JPH08231514A - Phenylbenzimidazole derivative - Google Patents

Abstract

PURPOSE: To obtain a new compound capable of being combined with DNA to inhibit the growth of cells and useful for anticancer medicines, antibacterial medicines or antiviral medicines. CONSTITUTION: A compound of formula I (m), (n) are 0-3; R1 , R2 are H, a halogen, a 1-8C alkylthio, a (substituted)amino, a (substituted)ammonium, a (substituted)sulfonium, a (substituted)phenyl, a (substituted)heterogeneous five- membered ring, a (substituted)heterogenous six-membered ring, amidino; a group of formula II R3 is a direct bond, O; R4 is H, a 1-8C alkyl, etc.; R5 is H, a 1-8C alkyl, etc.; R6 is (CH2 )p N(R8 )2 [p is 0-5; R8 is a CH2 CH2 W (W is a halogen, etc.)], etc.}. For example, 1H-2-[3-[[4-[4-N,N-bis-(2-chloroethyl)amino]phenyl]- butylyl]amino]phenyl]benzimidazole-5-[N-(2-amidinoethyl)]-carboxamide hydrochloride. The compound of formula I is synthesized by starting from the reaction of nitrobenzaldehyde of formula III with a compound of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to binding to DNA,
The present invention relates to a compound which is a novel phenylbenzimidazole derivative that suppresses cell proliferation, and a pharmaceutical composition containing the same, particularly the use thereof in anticancer agents, antibacterial agents, antiviral agents and the like.

[0002]

2. Description of the Related Art Some compounds that act on DNA are used as anticancer agents. For example, adriamycin is useful as an anticancer agent that intercalates with DNA. In addition, cisplatin and mitomycin
Compounds that react with DNA such as ycin) are also often used. The anticancer effect of acting on DNA in this way is considered to have been established, if not all of it can be explained. On the other hand, recently, distamycin (Distamycin) or netropsin (Netropsin) is known to bind to DNA and have an antitumor activity (Nature, 19).
64, 203, 1064-65). These are attracting attention as groove binders that differ from conventional anti-cancer agents in the manner of binding to DNA. Other Hoechst
33258 (Nucleic Acids Rease
Compounds whose binding to DNA has been confirmed, such as rch, 1988, Vol. 16, pp. 2671-90) are also known.

[0003] However, the knowledge about anti-cancer agents up to now predicts which partial structure in a compound is a really necessary structure or what kind of structure can substitute for the interaction with DNA. That is not possible at present. However, it is worth predicting and exploring the presence of compounds with other desirable structures. It is considered that the search for such a new structure is particularly required for the creation of a new anticancer drug.

Further, a compound in which an alkylating agent is bound to a distamycin derivative is known. To give a typical example, J. Am. Chem. Soc. 1985 10
Volume 7, pages 8266, EP246868, WO93-137.
39, J. Med. Chem. 1989, Volume 32, 774
There are pages etc. A compound in which an alkylating agent is bound to a compound similar to distamycin, in which N-methylimidazole is used as a partial structure and is linked by an amide bond, is also known (US5273991). Among these, there is one in which a bis (2-chloroethyl) amino residue is used as an alkylating agent, and this residue is already known to be a part of the structure of an anticancer agent. For example, Chlorambucil is known as an anticancer drug having a bis (2-chloroethyl) amino residue in the molecule. The anti-cancer activity of this compound is believed to be the result of alkylation to DNA, enzymes and the like. However, the value of adding an alkylating agent having a chloroethylamine structure as a part of the structure of an anticancer agent that binds to DNA is not yet established.

[0005]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The present invention is to provide a new compound that acts on the above-mentioned compound, or a new compound having a partial structure that acts on DNA and useful as an anticancer agent.

[0006]

DISAMYCIN is a typical example of a compound that binds to DNA, but a compound that has benzimidazole in its molecule and that binds to DNA is also known. For example, Hoechst 33258
Two benzimidazoles are bound, and further phenol,
It has a bonded structure of piperazine. However, the characteristic that aromatic rings are connected by an amide bond is not found like distamycin. When these structures are compared, the structures that bind to DNA are clearly different. That is, there are several types of structures that bind to DNA, and it is not possible to see an example in which the superiority or inferiority of each usefulness is examined. From this, the present inventor expects that there are other compounds having a structure different from the known compound and having an anticancer action while retaining the structure of benzimidazole in part, and thus a new structure I searched for. As a result, a novel compound having a structure in which a phenyl group and a benzimidazole were directly bonded and having a structure in which another substituent was added by an amide bond was selected as a compound useful as an anticancer agent. Particularly, of these, the 1H-2-phenylbenzimidazole-5-carboxamide derivative was selected. These compounds have a novel structure and are not known at all as anticancer agents. And these compounds showed the tumor cell growth inhibitory activity equivalent to distamycin in vitro.

The activity of these anticancer agents may be enhanced by the addition of alkylating agents. When this was also investigated at the same time, the compound containing the alkylating agent showed higher antitumor activity than the compound containing no alkylating agent. From this, it was found that a compound having a phenylbenzimidazole skeleton becomes a highly active anticancer agent by adding an alkylating agent in the same molecule. From the above, we have completed the invention of a new anticancer agent. That is, the present invention

[1] A compound represented by the general formula (1) [Chemical Formula 3] or a pharmaceutically acceptable salt thereof.

[0009]

Embedded image [In the formula, m and n each independently represent an integer of 0 to 3, and R ₁ and R ₂ each independently represent a hydrogen atom, a halogen atom, an alkylthio group having 1 to 8 carbon atoms, or a substituent. Amino group, optionally substituted ammonium group, optionally substituted sulfonium group, optionally substituted phenyl group, optionally substituted hetero 5-membered ring group, optionally substituted hetero 6 It is a member ring group, an amidino group, a guanidino group, an amino acid residue or a group of the general formula (2) [Chemical formula 4].

[0010]

[Chemical 4]{In the formula, R_ThreeAre either directly bound or have an oxygen atom
Show (however R_ThreeWhen is an oxygen atom, R_ThreeJoins
(CH₂)_mOr (CH₂)_nM or n in
Not 0), R_FourIs a hydrogen atom, an alkyl having 1 to 8 carbon atoms
Group, alkoxy group having 1 to 8 carbon atoms, halogen atom,
Lifluoromethyl group, cyano group, amidino group, carboxy
Sil group or -COR₇(However, R₇Is the replaced
C1-C8 alkyl optionally substituted with a mino group
Substituted with an amino group, an optionally substituted phenyl group
Optionally substituted amino group, or optionally substituted
And R), and R₅Is a hydrogen atom, carbon
An alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms,
Indicates a halogen atom, R₆Is-(CH₂)_pN (R₈)
₂Or- (CH₂)_pNR₈R₉(However, p is 0
Indicates an integer of 5, R₈Is -CH₂CH₂Indicates W, R₉
Represents an alkyl group having 1 to 5 carbon atoms or a mesyl group, and W represents
Rogen atom, hydroxy group, mesyloxy group, tosylo
Xyl group or -OCOR₇(However, R₇Means the above
Is shown) is shown). } However, in the compound of the general formula (1)
Converting R₁(CH ₂)_mCONH group is a phenyl group
Any position can be substituted. ], And also

[2] The compound according to [1], wherein R ₁ is a halogen atom or a group represented by the general formula (2), or a pharmaceutically acceptable salt thereof, and [3] R ₂ is a halogen. An atom or a group represented by the formula (2), which is a compound according to [1] or a pharmaceutically acceptable salt thereof,
[4] R ₂ is an optionally substituted amino group,
A compound according to [2], which is a guanidino group or an amidino group, or a pharmaceutically acceptable salt thereof, and

[5] The compound according to [3], wherein R ₁ is an optionally substituted amino group, guanidino group or amidino group, or a pharmaceutically acceptable salt thereof,
[6] An anticancer agent comprising the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof as an active ingredient, and [7] [1] to [1] 5] An antibacterial agent comprising the compound according to any one of 5] or a pharmacologically acceptable salt thereof as an active ingredient, and [8] according to any one of [1] to [5]. An antiviral agent containing a compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below. The halogen atom of R ₁ and R ₂ means Cl, Br,
I is shown. The optionally substituted amino group refers to an amino group or a monoalkylamino group or a dialkylamino group substituted with a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methylamino group or an ethylamino group. , N-
Propylamino group, i-propylamino group, n-butylamino group, dimethylamino group, diethylamino group, dipropylamino group and diisopropylamino group are desirable.

The term "C1-8 alkylthio group" means a straight or branched alkylthio group having 1-8 carbon atoms, such as an alkyl methylthio group, ethylthio group, n-propylthio group, i-propylthio group, or n. -Butylthio group, i-butylthio group, t-butylthio group, n-pentylthio group,
An n-hexylthio group, an n-heptylthio group and an n-octylthio group are desirable.

An optionally substituted ammonium group and
Is a trimethylammonium group, triethylammonium
Group or an ammonium group represented by the general formula (3)
It However, by binding to the ammonium group shown in this section
Acid residues that can be used as pharmaceuticals.
Hydrogen chloride, hydrogen iodide, hydrogen bromide, and tetrafluoride.
Inorganic acid residues such as uric acid, perchloric acid and phosphoric acid, methanesulfur
Fonic acid, toluene sulfonic acid, camphor sulfonic acid,
Organic sulfonic acid residue such as 1,5-naphthalenedisulfonic acid
Groups and carboxylic acid residues such as lactic acid, maleic acid and malonic acid
Is mentioned. R ₁₁And R₁₂Is a straight chain having 1 to 8 carbon atoms or
A branched alkyl group such as a methyl group or ethyl
Group, n-propyl group, i-propyl group, n-butyl group,
i-butyl group, t-butyl group, n-pentyl group, n-hexyl group
A xyl group, an n-heptyl group, and an n-octyl group are desired.
Yes.

[0016]

Embedded image The optionally substituted sulfonium group has 1 to 1 carbon atoms.
A sulfonium group substituted with a linear or branched alkyl group of 3 (for example, a dimethylsulfonium group, a diethylsulfonium group, a methylethylsulfonium group, a methylpropylsulfonium group, a diisopropylsulfonium group, a methylisopropylsulfonium group) or a general formula ( 4) The sulfonium group of [Chemical Formula 6]. However, the acid residue bonded to the sulfonium group shown in this section may be any one that can be used as a drug, such as hydrogen chloride, hydrogen iodide, hydrogen bromide, tetrafluoroboric acid, and perchlorine. Inorganic acid residues such as acids and phosphoric acids, organic sulfonic acid residues such as methanesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, and 1,5-naphthalenedisulfonic acid, and carboxylic acid residues such as lactic acid, maleic acid and malonic acid Groups.
R ₁₁ is a linear or branched alkyl group having 1 to 8 carbon atoms, for example, methyl group, ethyl group, n-propyl group, i
-Propyl group, n-butyl group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group, n-heptyl group and n-octyl group are desirable.

[0017]

[Chemical 6] The phenyl group which may be substituted is a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), a straight chain or branched alkyl group having 1 to 5 carbon atoms, a straight chain having 1 to 3 carbon atoms or A branched alkoxy group, an alkoxycarbonyl group having 1 to 3 carbon atoms, a trifluoromethyl group, a cyano group,
Amidino group, guanidino group, phenyl group which may be substituted with dialkylamino group having 1 to 3 carbon atoms, for example, chlorophenyl group, dichlorophenyl group, trichlorophenyl group, bromophenyl group, dibromophenyl group, tribromophenyl group , Fluorophenyl group, difluorophenyl group, trifluorophenyl group, methylphenyl group, ethylphenyl group, n-propylphenyl group, i-propylphenyl group, n-butylphenyl group,
i-butylphenyl group, t-butylphenyl group, n-pentylphenyl group, methoxyphenyl group, ethoxyphenyl group, n-propyloxyphenyl group, i-propyloxyphenyl group, methoxycarbonylphenyl group, ethoxycarbonylphenyl group, n-propyloxycarbonylphenyl group, trifluoromethylphenyl group, cyanophenyl group, amidinophenyl group, guanidinophenyl group, dimethylaminophenyl group, diethylaminophenyl group, dipropylaminophenyl group, methoxyphenyl group, 3,4,5 -Trimethoxyphenyl group is preferred. If there is no indication about the substitution position of the above substituents,
In the case of mono-substitution, the 2,3- or 4-position is shown, in the case of di-substitution, two of 2,3,4,5,6 are shown, and in the case of tri-substitution, 2,3,4,5,6. 3 of these positions are shown.

The hetero 5-membered ring group of the optionally substituted hetero 5-membered ring group means a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a pyrazolyl group,
Thiazolyl group, isothiazolyl group, isoxazolyl group,
A pyrrolinyl group, an imidazolidinyl group, a pyrazolidinyl group, a pyrazolinyl group, a flazanyl group, a tetrahydrofuranyl group, a triazolyl group and a tetrazoyl group are preferable.

The hetero 6-membered ring group of the optionally substituted hetero 6-membered ring group means a pyridyl group, a pyrimidinyl group, a pyranyl group, a pyrazinyl group, a pyridazinyl group, a piperidyl group, a piperazinyl group, a thiomorpholino group, 4- Methyl-
1-piperazino group, 4-benzyl-1-piperazino group,
A 1-morpholino group, a 1-piperidino group, a 4-piperidino group and a 4-methyl-1-piperidino group are desirable.

However, in the optionally substituted hetero 5-membered ring group and the optionally substituted hetero 6-membered ring group, these substituents are halogen atoms (fluorine atom, chlorine atom). Atom, bromine atom, iodine atom),
A straight-chain or branched alkyl group having 1 to 3 carbon atoms, 1 carbon atom
Substituted with a linear or branched alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, a cyano group, an amidino group, or a dialkylamino group having 1 to 3 carbon atoms. Indicates that it is okay.

The amino acid residue defined herein is a portion of the amino acid excluding the carboxyl group, and arginine, histidine and lysine are preferable as the amino acid. R
The direct bond in ₃ means that the substituent of the general formula (2) is bonded without R ₃ . R ₄ , R ₅
The halogen atom of refers to F, Cl, Br, or I. The halogen atom of W is preferably Cl or Br. R ₄ ,
The alkyl group having 1 to 8 carbon atoms of R ₅ is a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, an n-pentyl group, n
-Hexyl group, n-heptyl group and n-octyl group are preferred.

The alkoxy group having 1 to 8 carbon atoms represented by R ₄ and R ₅ is a methoxy group, an ethoxy group, an n-propyloxy group,
An i-propyloxy group, an n-butoxy group, an i-butoxy group, a t-butoxy group, an n-pentyloxy group, an n-hexyloxy group, an n-heptyloxy group and an n-octyloxy group are preferable.

The alkylamino group which may be substituted with a substituted amino group of R ₇ is a dimethylaminoethyl group, a dimethylaminopropyl group, a dimethylaminobutyl group, a diethylaminoethyl group, a diethylaminopropyl group, a diethylaminobutyl group. , Dipropylaminoethyl group, dipropylaminopropyl group, dipropylaminobutyl group, diisopropylaminoethyl group, diisopropylaminopropyl group, diisopropylaminobutyl group are desirable. As the amino group which may be substituted with an optionally substituted phenyl group of R ₇ , aniline, 4-dimethylaminoaniline and 4-chloroaniline are preferable. The optionally substituted benzylamino group for R ₇ is preferably benzylamine or 4-dimethylaminobenzylamine. The R ₁ (CH ₂ ) _m CONH group substituted on the phenyl group in the compound of the general formula (1) may be substituted on any position of the phenyl group, but is preferably at the 3 or 4 position.

Any pharmacologically acceptable salt may be used so long as it can be used as a pharmaceutical product. For example, hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates and phosphoric acid of these salts can be used. Inorganic acid salts such as salts, or organic acid salts such as methanesulfonate, toluenesulfonate, camphorsulfonate, acetate, fumarate, maleate, citrate, oxalate, tartrate, etc. Can be mentioned.

The compounds represented by the general formula (1) will be described below by dividing them into the following A and B groups. First, the group A is a compound or a pharmaceutically acceptable salt thereof in which R ₁ is a hydrogen atom, a halogen atom or a group represented by the general formula (2) in the general formula (1). Next, the group B is a compound or a pharmaceutically acceptable salt thereof in which R ₂ is a hydrogen atom, a halogen atom or a group represented by the general formula (2) in the general formula (1).

The synthesis of these compounds will be described.
In the following description or examples, DCC is N, N'-
Dicyclohexylcarbodiimide, CDI is N, N'-
Carbonyldiimidazole, HOSu is N-hydroxysuccinimide, EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, DEC
P is diethyl cyanophosphonate, HOBt is 1-hydroxybenzotriazole, DMAP is 4-dimethylaminopyridine, DMF is dimethylformamide, and THF.
Represents tetrahydrofuran. DMSO represents dimethyl sulfoxide, and IPA represents isopropanol. Chlorambucil refers to 4- [4- [bis (2-chloroethyl) amino] phenyl] butyric acid. Pd / C represents activated carbon with palladium, and the content of palladium is usually 5 to 10%.

A method for synthesizing the compound represented by the general formula (5) which is a main intermediate will be described. An aldehyde of the general formula (6) represented by the following reaction formula (1) [Chemical formula 7] and 3,4-diaminobenzoic acid of the general formula (7) or an ester thereof are heated in nitrobenzene at 100 ° C to a reflux temperature, preferably Thirteen
By heating at 0 to 200 ° C. and returning to room temperature, the produced 1H-2-phenylbenzimidazole-5-carboxylic acid derivative represented by the general formula (5) or its ester derivative can be collected by filtration. When an ester is obtained here, 1H-2- shown in the general formula (8) is obtained by hydrolyzing this ester as shown in the reaction formula (2) [Chemical formula 8].
Phenylbenzimidazole-5-carboxylic acid derivative can be obtained. The amounts of the aldehyde of the general formula (6) and the 3,4-diaminobenzoic acid ester of the general formula (7) are not particularly limited, but the latter is usually 80 to 120 parts by mol relative to 100 parts by mol of the former.

The reaction in nitrobenzene may be carried out by observing the progress of the reaction and heating until the raw materials disappear, and any heating time gives good results for 5 to 100 hours. The heating time may be continuous or may be intermittent so that the total time is the above time. Further, hydrolysis of the ester may be carried out by using sodium hydroxide or potassium hydroxide and heating in a mixed solvent of water and ethanol or water and methanol. The ratio of water at this time is 5 to 90
%, But 40-60% by weight gives good results. The heating temperature is 50 ° C to the reflux temperature.

[0029]

[Chemical 7]

[0030]

Embedded image Specifically, if 3-nitrobenzaldehyde or 4-nitrobenzaldehyde is selected as a starting material, the same operation is performed to perform 1H-2- (3-nitrophenyl) benzimidazole-5-carboxylic acid, 1H-2 -(4-Nitrophenyl) benzimidazole-5-carboxylic acid can be synthesized.

Next, the synthesis of each group of compounds will be described. As shown in the reaction formula (3) [Chemical formula 9], the compound of the group A is generally prepared by reacting the amino compound represented by the general formula (9) containing the moiety defined by R ₂ with the general formula (8). Carboxylic acids and suitable condensing agents such as DCC, CDI, EDCI, D
ECP or the like is used for binding, and the general formula (1
The nitro group of the intermediate of 0) is reduced to the corresponding amino compound of the general formula (11) by catalytic hydrogenation, and the carboxylic acid compound represented by the general formula (12) containing a moiety defined by R ₁ is reacted. Compounds of formula (1) can be synthesized.

[0032]

[Chemical 9] As the amino compound represented by the general formula (9) containing the moiety defined by R ₂ , a commercially available reagent or a compound that can be synthesized by combining known reactions can be used. Examples are amino compounds substituted by using, for example, dimethylaminopropylamine, diethylaminopropylamine, dipropylaminopropylamine and the like. Alternatively, examples of the alkylthio group can be obtained by using methylthiopropylamine, ethylthiopropylamine, propylthiopropylamine, butylthiopropylamine and the like. An example of an ammonium group can be obtained by using aminopropyltrimethylammonium, aminopropyltriethylammonium and the like.

The optionally substituted phenyl group, the optionally substituted hetero 5-membered ring group, and the optionally substituted hetero 6-membered ring group are used in the reaction by using a derivative containing each amino group, A compound in which each of the optionally substituted phenyl group, the optionally substituted hetero 5-membered ring group, and the optionally substituted hetero 6-membered ring group is a substituent of R ₂ can be synthesized. These amino compounds are combined with a carboxylic acid of the general formula (8) and a suitable condensing agent such as DCC or C.
When coupling using DI, EDCI, DECP, etc., the solvent may be an ordinary solvent, but DMF or a mixed solvent containing DMF gives relatively good results. The reaction is -5
It is better to carry out at 30 ° C. It may be carried out while checking the progress of the reaction, but the reaction time is usually 1 to 50 hours.

The compound having an amidino group in R ₂ can be synthesized as follows. First, as shown in the reaction formula (4) [Chemical formula 10], the carboxylic acid of the general formula (8) and β-aminopropionitrile are bonded. At this time, DCC as a condensing agent,
Common ones such as CDI, EDCI and DECP can be used. A method such as adding HOBt or HOSu to DCC can also be used. It is desirable to carry out the reaction at 0 to 30 ° C. This is suspended in ethanol, hydrogen chloride gas is passed through,
The crystals formed are filtered off. The desired amidino compound is obtained by dissolving or suspending this in a solvent and then passing ammonia gas through. At this time, the solvent is preferably ethanol or a mixed solvent of ethanol and methanol. The ratio of ethanol in the mixed solvent can be freely selected from 10 to 100%.

[0035]

[Chemical 10] As a specific example of the compound of the general formula (8), 1H-2-
Reaction formula (3) using (3-nitrophenyl) benzimidazole-5-carboxylic acid as a precursor and 1H-2- (4-nitrophenyl) benzimidazole-5-carboxylic acid as a precursor.
The reactions (4) to (4) can be carried out.

Next, a method for synthesizing the side chain corresponding to R ₁ will be described. First, as a side chain corresponding to R ₁ , for example, a method for synthesizing a substituent represented by the general formula (2) will be shown. As the carboxylic acid derivative having a nitro group used here, a commercially available reagent or a compound that can be synthesized using a known reaction can be used. General formula (15) shown in reaction formula (5) [Chemical formula 11]
A carboxylic acid ester derivative having a nitro group of Pd /
The general formula (1) corresponding to catalytic hydrogenation using C as a catalyst
Reduction to the amino compound of 6). As the solvent at this time, methanol, ethanol, DMF or the like can be used alone or in combination of two or more. The reaction is preferably carried out at 0 to 30 ° C. The reaction time is 30 minutes to 2 hours. As shown in the following reaction formula, the amino compound of the general formula (16) produced here is reacted with ethylene oxide to obtain a compound of the general formula (17). The solvent at this time is water, T
A solvent such as HF, dichloromethane or benzene and acetic acid can be mixed and used at an arbitrary ratio. The reaction is -20 to
It is better to carry out at 120 ° C. A reaction time of 1 to 50 hours is suitable.

Further, the compound of the general formula (17) is thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, mesyl chloride (in DMF) or mesyl chloride and sodium chloride, mesyl chloride and lithium chloride, dichlorotriphenylphosphonate. By converting the OH group into a Cl group using an appropriate reagent such as orchid, the general formula (1
The compound of 8) can be obtained. Reaction is 0-100 ° C
Done in. The reaction time is 20 minutes to 5 hours. As the solvent, general solvents such as chloroform, benzene and toluene can be used. Also, DMF can be mixed with these solvents. In addition, thionyl chloride, oxalyl chloride and the like can be reacted without a solvent. General formula (1
The compound shown in 8) can be hydrolyzed with an acid to obtain the carboxylic acid derivative shown in the general formula (19).
For example, concentrated hydrochloric acid may be used for heating at 80 to the reflux temperature. The reaction time is preferably 30 minutes to 5 hours.

[0038]

[Chemical 11] Side chains other than those shown here can also be prepared by carrying out several steps of commercially available reagents or known reactions.

For example, the compound represented by the general formula (11) and the compound represented by the general formula (19) can be combined with each other using a suitable condensing agent such as DCC, CDI, EDCI and DECP. The solvent may be an ordinary solvent, but DMF or a mixed solvent containing DMF gives relatively good results.
The reaction is preferably carried out at -5 to 30 ° C. It may be carried out while checking the progress of the reaction, but the reaction time is usually 1 to 50 hours. Alternatively, the compound of the general formula (19) can be converted to a general solvent (for example, methylene chloride, chloroform, toluene, DM
F or the like can be used alone or in combination of two or more) to obtain an acid chloride using thionyl chloride, oxalyl chloride or the like, and to obtain the acid chloride as a compound represented by the general formula (11). Can be combined. Here the reaction is -5
It is better to carry out at -30 ° C. It may be carried out while checking the progress of the reaction, but the reaction time is usually 1 to 50 hours. As described above, the partial structure of R ₁ can be bonded.

Next, the synthesis of the group B compound will be described. First, the synthesis of the side chain corresponding to R ₂ will be described. First, as a side chain corresponding to R ₂ , for example, a method for synthesizing the substituent represented by the general formula (2) will be described. The introduction of the moiety corresponding to R ₆ into the substituent represented by the general formula (2) can be generally performed by the following two methods.

First, the first method will be described. A halogenated benzene derivative containing a nitro group represented by the general formula (20) and an appropriate substituent as shown in the reaction formula (6) [Chemical Formula 12] (in the general formula (20), F is shown as an example of a halogen atom) Then, N, N-bis (2-hydroxyethyl) amine is allowed to act on the compound to obtain the compound of the general formula (21). The solvent at this time is DMSO, and the reaction temperature is 20 to 150 ° C. The reaction time is preferably 30 minutes to 10 hours. As the halogenated benzene derivative containing an appropriate substituent, a commercially available reagent or a compound that can be synthesized by a known reaction can be used. For example, a halogenated benzene derivative containing an amidino group can be derived from a halogenated benzene derivative containing a cyano group by using a known reaction.

The intermediate of the general formula (21) is thionyl chloride,
Oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, mesyl chloride or mesyl chloride (in DMF) can be reacted with a suitable chlorinating agent such as sodium chloride to give the chloride of general formula (22). Reaction is 0 to 1
It is carried out at 50 ° C. and the reaction time is 5 minutes to 5 hours. As the solvent, general solvents such as chloroform, benzene and toluene can be used. Also, DMF can be mixed with these solvents. It is also possible to react without a solvent.

[0043]

[Chemical 12] Next, the second method will be described. Reaction formula (7)
[3] The nitro group of the general formula (23) and an appropriate substituent containing an aniline derivative (when p = 0) or an aminoalkylbenzene derivative (when p is 1 or more) is reacted with ethylene oxide to give a compound of the general formula (24). Obtain the compound. As the solvent at this time, a solvent such as water, THF, dichloromethane, benzene or the like and acetic acid can be mixed at an arbitrary ratio and used.

The reaction is preferably carried out at -20 to 120 ° C, and the reaction time is suitably 1 to 50 hours. As the aniline derivative or the aminoalkylbenzene derivative containing a nitro group and an appropriate substituent, a commercially available reagent or a compound which can be synthesized by a known reaction can be used. The compound of the general formula (24) is chlorinated with an appropriate chlorinating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, mesyl chloride (in DMF) or mesyl chloride and sodium chloride. The compound of (25) can be obtained. Reaction is 0
It is desirable to carry out at -150 ° C, and the reaction time is 5 minutes to 5 hours. As the solvent, general solvents such as chloroform, benzene and toluene can be used. Also, DMF can be mixed with these solvents. In addition, thionyl chloride, oxalyl chloride and the like can be reacted without a solvent.

[0045]

[Chemical 13] As shown in the reaction formula (8) [Chemical formula 14], the nitro compound of the general formula (22) obtained in the reaction formula (6) is converted into an amino compound of the general formula (26) by catalytic hydrogenation. In the case of the nitro compound of the general formula (25), it can be similarly converted into an amino compound. During catalytic hydrogenation, an amino compound can be stably obtained by adding hydrochloric acid in an equimolar amount or more, usually 1 to 1.2 times by mol, that of the nitro compound. Catalytic hydrogenation is 5-30 ℃
It is desirable to carry out the above, and the solvent used is a general solvent. For example, DMF or a mixed solvent of DMF and methanol is desirable. The DMF of this mixed solvent is 5
It can be selected in the range of up to 100%, but is preferably 2
It is 0 to 100%.

[0046]

Embedded image When synthesizing a corresponding amino compound from a nitrobenzene derivative, catalytic hydrogenation using Pd / C as a catalyst or reaction using tin chloride and hydrochloric acid is a general method.
However, a reduction method particularly in the case of the above-mentioned nitrobenzene derivative having an N, N-bis (2-chloroethyl) amino group bonded thereto is described in J. Chem. Soc. 194
1972, pages 1972-1983, or J. Med. Ch
em. As shown in 1990, vol. 33, pages 112-121, a method of reducing with tin chloride or hydrochloric acid has been generally known. However, this reduction reaction can be efficiently performed by the following method, and the treatment after the reaction can be performed more easily. That is, first, a nitro compound as a raw material is treated with an appropriate solvent such as ethanol, methanol,
Dissolved in ethyl acetate, THF, DMF alone or in a mixed solvent of two or more kinds, and added Pd / C to 0.5 to 0.5% of nitro compound.
A 50% weight equivalent is added and hydrogenated at room temperature and atmospheric pressure to obtain the corresponding amino compound. At this time, hydrochloric acid can be added in an equimolar number or more, usually 1 to 1.2 times by mole, of the nitro compound. The desired hydrochloride can be easily obtained by filtering off the catalyst, distilling off the solvent, and treating with a suitable solvent such as ethanol, IPA, or ether alone or in combination of two or more kinds.

Further, as shown in reaction formula (9) [Chem. Med. Chem. 1990 Volume 33 1430
In accordance with the method shown on page -3019, the general formula (27)
It is possible to synthesize the amino compound of the general formula (28) from the carboxylic acid of Using this method, an aminoalkylbenzene derivative having two or more methylene chains in the R ₃ portion can be synthesized.

[0048]

[Chemical 15] Here, the compound of the general formula (26) can be treated as a compound corresponding to the case where n = 0 in the general formula (28) and R ₆ is an N, N-bis (2-chloroethyl) amino group. Therefore, hereinafter, the reaction equation (17) will be treated in the same manner.

As shown in the reaction formula (10) [Chemical formula 16], the benzimidazole derivative of the general formula (8) and the general formula (2)
8) The amino compound of general condensing agent (CDI, DEC
P, DCC or DCC and HOBt etc.) can be used to synthesize the compound of the general formula (29).
DMF is preferred as the solvent, but other common solvents can be used. It may be confirmed that the reaction is completed while checking the reaction state by TLC or the like, but it is preferably carried out in 1 to 40 hours. The reaction temperature is preferably -5 ° C to 40 ° C.

[0050]

Embedded image As shown in the reaction formula (11) [Chemical formula 17], the general formula (2
The nitro group of the compound of 9) can be reduced to the corresponding amino group by catalytic hydrogenation using Pd / C as a catalyst.
The reaction proceeds almost quantitatively. At this time, the solvent is ethanol, methanol, or DMF alone or 2
A mixture of two or more species can be used. At this time, hydrochloric acid can be added in an equimolar number or more than that of the nitro compound, usually 1 to 1.2 times by mole. The reaction is preferably carried out at 0-40 ° C. The reaction is preferably carried out for 10 minutes to 20 hours.

[0051]

[Chemical 17] The binding of the aniline derivative in the above reaction formula (10) and the subsequent reduction reaction in the reaction formula (11) are new synthetic routes that have not been found in the literatures so far. For example, a binding reaction between a distamycin derivative and N, N-bis (2-chloroethyl) -1,4-phenylenediamine is found in JP-A-6-92933. Here, the distamycin moiety is first synthesized, Finally, N, N-bis (2-
The binding reaction of chloroethyl) -1,4-phenylenediamine is performed. This is a chemically highly reactive N, N-
That is, the binding of the bis (2-chloroethyl) amino group is the last. However, the present inventors have shown that contrary to this seemingly obvious reaction route, the target compound can be obtained in a high yield even if the aniline derivative moiety is introduced into the molecule first.

As shown in reaction formula (12) [Chemical formula 18],
The amino compound of the general formula (30) obtained by the above reduction reaction is reacted with the carboxylic acid derivative of the general formula (12), for example, DCC, C.
The R ₁ moiety can be introduced by condensation with a common condensing agent such as DI, EDCI or DECP. The solvent used in these reactions may be a common solvent, but DM
F or a mixed solvent containing it gives good results. The reaction is preferably performed at 0 ° C to 40 ° C. Reaction time is 30
Minutes to 40 hours is desirable.

[0053]

Embedded image Further, for example, as shown in reaction formula (13) [Chemical formula 19],
The compound represented by the general formula (32) was prepared according to J. Org. Che
m. 1960 Vol. 25, pp. 804-807, or by methylation with a general methylating agent (eg, methyl iodide, dimethylsulfate, methyl p-toluenesulfonate, etc.), the sulfonium derivative represented by the general formula (33). Can be obtained. As the solvent here, formic acid, acetic acid, acetone or the like is used. Alternatively, the reaction can be performed without a solvent. The reaction is preferably performed at 0 ° C to 60 ° C. The reaction time is preferably 1 to 60 hours.

[0054]

[Chemical 19] The counter anion (I ⁻ ) of the sulfonium compound obtained here can be changed to another anion by a known method. For example, DOWEX 1 × 8, Cl ⁻ type ion exchange resin can be used to exchange I ⁻ for Cl ⁻ .
Similarly, a compound having an amino group in R ₁ which is substituted with two alkyl groups can be further alkylated to obtain an ammonium compound.

Further, as shown in the reaction formula (14) [Chemical formula 20], the compound represented by the general formula (34) can be methylated with methyl iodide to obtain the compound represented by the general formula (35). it can. As the solvent at this time, a common solvent such as methanol, acetone, chloroform, methylene chloride or the like is used. The reaction is preferably performed at -5 ° C to 50 ° C.
The reaction time is preferably 1 to 50 hours.

[0056]

Embedded image As shown in the reaction formula (15) [Chemical Formula 21], the general formula (3
By reacting the amino compound of 0) with guanidine acetic acid, a compound of the general formula (36) in which guanidine is introduced into R ₁ can be synthesized.

[0057]

[Chemical 21] Further, a compound in which an amidino group is introduced into R ₁ can be synthesized as follows. First, the amino compound of the general formula (30) and 3
-A carboxylic acid derivative containing a cyano group such as cyanopropionic acid is bound with a general condensing agent such as DCC, CDI, EDCI or DECP. The solvent used in this reaction may be a common solvent, but DMF or a mixed solvent containing it gives good results. The reaction time is preferably 1 to 24 hours. The reaction is preferably performed at 0 ° C to 40 ° C. This is dissolved or suspended in ethanol and blown with hydrochloric acid gas to obtain an imidate body. A compound in which an amidino group is introduced into R ₁ can be synthesized by dissolving or suspending this in a solvent and then blowing in ammonia gas. As the solvent, ethanol, methanol, a mixed solvent thereof or the like is used. The reaction temperature is preferably 0 to 40 ° C. The reaction time is preferably 30 minutes to 24 hours. Other compounds can also be synthesized by changing the raw materials under the above conditions.

Next, the compound in which the moiety corresponding to the general formula (2) is bonded to the moieties R ₁ and R ₂ will be described. As shown in the reaction formula (16) [Chemical Formula 22], the compound represented by the general formula (37) is reduced to the corresponding amino compound of the general formula (38) by catalytic hydrogenation using Pd / C as a catalyst. As the solvent, ethanol, methanol, or DMF can be used alone or in combination of two or more. At this time, the number of moles is equal to or more than that of the nitro compound, usually 1 to
1.2 times the molar hydrochloric acid can be added. 10 reactions
It is desirable to perform the operation in minutes to 20 hours. After this, the reaction formula (1
7) The amino compound of the general formula (38) shown in [Chemical Formula 23] is reacted with the carboxylic acid derivative of the general formula (39).
The compound shown in 0) can be obtained. At this time, common condensing agents (eg, DCC, CDI, EDCI, DECP)
Etc.) can be used. The solvent used in the reaction may be a general one, but DMF or a mixed solvent containing it gives good results. The reaction is preferably performed at 0 ° C to 40 ° C. The reaction time is preferably 30 minutes to 40 hours.

[0059]

[Chemical formula 22]

[0060]

[Chemical formula 23] Examples of compounds included in the general formula (1) of the present invention are shown in Table-1.
It shows in Table-2 [Tables 1-34]. Although the counter anions of ammonium group and sulfonium group are not shown in this table, any counter anion may be used as long as it is pharmacologically recognized. When it is necessary to specify the counter anion, it will be specifically described in each case.

The compound numbers in this document are shown in Table-1.
The numbers of the compounds shown in [Tables 1 to 12] to [Table 2] [Tables 13 to 34] are shown.

[0062]

[Table 1] [Table-1]

[0063]

[Table 2] [Table-1] Continuation 1

[0064]

[Table 3] [Table-1] Continued 2

[0065]

[Table 4] [Table-1] Continued 3

[0066]

[Table 5] [Table-1] Continued 4

[0067]

[Table 6] [Table-1] Continued 5

[0068]

[Table 7] [Table-1] Continued 6

[0069]

[Table 8] [Table-1] Continued 7

[0070]

[Table 9] [Table-1] Continued 8

[0071]

[Table 10] [Table-1] Continued 9

[0072]

[Table 11] [Table-1] Continued 10

[0073]

[Table 12] [Table-1] Continued 11

[0074]

[Table 13] [Table-2]

[0075]

[Table 14] [Table-2] Continuation 1

[0076]

[Table 15] [Table-2] Continued 2

[0077]

[Table 16] [Table-2] Continued 3

[0078]

[Table 17] [Table-2] Continued 4

[0079]

[Table 18] [Table-2] Continued 5

[0080]

[Table 19] [Table-2] Continued 6

[0081]

[Table 20] [Table-2] Continued 7

[0082]

[Table 21] [Table-2] Continued 8

[0083]

[Table 22] [Table-2] Continued 9

[0084]

[Table 23] [Table-2] Continued 10

[0085]

[Table 24] [Table-2] Continued 11

[0086]

[Table 25] [Table-2] Continued 12

[0087]

[Table 26] [Table-2] Continued 13

[0088]

[Table 27] [Table-2] Continued 14

[0089]

[Table 28] [Table-2] Continued 15

[0090]

[Table 29] [Table-2] Continued 16

[0091]

[Table 30] [Table-2] Continued 17

[0092]

[Table 31] [Table-2] Continued 18

[0093]

[Table 32] [Table-2] Continued 19

[0094]

[Table 33] [Table-2] Continued 20

[0095]

[Table 34] [Table-2] Continued 21 The compound of the present invention can be used as an anticancer agent having excellent activity. The carcinoma used is leukemia, osteosarcoma, breast cancer, ovarian cancer, gastric cancer, colon cancer, lung cancer, head and neck cancer and the like. Alternatively, these compounds can also be used as antibacterial agents and antiviral agents.

Formulation can be carried out by a known method.
Various dosage forms can be selected according to the purpose of treatment, and typical examples thereof include solid preparations, liquid preparations, and other suppositories. More specifically, it is the following various preparations. As solid preparations, tablets, pills, powders, granules, capsules and the like, as liquid preparations, injections as solutions, suspensions, syrups, emulsions and the like, and as other preparations, suppositories, etc. Can be considered.

When molding into tablets, various carriers well known in the art can be widely used as carriers. Examples thereof include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid,
Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, shellac solution, methylcellulose solution, hydroxypropylcellulose solution, polyvinylpyrrolidone solution, carboxymethylcellulose solution and other binders, dry starch, sodium alginate, agar powder, Disintegrators such as sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose, disintegration inhibitors such as sucrose, stearic acid, cocoa butter and hydrogenated oil, 4th Absorption agents such as high-grade ammonium base, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, crystalline cellulose, light anhydrous Adsorbent such as Lee acid, talc, stearic acid salts, boric acid powder, and lubricating agents such as polyethylene glycol. Further, in the case of tablets, tablets which are coated with a usual coating, if necessary, can be prepared, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or bilayer tablets and multilayer tablets.

In the case of molding in the form of pills, carriers conventionally known in this field can be widely used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin, talc, etc., gum arabic powder, tragacanth powder, binders such as gelatin, disintegrants such as carmellose calcium, agar and the like. Can be mentioned. Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling hard gelatin capsules, soft capsules and the like.

When it is prepared as an injection, when it is formed into a solution, emulsion and suspension, it is a diluent generally used in this field, for example, water, ethanol, macrogol, propylene glycol, ethoxylated. Isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, cottonseed oil, corn oil, peanut oil, olive oil and the like can be used. Further, water is added to the compound of the present invention to prepare a suspension aqueous solution in the presence of a suitable surfactant, and further polyoxyethylene hydrogenated castor oil 60 (H
It is used as an emulsion containing a surfactant such as CO-60). In addition, salt, glucose, or glycerin may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added.

[0100] For shaping into a suppository, any conventionally known carrier can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides.
Furthermore, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, and other pharmaceuticals can be contained in the pharmaceutical preparation.

The administration method of these pharmaceutical preparations of the present invention is not particularly limited, and the pharmaceutical preparations may be administered according to various preparation forms, age, sex and other conditions of patients, and degree of disease. For example,
In the case of tablets, pills, solutions, suspensions, emulsions, powders, granules, syrups and capsules, they are orally administered.
In the case of an injection, it is intravenously administered alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and further, if necessary, is intramuscularly, subcutaneously or intraperitoneally administered alone.
Suppositories are administered rectally.

The dose of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, age of the patient, sex and other conditions, and degree of disease. Usually, the amount of the active ingredient compound is about 0.001 to 1,000 mg per day for an adult. It is good to say Further, the active ingredient compound is contained in the dosage unit form of about 0.001 to 1,000.
It is desirable to be contained in the range of mg.

Generally speaking, anticancer agents cannot be said to have small side effects even if they are commonly used agents such as adriamycin and cisplatin. At the current level of technology, side effects should be judged in consideration of their relationship with the effect intensity, and are inevitable problems to some extent. The side effects of the compound of the present invention are at a level that poses no problem when used as an anticancer agent.

[0104]

The present invention will be described below with reference to examples, but the present invention is not limited to these examples. The compound numbers shown in parentheses after the example numbers are shown in Table-1 to Table-
It corresponds to the compound number shown in 2. Example 1 (Compound 47) 1H-2- [3-[[4- [4- [N, N-bis (2-
Chloroethyl) amino] phenyl] butyryl] amino]
Phenyl] benzimidazole-5- [N- (2-ami
Dinoethyl)] carboxamide hydrochloride (reaction 1) 1H-2- (3-nitrophenyl) benzii
Midazole-5-carboxylic acid 3,4-diaminobenzoic acid 2.0 g (13.1 mmo
1, 1.0 eq) and m-nitrobenzaldehyde 2.0
g (13.2 mmol) was dissolved in 100 mL of nitrobenzene, and the mixture was heated with stirring in an oil bath at 155 ° C. for 21.5 hours. The resulting solid was collected by filtration and washed with IPA to give 1.88 g (6.64 mmol, 50.
3%) was obtained as yellow-green white crystals. mp:> 270 ° C. NMR (DMSO-d ₆ ) δ: 9.03 (s, 1H),
8.64 (d, 1H), 8.36 (d, 1H), 8.3
1-8.17 (m, 1H), 7.89 (t, 2H),
7.80-7.68 (m, 1H)

(Reaction 2) 1H-2- (3-nitrophenyl)
Le) benzimidazole-5- [N- (2-cyanoethyl
)] Carboxamide 1H-2- (3-nitrophenyl) benzimidazole-5-carboxylic acid 1.0 g (3.53 mmol) in DM
Suspended in 20 mL of F, 0.69 g of CDI (4.26 mm
ol, 1.2 eq) was added and the mixture was stirred at room temperature under a nitrogen atmosphere. After 3.5 hours, the mixture was ice-cooled, β-aminopropionitrile (0.27 mL, 3.65 mmol, 1.0 eq) was added, the mixture was returned to room temperature, stirred for 3 hours and left overnight. The mixture was concentrated under reduced pressure and the residue was crystallized from methanol to give the title compound (1.08 g, 3.19 mmol, 90.4%) as ocher crystals. mp:> 270 ° C. NMR (DMSO-d ₆ ) δ: 9.04 (s, 1H),
8.90 (m, 1H), 8.64 (d, 1H), 8.3
7 (d, 1H), 8.25-8.14 (m, 1H),
7.89 (t, 1H), 7.83-7.67 (m, 2
H), 3.54 (q, 2H), 2.82 (t, 2H)

(Reaction 3) 1H-2- (3-nitrophenyl)
Le) benzimidazole-5- [N- (2-amidinoe
Chill)] carboxamide hydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- (2-cyanoethyl)] carboxamide 1.08 g (3.22 mmol) in 40 mL of ethanol.
The mixture was suspended in water and blown with hydrochloric acid gas under ice cooling. After being saturated for 30 minutes, the mixture was returned to room temperature, stirred for 3 hours, and concentrated under reduced pressure.
The residue was decanted twice with ether and then ethanol 40
It was suspended in mL, and ammonia gas was blown into it while cooling with ice. 5
After saturating for 0 minutes, the mixture was stirred at room temperature for 3 hours and left overnight. After concentration under reduced pressure, the residue was sludged with methanol / acetone. The obtained solid is purified by silica gel column chromatography (ethyl acetate / IPA / water = 5
/ 2/1), methylene chloride, followed by 0.67 g (1.72 mm) of the title compound by sludging with IPA.
ol, 53.5%) as cream crystals. mp:> 270 ° C. NMR (DMSO-d ₆ ) δ: 9.10-9.06
(M, 3H), 8.88 (t, 0.5H), 8.79
(T, 0.5H), 8.71 (bs, 3H), 8.35
(D, 1H), 8.31 (s, 0.5H), 8.15
(S, 0.5H), 7.88 (t, 1H), 7.88
(D, 1H), 7.75 (d, 0.5H), 7.63
(D, 1H), 3.65 (q, 2H), 2.73 (t,
2H)

(Reaction 4) 1H-2- [3-[[4- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
Lu] butyryl] Amino] phenyl] benzimidazole
-5- [N- (2-amidinoethyl)] carboxamide
Hydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 0.33 g (0.83 mmol) was suspended in a mixed solvent of DMF and methanol to obtain 10%. Catalytic hydrogenation was performed using Pd / C as a catalyst to lead to the corresponding amino form. A DMF solution of this product was stirred under ice-cooling under a nitrogen stream to give 4- [4
0.55 g (4.6 mmol, 5.0 eq) of thionyl chloride was added to a methylene chloride solution of-[N, N-bis (2-chloroethyl) amino] phenyl] butyryl chloride {chlorambucil 0.28 g (0.92 mmol). 5,
After that, thionyl chloride was removed under reduced pressure, and the mixture was further prepared by azeotropic distillation with benzene twice}. Return to room temperature,
It was stirred for another 7 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / I
PA / water = 6/2/1) and 0.23 g (0.36 mmol, 43.
4%) as a pale yellowish white solid.

Mp: No clear melting point. NMR (DMSO-d ₆ ) δ: 10.31 (s, 1
H), 9.09 (s, 2H), 8.98 (t, 1H),
8.68 (s, 1H) 8.66 (s, 2H), 8.27
(S, 1H), 7.97 (d, 2H), 7.78 (d,
1H), 7.70 (d, 1H), 7.58 (t, 1
H), 7.07 (d, 2H), 6.68 (d, 2H),
3.65 (m, 2H), 2.72 (t, 2H), 2.5
5 (m, 2H), 2.40 (t, 2H), 1.89
(M, 2H) IR (KBr) cm ⁻¹ : 3064, 1690, 151
9, 1310, 1245, 810, 723 Elemental analysis: Calculated value (C ₃₁ H ₃₅ Cl ₂ N ₇ O ₂ .2HCl.
_{3H 2 O) C: 50.62,} H: 5.89, N: 13.
33, Cl: 19.28, analytical value C: 50.36, H:
5.61, N: 12.77, Cl: 19.76.

Example 2 (Compound 2) 1H-2- [4-[[4- [4- [N, N-bis (2-
Chloroethyl) amino] phenyl] butyryl] amino]
Phenyl] benzimidazole-5- [N- (2-ami
Dinoethyl)] carboxamide hydrochloride (reaction 1) 3.0 g of methyl 3,4-diaminobenzoate 3,4-diaminobenzoic acid was suspended in methanol, and 1.86 mL of thionyl chloride was added dropwise. Thionyl chloride was added twice with 0.5 mL each, and the mixture was heated under reflux for 11 hours. Thionyl chloride and methanol were distilled off under reduced pressure, the residue was dissolved in methylene chloride, washed with 0.5N aqueous sodium hydroxide solution and saturated brine, and dried over sodium sulfate.
After distilling off the solvent, the residue was sludged with n-hexane to obtain 3.04 g (93%) of the title compound. NMR (CDCl ₃ ) δ: 7.47 (dd, 1H),
7.41 (d, 1H), 6.67 (d, 1H), 3.8
5 (s, 3H)

(Reaction 2) 1H-2- (4-nitrophenyl)
B) Methyl benzimidazole-5-carboxylate Methyl 3,4-diaminobenzoate 1.0 g (6.0 mm
ol) and 0.91 g of p-nitrobenzaldehyde (6.
(0 mmol) was dissolved in nitrobenzene (60 mL) (remains slightly dissolved) and heated in an oil bath at 150 ° C. for 39 hours. The mixture was cooled with ice water, and the formed crystals were collected by filtration to give the title compound (1.54 g, 5.2 mmol, 86.5%) as brown crystals. mp:> 280 ° C NMR (DMSO-d ₆ ) δ: 8.44 (d, 2H),
8.31 (d, 2H), 8.16 (s, 1H), 7.9
-7.7 (m, 2H), 3.9 (s, 3H)

(Reaction 3) 1H-2- (4-nitrophenyl)
B) Benzimidazole-5-carboxylic acid 1H-2- (4-nitrophenyl) methyl benzimidazole-5-carboxylate (1.0 g, 3.4 mmol) was suspended in methanol (20 mL), and 1N aqueous sodium hydroxide solution (20 mL) was added. The mixture was heated and stirred at 60 ° C. for 1 hour. A portion corresponding to methanol was distilled off under reduced pressure. Water was added to the remaining reaction solution, acidified with 4N hydrochloric acid, and the resulting crystals were collected by filtration to give the title compound (0.94 g, 3.3 mmo).
1, 97.6%) was obtained as yellowish white crystals. mp:> 278 ° C NMR (DMSO-d ₆ ) δ: 8.47 (d, 2H),
8.43 (d, 2H), 8.25 (s, 1H), 7.9
(D, 1H), 7.7 (d, 1H)

(Reaction 4) 1H-2- (4-nitrophenyl)
Le) benzimidazole-5- [N- (2-cyanoethyl
)] Carboxamide 1H-2- (4-nitrophenyl) benzimidazole-5-carboxylic acid 0.48 g (1.69 mmol)
Dissolved in 42 mL of MF, 0.33 g of CDI (2.04 m
mol, 1.2 eq) was added and the mixture was stirred at room temperature under a nitrogen stream. After cooling for 3 hours with ice, β-aminopropionitrile 0.1
4 mL (1.9 mmol, 1.1 eq) was added, and the mixture was stirred at room temperature for 3 hours and left overnight. Concentrate under reduced pressure and sludge the residue with methanol to give the title compound 0.4
7 g (1.4 mmol, 82.9%) was obtained as yellow crystals. mp:> 270 ° C NMR (DMSO-d ₆ ) δ: 8.94-8.9 (m,
1H), 8.45 (s, 4H), 8.3 (s, 0.5
H), 8.1 (s, 0.5H), 7.85 (d, 0.5)
H), 7.65 (d, 0.5H), 3.54 (q, 2)
H), 2.82 (t, 2H)

(Reaction 5) 1H-2- (4-nitrophe
Nyl) benzimidazole-5- [N- (2-amidino
Ethyl)] carboxamide hydrochloride 1H-2- (4-nitrophenyl) benzimidazole-5- [N- (2-cyanoethyl)] carboxamide 0.47 g (1.4 mmol) was suspended in 10 mL of ethanol, and hydrochloric acid was added under ice cooling. After gas was blown into the mixture for 30 minutes to saturate it, the mixture was stirred at room temperature for 2 hours, and once dissolved, a solid was precipitated. The mixture was concentrated under reduced pressure, the residue was sludged with ether, and the filtered material was suspended in 15 mL of ethanol. When ammonia gas was blown into the mixture at room temperature for 2 hours to be saturated, it was once dissolved and then precipitated as a solid. It was left as it was overnight.
0.42 g (1.1 mm) of the title compound was obtained by adding methanol and acetone to the reaction solution and collecting the undissolved residue by filtration.
ol, 77.9%) as yellow crystals. mp:> 279 ° C NMR (DMSO-d ₆ ) δ: 9.5 (bs, 3H),
8.83 (m, 1H), 8.5 (d, 2H), 8.43
(S, 1H), 8.24 (s, 1H), 7.83 (d,
1H), 7.7 (d, 1H), 3.65 (m, 2H),
2.72 (t, 2H)

(Reaction 6) 1H-2- [4-[[4-
[4- [N, N-bis (2-chloroethyl) amino] fu
[Phenyl] butyryl] amino] phenyl] benzimidazo
-5- [N- (2-amidinoethyl)] carboxa
0.24 g (3.3 mmol) of thionyl chloride was added to 0.12 g (0.39 mmol) of amide hydrochloride chlorambucil,
The mixture was stirred at room temperature for 5 minutes. Thionyl chloride was distilled off under reduced pressure, and the residue was azeotropically removed twice with benzene, and methylene chloride was added. This solution was added to 1H-2- (4-aminophenyl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 0.54 mmol DM.
To the F solution (the nitro form of Reaction 5 was obtained by catalytic hydrogenation using 10% Pd / C as a catalyst) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours and then left overnight. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride / methanol / acetic acid = 80/20/1), and crystallized from ether to give the title compound. 71 mg (0.11 mmol, 20.4
%) As light brown crystals.

Mp: decomposed from 209 ° C. NMR (DMSO-d ₆ ) δ: 10.4 (s, 1H),
9.07 (s, 2H), 8.97 (m, 1H), 8.6
4 (s, 2H), 8.29 (d, 2H), 8.24
(S, 1H), 7.95 (d, 1H), 7.87 (d,
2H), 7.77 (d, 1H), 7.07 (d, 2)
H), 6.67 (d, 2H), 3.70 (s, 8H),
3.64 (m, 2H), 2.71 (m, 2H), 2.3
9 (m, 2H), 1.88 (m, 2H) IR (KBr) cm ⁻¹ : 3100, 1686, 151
9,1322,1258,1193,843,740 Elemental analysis: Calculated value (C ₃₁ H ₃₅ Cl ₂ N ₇ O ₂ .2HCl.
_{3H 2 O) C: 50.62,} H: 5.89, N: 13.
33, Cl: 19.28, analytical value C: 50.68, H:
5.48, N: 13.63, Cl: 18.88

Example 3 (Compound 90) 2- [3- (formylamino) phenyl] benzimidazole
Zol-5- [N- (2-amidinoethyl)] carboxy
Samide hydrochloride (reaction 1) 1H-2- (3-nitrophenyl) benzii
Midazole-5- [N- (2-amidinoethyl)] calc
Voxamide hydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- (2-cyanoethyl)] carboxamide 1.08 g (3.22 mmol) in ethanol 40 mL
Then, the mixture was suspended in water, and hydrochloric acid gas was blown into the mixture under ice cooling over 30 minutes until it was saturated. The mixture was returned to room temperature, stirred for 3 hours, and concentrated under reduced pressure. After decanting the residue twice with ether, 40m of ethanol
It was suspended in L, and ammonia gas was blown into it under ice cooling over 50 minutes until it was saturated. The mixture was returned to room temperature, stirred for 3 hours and left overnight. The mixture was concentrated under reduced pressure, the residue was sludged with methanol / acetone, and the resulting solid was purified by silica gel column chromatography (ethyl acetate / IPA / water = 5/2 /
1), and by further sludging with methylene chloride and IPA, 0.67 g (1.72 mmol,
53.5%) was obtained as cream colored crystals.

Mp:> 270 ° C. NMR (DMSO-d ₆ ) δ: 9.10-9.06
(M, 3H), 8.88 (t, 0.5H), 8.79
(T, 0.5H), 8.71 (bs, 3H), 8.35
(D, 1H), 8.31 (s, 0.5H), 8.15
(S, 0.5H), 7.88 (t, 1H), 7.88
(D, 1H), 7.75 (d, 0.5H), 7.63
(D, 1H), 3.65 (q, 2H), 2.73 (t,
2H)

(Reaction 2) 1H-2- [3- (formylurea
Mino) phenyl] benzimidazole-5- [N- (2
-Amidinoethyl)] carboxamide hydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 0.65 g (1.67 mmol) in DMF 8 mL
Suspended in a mixed solvent of 8 mL of methanol and 10 mL of 10% Pd /
Catalytic hydrogenation was carried out using 0.28 g of C as a catalyst. Concentrate under reduced pressure and formyl imidazole / THF solution [C] in 1/2 volume (DMF about 4 mL solution) under an ice-cold nitrogen atmosphere.
Formic acid 0.16 mL (4.2 mmol) was added to DI 0.67 g (4.1 mmol) / THF 12 mL, and the mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate /
IPA / H ₂ O = 6/2/1), further purified twice by preparative TLC (ethyl acetate / IPA / H ₂ O = 5/2/1), and solidified with IPA-ether to give 17 mg of the title compound. (0.044 mmol, 5.3%) was obtained as a yellow amorphous powder.

NMR (DMSO-d ₆ ) δ: 10.31
(S, 1H), 9.09 (s, 2H), 8.98 (t,
1H), 8.68 (s, 1H), 8.66 (s, 2)
H), 8.27 (s, 1H), 7.97 (d, 2H),
7.78 (d, 1H), 7.70 (d, 1H), 7.5
8 (t, 1H), 7.07 (d, 2H), 6.68
(D, 2H), 3.65 (m, 2H), 2.72 (t,
2H), 2.55 (m, 2H), 2.40 (t, 2)
H), 1.89 (m, 2H) IR (KBr) cm ^-1 : 3064, 1690, 151
9, 1310, 1245, 810, 723 Elemental analysis: Calculated value (C ₃₁ H ₃₅ Cl ₂ N ₇ O ₂ .2HCl.
_{3H 2 O) C: 50.62,} H: 5.89, N: 13.
33, Cl: 19.28: analytical value C: 50.36, H:
5.61, N: 12.77, Cl: 19.76.

Example 4 (Compound 45) 2- [4- (formylamino) phenyl] benzimidazole
Zol-5- [N- (2-amidinoethyl)] carboxy
Samide hydrochloride (reaction 1) 1H-2- (4-aminophenyl) benzii
Midazole-5- [N- (2-amidinoethyl)] calc
Voxamide hydrochloride 1H-2- (4-nitrophenyl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 0.42 g (1.08 mmol) in DMF 4 mL
Dissolved in a mixed solution of 4 mL of methanol and 10 mL of Pd /
Catalytic hydrogenation was performed using 0.18 g of C as a catalyst. The catalyst was removed, methanol was distilled off, and half the amount of the DMF remaining was taken and used for the next reaction.

(Reaction 2) 1H-2- [4- (formylurea
Mino) phenyl] benzimidazole-5- [N- (2
-Amidinoethyl )] carboxamide hydrochloride To a solution of 0.44 g (2.7 mmol) of CDI in 4 mL of THF was added 0.10 mL (2.65 mmol) of formic acid,
A solution prepared by stirring for 30 minutes at room temperature under a nitrogen stream was used for 1H.
-2- (4-aminophenyl) benzimidazole-5
-[N- (2-amidinoethyl)] carboxamide hydrochloride was added dropwise to a solution of 0.54 mmol of DMF with stirring under ice cooling under a nitrogen stream. It returned to room temperature and stirred for 6.5 hours. After concentration under reduced pressure, the residue was purified by reverse phase silica gel column chromatography (ODS, water / methanol = 5).
0%), and 36 mg (0.093 mmol, 17.2) of the title compound by crystallization from ethanol / ether.
%) As white crystals.

Mp: 220-229 ° C. NMR (DMSO-d ₆ , 80 ° C.) δ: 10.80
(S, 1H), 9.06 (bs, 2H), 8.80 (b
s, 3H), 8.40 (s, 1H), 8.17 (d, 1)
H), 8.12 (s, 1H), 7.93 (d, 2H),
7.72 (d, 1H), 6.83 (d, 2H), 3.4
5 (m, 2H), 2.44 (m, 2H) IR (KBr) cm ^-1 : 3422, 1648, 160
6,1499,1400,1195,840

Example 5 (Compound 44) 1H-2- [4- (formylamino) phenyl] benz
Imidazole-5- [N- [3- (dimethylamino) propyl
Ropil]] carboxamide (reaction 1) 1H-2- (4-nitrophenyl) benzii
Midazole-5- [N- [3- (dimethylamino) pro
Pill]] Carboxamide 1H-2- (4-nitrophenyl) benzimidazole-5-carboxylic acid 0.50 g (1.77 mmol) D
Dissolved in 50 mL of MF, 0.34 g of CDI (2.1 mm
ol, 1.2 eq) was added and the mixture was stirred at room temperature under a nitrogen atmosphere. After cooling for 4 hours with ice, 0.24 mL (1.9 mmol, 1.1e) of N, N-dimethyl-1,3-propanediamine.
q) was added, and the mixture was returned to room temperature and left overnight. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was sludged with methanol to give 0.52 g (1.42 mmol) of the title compound.
1, 80.2%) was obtained as yellowish white crystals. mp: 261-265 ° C NMR (DMSO-d ₆ ) δ: 8.57 (t, 1H),
8.45 (s, 4H), 8.17 (s, 1H), 7.8
0 (d, 1H), 7.71 (d, 1H), 3.33
(Q, 2H), 2.30 (t, 2H), 1.70 (m,
2H)

(Reaction 2) 1H-2- [4- (formylurea
Mino) phenyl] benzimidazole-5- [N- [3
-(Dimethylamino) propyl]] carboxamide 1H-2- (4-nitrophenyl) benzimidazole-5- [N- [3- (dimethylamino) propyl]] carboxamide 0.18 g (0.49 mmol) in DMF
Suspended in a mixed solution of 6 mL and 4 mL of methanol, 10%
Catalytic hydrogenation was carried out using Pd / C as a catalyst to lead to the corresponding amino form. This was dissolved in 8 mL of DMF, cooled with ice, and a formylimidazole / THF solution (C
DI 0.38 g (2.34 mmol), formic acid 88 μL /
(Prepared from 4 mL of THF) was added dropwise. Return to room temperature 7.
After stirring for 5 hours, the mixture was left overnight. After concentration under reduced pressure, the residue was subjected to alumina column chromatography (ICN Almina
0.19 g of the title compound was obtained by adding N and water and preparing it in Grade 3) and purifying it (chloroform / methanol = 8-10%) and crystallizing from ethanol / ether.
(0.30 mmol, 64.0%) was obtained as yellowish white crystals.

Mp: 126-132 ° C NMR (DMSO-d ₆ ) δ: 10.43 (s, 1)
H), 8.45 (bs, 1H), 8.35 (s, 0.5
H), 7.98 (s, 0.5H), 8.14 (d, 2)
H), 7.77 (d, 2H), 7.68 (bs, 1
H), 7.54 (d, 0.5H), 7.40 (d, 0.
5H), 3.32 (m, 2H), 2.29 (t, 2)
H), 2.16 (s, 3H) IR (KBr) cm ^-1 : 3379, 2949, 169
2,1608,1545,1290,844,737 Calcd _{(C 20 H 23 N 5 O} 2 · 0.5H 2 O)
C: 64.15, H: 6.46, N: 18.70, analytical value C: 64.25, H: 6.67, N: 18.50.

Example 6 (Compound 29) 1H-2- [4-[[4- [4- [N, N-bis (2-
Chloroethyl) amino] phenyl] butyryl] amino]
Phenyl] benzimidazole-5- [N- [3- (di
Methylamino) propyl]] carboxamide 1H-2- (4-nitrophenyl) benzimidazole-5- [N- [3- (dimethylamino) propyl]] carboxamide 0.15 g (0.41 mmol) in DMF
It was suspended in 6 mL and 4 mL of methanol, and catalytic hydrogenation was performed using 10% Pd / C as a catalyst to lead to the corresponding amino compound. This product was dissolved in 8 mL of DMF, and 0.12 g (0.39 mmol, 0.96 eq) of chlorambucil and H were added.
OBt 61 mg (0.45 mmol, 1.1 eq) was added, and DCC 96 mg (0.4
7 mmol, 1.1 eq) and then return to room temperature 7
After stirring for an hour, it was left overnight. Since the reaction was not completed, 0.12 g (0.39 mmol, 0.
95 eq) was reacted with 0.24 g of thionyl chloride at room temperature for 5 minutes, and thiobenzene was azeotropically distilled to remove thionyl chloride and dissolved in methylene chloride, and the mixture was stirred for 10 hours. After confirmation of completion of the reaction, the solid formed was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by alumina column chromatography (IC
N Almina N, methylene chloride / methanol = 2
%), The title compound was crystallized from ether.
0.13 g (0.21 mmol, 51.2%) was obtained as white crystals.

Mp: 200-210 ° C. (decomposition) NMR (DMSO-d ₆ ) δ: 10.14 (s, 1)
H), 8.54-8.50 (m, 1H), 8.15.
(S, 0.5H), 8.00 (S, 0.5H), 8.1
0 (d, 1H), 7.80 (d, 2H), 7.70-
7.51 (m, 2H), 7.12 (d, 2H), 6.7
1 (d, 2H), 3.70 (s, 8H), 3.34-
3.36 (m, 2H), 2.53 (m, 2H), 2.4
1-2.33 (m, 4H), 2.17 (s, 6H),
1.92 (m, 2H), 1.70 (m, 2H) IR (KBr) cm ⁻¹ : 2947, 1615, 151
9,1311,1252,846 Calcd _{(C 33 H 40 Cl 2 N} 6 O 2) C: 63.
56, H: 6.46, N: 13.48, analytical value C: 6
3.10, H: 6.53, N: 13.15

Example 7 (Compound 1001) 1H-2- [4- (guanidinoacetylamino ) phenyl
] Benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
Xamide dihydrochloride (reaction 1) 1H-2- (4-nitrophenyl) benzii
Midazole-5- [N- [4- [N, N-bis (2-q
Roloethyl) amino] phenyl]] carboxamide 1H-2- (4-nitrophenyl) benzimidazole-5-carboxylic acid 0.26 g (0.96 mmol),
0.27 g (0.95 mmol) of N, N-bis (2-chloroethyl) -1,4-phenylenediamine hydrochloride was added to D
Suspended in 8 mL of MF, and stirred under ice cooling under a nitrogen stream. Triethylamine 0.40 mL (2.87 mmol, 3.0e)
q), 0.22 mL DECP (1.45 mmol, 1.
5 eq) were sequentially added, and the mixture was stirred as it was for 3 hours and left overnight. The mixture was concentrated under reduced pressure, and the residue was sludged with methanol to give 0.33 g (0.66 mmo) of the title compound.
It was obtained as light brown crystals. mp:> 250 ° C NMR (DMSO-d ₆ ) δ: 10.11 (s, 0.5
H), 10.05 (s, 0.5H), 8.46 (s, 4)
H), 8.42 (s, 0.5H), 8.17 (s, 0.
5H), 7.95-7.84 (m, 1.5H), 7.6.
8 (d, 0.5H), 6.77 (d, 2H), 6.64
(D, 2H), 3.74 (s, 8H)

(Reaction 2) 1H-2- [4- (guanidinium
Noacetylamino) phenyl] benzimidazole-5
-[N- [4- [N, N-bis (2-chloroethyl) a]
Mino] phenyl]] carboxamide dihydrochloride 1H-2- (4-nitrophenyl) benzimidazole-5- [N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 50 mg
(0.10 mmol) was dissolved in a mixed solvent of DMF and methanol, 0.12 mL of 1N hydrochloric acid was added, and 10% Pd was added.
Catalytic hydrogenation using / C as a catalyst led to the corresponding amino form. A solution of this amino compound in DMF was stirred under a nitrogen stream under ice-cooling to give 20 μL of triethylamine (0.14 mm
ol, 1.4 eq), guanidine acetic acid hydrochloride 46 mg
(0.30 mmol, 3.0 eq), DCC 62 mg
(0.30 mmol, 3.0 eq) were added in that order, the mixture was returned to room temperature, stirred for 2 hours and then left overnight. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to gel filtration (Se
(Phadex LH-20, methanol), 4N hydrochloric acid / dioxane was added to the elution fraction, the mixture was concentrated and sludged with ethanol to give 10 mg of the title compound.
(0.016 mmol, 15.6%) was obtained as white crystals.

Mp: 215-227 ° C. (dec.) NMR (DMSO-d ₆ ) δ: 10.30 (s, 1)
H), 8.35 (d, 2H), 8.32 (s, 1H),
8.05 (d, 1H), 7.93 (d, 2H), 7.8
3 (d, 1H), 7.63 (d, 3H), 7.50-
7.20 (bs, 4H), 6.78 (d, 2H), 4.
16 (d, 2H), 3.74 (s, 8H) IR (KBr) cm ^-1 : 3332, 1652, 160
2,1516,1328,737

Example 8 (Compound 1010) 1H-2- [4- (guanidinoacetylamino ) phenyl
Le] benzimidazole-5- [N- [3- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
Xamide (reaction 1) m- [N, N-bis (2-hydroxyethyl)
) Amino] nitrobenzene m- aminonitrobenzene 5.0g (36.2mmo
l) was dissolved in 36 mL of 30% acetic acid, 22.9 mL of ethylene oxide was added under ice cooling, and the mixture was stirred overnight at room temperature. The mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The residue was slid with ether to give the title compound (5.21 g, 23.0 mmol, 63.6%) as yellow crystals. mp: 98.5-100 ° C NMR (DMSO-d ₆ ) δ: 7.51 (d, 1H),
7.51 (s, 1H), 7.32 (t, 1H), 6.9
9 (d, 1H), 3.89 (t, 4H), 3.73 (b
s, 2H), 3.65 (t, 4H)

(Reaction 2) 3- [N, N-bis (2-chloro)
(Roethyl) amino] nitrobenzene 3- [N, N-bis (2-hydroxyethyl) amino]
2.5 g (11.0 mmol) of nitrobenzene was suspended in 25 mL of toluene, and 10.2 g of thionyl chloride was cooled with ice.
(85.7 mmol, 7.8 eq) was added, and the mixture was heated with stirring in an oil bath at 70 ° C. for 5 hours. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was sludged with ether to give 2.67 g (1
0.1 mmol, 92.2%) was obtained as yellow crystals. mp: 112-113 ° C NMR (CDCl ₃ ) δ: 7.61 (d, 1H), 7.
50 (t, 1H), 7.39 (t, 1H), 6.98
(D, 1H), 3.83 (t, 4H), 3.68 (t,
4H)

(Reaction 3) N, N-bis (2-chloroethyl)
) -1,3-Phenylenediamine hydrochloride 3- [N, N-bis (2-chloroethyl) amino] nitrobenzene 2.0 g (7.6 mmol) was added to concentrated hydrochloric acid 35 m.
Dissolved in L, and tin (II) chloride dihydrate 6.9 g (3
0.6 mmol, 4.0 eq) was added, and the mixture was heated with stirring in an oil bath at 100 ° C. for 1 hour. The mixture was allowed to cool to room temperature, diluted with water, made basic with concentrated aqueous ammonia, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
4N Hydrochloric acid / dioxane was added to the residue and the mixture was concentrated, and the residue was crystallized from a small amount of methanol / ether to give 1.97 g (7.3 mmol, 96.1%) of the title compound as yellow crystals. mp: 195-201 ° C NMR (DMSO-d ₆ ) δ: 10.30-9.80
(Bs, 3H), 7.27 (t, 1H), 6.76
(D, 1H), 6.73 (s, 1H), 6.63 (d,
1H), 3.74 (s, 8H)

(Reaction 4) 1H-2- (4-nitrophenyl)
Le) Benzimidazole-5- [N-3- [N, N-bi
Su (2-chloroethyl) amino] phenyl] carboxa
Mido 1H-2- (4-nitrophenyl) benzimidazole-5-carboxylic acid 0.30 g (1.06 mmol),
N, N-bis (2-chloroethyl) -1,3-phenylenediamine hydrochloride 0.29 g (1.08 mmol, 1.
0 eq) was dissolved in 10 mL of DMF, and the mixture was stirred under ice cooling under a nitrogen stream. Triethylamine 0.44 mL (3.15 m
mol, 3.0 eq), DECP 0.24 mL (1.5
(8 mmol, 1.5 eq) were sequentially added, and the mixture was stirred as it was for 9 hours and then left overnight. After concentration under reduced pressure, the residue is purified by silica gel column chromatography (chloroform /
0.23 g (0.46 mmo) of the title compound was obtained by sludging with methanol = 2 to 4%) and ethanol.
1, 43.5%) was obtained as yellowish white crystals. mp: 213-217 ° C NMR (DMSO-d ₆ ) δ: 10.20 (s, 0.5
H), 10.11 (s, 0.5H), 8.47 (s, 4)
H), 8.43 (s, 1H), 8.16 (s, 0.5
H), 7.92 (d, 0.5H), 7.86 (s, 0.
5H), 7.71 (d, 0.5H), 7.31-7.1.
5 (m, 3H), 6.51 (d, 1H), 3.80-
3.74 (m, 8H)

(Reaction 5) 1H-2- [4- (guanidino
Acetylamino) phenyl] benzimidazole-5-
[N- [3- [N, N-bis (2-chloroethyl) ami]
No] phenyl]] carboxamide dihydrochloride 1H-2- (4-nitrophenyl) benzimidazole-5- [N- [3- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 50 mg
(0.10 mmol) in DMF-methanol, 10%
It was led to the corresponding amino compound by catalytic hydrogenation using Pd / C as a catalyst. A solution of this amino compound in DMF was stirred under a nitrogen stream under ice cooling to give 44 mg of guanidine acetic acid hydrochloride (0.
29 mmol, 2.9 eq), DCC 59 mg (0.2
9 mmol, 2.9 eq) are added in order and the temperature is returned to room temperature.
After stirring for an hour, the mixture was left overnight. The generated solid was filtered off, the filtrate was concentrated under reduced pressure, DMF was added to the residue, and the generated crystal was filtered off. The concentrated residue of the filtrate was subjected to gel filtration (Sephad
ex LH-20, methanol), 4N hydrochloric acid / dioxane was added to the eluate fraction, and the mixture was concentrated and crystallized from ether to give 31 mg (0.048 mm) of the title compound.
ol, 48.0%) was obtained as pale yellowish white crystals.

Mp: 200-210 ° C. NMR (DMSO-d ₆ ) δ: 10.27 (s, 1
H), 9.41 (s, 1H), 8.33 (d, 2H),
8.30 (s, 1H), 7.96 (d, 1H), 7.9
0 (d, 2H), 7.80 (d, 1H), 7.64
(T, 1H), 7.50-7.15 (m, 7H), 6.
51 (d, 1H), 4.16 (d, 2H), 3.76
(M, 8H) IR (KBr) cm ⁻¹ : 3339, 1654, 160
4,1542

Example 9 (Compound 2001) 1H-2- [3- (guanidinoacetylamino ) phenyl
] Benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
Xamide dihydrochloride (reaction 1) 1H-2- (3-nitrophenyl) benzii
Midazole-5- [N- [4- [N, N-bis (2-q
Roloethyl) amino] phenyl]] carboxamide 1H-2- (3-nitrophenyl) benzimidazole-5-carboxylic acid 0.30 g (1.06 mmol),
N, N-bis (2-chloroethyl) -1,4-phenylenediamine hydrochloride 0.29 g (1.08 mmol, 1.
0 eq) was dissolved in 12 mL of DMF, and the mixture was stirred under ice cooling under a nitrogen stream. Triethylamine 0.45 mL (3.23 mm
ol, 3.0 eq), DECP 0.24 mL (1.58
(mmol, 1.5 eq) were sequentially added, and the mixture was stirred as it was for 3 hours and then left overnight. The mixture was concentrated under reduced pressure, methanol was added to the residue, the mixture was left standing for 3 hours, and the resulting solid was collected by filtration to give the title compound (0.45 g, 0.90 mmol, 85.2).
%) As an ocher powder. mp: has no clear melting point. NMR (DMSO-d ₆ ) δ: 10.06 (bs, 1
H), 9.06 (s, 1H), 8.66 (d, 1H),
8.38 (d, 1H), 8.36 (s, 0.5H),
8.16 (s, 0.5H), 7.90 (t, 1H),
7.93-7.70 (m, 2H), 7.63 (d, 2)
H), 6.77 (d, 2H), 3.74 (s, 8H)

(Reaction 2) 1H-2- [3- (guanidino
Acetylamino) phenyl] benzimidazole-5-
[N- [4- [N, N-bis (2-chloroethyl) ami]
No] phenyl]] carboxamide dihydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 0.15 g
(0.30 mmol) 10% P in DMF-methanol
It was led to the corresponding amino compound by catalytic hydrogenation using d / C as a catalyst. A DMF solution of this product was stirred under ice-cooling under a nitrogen stream to give 0.14 g (0.91 m) of guanidine acetate hydrochloride.
mol, 3.0eq), DCC 0.19g (0.92m)
mol, 3.0 eq) were added in that order, and the mixture was returned to room temperature, stirred for 9 hours, and left overnight. The generated solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to gel filtration (Sephadex).
0.13 g (0.20 mmol, 0.20 mmol,
67.7%) was obtained as pale yellowish white crystals.

Mp:> 250 ° C. NMR (DMSO-d ₆ ) δ: 10.71 (s, 1)
H), 10.23 (s, 1H), 8.65 (s, 1
H), 8.31 (s, 1H), 8.01 (d, 2H),
7.82-7.77 (m, 2H), 7.64 (m, 4)
H), 7.60-7.20 (bs, 4H), 6.77.
(D, 2H), 4.16 (d, 2H), 3.74 (s,
8H) IR (KBr) cm ⁻¹ : 3310, 1652, 1517 Elemental analysis: Calculated value (C ₂₇ H ₂₈ Cl ₂ N ₈ O ₂ .2HCl.
H ₂ O) C: 49.25, H: 4.90, N: 17.0
2, Cl: 21.54, analytical value C: 49.30, H:
4.70, N: 16.91, Cl: 21.61

Example 10 (Compound 2004) 1H-2- [3- (guanidinoacetylamino ) phenyl
Lu] benzimidazole-5- [N- [3-methyl-4]
-[N, N-bis (2-chloroethyl) amino] phenyl
]] Carboxamide dihydrochloride (reaction 1) 1H-2- (3-nitrophenyl) benzii
Midazole-5- [N- [3-methyl-4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
Xamide 1H-2- (3-nitrophenyl) benzimidazole-5-carboxylic acid 3.1 g (11 mmol), 3-methyl-4- [N, N-bis (2-chloroethyl) amino]
Aniline hydrochloride 3.1 g (11 mmol, 1.0 eq)
Was dissolved in 30 mL of DMF, and the mixture was stirred under ice cooling under a nitrogen stream.
DECP 2.5 mL (16 mmol, 1.5 eq), triethylamine 4.6 mL (33 mmol, 3.0 e)
q) were sequentially added, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 3 hours, and then left overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetone. Silica gel was added to this and dried under reduced pressure,
Silica gel column chromatography (chloroform /
It was purified with methanol = 8/2). After the solvent was distilled off under reduced pressure, the residue was sludged with chloroform and a small amount of methanol. The resulting powder was collected by filtration and washed with methanol to obtain 4.2 g (yield 75%) of ocherous powder.

Mp: No clear melting point. NMR (DMSO-d ₆ ) δ: 10.22 (s, 0.5
H), 10.16 (s, 0.5H), 9.06 (s, 1
H), 8.66 (d, 1H), 8.42-8.36.
(M, 1.5H), 8.17 (s, 0.5H), 7.9
3-7.62 (m, 5H), 7.24 (d, 1H),
3.57 (t, 4H), 3.39 (t, 4H), 2.3
1 (s, 3H)

(Reaction 2) 1H-2- [3- (guanidino
Acetylamino) phenyl] benzimidazole-5-
[N- [3-methyl-4- [N, N-bis (2-chloro
Ethyl) amino] phenyl]] carboxamide dihydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-methyl-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.40 g (0.78 mmol) was led to the corresponding amino compound by catalytic hydrogenation using 10% Pd / C in 5 mL DMF-5 mL methanol as a catalyst. DM of this thing
The F solution was stirred under ice-cooling under a nitrogen stream, and guanidine acetic acid hydrochloride 281 mg (2.3 mmol, 3 eq) was added to DCC483.
mg (2.3 mmol, 3 eq) was sequentially added, and the mixture was stirred at 0 ° C. for 30 minutes, further stirred at room temperature for 6 hours, and then left overnight. The resulting precipitate was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 95/5). After the solvent was distilled off under reduced pressure, the residue was dissolved in methanol, and ether was added for reprecipitation to obtain 155 mg of white powder (yield 34%).

NMR (DMSO-d₆) Δ: 10.83
(S, 1H), 10.44 (s, 1H), 8.68
(S, 1H), 8.37 (s, 1H), 8.09 (d,
2H), 7.89 (d, 1H), 7.82 (d, 1)
H), 7.73-7.63 (m, 3H), 7.44 (b
s, 4H), 7.25 (d, 1H), 4.19 (d, 2)
H), 3.57 (t, 4H), 3.37 (t, 4H),
2.31 (s, 3H) IR (KBr) cm ^-1: 3348, 1665, 150
4,1308,1263,884

Example 11 (Compound 2006) 1H-2- [3- (guanidinoacetylamino ) phenyl
] Benzimidazole-5- [N- [3-chloro-4]
-[N, N-bis (2-chloroethyl) amino] phenyl
]] Carboxamide dihydrochloride (reaction 1) 1H-2- (3-nitrophenyl) benzii
Midazole-5- [N- [3-chloro-4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
D. Xamide 1H-2- (3-nitrophenyl) benzimidazole-5-carboxylic acid 0.60 g (2.12 mmol)
It was dissolved in MF (7 mL) and stirred under ice cooling under a nitrogen stream. 3-chloro-4- [N, N-bis (2-chloroethyl) amino] aniline hydrochloride 2.45 mmol {synthesized by catalytic hydrogenation from 0.73 g (2.45 mmol) of the corresponding nitro compound}, triethylamine 0.89 mL (6.38
mmol, 3.0 eq) in that order, DMF 5 mL was added, and DECP 0.48 mL (3.16 mmol, 1.
5 eq) was added, and the mixture was stirred as it was for 6 hours and then left overnight.
After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol = 4%),
Crystallized from ethyl acetate. As a result of confirmation by NMR, it was found that triethylamine hydrochloride was mixed in, and therefore the mixture was combined with the filtrate and subjected to gel filtration (Sephdex LH-20, methanol). By solidifying with ether, 0.48 g (0.90 mmol, 42.0%) of the title compound was obtained as an ocher solid.

Mp: has no definite melting point. NMR (DMSO-d ₆ ) δ: 10.39 (s, 1
H), 9.06 (s, 1H), 8.66 (d, 1H),
8.38 (d, 1H), 8.32 (s, 1H), 8.0
3 (d, 1H), 7.93-7.87 (m, 2H),
7.76 (d, 1H), 7.73 (dd, 1H), 7.
37 (d, 1H), 3.64-3.48 (m, 8H)

(Reaction 2) 1H-2- [3- (guanidino
Acetylamino) phenyl] benzimidazole-5-
[N- [3-chloro-4- [N, N-bis (2-chloro
Ethyl) amino] phenyl]] carboxamide dihydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-chloro-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.21 g (0.40 mmol) was led to the corresponding amino compound by catalytic hydrogenation using 10% Pd / C in DMF-methanol as a catalyst. A DMF solution of this was stirred under a nitrogen stream under ice cooling to give 0.18 g of guanidine acetate hydrochloride.
(1.17 mmol, 3.0 eq), DCC 0.24 g
(1.16 mmol, 3.0 eq) were added in that order, the mixture was returned to room temperature, stirred for 2 hours and then left overnight. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to gel filtration (Se
(Phadex LH-20, methanol), 4N hydrochloric acid / dioxane was added to the elution fraction, and the mixture was concentrated and solidified with ether to give the title compound (0.15 g, 0.22).
mmol, 55.7%) was obtained as a pale yellowish white powder.

Mp: No clear melting point. NMR (DMSO-d ₆ ) δ: 10.78 (s, 1
H), 10.63 (s, 1H), 8.67 (s, 1)
H), 8.37 (s, 1H), 8.04 (m, 2H),
7.88-7.63 (m, 5H), 7.60-7.25
(Bs, 4H), 7.37 (d, 1H), 4.18
(D, 2H), 3.62 (t, 4H), 3.51 (t,
4H) IR (KBr) cm ⁻¹ : 3313, 1673, 149
8,1385,1307,1252 Elemental analysis: Calculated value (C ₂₇ H ₂₇ Cl ₃ N ₈ O ₂ .2HCl.
_{5H 2 O) C: 42.40,} H: 5.14, N: 14.
65, analytical value C: 42.48, H: 4.73, N: 1
4.67

Example 12 (Compound 2011) 1H-2- [3-[[4- (guanidino) butyryl] a
Mino] phenyl] benzimidazole-5- [N- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
]] Carboxamide dihydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 0.20 g
(0.40 mmol) 10% P in DMF-methanol
It was led to the corresponding amino compound by catalytic hydrogenation using d / C as a catalyst. A DMF solution of this was stirred under a nitrogen stream under ice cooling to give 4-guanidinobutyric acid hydrochloride (0.22 g, 1.2 g).
1 mmol, 3.0 eq), DCC 0.25 g (1.2
1 mmol, 3.0 eq) are added in order, and the mixture is returned to room temperature 3
After stirring for an hour, the mixture was left overnight. The solid formed was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / IPA / water = 6/2 /
1), and further gel filtration (Sephadex LH-2
(0, methanol), and the elution fraction was concentrated by adding 4N hydrochloric acid / dioxane. The residue was solidified with ether to give the title compound (0.10 g, 0.15 mmo).
l, 37.5%) was obtained as a hygroscopic yellow powder.

Mp: No clear melting point NMR (DMSO-d ₆ ) δ: 10.59 (s, 1
H), 10.32 (s, 1H), 8.69 (s, 1
H), 8.36 (s, 1H), 8.10 (d, 1H),
8.05 (d, 1H), 7.95 (t, 1H), 7.8
7 (d, 1H), 7.79 (d, 1H), 7.65
(M, 3H), 7.50-7.00 (bs, 4H),
6.77 (d, 2H), 3.74 (s, 8H), 3.1
8 (q, 2H), 1.85 (m, 2H) IR (KBr) cm ⁻¹ : 3164, 1655, 151
7, 1330, 1247, 1182 Elemental analysis: Calculated value (C ₂₉ H ₃₂ Cl ₂ N ₈ O ₂ .2HCl.
3.3H ₂ O) C: 47.85, H: 5.62, N: 1
5.39, Cl: 19.48, analytical value C: 47.95,
H: 5.49, N: 15.10, Cl: 19.35.

Example 13 (Compound 2014) 1H-2- [3-[[4- (guanidino) butyryl] a
Mino] phenyl] benzimidazole-5- [N- [3
-Methyl-4- [N, N-bis (2-chloroethyl) a
Mino] phenyl]] carboxamide dihydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-methyl-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.40 g (0.78 mmol) was led to the corresponding amino compound by catalytic hydrogenation using 10% Pd / C (wet) in 5 mL of DMF-5 mL of methanol as a catalyst. A DMF solution of this product was stirred under ice-cooling under a nitrogen stream to give 4-guanidinobutyric acid hydrochloride (426 mg, 2.4 mmol, 3e).
q), EDCI 450 mg (2.4 mmol, 3 eq)
Were sequentially added, and the mixture was stirred at 0 ° C. for 30 minutes, further stirred at room temperature for 3 hours, and then left overnight. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate / IPA / water = 5/2/1). After distilling off the solvent under reduced pressure, the residue was dissolved in methanol and further subjected to gel filtration column chromatography (Sephadex LH-2).
(0, methanol). After distilling off the solvent under reduced pressure, by sludging with acetone-IPA,
113 mg (21% yield) of pale yellow powder was obtained.

NMR (DMSO-d ₆ ) δ: 10.58
(S, 1H), 10.44 (s, 1H), 8.69
(S, 1H), 8.36 (s, 1H), 8.11-7.
61 (m, 7H), 7.25 (bs, 4H), 7.25
(D, 1H), 4.03 (q, 1H), 3.57 (t,
4H), 3.37 (t, 4H), 3.26 (q, 2)
H), 2.50 (t, 2H), 2.31 (s, 3H),
1.84 (m, 2H) IR (KBr) cm ⁻¹ : 3357, 1664, 150
4,1308,1180,886

Example 14 (Compound 2016) 1H-2- [3-[[4- (guanidino) butyryl] a
Mino] phenyl] benzimidazole-5- [N- [3
-Chloro-4- [N, N-bis (2-chloroethyl) a
Mino] phenyl]] carboxamide dihydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-chloro-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.31 g (0.58 mmol) was led to the corresponding amino compound by catalytic hydrogenation using 10% Pd / C in DMF-methanol as a catalyst. A DMF solution of this product was stirred under a nitrogen stream under ice-cooling to give 4-guanidinobutyric acid hydrochloride 0.3.
2 g (1.76 mmol, 3.0 eq), DCC 0.3
6 g (1.74 mmol, 3.0 eq) was added in order, the mixture was returned to room temperature, stirred for 3 hours, and left overnight. The next day, the raw material had not disappeared, so 4-guanidinobutyric acid hydrochloride 0.1
1 g and DCC 0.12 g were added, and the mixture was further stirred for 2 hours. The solid formed was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / I
PA / water = 6/2/1) and gel filtration (Se
(Phadex LH-20, methanol). To the eluted fraction, 4N hydrochloric acid / dioxane was added and concentrated. 73 mg of the title compound was obtained by scraping off the residue.
(0.10 mmol, 17.9%) was obtained as a white solid.

Mp: No clear melting point. NMR (DMSO-d ₆ ) δ: 10.37 (s, 1
H), 10.29 (s, 1H), 8.59 (s, 1
H), 8.29 (bs, 1H), 8.03 (s, 1
H), 7.88-7.72 (m, 6H), 7.51.
(T, 1H), 7.36 (d, 1H), 7.40-6.
80 (bs, 4H), 3.62 (m, 4H), 3.50
(M, 4H), 3.19 (m, 2H), 2.46 (m,
2H), 1.84 (m, 2H) IR (KBr) c
m ⁻¹ : 3178, 1662, 1498, 1393, 13
04 Elemental analysis: Calculated value (C ₂₉ H ₃₁ Cl ₃ N ₈ O ₂ .2H
Cl.0.5H ₂ O) C: 48.93, H: 4.81,
N: 15.74, analytical value C: 48.65, H: 5.1
6, N: 15.65

Example 15 (Compound 2031) 1H-2- [3-[[4- (dimethylamino) butyryl]
Lu] amino] phenyl] benzimidazole-5- [N
-[4- [N, N-bis (2-chloroethyl) amino]]
Phenyl]] carboxamide hydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 0.20 g
(0.40 mmol) 10% P in DMF-methanol
It was led to the corresponding amino compound by catalytic hydrogenation using d / C as a catalyst. A DMF solution of this was stirred under a nitrogen stream under ice-cooling to give 4-dimethylaminobutyric acid hydrochloride (0.20 g).
(1.19 mmol, 3.0 eq), DCC 0.25 g
(1.21 mmol, 3.0 eq) were added in that order, the mixture was returned to room temperature, stirred for 4.5 hours, and left overnight. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / IPA / water = 5/2 /
1) and gel filtration (Sephadex LH
-20, methanol).

Since impurities were found to be mixed in, the mixture was again subjected to silica gel column chromatography (ethyl acetate / methanol = 1/1) and further subjected to gel filtration (Sephade).
xLH-20, methanol). 89 mg (0.14 mmo) of the title compound was obtained by solidifying with ether.
l, 34.0%) was obtained as a pale yellowish white solid.

Mp: has no definite melting point. NMR (DMSO-d ₆ ) δ: 10.25 (s, 1
H), 10.07 (s, 0.5H), 10.01 (s,
0.5H), 8.59 (s, 0.5H), 8.57
(S, 0.5H), 8.33 (s, 0.5H), 8.1
2 (s, 0.5H), 7.88-7.48 (m, 7
H), 6.77 (d, 2H), 3.74 (s, 8H),
2.75 (m, 2H), 2.54 (s, 6H), 2.4
5 (s, 6H), 1.90 (m, 2H) IR (KBr) cm ^-1 : 3214, 1614, 151
8,1328,1244,1182 Calcd _{(C 30 H 34 Cl 2 N} 6 O 2 · HCl · H 2
O) C: 56.65, H: 5.86, N: 13.21,
Analytical value C: 56.60, H: 5.78, N: 13.00

Example 16 (Compound 2091) 1H-2- [3-[[3- (methylthio) propioni]
Lu] amino] phenyl] benzimidazole-5- [N
-[4- [N, N-bis (2-chloroethyl) amino]]
Phenyl]] carboxamide 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 0.27 g
(0.54 mmol) DMF 5 mL-methanol 3 m
Catalytic hydrogenation led to the corresponding amino form using 10% Pd / C in L as a catalyst. A DMF solution of this product was stirred under a nitrogen stream under ice-cooling to give 3- (methylthio) propionic acid 70 μL (0.68 mmol, 1.25 eq), DCC.
0.13 g (0.63 mmol, 1.2 eq) was added in order, the temperature was returned to room temperature, the mixture was stirred for 2.5 hours and left overnight. Since the progress of the reaction had stopped the next day, 70 μL of 3- (methylthio) propionic acid (0.68 mmol), DCC0.
13 g (0.63 mmol) was added, and the mixture was stirred for 10 hours and left overnight.

The resulting solid was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 4%) and crystallized from ether to give the title compound (0.17 g, 0.30 mmo).
1, 55.2%) was obtained as pale yellowish white crystals.

Mp: 142-146 ° C. NMR (DMSO-d ₆ ) δ: 10.21 (s, 1)
H), 10.07 (s, 0.4H), 10.01 (s,
0.6H), 8.55 (m, 1H), 8.33 (s,
0.6H), 8.11 (s, 0.4H), 7.87-
7.59 (m, 6H), 7.51 (t, 1H), 6.7
7 (d, 2H), 3.74 (s, 8H), 2.82-
2.65 (m, 4H), 2.12 (s, 3H) IR (KBr) cm ^-1 : 3259, 1644, 151
8,1327,1248,1181,814 Calcd _{(C 28 H 29 Cl 2 N} 6 O 2 S · H 2 O)
C: 57.14, H: 5.31, N: 11.90, analytical value C: 57.09, H: 5.40, N: 11.67.

Example 17 (Compound 2041) 2- [N- [3- [5- [N- [4- [N, N-bis
(2-chloroethyl) amino] phenyl] carbamoy
]]-1H-Benzimidazol-2-yl] phenyl
]] Carbamoylethyl-dimethylsulfonium eye
Odaid 1H-2- [3-[[3- (methylthio) propionyl] amino] phenyl] benzimidazole-5- [N
-[4- [N, N-bis (2-chloroethyl) amino]]
Phenyl]] carboxamide 0.10 g (0.18 m
80% formic acid 0.5 mL, acetic acid 0.25 mL,
It was dissolved in 0.2 mL of methyl iodide, stirred at room temperature for 9 hours under light shielding, and left overnight. After concentration under reduced pressure, the residue was subjected to gel filtration (Sephadex LH-20, methanol, 2
(Runs twice) and solidified from ether to give 47 mg (0.07 mmol, 36.6%) of the title compound as a pale yellowish white powder.

Mp: has no definite melting point. NMR (DMSO-d ₆ ) δ: 10.49 (s, 1
H), 10.05 (s, 1H), 8.58 (s, 1
H), 8.24 (s, 1H), 7.87 (m, 2H),
7.70-7.47 (m, 5H), 6.77 (d, 2)
H), 3.74 (s, 8H), 3.57 (t, 2H),
3.04 (t, 2H), 2.97 (s, 6H) IR (KBr) cm ^-1 : 3407, 1645, 161
4,1517,1328,1249,1181 Elemental analysis: Calculated value (C ₂₉ H ₃₂ Cl ₂ IN ₅ O ₂ S.HC
l) C: 46.51, H: 4.44, N: 9.35, analytical value C: 46.20, H: 4.24, N: 9.08

Example 18 (Compound 2092) 1H-2- [3-[[3- (methylthio) propioni]
Lu] amino] phenyl] benzimidazole-5- [N
-[3-Methyl-4- [N, N-bis (2-chloroethyl)
L) amino] phenyl]] carboxamide 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-methyl-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.40 g (0.78 mmol) was led to the corresponding amino compound by catalytic hydrogenation using 10% Pd / C in 5 mL DMF-5 mL methanol as a catalyst. DM of this thing
The F solution was stirred under ice-cooling under a nitrogen stream, and 281 mg (2.3 mmol, 3 eq) of 3- (methylthio) propionic acid, D
CC483 mg (2.3 mmol, 3 eq) was sequentially added, and the mixture was stirred at 0 ° C. for 30 minutes, further stirred at room temperature for 6 hours, and then left overnight. The resulting precipitate was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 95/5). After the solvent was distilled off under reduced pressure, the residue was dissolved in methanol, ether was added to reprecipitate, and white powder 155 mg
(Yield 34%) was obtained.

NMR (DMSO-d ₆ ) δ: 10.21
(S, 1H), 10.16 (s, 1H), 8.57
(S, 1H), 8.24 (bs, 1H), 7.86
(D, 2H), 7.72-7.49 (m, 5H), 7.
24 (d, 1H), 3.57 (t, 4H), 3.36
(T, 4H), 2.80 (t, 2H), 2.68 (t,
2H), 2.37 (s, 3H), 2.12 (s, 3H)

Example 19 (Compound 2044) 2- [N- [3- [5- [N- [3-methyl-4-
[N, N-bis (2-chloroethyl) amino] phenyl
] Carbamoyl] -1H-benzimidazole-2-
Ill] phenyl]] carbamoylethyl-dimethylsul
Fonium iodide 1H-2- [3-[[3- (methylthio) propionyl] amino] phenyl] benzimidazol-5- [N
-[3-Methyl-4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 0.10 g
(0.17 mmol) was dissolved in 80% formic acid (0.6 mL), acetic acid (0.3 mL) and methyl iodide (0.5 mL), and the mixture was stirred at room temperature for 3 hours in the dark, and allowed to stand overnight. After concentration under reduced pressure, the residue is subjected to gel filtration column chromatography (Sephade).
x LH-20, methanol, run twice). After distilling off the solvent under reduced pressure, the residue was dissolved in methanol and IPA was added for reprecipitation to obtain 58 mg of a pale yellow powder.
(Yield 47%) was obtained.

NMR (DMSO-d ₆ ) δ: 10.56
(S, 1H), 10.20 (s, 1H), 8.59
(S, 1H), 8.27 (s, 1H), 7.91 (d,
2H), 7.78-7.55 (m, 5H), 7.24
(D, 1H), 3.57 (t, 4H), 3.37 (t,
4H), 3.21 (t, 2H), 3.05 (t, 2)
H), 2.97 (s, 6H), 2.31 (s, 3H) IR (KBr) cm ^-1 : 3422, 1654, 150
2,1313,1118,885

Example 20 (Compound 2093) 1H-2- [3- [3- (methylthio) propionyla]
Mino] phenyl] benzimidazole-5- [N- [3
-Chloro-4- [N, N-bis (2-chloroethyl) a
Mino] phenyl]] carboxamide 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-chloro-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.21 g (0.40 mmol) was led to the corresponding amino compound by catalytic hydrogenation using 10% Pd / C in DMF-methanol as a catalyst. A DMF solution of this product was stirred under ice-cooling under a nitrogen stream to give 3-methylthiopropionic acid (0.1%).
12 mL (1.16 mmol, 2.9 eq), DCC
0.24 g (1.16 mmol, 2.9 eq) was sequentially added, the mixture was returned to room temperature, stirred for 2 hours, and then left overnight. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform / methanol = 4%), and solidified from ether to give the title compound 0.18 g (0.30 mmol, 75%). .3%) as a pale yellowish white powder. mp: has no clear melting point. NMR (DMSO-d ₆ ) δ: 10.36 (s, 1
H), 10.23 (s, 1H), 8.58 (s, 1
H), 8.25 (s, 1H), 8.02 (d, 1H),
7.85 (d, 2H), 7.75-7.69 (m, 3
H), 7.52 (t, 1H), 7.37 (d, 1H),
3.62 (t, 4H), 3.50 (t, 4H), 2.8
0 (t, 2H), 2.68 (t, 2H)

Example 21 (Compound 2046) 2- [N- [3- [5- [N- [3-chloro-4-
[N, N-bis (2-chloroethyl) amino] phenyl
] Carbamoyl] -1H-benzimidazole-2-
Ill] phenyl] carbamoylethyl] dimethylsulfone
Nium iodide 1H-2- [3- (3-methylthiopropionylamino) phenyl] benzimidazole-5- [N- [3-
Chloro-4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 0.10 g (0.1
7 mmol) 85% formic acid 0.5 mL, acetic acid 0.25 m
It was dissolved in L, 0.2 mL of methyl iodide was added, and the mixture was stirred for 3 days at room temperature under shading. After concentrating under reduced pressure, the residue was subjected to gel filtration (Sephadex LH-20, methanol) and solidified from ether to give 0.10 g of the title compound.
(0.13 mmol, 81.2%) was obtained as a pale yellowish white powder.

Mp: No clear melting point NMR (DMSO-d ₆ ) δ: 10.48 (s, 1
H), 10.35 (s, 1H), 8.58 (s, 1
H), 8.25 (s, 1H), 8.02 (s, 1H),
7.86 (m, 2H), 7.71 (m, 3H), 7.5
5 (t, 1H), 7.36 (d, 1H), 3.64-
3.48 (m, 8H), 3.03 (t, 2H), 2.9
7 (s, 6H) IR (KBr) cm ^-1 : 3248, 1655, 157
7, 1497, 1389, 1307 Elemental analysis: Calculated value (C ₂₉ H ₃₁ Cl ₃ IN ₅ O ₃ S.2.
5H ₂ O) C: 43.98, H: 4.58, N: 8.8
4, analytical value C: 44.00, H: 4.26, N: 8.6
Two

Example 22 (Compound 2051) 1H-2- [3-[(3-morpholinopropionyl) a]
Mino] phenyl] benzimidazole-5- [N- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
]] Carboxamide hydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 0.51 g
(1.02 mmol) in 10% P in DMF-methanol
It was led to the corresponding amino compound by catalytic hydrogenation using d / C as a catalyst. A DMF solution of this was stirred under a nitrogen stream under ice cooling to give 0.21 mL (1.51 mm) of triethylamine.
ol, 1.5 eq), 1.53 mmol of 3-morpholinopropionyl chloride in chloroform {in chloroform, 0.30 g of 3-morpholinopropionic acid (1.
(53 mmol) and thionyl chloride (1 mL) were added in that order, the mixture was returned to room temperature, stirred for 3 hours, and then left overnight. Since the raw material had not disappeared the next day, a chloroform solution of 3-morpholinopropionyl chloride 1.53 mmol was added. After stirring for 9 hours, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol = 8-12%). The eluted fraction was concentrated, methanol was added, and the resulting solid was collected by filtration to give the title compound (0.18 g, 0.28 mmol, 27.3).
%) As a pale yellowish white powder. Further, the filtrate was subjected to gel filtration (Sephadex LH-20, methanol), and solidified from ether to give the title compound 0.1.
1 g (0.17 mmol, 16.7%) was obtained as a white powder. (44.0% in total)

Mp: No clear melting point NMR (DMSO-d ₆ ) δ: 10.30 (s, 1
H), 10.08 (s, 0.4H), 10.01 (s,
0.6H), 8.57 (s, 0.4H), 8.54
(S, 0.6H), 8.33 (s, 0.6H), 8.1
2 (s, 0.4H), 7.88-7.47 (m, 7
H), 6.77 (d, 2H), 3.74 (s, 8H),
3.60 (m, 4H), 2.67 (m, 2H), 2.5
5-2.44 (m, 6H) IR (KBr) cm ⁻¹ : 3120, 1622, 159
1,1519,1341,1183,1115 Calcd _{(C 31 H 34 Cl 2 N} 6 O 3 · HCl · 4
H ₂ O) C: 51.85, H: 6.04, N: 11.7
0, analytical value C: 51.81, H: 6.22, N: 12.
12

Example 23 (Compound 2053) 1H-2- [3-[(3-morpholinopropionyl) a]
Mino] phenyl] benzimidazole-5- [N- [4
-[N, N-bis (2-chloroethyl)] amino-3-
Methyl] phenyl] carboxamide hydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [4- [N, N-bis (2-chloroethyl)] amino-3-methyl] phenyl] carboxamide 0 .50 g (1.00 mmol) was dissolved in 10 mL of DMF and 10 mL of methanol, and 10% Pd was added under a nitrogen atmosphere.
Using / C as a catalyst, it was led to the corresponding amino compound by catalytic hydrogenation. A DMF solution of this product was stirred under a nitrogen stream under ice cooling to give 0.59 g of morpholinoethylcarboxylic acid hydrochloride.
(3.0 mmol), DCC 0.62 g (3.00 mm
ol) was added in that order and the mixture was returned to room temperature and left overnight. After the reaction, the reaction solution was concentrated under reduced pressure, and the brown syrupy residue was purified by silica gel column chromatography (chloroform / methanol = 20/1 to 10/1). The fluorescent fraction was collected, concentrated, and sludged with ether / chloroform to give 0.25 g (0.38 mm) of the title compound.
ol, 38.0%) was obtained as a white powder.

Mp: No clear melting point NMR (DMSO-d ₆ ) δ: 10.25 (s, 1
H), 10.18 (s, 0.5H), 10.13 (s,
0.5H), 8.55 (d, 1H), 8.34 (s,
0.5H), 8.12 (s, 0.5H), 7.88-
7.48 (m, 7H), 7.24 (d, 1H), 3.6
1-3.50 (m, 8H), 3.64 (t, 4H),
2.67 (t, 2H), 2.54 (t, 2H), 2.4
3 (bs, 4H), 2.31 (s, 3H) IR (KBr) cm ^-1 : 3258, 2963, 164
8,1502,1446,1314,1115

Example 24 (Compound 2054) 1H-2- [3-[(3-morpholinopropionyl) a]
Mino] phenyl] benzimidazole-5- [N- [3
-Chloro-4- [N-bis (2-chloroethyl) ami
No] phenyl]] carboxamide hydrochloride 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-chloro-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.30 g (0.56 mmol) was introduced into the corresponding amino compound by catalytic hydrogenation using 10% Pd / C as a catalyst in DMF-methanol. A DMF solution of this product was mixed with triethylamine 0.16 while stirring in a nitrogen stream under ice cooling.
mL (1.15 mmol, 2.0 eq), chloroform solution of 3-morpholinopropionyl chloride 1.13 mmol {in chloroform, 0.22 g (1.13 mmol) of 3-morpholinopropionic acid, 1 m of thionyl chloride.
Preparation from L} was added in that order, and the mixture was returned to room temperature and stirred. After 3 hours, 0.16 mL of triethylamine (1.15 mmo
l), 3-morpholinopropionyl chloride 1.13
A mmol chloroform solution was added and left overnight.
After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform / methanol = 12%).
The elution fraction was further subjected to gel filtration (Sephadex).
0.13 g (0.18 mm) of the title compound by subjecting to LH-20, methanol), adding 4N hydrochloric acid / dioxane and concentrating and solidifying with a small amount of ethanol-ether.
ol, 32.4%) was obtained as a pale yellowish white amorphous powder.

Mp: has no definite melting point. NMR (DMSO-d ₆ ) δ: 10.80 (s, 1
H), 10.61 (s, 1H), 8.62 (s, 1
H), 8.37 (s, 1H), 8.04 (m, 3H),
7.87-7.73 (m, 3H), 7.64 (t, 1
H), 7.37 (d, 1H), 3.87-3.79.
(M, 4H), 3.62 (t, 4H), 3.51 (t,
4H), 3.44 (m, 4H), 3.06 (m, 4H) IR (KBr) cm ^-1 : 3214, 1671, 157
6,1497, 1394, 1307, 1128, 108
7 Elemental analysis: Calculated value (C ₃₁ H ₃₃ Cl ₃ N ₆ O ₃ · HCl ·
6.5H ₂ O) C: 46.69, H: 5.94, N: 1
0.54, analytical value C: 46.53, H: 5.95, N:
10.45

Example 25 (Compound 2061) 1H-2- [3- (3-pyridylacetylamino) phen
Nyl] benzimidazole-5- [N- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl]] calc
Voxamide 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 0.40 g
(0.80 mmol) in DMF-methanol 10%
It was led to the corresponding amino compound by catalytic hydrogenation using Pd / C as a catalyst. DMF solution of this under nitrogen stream,
The mixture was stirred under ice-cooling, and 0.21 g of 3-pyridylacetic acid hydrochloride (1.
21 mmol, 1.5 eq), EDCI 0.23 g
(1.20 mmol, 1.5 eq) were sequentially added, and the mixture was returned to room temperature and stirred for 2.5 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform / methanol = 8%) and solidified with ether. Since it contained some impurities, insoluble matter was precipitated by performing a liquid separation operation with chloroform and dilute aqueous ammonia. The insoluble material was collected by filtration to give 49 mg (0.08) of the title compound.
3 mmol, 10.4%) was obtained as a light brown solid. The chloroform layer was concentrated and solidified with ether to give 65 mg (0.10 mmo) of the hydrochloride of the title compound.
1, 12.5%) as a light brown powder.

Mp: No clear melting point Free form: NMR (DMSO-d ₆ ) δ: 10.47
(S, 1H), 10.00 (s, 0.5H), 8.57
(S, 1H), 8.55 (d, 1H), 8.48 (d,
1H), 8.32 (s, 0.5H), 8.10 (s,
0.5H), 7.87-7.49 (m, 8H), 7.3
8 (t, 1H), 6.77 (d, 2H), 3.77
(S, 2H), 3.73 ( s, 8H) _{hydrochloride: NMR (DMSO-d 6)} δ: 10.52
(S, 1H), 10.03 (s, 1H), 8.62
(S, 1H), 8.54 (m, 2H), 8.22 (s,
1H), 7.91-7.84 (m, 3H), 7.72-
7.62 (m, 4H), 7.55-7.45 (m, 2
H), 6.77 (d, 2H), 3.81 (s, 2H),
3.73 (s, 8H) IR (KBr) cm ^-1 : 3070, 1617, 151
8,1328,1184,1141 Elemental analysis (free form): Calculated value (C ₃₁ H ₂₈ Cl ₂ N ₆ O _{2
· 2.5H 2 O) C: 58.86} , H: 5.26, N:
13.29, analytical value C: 58.86, H: 5.44,
N: 13.28

Example 26 (Compound 2063) 1H-2- [3- (3-pyridylacetylamino) phen
Nyl] benzimidazole-5- [N- [3-methyl-
4- [N, N-bis (2-chloroethyl) amino] phen
Nyl]] carboxamide 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-methyl-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.40 g (0.80 mmol) was introduced into the corresponding amino compound by catalytic hydrogenation using 10% Pd / C as a catalyst in 10 mL of DMF-methanol 1: 1 mixed solvent. A DMF solution of this product was stirred under a nitrogen stream under ice cooling to give 0.4 g (2.3 mmol, 3e) of 3-pyridylacetic acid hydrochloride.
q), EDCI 0.45 g (2.4 mmol, 3 eq)
Were sequentially added, and the mixture was stirred as it was for 30 minutes. 3 at room temperature
After stirring for an hour, it was left overnight. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol = 95/5). After distilling off the solvent, the residue was dissolved in methanol, and isopropyl ether was added for reprecipitation to obtain 153 mg of white powder.
(Yield 33%) was obtained. NMR (DMSO-d ₆ ) δ: 10.48 (s, 1
H), 10.18 (bs, 0.5H), 10.13 (b
s, 0.5H), 8.61-7.36 (m, 13H),
7.23 (d, 1H), 3.77 (s, 2H), 3.5
9 (t, 4H), 3.36 (t, 4H), 2.31
(S, 3H) IR (KBr) cm ^-1 : 3348,1665,150
4,1308,1263,884

Example 27 (Compound 2064) 1H-2- [3- (3-pyridylacetylamino) phene
Nyl] benzimidazole-5- [N- [3-chloro-
4- [N, N-bis (2-chloroethyl) amino] phen
Nyl]] carboxamide 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-chloro-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.40 g (0.75 mmol) was led to the corresponding amino compound by catalytic hydrogenation using 10% Pd / C as a catalyst in DMF-methanol. A DMF solution of this product was stirred under a nitrogen stream under ice-cooling to give 3-pyridylacetic acid 0.21.
g (1.21 mmol, 1.6 eq), EDCI 0.2
2 g (1.15 mmol, 1.5 eq) was sequentially added, and the mixture was returned to room temperature and stirred for 3.5 hours. The mixture was concentrated under reduced pressure, and the residue was subjected to a liquid separation operation with chloroform and water to precipitate a gel-like insoluble material. The aqueous layer is p with an aqueous solution of sodium hydroxide
It was adjusted to about H11 and extracted twice with chloroform. The chloroform layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified with ether to give the title compound (96 mg, 0.15 mmol, 20.6%) as a light brown powder.

Mp: No clear melting point NMR (DMSO-d ₆ ) δ: 10.47 (s, 1
H), 10.37 (s, 0.4H), 10.31 (s,
0.6H), 8.57 (s, 1H), 8.48 (d, 1)
H), 8.34 (s, 0.6H), 8.11 (s, 0.
4H), 8.02 (s, 1H), 7.87-7.61.
(M, 7H), 7.52 (t, 1H), 7.40-7.
35 (m, 2H), 3.77 (s, 2H), 3.61
(T, 4H), 3.50 (t, 4H) IR (KBr) cm ⁻¹ : 3191, 1631, 158
2,1498,1390,1309

Example 28 (Compound 2073) 1H-2- [3- (4-pyridylacetylamino) phen
Nyl] benzimidazole-5- [N- [3-methyl-
4- [N, N-bis (2-chloroethyl) amino] phen
Nyl]] carboxamide 1H-2- (3-nitrophenyl) benzimidazole-5- [N- [3-methyl-4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.40 g (0.80 mmol) was led to the corresponding amino compound by catalytic hydrogenation using 10% Pd / C in 10 mL of DMF-methanol 1: 1 mixed solvent as a catalyst. A DMF solution of this product was stirred under ice-cooling under a nitrogen stream to give 4-pyridylacetic acid hydrochloride (0.4 g, 2.3 mmol, 3 eq),
0.45 g (2.4 mmol, 3 eq) of EDCI was sequentially added, and the mixture was stirred for 30 minutes as it was. After further stirring at room temperature for 6 hours, it was left overnight. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol = 6/1). After the solvent was distilled off, the residue was further purified by silica gel column chromatography (chloroform / methanol = 8/1). After the solvent was distilled off under reduced pressure, the residue was dissolved in methanol, and isopropyl ether was added for reprecipitation to obtain 50 m of a pale yellow powder.
g (yield 11%) was obtained.

NMR (DMSO-d ₆ ) δ: 10.51
(S, 1H), 10.18 (bs, 0.5H), 10.
13 (bs, 0.5H), 8.61 (s, 1H), 8.
55 (d, 2H), 8.33 (s, 0.5H), 8.1
1 (s, 0.5H), 7.89-7.49 (m, 7
H), 7.39 (d, 2H), 7.23 (d, 1H),
3.77 (s, 2H), 3.57 (t, 4H), 3.3
6 (t, 4H), 2.31 (s, 3H) IR (KBr) cm ^-1 : 3422, 1647, 150
8,1318,1239,829

Test Example 1 Binding of these compounds to DNA was examined. The method is to measure the Tm (melting point) of DNA and
The method of comparing the Tm value of the solution with and without addition to the NA solution was used. That is, poly d
(AT) -d (AT) was used. Dissolve this DNA in a buffer,
Further, the compound was added and the value of Tm was determined. Separately, the Tm value of only DNA was obtained, and the difference (ΔTm) was calculated. A Hitachi U-3200 spectrophotometer was used for measurement, and a Hitachi SPR-10 type temperature control unit was used for temperature control. ΔTm of Compound 2001 was calculated to be 1
It was 4 ° C.

Test Example 2 The anticancer activity of these compounds will be described. Table-3
[Table 35] shows the antitumor activity of representative compounds. The method is an in vitro measurement of tumor cell growth inhibitory effect.
Mouse B16 melanoma cells were seeded in a 96-well culture plate, the compound was added one day later, and the mixture was added for 3 days in 5% CO ₂ 3
The cells were cultured at 7 ° C. Cancer. Res. 1988 4
According to the method shown in Volume 8, pages 589-601, 50%
The compound concentration (IC ₅₀ ) required to cause the growth inhibition of C. alba was determined. The unit is μg / mL. As a comparative example, the results of distamycin are also shown.

[0184]

[Table 35]

Test Example 3 Colon26 mouse colon cancer cells 1 × 10 ⁷ cells / mL HBS
A cell suspension having a concentration of S (Hanks' Balanced Salt Solution) was prepared. Add 0.1 mL of this cell suspension to a female CD
It was transplanted into F ₁ mice flanks subcutaneously (day 0). After measuring the body weight of the mouse on the day after the tumor transplantation (day 1),
A solution of compound (5% glucose solution containing 5% polysorbate 80) was administered into the tail vein of mice. day
The tumor was excised in 15 and its weight was measured. The ratio of the average tumor weight of the experimental group when the average tumor weight of the control group to which the compound was not administered was 100% was calculated as the T / C value. The results are shown in Table 4 [Table 36] below. The T / C is shown corresponding to the compound number, and the concentration of the drug when it is shown in () is shown.

[0186]

[Table 36]

Formulation Example 1 (tablet by dry tableting method) Compound 2053 30 g Lactose 68 g Crystalline cellulose 20 g Magnesium stearate 2 g According to the above-mentioned formulation formulation, the compound of the present invention 2053 (active ingredient), lactose, crystalline cellulose, and magnesium stearate. Weigh and mix well. This is tableted by a tableting machine to obtain a round uncoated tablet having a diameter of 7 mm and 120 mg (containing 30 mg of compound) / tablet. This is coated with varnish. That is, talc is sprinkled and the undercoat layer is coated on the periphery. Apply the varnish a sufficient number of times to suit internal use. Color coating can then be applied and after drying the coated tablets can be waxed to give tablets of uniform gloss.

Formulation Example 2 (Injection) Compound 2053 1 g Propylene glycol 1,000 ml According to the above formulation, the compound 2053 of the present invention (active ingredient) is weighed and dissolved in sterile propylene glycol.
Each 5 ml of this can be enclosed in an ampoule to produce a 5 mg injection.

[0189]

The compound of the present invention acts on DNA and is useful as an anticancer agent, antiviral agent or antibacterial agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 401/12 235 C07D 401/12 235 403/12 233 403/12 233 405/12 235 405/12 235 (72) Inventor Hiroshi Okochi 1144, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd. (72) Inventor, Daiji Iwata 1-248, Togo, Mobara-shi, Chiba (72) Inventor, Hajime Edashi Chiba 1900 Togo, Mobara-shi 1 Mitsui Toatsu Chemical Co., Ltd.

Claims (8)

[Claims] 1. A compound represented by the general formula (1) [Chemical formula 1] or a pharmaceutically acceptable salt thereof. Embedded image [In the formula, m and n each independently represent an integer of 0 to 3, and R ₁ and R ₂ each independently represent a hydrogen atom, a halogen atom, an alkylthio group having 1 to 8 carbon atoms, or a substituent. Amino group, optionally substituted ammonium group, optionally substituted sulfonium group, optionally substituted phenyl group, optionally substituted hetero 5
Membered ring group, optionally substituted hetero 6-membered ring group, amidino group, guanidino group, amino acid residue or general formula (2)
It is a group of [Chemical Formula 2]. Embedded image {In the formula, R ₃ is directly bonded or represents an oxygen atom (provided that when R ₃ is an oxygen atom, R ₃ is bonded (C
H ₂ ) _m or _m or _n in (CH ₂ ) _n is not 0), R ₄ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, trifluoromethyl Group, cyano group, amidino group, carboxyl group or -COR ₇ (wherein R ₇ is an alkylamino group having 1 to 8 carbon atoms which may be substituted with a substituted amino group,
Represents an amino group which may be substituted with an optionally substituted phenyl group, or an optionally substituted benzylamino group), and R ₅ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a carbon atom. An alkoxy group of formulas 1 to 8 or a halogen atom, wherein R ₆ is — (CH ₂ ) _p N (R ₈ ) ₂ or — (C
H ₂ ) _p NR ₈ R ₉ (where p is an integer of 0 to 5 and R
₈ represents -CH ₂ CH ₂ W, R ₉ represents an alkyl group having 1 to 5 carbon atoms or a mesyl group, W represents a halogen atom, a hydroxy group, a mesyloxy group, a tosyloxy group or -OCOR.
₇ (provided that R ₇ has the above meaning). However, the R ₁ (CH ₂ ) _m CONH group substituted on the phenyl group in the compound of the general formula (1) may be substituted on any position of the phenyl group. ] 2. R ₁ is a halogen atom or the general formula (2).
The compound or pharmacologically acceptable salt thereof according to claim 1, which is a group represented by: 3. R ₂ is a halogen atom or the general formula (2)
The compound or pharmacologically acceptable salt thereof according to claim 1, which is a group represented by: 4. An amino group in which R ₂ is optionally substituted,
The compound according to claim 2, which is a guanidino group or an amidino group, or a pharmaceutically acceptable salt thereof. 5. An amino group in which R ₁ is optionally substituted,
The compound according to claim 3, which is a guanidino group or an amidino group, or a pharmaceutically acceptable salt thereof. 6. An anticancer agent containing the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient. 7. An antibacterial agent containing the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient. 8. An antiviral agent containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.