemically processed product) (3.03 g), followed by stirring at 70 C for 2 hours. After completion of the reaction, the catalyst was removed through CeliteTM
filtration and the solvent was then concentrated. Then, the residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (419.8 mg) as a pale-orange colored liquid.

MS(FAB,Pos.) :m/z=122 [M+H]+

2-hydroxymethylpyridine (1.30 g). A 605.3 mg part thereof was dissolved in chloroform (30 ml) and then added with manganese dioxide (chemically processed product) (3.03 g), followed by stirring at 70 C for 2 hours. After completion of the reaction, the catalyst was removed through Celite filtration and the solvent was then concentrated. Then, the residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (419.8 mg) as a pale-orange colored liquid.

MS(FAB,Pos.):m/z=122[M+H]+

NMR(500MHz,CDC13):6=2.67(3H,s),7.40(1H,dd,J=7.8,4.6Hz),7.64( 1H, d, J=7 . 8Hz) , 8.6'7 (1H, d, J=4 . 6Hz) , 10 .2 (1H, s) .

Example 53-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(lH-imidazol-2-ylmethyl)-(3-methylpyridin-2-ylmethyl)-amino]-methyl}-bernzamide [Compound No.53]

The compound (104.9 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with the compound (36.3 mg) obtained in Example 53-1 and sodium cyanoborohydride (31.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (91.5 mg) of the subject compound as a white solid.

MS (FAB, Pos. )m/z=525 [M+H]+

1H-NMR (500MHz, DMSC-d6) :6=0. 88 (6H, t, J=7 . 3Hz) ,1.60-1.80 (4H,m) , 2.37 (3H, s) , 2.95 (4H, t, J=7 . 1Hz) , 3.84 (2H, s) , 4.16 (2H, s),4.25(2H,s),4.28(2H,s),7.53(2H,d,J=8.5Hz),7.55(2H,d,J=8.3H
z),7.62(2H,s),7.76(1H,dd,J=4.8,7.6Hz),7.83(2H,d,J=8.5Hz),7.8 6 (2H, d, J=8 . 3Hz) , 8 .22 (1H, d, J=7 . 6Hz) , 8.65 (1H, d, J=4 . 9Hz) .

Production Example 54: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.54]

Example 54-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(lH-imidazol-2-ylmethyl)-(quinolin-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.54]

The compound (104.9 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with quinoline-4-aldehyde (47.2 mg) and sodium cyanoborohydride (31.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed. by separation/extraction with chloroform.
The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (76.4 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=561[M+H]+

1H-NMR(500MHz,DMS0-d6):6=0.88(6H,t,J=7.3Hz),1.60-1.80(4H,m),2.95(4H,br),3.92(2H,s),4.17(2H,s),4,28(2H,s),4.41 (2H,s),7.48-7.60(6H,m),7.82-7.96(5H,m),8.02-8.28 (3H,m) , 8.40 (1H,d, J=8.3Hz) , 9.16 (1H,d, J=5.4Hz) .

Production Example 55: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.55]

Example 55-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.55]

The compound (81.2 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with quinoline-2-aldehyde (36.5 mg) and sodium cyanoborohydride (24.3 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform.
The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (77.8 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=560[M+H]+

1H-NMR (500MHz, DMSO-d6) : 6=0.88 (6H, t, J=7 . 3Hz) , 1. 60-1.80(4H,m),2.96(4H,br),3.88(2H,s),4.03(2H,s),4.18(2H,s),4.28 (2H,s),7.50-7.61(6H,m),7.70-8.04(7H,m),8.13(1.H,d,J=8.lHz),8.20(1H,d,J=8.8Hz),8.70(1H,d,J
=8.3Hz).

Production Example 56: Synthesis of N-(4-dipropylaminomethylphenyl)-4-.{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-ami.no]-methyl}-benzamide [Compound No.56]

Example 56-1: Synthesis of 5-methyl-2-pyridine aldehyde By the similar procedures as those of Example 53-1, except of using 2,5-lutidine as a raw material, 5-methylpyridine-2-aldehyde (439.9 mg) was obtained.

MS (FAB, Pos.) :m/z=122 [M+H]+

NMR(500MHz,CDC13):6=2.46(3H,s),7.67(1H,dd,J=7. 9,1.4Hz),7.89( 1H,d,J=7.9Hz),8.62(1H,d,J=1.4Hz),10.05(1H,s).
Example 56-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.56]

The compound (79.4 mg) obtained in Example 47-3 was dissolved in methanol (2.4 ml) and then added with the compound (27.5 mg) obtained in Example 56-1 and sodium cyanoborohydride (23.8 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (63.0 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=525[M+H]+

1H-NMR(500MHz,DMSC)-d6):6=0.88(6H,t,J=7.3Hz),1.60-1.80(4H,m),2.44 (3H,s),2.95(4H,br),3.80(2H,s),4.13(2H,s),4.16 (2H,s),4.28(2H,s),7.53(2H,d,J=7.8Hz),7.55(2H,d,J=7.8Hz),7.58 (2H,s),7.86(4H,d,J=7.8Hz),7.95(1H,d,J=8.3Hz),8.30(1H,dd,J=1.
5, 8 . 3Hz) , 8.66 (1H, d, J=1 . 5Hz) .

Production Example 57: Synthesis of N-(4-dipropylaminometh)7lphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.57]

Example 57-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-3-ylmethyl)-amino]-methyl}-benz amide [Compound No.57]

The compound (100 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with pyridin-3-aldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (44.8 l), followed by the addition of sodium cyanoborohydride (44.9 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 65 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (95.8 mg) of the subject compound as a white solid.

MS (FAB, Pos.) :m/z='511 [M+H]+
1H-NMR(50OMHz,DMSC)-d6):8=O.87(6H,t,J=7.2Hz),1.68-1.79(4H,m),2.85-2.96(4H,m),3.78-4.06(5H,m),4.25(2H,d,J=5.3Hz),7.59-7 . 63 (6H, m) , 7 . 8 9 (2H, d, J=8.7Hz) , 7.95 (2H, d, J=8 . 5Hz) , 7 . 98-8.00(1H,m),8.66(1H,d,J=8.lHz),8.79(1H,d,J=5.OHz),9.10(1H,s), 10.48(1H,s),10.65(1H,brs),14.78(1H,brs).
Production Example 58: Synthesis of N-(4-dipropylaminomethvlphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.58]

Example 58-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.58]

The compound (100 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with pyridin-4-aldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (44.8 l), followed by the addition of sodium cyanoborohydride (44.9 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 65 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (106 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=511[M+H]+
1H-NMR(500MHz,DMSO-d6):b=0.87(6H,t,J=7.4Hz),1.68-1.78(4H,m),2.85-2.94(4H,m),3.81-4.08(5H,m),4.25(2H,d,J=5.3Hz),7.59-7. 64 (6H,m) , 7.89 (2H,d, J=8.8Hz) , 7.96 (2H,d, J=8.4Hz) , 8.20 (2H,d, J
=6.6Hz),8.86(2H,d,J=6.6Hz),10.50(1H,s),10.73(1H,brs),14.87(1 H, brs) .

Production Example 59: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-ethoxypyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.59]

Example 59-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)--(3-ethoxypyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.59]

The compound (104 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with 3-ethoxy-2-pyridine aldehyde (74.7 mg) synthesized by the method described in Marsais, F et al, Synthesis, 235 (1982), followed by the addition of sodium cyanoborohydride (46.6 mg). After that, the reaction solution was adjusted to about pH 5 with acetic acid and then stirred at room temperature for 65 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (132 mg) of the subject compound as a white solid.

MS (FAB, Pos.) :m/z=`555 [M+H]+
1H-NMR (500MHz, DMSO-d6):6=0.87(6H,t,J=7.3Hz),1.37(3H,t,J=7.0Hz),1.67-1.79(4H,m),2.86-2.96(4H,m),3.42-3.82(2H,m),4.12-4.20(4H,m),4.25-4.30(4H,m),7.65(2H,s),7.77(1H,brs),7.86-7.88(4H,m),7.98(1H,brs),8.40(1H,d,J=5.lHz),10.39(1H,brs),10.
57 (1H, brs) .

Production Example 60: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-butyl]-dipropylamine [Compound No.60]

Example 60-1: Synthesis of 4--{N-Boc(N-1-methanesulfonyl-lH-imidazol-2-ylmethyl) amino]methyl}benzylchloride The compound (257 mg) obtained in Example 35-2 was dissolved in dichloromethane (5.0 ml). The solution was added with diisopropyl ethylamine (423 l) and then added with methanesulfonylchloride (157 l) in an ice bath, followed by stirring overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added to the solution, and the whole was stirred. The resultant solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and saturated saline solution, followed by drying of the organic layer with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (hexane/acetone), thereby obtaining the compound (302 mg) as a yellow oily substance.
MS(FAB,Pos.):m/z=414[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=1.31(9H,s),3.59(3H,brs),,4.51(2H,s),4.63(2H,brs),4.74 (2 H, s) , 7.05 (1H, d, J=1 . 7Hz) , 7.26 (2H, d, J=8 . 1Hz) , 7.40 (2H, d, J=8 .
lHz 7.52 (1H, d, J=1. 7Hz) Example 60-2: Synthesis of 4-dipropylamino-l-butanol In anhydrous methanol (20 ml), 4-amino-l-butanol (manufactured by 'Tokyo Kasei Kogyo Co., Ltd.) (1.03 g) was dissolved. Then, the solution was added with sodium cyanoborohydride (2.18 g), acetic acid (5.00 ml), and propionaldehyde (2.08 ml), followed by stirring under a nitrogen atmosphere at room temperature for 1 week. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by stirring after the addition of a saturated aqueous sodium bicarbonate solution. The resultant solution was subjected to extraction with chloroform. The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution, followed by drying of the organic layer with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (2.54 g) as a colorless liquid.

MS(FAB,Pos.):m/z=174[M+H]+
Example 60-3: Synthesis of [4-(4-{[N-Boc(N-1-methanesulfonyl-1H-imidazol-2-ylmethyl) amino]methyl}benzyloxyl) butyl]dipropylamine The compound (146 mg) obtained in Example 60-1 was dissolved in dichloromethane (2.0 ml). The solution was added with potassium bicarbonate (53.0 mg) and the compound (61.1 mg) obtained in Example 60-2, followed by stirring at room temperature for 6 days. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the solution, and the whole stirred. The solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution. Then, the organic layer was dried with anhydrous sodium sulfate.

Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (158 mg) as a colorless crystal.
MS(FAB,Pos.):m/z=551[M+H]+
1H-NMR (500MHz, DMSO-d6) :6=1.04 (6H, t, J=7 . 3Hz) 1.44 (9H, s) , 1. 63-1. 68 (2H,m) , 1.86-1.95 (4H,m) , 2.07-2.12 (2H,m) , 3.09-3.22(4H,m),3.41(3H,brs),3.49(2H,m),3.75(2H,s),4.65(2H,s),4.7 4 (2H, s) , 7.04 (1H, d, J=1. 7Hz) , 7.31 (1H, d, J=1 . 7Hz) , 7.36 (2H, d, J=8 .
1Hz),7.45(1H,d,J=8.1Hz).

Example 60-4: Synthesis of [4- (4-{[N-(1H-imidazol-2-ylmethyl)amino]methyl}benzyloxy)butyl]dipropylamine The compound (158 mg) obtained in Example 60-3 was dissolved in anhydrous methanol (1.0 ml) and then added with a 1 mol/1 hydrogen chloride/diethyl ether solution (5.00 ml), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off.
The residue was added with a 1 mol/l sodium hydroxide aqueous solution and washed with chloroform. The aqueous layer was evaporated to dryness and then subjected to extraction with chloroform, thereby obtaining the subject compound (81.2 mg) as a white crystal.
MS(FAB,Pos.):m/z=373[M+H]+

Example 60-5: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-butyl]-dipropylamine [Compound No.60]

The compound (81.2 mg) obtained in Example 60-4 was dissolved in anhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride (27.4 mg), acetic acid (3.00 ml), and 2-imidazole carboxaldehyde (31.4 mg), followed by stirring under a nitrogen atmosphere at 60 C for 4 days.
After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The aqueous layer was washed with chloroform and then evaporated to dryness. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (63.0 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=453[M+H]+
1H-NMR (500MHz, DMSO-d6+D2O) :6=0.88 (6H, t, J=7 .2Hz) , 1.42 (2H, t, J=6. 9Hz) , 1. 69-1.79(6H,m),2.89-2.91(4H,m),2.92-3.00(2H,m),3.44(2H,t,J=6.lHz),4.16(4H,s),4.39(2H,s),4.72(2H, s) , 7 .27 (2H, d, J=8 .2Hz) , 7 .43 (2H, d, J=8 .2Hz) , 7.50 (2H, s) , 7.52 (2H, S).

Production Example 61: Synthesis of N-(4-dipropylaminomethylphenyl)-4--{[(1H-imidazol-2-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.61]

Example 61-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)--(1H-benzimidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.61]

The compound (99.3 mg) obtained in Example 47-3 was dissolved in DMF (3.0 ml) and added with potassium carbonate (81.8 mg) and 2-chloromethylbenzimidazole (manufactured by Aldrich Corporation) (43.4 mg), followed by stirring at 60 C
for 17 hours. After completion of the reaction, the reaction solvent was distilled off and water was then added, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate.
Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (70.0 mg) as a white solid.
MS(FAB,Pos.):m/z=550[M+H]+

1H-NMR(500MHz,DMSO-d6) :6=0.82 (6H, t, J==7 . 1Hz) , 1.42 (4H, sext . , J=7 . lHz) , 2.31 (4H, t, J=
7.1Hz),3.47(2H,s),3.71(2H,s),3.72(2H,s),3.85(2H,s),7.26(2H,d ,J=8.5Hz),7.44-7 . 62 (4H, m) , 7.60 (2H, d, J=8 . 3Hz) , 7.68 (2H, d, J=8 . 5Hz) , 7.91 (2H, d, J
=8.3Hz).

Production Example 62: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(2-methylthiazol-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.62]

Example 62-1: Synthesis of N--(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(2-methylthiazol-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.62]

The compound (99.3 mg) obtained in Example 47-3 was dissolved in DMF (3.0 ml) and then added with potassium carbonate (81.8 mg) and 4-chloromethyl-2-methyl thiazole (manufactured by Lancaster Synthesis Inc.) (47.9 mg), followed by stirring 60 C for 17 hours. After completion of the reaction, the reaction solvent was distilled off and the residue was then added with water, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate. Then, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining hydrochloride (31.2 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=531[M+H]+
1H-NMR(500MHz,DMSO-d6):6=0.87(6H,t,J=7.3Hz),1.62-1.81(4H,m),2.68(3H, s),2.91(4H,br),3.82(2H,s),4.10(2H,s),4.26 (4H, s) , 7.52-7 . 70 ('7H, m) , 7.88 (2H, d, J=8 . 5Hz) , 7.95 (2H, d, J=8 .
lHz) .
Production Example 63: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-1-ylmethyl)-amino]-methyl}-benzamide [Compound No.63]

Example 63-1: Synthesis of isoquinoline-l-aldehyde Isoquinolin-l-yl-methanol (123.7 mg) was dissolved in chloroform (6.2 ml) and then added with manganese dioxide (chemically processed product) (1.24 g), followed by stirring at room temperature for 30 minutes. The reaction solution was filtrated through Celite and the solvent was then distilled off. The residue was dried under vacuum, thereby obtaining the subject: compound (103.9 mg) as a brown solid.

1H-NMR(50OMHz,CDC13):6=7.72-7.80(2H,m),7.88-7 . 96 (2H,m) , 8.77 (1H, d, J=5. 4Hz) , 9.30-9.36 (1H,m) , 10.3 (1H, s) .
Example 63-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-l-ylmethyl)-amino]-methyl}-benzamide [Compound No.63]

The compound (80 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with the compound (59.9 mg) obtained in Example 63-1, followed by the addition of sodium cyanoborohydride (35.9 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform.

The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (97.1 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=561[M+H]+

(4-methoxy-3,5-dimethyl-pyridin-2-yl)methanol (Tokyo Kasei Kogyo Co., Ltd.) (300 mg) was dissolved in chloroform (15 ml) and added with manganese dioxide (chemically processed product) (3.00 g), followed by stirring for 3 hours. After completion of the reaction, the solution was filtrated through CeliteTM and the solvent was then distilled off, thereby obtaining the subject compound (297 mg) as a white solid.

Example 64-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.64]

The compound (70.1 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with the compound (55.2 mg) obtained in Example 64-1, followed by the addition of sodium cyanoborohydride (31.5 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 21 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform.

The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (36.4 mg) of the subject compound as a white solid.

MS (FAB, Pos .) :m/z=569 [M+H] +

solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 21 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform.
The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (36.4 mg) of the subject compound as a white solid.

MS (FAB, Pos.) :m/z=`569 [M+H]+
iH-NMR(500MHz,DMSO-d6):S=O.87(6H,t,J=7.3Hz),1.69-1.78(4H,m),2.18(3H,s),2.31(3H,s),2.86-2.95(4H,m),3.79(2H,s),3.96(3H,s),4.13(2H,s),4.25-4.26(4H,m),7.57-7.61(4H,m),7.67(2H,s),7.84-7.87 (4H,m),8.56(1H,s) .

Production Example 65: Synthesis of 4-({bis[1-(toluene-4-sulfonyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-N-(4-dipropylaminometh)ilphenyl)-benzamide [Compound No.65]
Example 65-1: Synthesis of 4-({bis[1-(toluene-4-sulfonyl)-1H-imidazol-2-ylmethyl]-amino}-methyl)-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.65]

The compound (50.8 mg) obtained in Example 19-3 was dissolved in anhydrous chloroform (2.0 ml). The solution was added with triethylamine (0.049 ml) and then added with p-toluenesulfonyl chloride (manufactured by Kanto Kagaku) (57.2 mg), followed by stirring at room temperature for 16 hours. After completion of the reaction, chloroform (3.0 ml) was added to the solution, and the whole was washed with water. The organic layer was dried with anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (hexane/ethyl acetate), thereby obtaining the subject compound (15.2 mg) as a white solid.
MS(FAB,Pos.):m/z=809[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=0. 82 (6H, t, J=7. 3Hz) , 1.42 (4H, sext. , J=7. 5Hz) , 2.32 (4H, t, J=
7. 3Hz) , 2.37 (6H, s) 3.48 (2H, s) , 4.00 (2H, s) , 4.05 (4H, s) , 7.04 (2H, d, J=8 . 4Hz) , 7.08 (2H, d, J=1. 8Hz) , 7 .27 (2H, d, J=8 . 5Hz) , 7.35 (4H, d, J=8 .lHz),7.70-7.77(10H,m),10.14(1H,s).

Production Example 66: Synthesis of 4-{[bis(1-methanesulfonyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.66]
Example 66-1: Synthesis of 4-{[bis(1-methanesulfonyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.66]

The compound (52.9 mg) obtained in Example 19-3 was dissolved in anhydrous chloroform (2.0 ml). The solution was added with triethylamine (0.054 ml) and then added with methanesulfonyl chloride (manufactured by Kanto Kagaku) (0.027 ml), followed by stirring at room temperature for 17 hours. After completion of the reaction, chloroform (3.0 ml) was added to the solution, and the whole was washed with water. The organic layer was dried with anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (hexane/ethyl acetate), thereby obtaining the subject compound (31.7 mg) as a white solid.
MS(FAB,Pos.):m/z=656[M+H]+

1H-NMR (500MHz, DMSC)-d6) : 6=0.82 (6H, t, J=7 . 3Hz) , 1.42 (4H, sext. , J=7 .2Hz) , 2.32 (4H, t, J=
7.0Hz),3.47(2H,s),,3.66(6H,s),4.01(2H,s),4.04(4H,s),7.03(2H,d ,J=1.8Hz),7.26(2H,d,J=8.4Hz),7.41(2H,d,J=8.2Hz),7.52(2H,d,J=
1.7Hz),7.69(2H,d,J=8.5Hz),7.89(2H,d,J=8.3Hz),10.17(1H,s) .
Production Example 67: Synthesis of 2-({[4-(4-dipropylaminomethyylphenylcarbamoyl)-benzyl]-(l-methyl-lH-imidazol-2-ylmethvl)-amino}-methyl)-imidazol-l-carboxylic acid ethyl ester [Compound No.67]

Example 67-1: Synthesis of 2-({[4-(4-dipropylaminometh)7lphenylcarbamoyl)-benzyl]-(1-methyl-lH-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-l-carboxylic acid ethyl ester [Compound No.67]

The compound (66.2 mg) obtained in Example 49-1 was dissolved in anhydrous chloroform (2.7 ml). Then, the solution was added with triethylamine (0.028 ml) and then added with methyl chloroformate (manufactured by Kanto Kagaku) (0.015 ml), followed by stirring at room temperature for 6 hours. After completion of the reaction, the solution d,J=8.2Hz),7.54(lH,d,J=1.7Hz),7.69(2H,d,J=8.4Hz),7.87(2H,d,J
=8.2Hz),10.14(1H,s).

Production Example 68: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-N-methylbenzamide [Compound No.68]

Example 68-1: Synthesis of N-(4-dipropylaminomethylphenyl)-methylamine Acetic anhydride (manufactured by Kanto Kagaku) (1.23 ml) was cooled with ice and then added with formic acid (manufactured by Kanto Kagaku) (0.604 ml), followed by stirring at 50 C for 2 hours. After the solution had been stood to cool, anhydrous THE (1.0 ml) was added to the solution, and the whole was stirred at 0 C. Then, the solution was added with a THE solution (2.0 ml) in which the compound (1.075 g) obtained in Example 19-2 was dissolved, followed by stirring for 15 minutes. After completion of the reaction, the solvent was distilled off.

Lithium aluminum hydride (manufactured by Wako Pure Chemical Industries, Ltd.) (493 mg) and anhydrous THE (10 ml) were stirred under ice-cooling. Then, the mixture was added with a solution (24 ml) of the previously prepared compound in THE and subjected to thermal ref lux for 4 hours.
The reaction was terminated with sodium sulfate decahydrate.
The resulting solution was added with a 20% sodium hydroxide aqueous solution (2.0 ml) and then filtrated through CeliteTM, followed by distilling the solvent off.
The residue was added with chloroform (50 ml) and followed by stirring for 15 minutes. After completion of the reaction, the solvent was distilled off.

Lithium aluminum hydride (manufactured by Wako Pure Chemical Industries, Ltd.) (493 mg) and anhydrous THE (10 ml) were stirred under ice-cooling. Then, the mixture was added with a solution (24 ml) of the previously prepared compound in THE and subjected to thermal reflux for 4 hours.
The reaction was terminated with sodium sulfate decahydrate.
The resulting solution was added with a 20% sodium hydroxide aqueous solution (2.0 ml) and then filtrated through Celite, followed by distilling the solvent off. The residue was added with chloroform (50 ml) and washed with saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (hexane/ethyl acetate), thereby obtaining the subject compound (131.2 mg) as a yellow oily substance.

MS(FAB,Pos.):m/z=221[M+H]+
1H-NMR (500MHz, DMSO-d6) :6=0.87 (6H, t, J=7. 3Hz) , 1 . 45-1.52(4H,m),2.35-2 . 38 (4H,m) , 2.85 (3H, s) , 3.48 (2H, s) , 6.59 (2H, d, J=8 . 3Hz) , 7.15 (2H, d, J=8 . 3Hz) .

Example 68-2: Synthesis of 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-N-methylbenzamide [Compound No.68]

The compound (278 mg) obtained in Example 2-2, HOBt (95.9 mg), and DCC (147 mg) were dissolved in anhydrous DMF

(11.0 ml), followed by stirring at room temperature for 19 hours. Then, the solution was added with a solution (1.2 ml) of the compound (128 mg) obtained in Example 68-1 in DMF
and stirred at room temperature for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and added with 1 mol/l hydrochloric acid to separate the solution into layers. The aqueous layer was added with a 1 mol/1 sodium hydroxide aqueous solution to adjust the solution to pH 11. The aqueous layer was extracted with chloroform and the organic layer was then dried with anhydrous magnesium sulfate. After having been treated with hydrochloric acid, the product was purified through silica gel. column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (10.2 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=514[M+H]+

1H-NMR(500MHz,DMSO-d6):6=0.78(6H,t,J=7.3Hz),1.63(4H,m),2.83(4H,m),3.36(3H,s)4.
06 (4H,s),4.22 (2H,s),7.14 (2H,d,J=8.1Hz),7.22 (2H,d,J=8.3Hz),7.
26(2H,d,J=8.3Hz),7.51(2H,d,J=8.3Hz),7.59(4H,s).
Production Example 69: Synthesis of N,N-bis(1H-imidazol-2-ylmethyl)-N',N'-dipropylnonane-1,9-diamine [Compound No.69]
Example 69-1: Synthesis of (9-aminononyl)carbamic acid t-butyl ester Nonan-1,9-diamine (230 mg) was dissolved in chloroform (5.0 ml) and DMF (10 ml) and then added with di-t-butoxydicarbonate (317 mg). After having been stirred at room temperature for 30 minutes, the solution was concentrated and then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (70.0 mg) as a colorless viscous liquid.
MS(FAB,Pos.):m/z=259[M+H]+

Example 69-2: Synthesis of (9-dipropyl)aminononylcarbamic acid t-butyl ester The compound (299 mg) obtained in Example 69-1 was dissolved in anhydrous methanol (7.0 ml) and then added with trimethyl orthoformate (0.633 ml). Then, the solution was gradually added with sodium borohydride (145 mg) under ice-cooling. Subsequently, the mixture was heated back to room temperature and then stirred for 1 hour. After completion of the reaction, methanol was distilled off and the organic layer was then extracted with the addition of water and chloroform. The extract was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (122 mg) as a pale-yellow viscous liquid.

MS (FAB, Pos.) :m/z=x;43 [M+H]+

Example 69-3: Synthesis of N,N-dipropylnonan-1,9-diamine The compound (122 mg) obtained in Example 69-2 was dissolved in methanol (1.0 ml) and then added with a 1 mol/l hydrogen chloride/diethyl ether solution (2.0 ml), followed by stirring at room temperature for 2 hours. The solution was concentrated and dried and then purified through column chromatography (chloroform/methanol), thereby obtaining hydrochloride (6.0 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=243[M+H]+
Example 69-4: Synthesis of N,N-bis(1H-imidazol-2-ylmethyl)-N',N'-dipropylnonane-l, 9-diamine [Compound No.69]

The compound (6.0 mg) obtained in Example 69-3 was dissolved in anhydrous methanol (2.0 ml) and added with 2-imidazole carboxaldehyde (6.00 mg), followed by gradual addition of sodium borohydride (3.00 mg) under ice-cooling.
The solution was heated back to room temperature and then stirred for 1 hour. After completion of the reaction, methanol was distilled off and the organic layer was extracted with the addition of water and chloroform. The extract was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), followed by washing with ethyl acetate. Consequently, hydrochloride (5.80 mg) of the subject compound was obtained as a pale-yellow viscous liquid.

MS(FAB,Pos.):m/z=403[M+H]+
1H-NMR (500MHz, DMSO-d6) :6=0.90 (6H, t, J=7 . 3Hz) , 1. 12-1.37(12H,m),1.60-1.68(6H,m),2.36-2.40(2H,m),2.94-3.02(6H,m),4.12(4H,s),7.67(4H,s) .

Production Example 70: Synthesis of N-(4-dipropylaminometh_ylphenyl)-{[(1H-imidazol-2-ylmethyl)-(quinolin-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.70]

Example 70-1: Synthesis of N-(4-dipropylaminomethylphenyl)-{[(1H-imidazol-2-vlmethyl)-(quinolin-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.70]

Under ice-cooling, the compound (80.0 mg) obtained in Example 47-3 and 3-quinoline carboxaldehyde (Aldrich Corporation) (43.3 mg) were dissolved by the addition of anhydrous methanol (4.0 ml). Subsequently, sodium cyanoborohydride (26.4 mg) and then acetic acid (1.0 ml) were added to adjust the solution to pH 5, followed by stirring for 5 minutes. The solution was taken out of the ice bath and stirred at room temperature for 16 hours.

After completion of the reaction, methanol was distilled off and the solution was then adjusted to pH 11 to 12 with the addition of a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous magnesium sulfate. After that, the solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (chloroform/ethyl acetate). The purified product was treated with hydrochloric acid, thereby obtaining hydrochloride (20.7 mg) of the subject compound as a white crystal.

MS(FAB,Pos.):m/z=561[M+H]+

1H-NMR (500MHz, DMS(D-d6+D20) :6=0.88 (6H, t, J=7. 3Hz) , 1. 62-1.76(4H,m),2.92-2.99(4H,m),3.82(2H,s),3.95(2H,s),4.06(2H,s),4.28(2H,s),7.52( 2H,d,J=8.5Hz),7.62(2H,d,J-8.5Hz),7.78-8. 00 (6H,m) , 8.15 (2H, d, J=8. 5Hz) , 8.75 (1H, s) , 9.17 (1H, s) .
Production Example 71: Synthesis of N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-4-dipropylaminomethylbenzamide [Compound No.71]

Example 71-1: Synthesis of 4-Boc-aminomethylaniline In dichloromethane (40 ml), 4-aminobenzylamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was dissolved.
Then, the solution was added with triethylamine (2.9 ml) and cooled to 0 C. To the solution, a solution of di-t-butyl dicarbonate (3.98 g) in dichloromethane (2.0 ml) was added dropwisely and then the whole 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 and then washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous sodium sulfate.
After filtration, the solvent was distilled off under reduced pressure and the residue was then dried under vacuum, thereby obtaining the subject compound (3.90 g) as a yellow solid.

MS(FAB,Pos.):m/z=223[M+H]+

'H-NMR(500MHz,CDC13):6=1.45(9H,s),3.65(2H,s),4.19(2H,d,J=5.6Hz) , 4.74 (1H,brs) , 6.64 (2H, d, J=8. 5Hz) , 7.07 (2H, d, J=8 . lHz) .

Example 71-2: Synthesis of 4-(N-Boc-aminomethylphenyl)-4-dipropylaminomethylbenzamide In methanol (4.5 ml), 4-aminomethylbenzoic acid (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (300 mg) was dissolved. Then, trimethyl orthoformate (300 l) and sodium cyanoborohydride (501 mg) were added to the solution, and then the whole was cooled to 0 C. Subsequently, the solution was added with propionaldehyde (357 ml) and then 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 and then washed with a 1 mol/l sodium hydroxide aqueous solution.
After that, chloroform was added. The aqueous layer was neutralized with 1 mol/l hydrochloric acid and extraction with chloroform was then carried out. The solvent was distilled off under reduced pressure and the residue was then dried under vacuum, thereby obtaining a crude product (193.3 mg) as a white viscous solid. Subsequently, the crude product was dissolved in DMF (3.0 ml) and then added with WSCI hydrochloride (236 mg) and HOBt (167 mg), followed by stirring at room temperature for 30 minutes. After that, the solution was added with the compound (183 mg) obtained in Example 71-1 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 and then washed with water, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution, followed by drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (213 mg) as a pale-yellow viscous liquid.
MS(FAB,Pos.)m/z=440[M+H]+

Example 71-3: Synthesis of N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-phenyl)-4-dipropylaminomethylbenzamide [Compound No.71]

The compound (213 mg) obtained in Example 71-2 was dissolved in methanol (1.1 ml) and then added with a 4 mol/1 hydrogen chloride/dioxane solution (1.1 ml), followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Then, the residue was then dissolved in chloroform and then washed with a 1 mol/1 sodium hydroxide aqueous solution, followed by extraction with chloroform. After that, the extract was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then dried under vacuum, thereby obtaining a crude product (145 mg) as a white solid. The white solid was dissolved in methanol (2.2 ml) and then added with 2-imidazole carboxaldehyde (123 mg) and acetic acid (145 l), followed by cooling to 0 C.

Subsequently, the solution was added with sodium cyanoborohydride (82.5 mg) 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 then washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous sodium sulfate.
After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (19.0 mg) of the subject compound as a white solid.

MS(FAB,Pos.)m/z=500[M+H]+
H-NMR(500MHz,DMSO-d6) :6=0.87(6H, t,J=7.3Hz),1.62-1.78(4H,m),2.94(4H,br),3.62(2H,s),4.12(4H,s),4.39(2H,d,J=5.2 Hz) , 7.49 (2H, d, J=8. 4Hz) , 7.62 (4H, s) , 7.72 (2H, d, J=8. 4Hz) , 7.80 (2H
, d, J=8. 1Hz) , 8.02 (2H, d, J=8. 1Hz) , 10.38 (1H, s) , 10.79 (1H,br) .
Production Example 72: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(8-hydroxyquinolin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.72]

Example 72-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(8-hydroxyquin(Dlin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.72]

The compound (103 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml). Then, the solution was added with 8-hydroxyquinon-2-aldehyde (85.2 mg) and sodium cyanoborohydride (46.4 mg) in this order, and then adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 18 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (93.4 mg) of the subject compound as a pale-yellow solid.

MS (FAB, Pos .) :m/z=577 [M+H] +
1H-NMR(500MHz,DMSO-d6):6=0.87(6H,t,J=7.2Hz),1.68-1.75(4H,m),2.84-2.96(4H,m),3.97-4.29(9H,m),7.37 (1F[,d,J=6.4Hz),7.54-7 . 62 (8H, m) , 7.87 (2F[, d, J=8.7Hz) , 7.93 (2H, d, J=8 . 5Hz) , 8.01 (lH, brs ),8.67(1H,brs),10.43(1H,s),10.65(1H,s),8.56(1H,brs).
Production Example 73: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyrazine-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.73]

Example 73-1: Synthesis of 5-rnethylpyrazine-2-aldehyde In methanol (15 ml), 5-rnethylpyrazine-2-carboxylic acid (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.25 g) was dissolved. Then, the solution was added with WSCI

anhydrous sodium sulfate, followed by distilling the solvent off. The residue was dissolved in chloroform (10 ml) and then added with manganese dioxide (chemically processed product) (2.2 g), followed by stirring at room temperature for 1 hour. After completion of the reaction, the catalyst was filtrated out through CeliteTM and the solvent was then distilled off. The crude product obtained was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (35.9 mg) as a colorless oily substance.

Example 73-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyrazine-2-ylmethyl)-amino]-methyl)-benzamide [Compound No.73]

The compound (82.2 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with the compound (35.9 mg) obtained in Example 73-1, followed by the addition of sodium cyanoborohydride (36.9 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform.

The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (84.0 mg) of the subject compound as a pale-yellow solid.

amino]-methyl}-benzamide [Compound No.73]

The compound (82.2 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with the compound (35.9 mg) obtained in Example 73-1, followed by the addition of sodium cyanoborohydride (36.9 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform.

The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (84.0 mg) of the subject compound as a pale-yellow solid.

MS (FAB, Pos.) :m/z=`i26 [M+H]+
1H-NMR(500MHz,DMSO-d6):5=0.87(6H,t,J=7.3Hz),1.69-1 . 78 (4H,m) , 2.47 (3H, s) , 2. 86-2.95(4H,m),3.82(2H,s),3.85(2H,s),4.11(2H,s),4.26(2H,d,J=5.2H
z),7.58-7.62(6H,m),7.88-7.89(2H,d,J=8.7Hz),7.95-7 . 96 (2H, d, J=8 . 4Hz) , 8.47 (1H, dd, J=0 . 6, 1 . 3Hz) , 8.69 (1H, d, J=1 . 4Hz , 10.47 (lH, s) , 10.70 (1H,brs) , 14.51 (1H,brs) .
Production Example 74: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.74]

Example 74-1: Synthesis of N-(4-dipropylaminobutyl)-4-{[(1H-imidazol-2-ylmeth_yl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.74]

Under ice-cooling, the compound (120 mg) obtained in Example 1-4 and the compound (5.4 mg) obtained in Example 56-1 were dissolved in anhydrous methanol (7.0 ml), and the solution was added with sodium cyanoborohydride (46.9 mg), and then adjusted to pH 5 by the addition of acetic acid (2.0 ml), followed by stirring for 5 minutes. After having been taken out from the ice bath, the solution was stirred at room temperature for 16 hours. After completion of the reaction, methanol was distilled off and then the residue was added with a 1 mol/l sodium hydroxide aqueous solution to adjust the solution to pH 11-12, followed by extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. After that, the solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (hexane/ethyl acetate). Then, the purified product was added with methanol and 1 mol/l hydrochloric acid and then distillated, thereby obtaining hydrochloride (89.7 mg) of the subject compound as a white crystal.
MS(FAB,Pos.):m/z=491[M+H]+

1H-NMR (500MHz, DMSO--d6+D20) :6=0. 90 (6H, t, J=7. 3Hz) , 1 . 54-1.62(2H,m),1.63-1.69(6H,m),2.43(3H,s),2.97-3. 00 (4H,m) , 3.07 (3H, t, J=8. 3Hz) , 3.28 (2H, t, J=6. 8Hz) , 3.75 (2H, s) , 4.08(2H,s),4.13(2H,s),7.45(2H,d,J=8.1Hz),7.58(2H,s),7.73(2H, d, J=8 . 1Hz) , 7.91 (1H, d, J=8 . lHz) , 8 .2 6 (1H, d, J=8 . 5Hz) , 8.65 (1H, s) .

Production Example 75: Synthesis of N-(4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridine-2-ylmethyl)-amino]-methyl}-benzyl)-N',N'-dipropylbutane-l,4-diamine [Compound No.75]
Example 75-1: Synthesis of (4-dipropylaminobutyl)-(4-{[(lH-imidazol-2-ylmethyl)amino]methyl}benzyl)carbamic acid t-butyl ester The compound (0.78 g) obtained in Example 25-4 was dissolved in methanol (20 ml) and added with 2-imidazole carboxaldehyde (214.6 mg), followed by stirring at room temperature for 17 hours. After the solvent had been distilled off, the residue was dried under vacuum and then dissolved in methanol (15 ml) and then added with sodium borohydride (217.8 mg), followed by stirring at room temperature for 45 minutes. The reaction solution was added with a saturated aqueous ammonium chloride solution (10 ml) and stirred at room temperature for 15 minutes. Then, the reaction solution was added with saturated saline solution and extracted with chloroform, followed by drying with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.01 g) as a yellow solid.

MS(FAB,Pos.):m/z=4:72[M+H]+
1H-NMR(500MHz,CDC13):8=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,br s) , 4.12 (1H,brs) , 4.13 (1H,brs) , 6.99 (2H, s) , 7.20 (2H,brs) , 7.25 (2H
, d, J=7. 5Hz) .

Example 75-2: Synthesis of (4-dipropylaminobutyl)-(4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)amino]methyl}benzyl)carbamic acid t-butyl ester The compound (61.6 mg) obtained in Example 75-1 was dissolved in methanol (2.0 ml) and then added with the compound (23.8 mg) obtained in Example 56-1, followed by the addition of sodium cyanoborohydride (15.8 mg). The reaction solution was added with acetic acid to adjust the solution to pH 5, followed by stirring at room temperature for 17 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. After that, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (36.7 mg) as a yellow solid.
MS(FAB,Pos.):m/z=577[M+H]+

1H-NMR(500MHz,CDC13):8=0.85(6H,t,J=7.3Hz),1.38-1.45(14H,m),1.49(3H,brs),2.31-2.53 (9H,m) , 3.11 (1H,brs) , 3.20 (1H,brs) , 3.63 (2H, s) , 3.67 (2H, s) , 3 .75(2H,s),4.37(1H,brs),4.41(1H,brs),7.05(2H,brs),7.16-7.19(3H,m),7.30(2H.,d,J=7.8Hz),7.49(1H,d,J=7. 6Hz),8.46(1H,brs Example 75-3: Synthesis of N-(4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridine-2-ylmethyl)-amino]-methyl}-benzyl)-N',N'-dipropylbutane-1,4-diamine [Compound No.75]

The compound (35.5 mg) obtained in Example 75-2 was dissolved in methanol (1.0 ml) and then added with a 1 mol/l hydrogen chloride/diethyl ether solution (2 ml), followed by stirring at 40 C for 1 hour. The solvent was distilled off, thereby obtaining hydrochloride (36.9 mg) of the subject compound as a yellow solid.
MS (FAB, Pos.) :m/z=477 [M+H]+

1H-NMR (500MHz, DMSO-d6) :6=0.91 (6H, t, J=7 . 3Hz) , 1 . 60-1.68(8H,m),2.38(3H,s),2.92-3.05(8H,m),3.71(2H,s),3.91(2H,brs),4.06(2H,s),4.09(2H,s),7.4 5(4H,s),7.56(2H,s),7.70(1H,d,J=7.8Hz),8.00(1H,d,J=7.8Hz),8.5 3 (1H, brs) .

Production Example 76: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.76]

Example 76-1: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(5-methylpyrid.in-2-ylmethyl)amino]methyl}benzamide The compound (98.9 mg) obtained in Example 47-3 was dissolved in methanol (3.0 ml) and then added with the compound (35.3 mg) obtained in Example 56-1, followed by stirring at room temperature for 15 hours. Subsequently, the reaction solvent was distilled off and the residue was then dried under vacuum. The residue was redissolved in methanol (3.0 ml) and then added with sodium borohydride (16.5 mg) while being stirred under ice-cooling, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the reaction solvent was distilled off and the residue was then added with water, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (40.0 mg) as a white solid.
MS(FAB,Pos.):m/z=445[M+H]+

Example 76-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1-methyl-lH-i.midazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.76]

The compound (40.0 mg) obtained in Example 76-1 was dissolved in methanol (1.2 ml) and then added with 1-methylimidazol-2-aldehyde (11.9 mg) and sodium cyanoborohydride (11.3 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and. the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated dissolved. Then, the solution was added with WSCI
hydrochloride (1.50 g) and HOBt (1.08 g), followed by stirring at room temperature at 1 hour. The reaction solution was added with the compound (1.23 g) obtained in Example 19-2 and chloroform (10 ml), followed by stirring at room temperature for 15 hours. The solvent was distilled off and the residue obtained was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (2.86 g) as a yellow oily substance.

MS (FAB, Pos .) :m/z=440 [M+H] +

Example 77-2: Synthesis of 4-aminomethyl-N-(4-dipropylaminomethylphenyl)benzamide The compound (1.38 g) obtained in Example 77-1 was dissolved in methanol (10 ml) and then added with a 4 mol/1 hydrogen chloride/dioxane solution (15 ml), followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and added with anion-exchange resin (AmberliteTM IRA-410) in methanol to adjust the solution to pH 8. After the resin had been removed through filtration, the solvent was distilled off, thereby obtaining the subject compound (0.79 g) as a yellow solid.

MS (FAB, Pos .) : m/z=340 [M+H] +

Example 77-3: Synthesis of 4-{[bis(5-methylpyridin-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.77]

Example 77-2: Synthesis of 4-aminomethyl-N-(4-dipropylaminomethylphenyl)benzamide The compound (1.38 g) obtained in Example 77-1 was dissolved in methanol (10 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (15 ml), followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and added with anion-exchange resin (Amberlite IRA-410) in methanol to adjust the solution to pH 8. After the resin had been removed through filtration, the solvent was distilled off, thereby obtaining the subject compound (0.79 g) as a yellow solid.

MS(FAB,Pos.):m/z=340[M+H]+
Example 77-3: Synthesis of 4-{[bis(5-methylpyridin-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.77]

The compound (105.7 mg) obtained in Example 77-2 was dissolved in methanol (3.2 ml) and then added with the compound (90.5 mg) obtained in Example 56-1 and sodium cyanoborohydride (58.7 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 16 hours. After completion of the reaction, the reaction solvent was distilled off and a 1 mol/l sodium hydroxide aqueous solution was added to the residue, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (36.0 mg) of the subject compound as a white solid.

MS (FAB, Pos.) :m/z=_`i50 [M+H]+
1H-NMR(500MHz,DMSO-d6):5=0.85(6H,t,J=7.3Hz),1.56-1.76(4H,m),2.37(6H,s),2.92(4H,br),4.00(2H,s),4.18(4H,s),4.25 (2H,s),7.49(2H,d,J=8.8Hz),7.53(2H,d,J=8.3Hz),7.71 (2H,d,J=8.1 Hz) , 7.81 (2H, d, J=8 . 1Hz) , 7.83 (2H, d, J=8 . 3Hz) , 8.05 (2H, d, J=8 .
lHz) , 8.57 (2H, s) .

Production Example 78: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[N-(1H-imidazol-2-ylmethyl)-(4-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.78]

Example 78-1: Synthesis of 4-methylpyridine-2-aldehyde By the same procedures as those of Example 53-1, except that 2,4-lu.tidine was used as a raw material, 4-methylpyridine-2-aldehyde (40.5 mg) was obtained.

MS(FAB,Pos.):m/z=122[M+H]+

NMR(500MHz,CDC13):6=2.46(3H,s),7.35(1H,d,J=4.9Hz),7.80(1H,s) , 8.65 (1H, d, J=4 . 9Hz) , 10.08 (1H, s) .

Example 78-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[N-(1H-imidazol-2-ylmethyl)-(4-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.78]

The compound (80.2 mg) obtained in Example 47-3 was dissolved in methanol (2.4 ml) and then added with the compound (34.6 mg) obtained in Example 78-1 and sodium cyanoborohydride (18.0 mg). The solution was adjusted to about pH 5 with acetic acid and then stirred at room temperature for 26 hours. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by washing with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution and drying with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel. column chromatography (chloroform/methanol), thereby obtaining the subject compound (40.1 mg) as a white solid.
MS(FAB,Pos.):m/z=525[M+H]+

1H-NMR (500MHz, DMSO-d6) :6=0.82 (6H, t, J='7 . 3Hz) , 1.42 (4H, sext. , J=7 . 3Hz) , 2.32 (4H, t, J=
7.3Hz),2.34(3H,s),3.47(2H,s),3.64(2H,s),3.65(2H,s),3.66(2H,s ),6.86(1H,s),7.09-7.11(2H,m),7.25(2H:,d,J=8.5Hz),7.48(1H,s),7.57(2H,d,J=8.5Hz), 7.69 (2H, d, J=8 . 3Hz) , 7.90 (2H, d, J=8. 3Hz) , 8.35 (1H, d, J=4 . 9Hz) , 10 .
17 (1H, s) , 11. 96 (1H,br) .

Production Example 79: Synthesis of {2-[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-phenyl]-ethyl}-dipropylamine [Compound No.79]

Example 79-1: Synthesis of 4-(2-dipropylaminoethyl)phenol Tyramine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (591 mg) was dissolved in anhydrous methanol (12 ml) and then added with sodium cyanoborohydride (812 mg), acetic acid (5.00 ml), and propionaldehyde (777 l), followed by stirring at room temperature under a nitrogen atmosphere for 2 days. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in diethyl ether and then stirred after the addition of distilled water.
The solution was subjected to extraction with diethyl ether and the extract was then washed with distilled water and a saturated aqueous ammonium chloride solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off, thereby obtaining the subject compound (412 mg) as a dark brown liquid.

MS (FAB, Pos.) :m/z=222 [M+H]+

Example 79-2: Synthesis of {2-[4-(4-{[N-Boc(N-1-methane sulfonyl-lH-imidazol-2-ylmethyl)amino]methyl}benzyloxy) phenyl]ethyl}dipropylamine The compound (260 mg) obtained in Example 60-1 was dissolved in DMF (2.0 ml) and then added with potassium carbonate (86.8 mg) and the compound (139 mg) obtained in Example 79-1, followed by stirring under a nitrogen atmosphere at 60 C for 3 days. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous ammonium chloride solution, followed by stirring.
The solution was extracted with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (149 mg) as a yellow oily substance.
MS(FAB,Pos.):m/z=599[M+H]+

Example 79-3: Synthesis of {2-[4-(4-{[N-(1H-imidazol-2-ylmethyl)amino]methyl}benzyloxy)phenyl] ethyl}dipropylamine The compound (149 mg) obtained in Example 79-2 was dissolved in anhydrous methanol (1.0 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (2.00 ml), followed by stirring at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off.
Then, the residue was added with a 1 mol/l sodium hydroxide aqueous solution and then washed with chloroform. The aqueous layer was evaporated to dryness and extracted with chloroform, thereby obtaining the subject compound (67.0 mg) as a colorless oily substance.

MS(FAB,Pos.):m/z=421[M+H]+
Example 79-4: Synthesis of {2-[4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-phenyl]-ethyl}-dipropylamine [Compound No.79]

The compound (67.0 mg) obtained in Example 79-3 was dissolved in anhydrous methanol (1.5 ml) and then added with sodium cyanoborohydride (20.0 mg), acetic acid (1.50 ml), and 2-imidazole carboxaldehyde (23.0 mg), followed by stirring under a nitrogen atmosphere at 60 C for 2 days.
After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (47.1 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=501[M+H]+
Production Example 80: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxymethyl)-benzyl]-dipropylamine [Compound No.80]

Example 80-1: Synthesis of methyl 4-dipropylaminomethylbenzoate In anhydrous methanol (30 ml), 4-aminomethylbenzoic acid methyl ester hydrochloride (1.15 g) was dissolved.
Then, the solution was added with sodium cyanoborohydride (1.08 g), acetic acid (5.00 ml), and propionaldehyde (1.03 ml), followed by stirring under a nitrogen atmosphere at room temperature for 1 week. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by the addition of a 1 mol/l sodium hydroxide aqueous solution to adjust the solution to pH 9. The solution was subjected to extraction with chloroform. Then, the extract was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off, thereby obtaining the subject compound (1.49 g) as a colorless liquid.

MS(FAB,Pos.):m/z=250[M+H]+

Example 80-2: Synthesis of 4-dipropylaminomethylbenzyl alcohol The compound (1.47 g) obtained in Example 80-1 was dissolved in anhydrous THE (50 ml). Then, the solution was added with lithium aluminum hydride (671 mg) in an ice bath, followed by stirring at room temperature for 1 hour. After completion of the reaction, the solution was added with methanol and then added with an aqueous potassium sodium tartrate solution, followed by stirring. The solution was extracted with chloroform and the extract was then washed with saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off, thereby obtaining the subject compound (1.20 g) as a colorless liquid.

MS(FAB,Pos.):m/z=222[M+H]+
Example 80-3: Synthesis of [4-(4-{[N-Boc(N-1-methanesulfonyl-lH-imidazol-2-ylmethyl)amino]methyl}benzyloxymethyl)benzyl]dipropylamine The compound (225 mg) obtained in Example 60-1 was dissolved in DMF (2.0 ml) and then added with potassium carbonate (75.2 mg) and the compound (120 mg) obtained in Example 80-2, followed by stirring under a nitrogen atmosphere at 60 C for 2 days. In addition, potassium iodide (18.0 mg) was added to the solution, and likewise the whole was stirred overnight at 60 C under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform Subsequently, a 4 mol/1 hydrogen chloride/dioxane solution (3.00 ml) was added to the solution to adjust the solution to pH 2, followed by stirring at room temperature for 1 hour.
After completion of the reaction, the solvent was distilled off and the residue was dissolved in methanol. Subsequently, the solution was added with an anion-exchange resin (AmberliteTM IRA-410) and left to stand. The resultant was filtrated and the solvent was then distilled off, thereby obtaining the subject compound (136 mg) as a colorless oily substance.

MS (FAB, Pos .) :m/z=421 [M+H] +

Example 80-5: Synthesis of [4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxymethyl)-benzyl]-dipropylamine [Compound No.80]

The compound (136 mg) obtained in Example 80-4 was dissolved in anhydrous methanol (3.0 ml) and then added with sodium cyanoborohydride (40.6 mg), acetic acid (1.00 ml), and 2-imidazole carboxaldehyde (46.6 mg), followed by stirring under a nitrogen atmosphere at 60 C overnight.
After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (109 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=501[M+H]+
1H-NMR(500MHz,DMSO-d6+D20):5=0. 87(6H,t,J=7.2Hz),1.78-1.90(4H,m),2.89-3.08(4H,m),4.11(2H,s),4.15(2H,s),4.58(4H,s),4.76(4H,s),7.41-7 . 53 (8H,m) , 7.55 (4H, s) .

Production Example 81: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(lH-imidazol-2-ylmethyl)-([1,2,3]-thiadiazole-4-ylmethyl)-amino]-methyl)-benzamide [Compound No.81]

Example 81-1: Synthesis of [1,2,3]thiadiazol-4-aldehyde [1,2,3]thiazol-4-carboxylic acid (manufactured by Avocado Co., Ltd.) (1.19 g) was dissolved in a 10% hydrogen chloride/methanol solution (35.7 ml), following thermal ref lux for 14 hours. The reaction solvent was distilled off and the residue was dried under vacuum. The dried product was dissolved in ethanol (18.0 ml) and THE (9.0 ml) and then added with calcium chloride (1.39 mg) and sodium borohydride (0.945 g), followed by stirring at room temperature for 30 minutes. The reaction solution was added with a 1 mol/l aqueous citric acid solution, followed by separation/extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution in this order, and then dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was redissolved in chloroform (10.5 ml) and then added with manganese dioxide (chemically processed product) (2.10 g), followed by stirring at room temperature for 1.5 hours. The reaction solution was filtrated using Celite'. The solvent was distilled off and the residue was then purified through reflux for 14 hours. The reaction solvent was distilled off and the residue was dried under vacuum. The dried product was dissolved in ethanol (18.0 ml) and THE (9.0 ml) and then added with calcium chloride (1.39 mg) and sodium borohydride (0.945 g), followed by stirring at room temperature for 30 minutes. The reaction solution was added with a 1 mol/l aqueous citric acid solution, followed by separation/extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution in this order, and then dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was redissolved in chloroform (10.5 ml) and then added with manganese dioxide (chemically processed product) (2.10 g), followed by stirring at room temperature for 1.5 hours. The reaction solution was filtrated using Celite. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (69.2 mg) as a white solid.

1H-NMR(500MHz,CDC13) :6=9.31( 1H, s), 10.6 (1H,s) Example 81-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2--ylmethyl)-([1,2,3]-thiadiazole-4-ylmethyl)-amino]-methyl}-benzamide [Compound No.81]

The compound (77.8 mg) obtained in Example 47-3 was dissolved in methanol (2.3 ml) and then added with the compound (23.3 mg) obtained in Example 81-1 and sodium cyanoborohydride (23.3 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 19 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (64.9 mg) of the subject compound as a white solid.
MS(FAB,Pos.):m/z=518[M+H]+

1H-NMR(500MHz,DMSO-d6):6=O.88(6H,t,J=7.3Hz),1.60-1.80(4H,m),2.96(4H,,br),3.81(2H,s),4.08(2H,s),4.26(2H,s),4.29 (2H, s) , 7 .53 (2H, d, J==8.3Hz) , 7.54 (2H, s) , 7 .59 (2H, d, J=8. 5Hz) , 7.87 (2H,d,J=8.5Hz),7.93(2H,d,J=8.3Hz),9.15(1H,s) .

Production Example 82: Synthesis of 4-{[(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.82] and synthesis of 4-{[bis(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.84]
Example 82-1: Synthesis of 4-{[(1-dimethylsulfamoyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.82] and synthesis of 4-{[bis(1-dimethylsulfamoyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.84]

The compound (55.7 mg) obtained in Example 19-3 was dissolved in anhydrous chloroform (2.2 ml). The solution was added with triethylamine (0.037 ml) and then dimethylsulfamoyl chloride (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.026 ml), followed by stirring at room temperature for 42 hours. After the reaction, the solution was added with chloroform (3.0 ml) and then washed with water and a saturated aqueous sodium bicarbonate solution.
The organic layer was dried with anhydrous magnesium sulfate.
The solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (chloroform/ethyl acetate), thereby obtaining 4-{[(1-dimethylsulfamoyl-lH-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No. 82] (14.7 mg) as a white solid.
MS(FAB,Pos.):m/z=607[M+H]+

1H-NMR (500MHz, DMSO--d6) : 6=0.82 (6H, t, J=7 . 3Hz) , 1.42 (4H, sext . , J=7 . 3Hz) , 2.31 (4H, t, J=
7.3Hz),2.76(6H,s),3.47(2H,s),3.85(2H,s),3.91(2H,s),3.95(2H,s ),6.85(1H,s),7.10(2H,d,J=1.7Hz),7.25(2H,d,J=8.5Hz),7.49(2H,d , J=8 . 5Hz) , 7.56 (1H, d, J=1 .7Hz) , 7.69 (2H, d, J=8 . 5Hz) , 7.88 (2H, d, J=
8. 3Hz), 10.15(1H,s),11.90(1H,brs).

Furthermore, as a white solid, 4-{[bis(1-dimethylsulfamoyl-1H-imidazol--2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide [Compound No.84]
(12.7 mg) was obtained from other fraction.
MS(FAB,Pos.):m/z=714[M+H]+

1H-NMR (500MHz, DMSO-d6) :8=0.82 (6H, t, J=7 . 3Hz) , 1.42 (4H, sext . , J=7 . 3Hz) , 2.32 (4H, t, J=
7.3Hz),2.78(12H,s),3.42(2H,s),4.14(6H,s),7.06(2H, d,J=1.7Hz), 7.26(2H,d,J=8.5Hz),7.39(2H,d,J=8.3Hz),7.55(2H,d,J=1.7Hz),7.6 9(2H,d,J=8.5Hz),7.86(2H,d,J=8.3Hz),10.15(1H,s).

Production Example 83: Synthesis of 2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-lH-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-l-carboxylic acid dimethylamide [Compound No.83]

Example 83-1: Synthesis of 2-({[4-(4-dipropylaminomethylphenylcarbamoyl)-benzyl]-(1-methyl-lH-imidazol-2-ylmethyl)-amino}-methyl)-imidazol-l-carboxylic acid dimethylamide [Compound No.83]

The compound (95.0 mg) obtained in Example 49-1 was dissolved in pyridine (5.0 ml) and added with N,N-dimethylcarbamoyl chloride (20.0 mg). After the solution had been stirred at room temperature for 15 hours, pyridine was distilled off and the residue was then added with a saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extract was concentrated and purified through column chromatography (chloroform/methanol), thereby obtaining the subject compound (45.4 mg) as a white solid.
MS(FAB,Pos.):m/z=585[M+H]+

1H-NMR (500MHz, DMSO-d6) :8=0.82 (6H, t, J=7 . 3Hz) , 1 . 38-1.45(4H,m),2.30-2.38(4H,m),2.73-2 . 97 (6H,m) , 3.33 (3H, s) , 3.47 (4H,m) , 3.62 (4H, d, J=5.8Hz) , 6.79 (1H, d, J=1.2Hz) , 6.97 (1H, d, J=1. 4Hz) , 7.07 (1H, d, J=1.2Hz) , 7 .2 6 (2H, d, J

layer was washed with a saturated sodium bicarbonate solution and dried with anhydrous magnesium sulfate.
Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate). The purified product was dissolved in chloroform (10 ml) and added with manganese dioxide (chemically processed product) (2.00 g), followed by stirring for 4 hours. The solution was filtrated through CeliteTM and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (56.0 mg).

MS (EI, Pos.) :m/z=108 [M] +

NMR(500MHz,CDC13):5=8.78(1H,d,J=2.4Hz),8.89(1H,d,J=2.4Hz),9.1 9(1H,s),10.17(1H,s).

Example 84-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyrazine-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.85]

The compound (99 mg) obtained in Example 47-3 and the compound (51.0 mg) obtained in Example 84-1 were dissolved in anhydrous methanol (5.0 ml). The solution was added with sodium cyanoborohydride (35.6 mg) and further added with acetic acid (1.0 ml) to adjust the solution to pH 5, followed by stirring for 5 minutes and then stirring at room temperature for 17 hours. After completion of the reaction, methanol was distilled off and the solution was then added with 1 mol/l sodium hydroxide to adjust the solution to pH

NMR(500MHz,CDC13):6=8.78(1H,d,J=2.4Hz),8.89(1H,d,J=2.4Hz),9.
19(1H,s),10.17(1H,s).

Example 84-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyrazine-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.85]

The compound (99 mg) obtained in Example 47-3 and the compound (51.0 mg) obtained in Example 84-1 were dissolved in anhydrous methanol (5.0 ml). The solution was added with sodium cyanoborohydride (35.6 mg) and further added with acetic acid (1.0 ml) to adjust the solution to pH 5, followed by stirring for 5 minutes and then stirring at room temperature for 17 hours. After completion of the reaction, methanol was distilled off and the solution was then added with 1 mol/1 sodium hydroxide to adjust the solution to pH

11, followed by extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. After that, the solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (16.8 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=512[M+H]+
1H-NMR(500MHz,DMSO-d6+D20) :6=0.82 (6H, t, J=7.3Hz) , 1.42 (4H, sext. , J=7. 3Hz) , 2.32 (4H, t,J=7.5Hz),3.48(2H,s),3.71(2H,s),3.73(2H,s),3.77(2H,s),6.85( 1H,s),7.11(1H,s),7.27(2H,d,J=8.5Hz),7.56(2H,d,J=8.3Hz),7.67( room temperature for 1 hour. After completion of the reaction, the resultant solution was added with anhydrous sodium sulfate and then added with a 20% sodium hydroxide aqueous solution (15 ml). The solution was filtrated through CeliteTM and the solvent was distilled off. The residue was dissolved in chloroform (85 ml) and added with manganese dioxide (chemically processed product) (17.0 g), followed by stirring for 4.5 hours. After completion of the reaction, the solution was filtrated through Celite and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (164 mg) as a white solid.

MS(EI,Pos.):m/z=1l1[M]+
1H-NMR(500MHz,CDC13):6=2.53(3H,s),6.39(lH,s), 10.12(1H,s).
Example 85-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylisoxazol-3-ylmethyl)-amino]-methyl)-benzamide [Compound No.86]

The compound (110 mg) obtained in Example 47-3 and the compound (58.0 mg) obtained in Example 85-1 were dissolved in anhydrous methanol (5.0 ml). The solution was added with sodium cyanoborohydride (39.4 mg) and then added with acetic acid (1.0 ml) to adjust the solution to pH 5, followed by stirring for 5 minute and then stirring at room temperature for 17 hours. After completion of the reaction, methanol was distilled off and a 1 mol/l sodium hydroxide aqueous solution was added to adjust the solution to pH 11, followed by extraction with chloroform. The organic layer was washed MS(EI,Pos.):m/z=111[M]+

1H-NMR(500MHz,CDC13) :c=2.53 (3H, s) , 6.39 (1H, s) , 10.12 (1H, s) .
Example 85-2: Synthesis of N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylisoxazol-3-ylmethyl)-amino]-methyl}-benzamide [Compound No.86]

The compound (110 mg) obtained in Example 47-3 and the compound (58.0 mg) obtained in Example 85-1 were dissolved in anhydrous methanol (5.0 ml). The solution was added with sodium cyanoborohydride (39.4 mg) and then added with acetic acid (1.0 ml) to adjust the solution to pH 5, followed by stirring for 5 minute and then stirring at room temperature for 17 hours. After completion of the reaction, methanol was distilled off and a 1 mol/l sodium hydroxide aqueous solution was added to adjust the solution to pH 11, followed by extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate, followed by distilling the solvent off.
Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), added with methanol and 1 mol/l hydrochloric acid, and distilled off, thereby obtaining hydrochloride (21.3 mg) of the subject compound as a white crystal.

MS(FAB,Pos.):m/z=515[M+H]+
1H-NMR (500MHz, DMSO--d6+D2O) : 6=0.82 (6H, t, J=7.3Hz) , 1.43 (4H, sext. , J=7 . 3Hz) , 2.32 (4H, t,J=7.5Hz),2.40(3H,s),3.48(2H,s),3.59(2H,s),3.67(2H,s),3.70( 2H,s),6.34(1H,s),6.87(1H,s),7.12(1H,s),7.27(2H,d,J=8.5Hz),7.
54 (2H, d, J=8 . 3Hz) , 7.68 (2H, J=8 . 5Hz) , 7.89 (2H, d, J=8 . lHz) .

Production Example 86: Synthesis of 4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]--methyl}-benzoyl)-(2-dipropylaminoethyl)-piperazine [Compound No.87]

Example 86-1: Synthesis of 4-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzoyl)-(2-dipropylaminoethyl)-piperazine [Compound No.87]

The compound (103.8 mg) obtained in Example 2-2 was dissolved in DMF (3.1 ml) and then added with DCC (68.8 mg) and HOBt (45.0 mg), followed by stirring at room temperature for 10 days. The solution was added with 1-(2-dipropylaminoethyl)piperazine (71.1 mg) and further stirred at the same temperature for 4 days. The reaction solvent was distilled off and the residue was then added with 1 mol/l hydrochloric acid, followed by washing with chloroform.
The aqueous layer was adjusted to pH 12 with a 1 mol/1 sodium hydroxide aqueous solution and then subjected to separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloride acid, thereby obtaining hydrochloride (52.5 mg) of the subject compound as a white solid.

MS(FAB,Pos.):m/z=506[M+H]+
1H-NMR (500MHz, DMSO--d6) :6=0.88 (6H, t, J=7 . 3Hz) , 1. 60-1.76(4H,m),2.78-3.26(12H,m),3.48-3.58(4H,m),3.71(2H,m),4.14(4H,m),7.24-7.56(8H,m).

Production Example 87: Synthesis of N-(4-cyclohexylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.88]

Example 87-1: Synthesis of cyclohexyl(4-nitrobenzyl)carbamic acid benzyl ester Commercially available 4-nitrobenzylamine hydrochloride (1.88 g) was added with a 1 mol/l sodium hydroxide aqueous solution (12 ml) and then the solution was subjected to extraction with chloroform. The solution was dried with anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dissolved in anhydrous methanol (45 ml) and then added with cyclohexanone (1.55 ml) and trimethyl orthoformate (3.28 ml), followed by stirring at room temperature for 2.5 hours. The solution was cooled with ice and added with sodium borohydride (1.13 g), followed by stirring for 4.5 hours. After completion of the reaction, the solvent was distilled off and the residue was then added with water, followed by extraction with chloroform. The extract was washed with saturated saline solution and dried with anhydrous magnesium sulfate, followed by distilling the solvent off. The residue was dissolved in dioxane (25 ml) and cooled with ice. To this solution, benzyloxycarbonyl chloride (1.57 ml) and a 4 mol/l sodium hydroxide aqueous solution (2.8 ml) were added, and the whole was stirred at room temperature for 4 hours.

After completion of the reaction, the solvent was distilled hydrazine monohydrate (0.89 ml) and then subjected to thermal ref lux for 3 hours. After completion of the reaction, the resultant was filtrated through CeliteTM and the solvent was then distilled off. The residue was dissolved in chloroform and washed with water. The solution was dried with anhydrous magnesium sulfate. The solvent was distilled off, thereby obtaining the subject compound (1.15 g) as a yellow viscous liquid.

MS (FAB, Pos.) :m/z=339 [M+H] +

Example 87-3: Synthesis of [4-(4-{[Boc-(1H-imidazol-2-ylmethyl)amino]methyl}benzoylamino)benzyl]cyclohexylcarbamic acid benzyl ester The compound (1.15 g) obtained in Example 87-2 was dissolved in anhydrous chloroform (23 ml) and then added with the compound (1.24 g) obtained in Example 1-1, WSCI
hydrochloride (717 mg), and HOBt (505 mg), followed by stirring at room temperature for 4 days. After completion of the reaction, the solution was washed with 1 mol/l hydrochloric acid, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution. The solution was dried with anhydrous magnesium sulfate, and the solvent was then distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.81 g) as a white solid.

MS (FAB, Pos .) : m/ z=652 [M+H] +
1H-NMR(500MHz,DMSO-d6):8=1.02(1H,br),1.21-1.24(2H,m),1.36(9H,s),1.41-1.43(2H,m),1.46-The compound (1.15 g) obtained in Example 87-2 was dissolved in anhydrous chloroform (23 ml) and then added with the compound (1.24 g) obtained in Example 1-1, WSCI
hydrochloride (717 mg), and HOBt (505 mg), followed by stirring at room temperature for 4 days. After completion of the reaction, the solution was washed with 1 mol/l hydrochloric acid, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution. The solution was dried with anhydrous magnesium sulfate, and the solvent was then distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.81 g) as a white solid.

MS(FAB,Pos.):m/z=652[M+H]+
1H-NMR(500MHz, DMSO-d6) :5=1.02 (1H,br) , 1.21-1.24(2H,m),1.36(9H,s),1.41-1.43(2H,m),1.46-1.58(3H,m),1.67(2H,br),3.84(1H,br),4.35-4.51(6H,m),5.08-5.12(2H,br),6.85(lH,s),7.05(1H,s),7.21(3H,m),7.32-7. 39 (4H,br) , 7.68 (2H,d, J=8. 6Hz) , 7.91 (2H,d, J=8. lHz) , 10.18 (1H,b rs),11.96(1H,br).

Example 87-4: Synthesis of cyclohexyl-[4-(4-{[(1H-imidazol-2-ylmethyl)amino]methyl}benzoylamino)benzyl]carbamic acid benzyl ester The compound (1.82 g) obtained in Example 87-3 was dissolved in methanol (18 ml) and then added with a 4 mol/1 hydrogen chloride/dioxane solution (18 ml), followed by stirring at room temperature for 2 hours. After the reaction, the solvent was distilled off. Then, the residue benzyl ester The compound (236 mg) obtained in Example 87-4 and 1-methyl-2-imidazole carboxaldehyde (46.5 mg) were dissolved in anhydrous methanol (7.1 ml). The solution was added with sodium cyanoborohydride (54.0 mg) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. After the reaction, the solvent was distilled off. A 1 mol/1 sodium hydroxide aqueous solution was added to the residue, and chloroform extraction was then carried out. The extract was washed with saturated saline solution and then dried with magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (212 mg) as a white solid.

MS (FAB, Pos .) :m/z=646 [M+H] +
Example 87-6: Synthesis of N-(4-cyclohexylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-lH-imidazol-2-ylmethyl)-amino]-methyl}-benzamide [Compound No.88]

The compound (212 mg) obtained in Example 87-5 was dissolved in methanol (10 ml). After having been cooled with ice, the solution was added with a suspension of 10%
palladium-carbon (105 mg) in ethanol (3.0 ml). After having been subjected to hydrogen displacement, the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After the reaction, the solution was filtrated through CeliteTM and the solvent was then distilled off. Then, DEMANDES OU BREVETS VOLUMINEUX
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Claims

1. A compound represented by the following general formula (1), a pharmacologically acceptable salt thereof:

wherein each of n1, n2, and n3 is an integer of 1;
each of R1, R2, R3, R4, R5, and R6 is a hydrogen atom;
A1 is a imidazole ring or an imidazole ring substituted with an alkyl group;
A2 is monocyclic or polycyclic heteroaromatic ring which may be substituted with an alkyl group, a hydroalkyl group, an alkoxy group, a hydroxyl group or a halogen atom;
W is a phenylene group or a naphthylene group;
X is CH2, -(C=O)- or NH;
D is a group represented by the following formula (6):
wherein Q is C=O when X is NH, or NR12 when X is -(C=O)- or CH2, wherein R12 is a hydrogen atom, or an alkyl group having 1 to 15 carbon atoms;
Y is a group represented by the following formula (7):
wherein m3 is an integer of 2 to 4;
each of R18 and R19 is a hydrogen atom;
each of m4 and m5 is an integer of 0 to 2;
each of R20, R21, R22, and R23 is a hydrogen atom;
z is a phenylene group and B is N(R25R26), wherein each of R25 and R26 is independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cyclic alkyl group having 3 to 6 carbon atoms;
wherein one or two or more asymmetric carbon atoms may exist in the compound represented by the general formula (1), where when one asymmetric carbon atom exists, the compound may be in the form of any one of a pure optically active substance represented by the absolute configuration R or S, a mixture thereof in a predetermined ratio, and a racemic mixture thereof or when two or more asymmetric carbon atoms exist, the compound may be in the form of any one of an optically pure diastereomer, a racemic mixture thereof, and a combination thereof in a predetermined ratio.

2. A compound, or a pharmacologically acceptable salt thereof according to claim 1, wherein A1 is an imidazole ring or an imidazole ring substituted with a methyl group.

3. A compound, or a pharmacologically acceptable salt thereof according to claim 1 or 2, wherein each of A2 is an imidazole ring which may be substituted with an alkyl group, a hydroxyalkyl group, an alkoxy group, a hydroxyl group or a halogen atom.

4. A compound, or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein X is a group represented by -C(=O)- and D is a group represented by the formula (6) where Q is a group represented by NR12.

5. A compound, or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein X is a group represented by -CH2- and D is a group represented by the formula (6) where Q is a group represented by NR12.

6. A compound, or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein X is a group represented by -C(=O)- or -CH2- and D is a group represented by the formula (6) in which Q is a group represented by NR12, and Y is a group represented by -(CR18R19)m3-.

7. A compound, or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein X is a group represented by -C(=O)- or -CH2- and D is a group represented by the formula (6) in which Q is a group represented by NR12, and Y is a group represented by -(CR20R21)m4-z- (CR22R23)m5-.

8. A compound, or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein D is a group represented by the formula (6) where B is represented by -NR25R26.

-9. A compound, or a pharmacologically acceptable salt thereof according to claim 1 selected from the group consisting of:
N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N',N'-dipropylbutane-1,4-diamine, N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N',N'-dipropylbutane-1,4-diamine, N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N',N'-dipropylbutane-1,4-diamine, N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N',N'-dipropylbutane-1,4-diamine, N-cyclohexyl-N'-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N'-methyl-butane-1,4-diamine.

10. A prodrug of the compound according to any one of claims 1 to 9, wherein one of a) alkoxycarbonyl group, b) dialkylamino sulfone group, or c) an ester group which utilizes alcohol or carboxylic acid group in the compound of formula (1) is bound to N in the ring or chain of the compound of formula (1).

11. A medical composition, comprising as the active ingredient the compound, the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, or the prodrug according to claim 10 and a pharmaceutically acceptable excipient.

12. A CXCR4 antagonist, comprising as the active ingredient the compound, the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, or the prodrug according to claim 10 and a pharmaceutically acceptable excipient.

13. An antiviral drug, comprising as the active ingredient the compound, the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, or the prodrug according to claim 10 and a pharmaceutically acceptable excipient.

14. A rheumatic disease improving agent, comprising as an active ingredient the compound, the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, or the prodrug according to claim 10 based on a CXCR4 antagonism and a pharmaceutically acceptable excipient.

15. A cancer metastatic disease improving agent, comprising as an active ingredient the compound, the pharmacologically acceptable salt thereof according to any one of claims 1 to 9, or the prodrug according to claim 10 based on CXCR4 antagonism and a pharmaceutically acceptable excipient.