JPH11171886A - Pyprolylbenzimidazole derivative having amidine or guanidine in side chain - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having the possibility for acting on a DNA, usability thereof as an anticancer agent and amidine or guanidine directly bound to the 4-position of pyrrole. SOLUTION: This compound is represented by formula I [R1 is a 1-8C alkyl or the like or denotes piperidine or the like by R1 N; (n) is 0-3; R2 is H, a 1-8C alkyl or the like] or formula II, e.g. 1H-2-(1-methyl-4-amidinopyrrol-2-yl) benzimidazole-5-[N-[4-N,N-bis(2-chloroethyl)amino]phenyl]carboxamide. The compound is obtained by reacting 1-methyl-4-cyanopyrrole-2-aldehyde with methyl 2,3-diaminobenzoate in nitrobenzene, hydrolyzing the methyl ester into a carboxylic acid, then binding the resultant carboxylic acid to an aniline derivative using a suitable condensing agent, subsequently blowing hydrochloric acid gas thereinto in ethanol, converting the cyano group into the corresponding imidate and further blowing ammonia gas thereinto.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound which is a novel pyrrolylbenzimidazole derivative which binds to DNA and exhibits an antitumor effect, and a pharmaceutical composition containing the compound, particularly to an anticancer drug.

[0002]

2. Description of the Related Art There are many anticancer agents which act by binding to DNA. Among them, an alkylating agent that alkylates DNA, an intercalator that fits between base pairs of DNA, and the like are representative. Anticancer agents such as cyclophosphamide and adriamycin are known, and they are used in clinical practice. Have been. It is already well known that there is another mode of binding to DNA, namely binding to a minor groove. However, anticancer drugs showing binding to the minor groove are still in the research stage. Typical examples thereof include derivatives of distamicin and derivatives of duocarmycin. Further, a group of compounds having a pyrrolylbenzimidazole skeleton as a substance that binds to DNA is disclosed in JP-A-09-003065.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a DN.
This is the creation of a new substance that acts on A and may be used as an anticancer agent.

[0004]

[Means for Solving the Problems] In the present study, Japanese Unexamined Patent Publication No.
Novel compounds were searched for using pyrrolylbenzimidazole disclosed in 03065 as a basic skeleton. JP 09-003065
In the publication, amidine and guanidine are used as side chains. These are substituents which are also found in distamicin described above, and are considered to have a function of strengthening the binding to DNA. Distamycin also
Also, among the above-mentioned patents, it is an obvious feature that amidine or guanidine as a side chain is bonded to pyrrole by an amide bond via a methylene chain.

[0005] We have synthesized a novel derivative in which amidine or guanidine is directly linked to the 4-position of pyrrole, which has not been studied at all in the aforementioned patents. As a result of examining their biological activities, a compound showing a growth inhibitory activity on tumor cells was found. That is, we have found that the following compounds have a novel structure and are useful as anticancer agents, and have completed the present invention.
That is, the present invention

[1] A compound represented by the general formula 1 or 2 and a pharmacologically acceptable salt

[0007]

Embedded image (Wherein, R _{1 is} a linear or branched alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a dialkylamino group, or R ₁ N is piperidine, N-methylpiperazine, morpholine) Represents phosphorus, and n represents an integer of 0 to _3. R ₂ is substituted with a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a dialkylamino group. An alkyl chain having 1 to 3 carbon atoms,
It represents a halogen atom, a cyano group, a trifluoromethyl group, or an amidino group. ) And

[2] 1H-2- (1-methyl-4-amidinopyrrol-2-yl) benzimidazole-5
[N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide and a pharmacologically acceptable salt;

[3] 1H-2- (1-methyl-4-guanidinopyrrol-2-yl) benzimidazole-5
-[N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide and a pharmacologically acceptable salt;

[4] An anticancer agent comprising the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. A linear or branched alkyl group having 1 to 8 carbon atoms means a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a t-butyl group, an n- A pentyl group, n-hexyl group, n-heptyl group, n-octyl group and the like are desirable. An alkoxy group having 1 to 8 carbon atoms refers to an alkoxy group having 1 carbon atom.
To 8 represent a group in which a linear or branched alkyl group is bonded to an oxygen atom.

1 carbon atom substituted by a dialkylamino group
And alkyl chains of 8 to 8 are a dimethylamino group, a diethylamino group, a dipropylamino group, an ethylmethylamino group,
Methylpropylamino group, methyl group substituted with ethylpropylamino group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, etc. desirable.

Halogen atoms are F, Cl, Br and I. D
CC is N, N'-dicyclohexylcarbodiimide,
CDI is N, N'-carbonyldiimidazole, ED
CI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, DECP is diethyl cyanophosphonate, and HOBt is 1-hydroxybenzotriazole.

DMF is dimethylformamide, DMSO
Represents dimethyl sulfoxide, and IPA represents isopropanol. Pd / C represents activated carbon with palladium, and its palladium is usually 5 to 10%.

Next, a method for synthesizing these compounds will be described.
1-methyl-4-cyanopyrrole-2-aldehyde and methyl 3,4-diaminobenzoate in nitrobenzene at 140-170 ° C
Heat for 1-50 hours. The methyl ester is hydrolyzed to the carboxylic acid and then coupled to the aniline derivative using a suitable condensing agent. As the condensing agent at this time, DCC, CD
I, EDCI and DECP are desirable, or a condensation aid such as HOBt can be added thereto. Next, hydrochloric acid gas is blown in ethanol to convert the cyano group into a corresponding imidate, and then ammonia gas is blown therein, whereby the amidine can be introduced. At this time, a substituted amidine derivative can be synthesized by reacting an appropriate amino compound instead of blowing ammonia gas (reaction formula 1).

[0016]

Embedded image

(Wherein R ₁ is a linear or branched alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by a dialkylamino group, or R ₁ N is piperidine, N- Represents methylpiperazine or morpholine, n represents an integer of 0 to _3. R ₂ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, dialkylamino. 1 to 3 carbon atoms substituted with a group
Represents an alkyl chain, a halogen atom, a cyano group, a trifluoromethyl group and an amidino group. ).

Further, 1-methyl-4-nitropyrrole-2-aldehyde and 3,4-diaminobenzoic acid are mixed in nitrobenzene,
Heat at 140-170 ° C for 1-50 hours. Next, the aniline derivative is bound using an appropriate condensing agent. As the condensing agent at this time, DCC, CDI, EDCI, and DECP are desirable, or a condensing aid such as HOBt can be added thereto. Next, the nitro group can be reduced and reacted with 3,5-dimethylpyrazole-1-carboxamide in the presence of triethylamine to give guanidine (reaction formula 2).

[0019]

Embedded image

(Wherein R ₂ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a carbon atom substituted with a dialkylamino group having 1 to 3 carbon atoms)
Represents an alkyl chain, a halogen atom, a cyano group, a trifluoromethyl group, or an amidino group, and n represents an integer of 0 to 3. ).

The compounds of the present invention can be used in the form of a salt with a suitable acid. The acid used is not particularly limited as long as it is pharmacologically possible, but hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, Examples include camphorsulfonic acid, formic acid, acetic acid, propionic acid, butyric acid, fumaric acid, maleic acid, oxalic acid, malonic acid, and succinic acid.

The salts of these compounds may be quaternary salts, but naturally also include them. The compounds of the present invention can be used as anti-cancer agents. The applicable cancer types are leukemia,
Osteosarcoma, breast cancer, ovarian cancer, stomach cancer, colon cancer, lung cancer, head and neck cancer and the like. These compounds are administered in various formulations depending on the purpose of the treatment. Formulation can be performed by a known method.

Various dosage forms can be selected depending on the purpose of treatment. Solid dosage forms include tablets, pills, powders,
As liquids such as granules and capsules, injections as solutions, suspensions, syrups, emulsions and the like, and suppositories as other preparations can be considered.

In the case of molding into tablets, various carriers well known in the art can be widely used as carriers. Examples thereof include excipients such as lactose, starch, microcrystalline cellulose, water, alcohols, simple syrups, starch solutions, gelatin solutions, binders such as methyl cellulose solutions, hydroxypropyl cellulose solutions, dried starch, sodium alginate, agar Powder, disintegrating agents such as starch, stearic acid, cocoa butter, disintegrating inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, humectants such as starch, kaolin, bentonite, Adsorbents such as colloidal silicic acid, crystalline cellulose, and light silicic anhydride; and lubricants such as talc and stearate. Further, in the case of tablets, tablets which have been coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multi-layer tablets can be prepared.

Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like according to a conventional method.

When prepared as an injection, when it is formed into a liquid, emulsion or suspension, it is generally used in the art as a diluent, for example, water, alcohols, polyoxyethylene sorbitan fatty acid esters. And vegetable oils. Further, water is added to the compound of the present invention, and a suspension aqueous solution in the presence of a suitable surfactant, and also a polyoxyethylene hydrogenated castor oil 60 (H
It is used as an emulsion using a surfactant such as CO-60). In addition, salt, glucose or glycerin may be contained in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent and the like may be added.

In shaping into a suppository, a wide variety of conventionally known carriers can be used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.
Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent or the like and other pharmaceuticals can be contained in the pharmaceutical preparation.

The administration method is not particularly limited, but the administration is carried out in accordance with various preparation forms, the age and sex of the patient, other conditions, and the degree of the disease. Usually, it is administered once or several times in one day to one month, and this can be repeated. In addition, dosage may vary depending on usage, patient age, gender, other conditions,
The content of the active ingredient per adult is 1 to 1,000 mg, which is appropriately considered depending on the degree of the disease.

In view of the current state of the art of anticancer drugs, even drugs such as adriamycin and cisplatin, which are widely used, cannot sufficiently separate the action and side effects. The side effects of the compounds of the present invention are at levels that can be used as anticancer agents.

[0030]

The present invention is further described by the following examples. However, the present invention is not limited to these examples. The compound numbers shown in parentheses correspond to the compound numbers shown in the test examples. Also, N, N-bis (2-chloroethyl) -1,4-phenylenediamine hydrochloride, 1H-
2- (1-Methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide is disclosed in The compounds were separately synthesized with reference to the examples in JP-A-003065.

Example 1 (Reaction 1) 1H-2- (4-cyano-1-methylpyrrol-2-yl) methyl benzimidazole-5-carboxylate 4-cyano-1-methyl-2-pyrrolecarboxaldehyde 1 .50 g (11.2 mmol) and 1.86 g (11.2 mmol) of methyl 3,4-diaminobenzoate were dissolved in 100 mL of nitrobenzene, and heated and stirred in a 150 ° C. oil bath for 38.5 hours. The mixture was allowed to cool to room temperature, and the resulting solid was collected by filtration and washed with IPA to give the title compound (2.19 g, 7.81 mmol, 69.8%) as pale brown crystals. mp:> 250 ° C NMR (DMSO-d ₆ ) δ: 8.26-8.10 (m, 1H), 7.93 (d, 1
(H, J = 1.5), 7.85 (d, 1H), 7.71-7.55 (m, 1H), 7.29 (d, 1H), 4.1
4 (s, 3H), 3.88 (s, 3H)

(Reaction 2) 1H-2- (4-cyano-1-)
Methylpyrrole-2-yl) benzimidazole-5
Carboxylic acid methyl 1H-2- (4-cyano-1-methylpyrrol-2-yl) benzimidazole-5-carboxylate 0.6
0 g (2.13 mmol) in ethanol 15 mL, 1N
It was suspended in 15 mL of an aqueous sodium hydroxide solution and heated and stirred in a 60 ° C. oil bath. Evaporate the ethanol under reduced pressure,
The remaining aqueous solution was acidified with 4N hydrochloric acid, and the resulting solid was collected by filtration and washed with water to give 0.48 g of the title compound (1.8).
mmol, 84.5%). mp:> 240 ° C NMR (DMSO-d ₆ ) δ: 8.16 (s, 1H), 7.93 (d, 1H), 7.
85 (d, 1H), 7.65 (d, 1H), 7.31 (s, 1H), 4.15 (s, 3H)

(Reaction 3) 1H-2- (4-cyano-1-)
Methylpyrrole-2-yl) benzimidazole-5
[N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 1H-2- (4-cyano-1-methylpyrrol-2-yl) benzimidazole-5-carboxylic acid 40g
(1.50 mmol), N, N-bis (2-chloroethyl) -1,4-phenylenediamine hydrochloride 0.41 g
(1.52 mmol) was dissolved in 10 mL of DMF, and the mixture was stirred under ice-cooling under a nitrogen stream. 0.63 mL of triethylamine
(4.52 mmol, 3.0 eq), DECP 0.34
mL (2.24 mmol, 1.5 eq) were added in order, and 4
After stirring for an hour, the mixture was left overnight. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (Kieselgel6).
0, chloroform / methanol = 4%) and crystallized from methanol to give 0.34 g of the title compound.
(0.71 mmol, 47.1%) were obtained as brown white crystals. mp: 140-150 ° C (dec.) NMR (DMSO-d ₆ ) δ: 10.06 (s, 0.4H), 10.00 (s, 0.
6H), 8.38 (s, 0.6H), 8.08 (s, 0.4H), 7.93 (s, 1H), 7.93-7.82
(m, 1H), 7.75-7.58 (m, 3H), 7.29 (d, 1H), 6.75 (d, 2H), 4.16
(s, 3H), 3.73 (s, 8H)

(Reaction 4) 1H-2- (1-methyl-4-)
Amidinopyrrole-2-yl) benzimidazole-5
-[N- [4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide dihydrochloride (Compound No. 1) 1H-2- (1-methyl-4-cyanopyrrol-2-yl) Benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carboxamide (0.17 g, 0.35 mmol) was suspended in ethanol (10 mL), and hydrochloric acid gas was blown into the solution over 30 minutes while stirring in an ice bath containing sodium chloride until saturation. (Internal temperature -5 to 10 ° C). The ice bath was removed, and the mixture was further stirred for 5 hours and concentrated under reduced pressure. After adding 10 mL of diethyl ether to the residue and decanting three times, 13 mL of ethanol was added.
And ammonia gas was blown into the solution over 40 minutes with stirring under ice cooling until the solution became saturated.

The ice bath was removed, and the mixture was further stirred for 2 hours and left overnight. The mixture was concentrated under reduced pressure, the residue was subjected to gel filtration column chromatography (Sephadex LH-20, methanol), methanol was added to the concentrated residue of the eluted fraction, and the solid which was not dissolved was collected by filtration.
14 g (0.24 mmol, 70.0%) were obtained as yellow crystals. mp. :> 240 ° C NMR (DMSO-d ₆ ) δ: 10.14 (s, 1H), 9.10 (bs, 2H),
8.74 (bs, 2H), 8.31 (s, 1H), 8.11 (s, 1H), 7.95 (d, 1H), 7.73
(d, 1H), 7.65 (d, 2H), 7.58 (s, 1H), 6.76 (d, 2H), 4.17 (s, 3
H), 3.74 (s, 8H) IR (KBr) cm ^-1 : 3214,1638,159
4,1518,1330,1184,818 Calcd _{(C 24 H 25 Cl 2 N} 7 O · 2HCl · 2
_{H 2 O) C: 47.46,} H: 5.14, N: 16.1
4. Analytical value C: 47.32, H: 4.74, N: 16.
05

Example 2 1H-2- (1-Methyl-4-iminomorpholinomethylpyrrol-2-yl) benzimidazole-5- [N-
[4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide dihydrochloride (Compound No. 2) 1H-2- (1-methyl-4-cyanopyrrol-2-yl) benzimidazole-5 -[N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carboxamide (0.30 g, 0.62 mmol) was suspended in ethanol (20 mL), and hydrochloric acid gas was blown into the solution over 30 minutes while stirring in an ice bath containing sodium chloride until saturation was reached ( (Internal temperature −5 to 10 ° C.). The ice bath was removed, and the mixture was further stirred for 3 hours and concentrated under reduced pressure. After adding 15 mL of diethyl ether to the residue and decanting twice, 15 mL of diethyl ether was added and the solid was collected by filtration. The collected matter was suspended in 10 mL of ethanol, and 0.17 mL of morpholine (1.9 m
mol, 3.0 eq) at room temperature. After stirring overnight, the resulting solid was collected by filtration, and 0.23 g (0.44 g of imidate compound) was obtained.
mmol).

This was suspended in 10 mL of ethanol, and 0.4 mL (4.6 mmol, 10 eq) of morpholine was added. After stirring at room temperature for 6 hours, the resulting solid was collected by filtration (solid 1). 4N hydrochloric acid / dioxane was added to the filtrate, and the mixture was concentrated under reduced pressure. Methanol was added to the residue, and the resulting solid was collected by filtration (solid 2). The solids 1 and 2 are combined and suspended in methanol and 4N
After adding hydrochloric acid / dioxane, the mixture was concentrated. The residue was sludged with diethyl ether to give 0.14 g (0.21 mmol, 47.0%) of the title compound as a hygroscopic powder. _{NMR (DMSO-d 6) δ} : 10.16 (s, 1H), 9.36 (s, 1H) 9.
12 (s, 1H), 8.32 (s, 1H), 7.95 (d, 1H), 7.85 (s, 1H), 7.74 (d, 1
H), 7.65 (d, 2H), 7.53 (s, 1H), 6.76 (d, 2H), 4.23 (s, 3H), 3.8
0 (s, 8H), 3.74 (s, 8H) IR (KBr) cm ^-1 : 3397,1654,159
5,1518,1331,1183,1114,760

Example 3 1H-2- [1-methyl-4-[(N ¹ -n-butyl)
Amidino] pyrrole-2-yl) benzimidazole-
5- [N- [4- [N, N-bis (2-chloroethyl)
Amino] phenyl]] carboxamide 2p-toluenesulfonate (Compound No. 3) 1H-2- (1-methyl-4-cyanopyrrol-2-yl) benzimidazole-5- [N- [4- [N, N −
Bis (2-chloroethyl) amino] phenyl]] carboxamide (0.31 g, 0.64 mmol) was suspended in ethanol (15 mL), and hydrochloric acid gas was blown into the ice bath to which sodium chloride was added for 30 minutes with stirring while stirring in an ice bath ( (Internal temperature −5 to 10 ° C.). The ice bath was removed, and the mixture was further stirred for 2 hours and concentrated under reduced pressure. 15 mL of diethyl ether was added to the residue, and the solid was collected by filtration. The collected material was suspended in 15 mL of ethanol, and 0.32 mL of n-butylamine was added under a nitrogen atmosphere.
(3.24 mmol, 5.0 eq) were added at room temperature. After standing overnight, the mixture was concentrated under reduced pressure.

The residue was subjected to gel filtration column chromatography (Seph).
dex LH-20, methanol). The eluted fraction was concentrated under reduced pressure, and the residue was dissolved in methanol.
0.24 g of p-toluenesulfonic acid (1.26 mmol
1, 2.0 eq) and concentrated. The title compound 7 was obtained by adding methanol to the residue and collecting the precipitated solid by filtration.
0 mg (0.078 mmol, 12.2%) was obtained as a hygroscopic powder. NMR (DMSO-d ₆ ) δ: 10.04 (s, 1H), 9.32 (s, 1H),
9.07 (s, 1H), 8.59 (s, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.89
(d, 1H), 7.68 (d, 1H), 7.64 (d, 2H), 7.48 (d, 4H, J = 8.1), 7.47
(s, 1H), 7.11 (d, 4H, J = 8.1), 6.77 (d, 2H), 4.17 (s, 3H), 3.73
(s, 8H), 3.36 (m, 2H), 2.29 (s, 6H), 1.60 (m, 2H), 1.39 (m, 2
H), 0.94 (t, 3H) IR (KBr) cm ^-1 : 3124,2961,162
5,1598,1517,1458,1330,118
1,1123,1035,1011,816,682

[0040] Example 4 1H-2- [1- ^{methyl--4- [N 1 - [3- (} N, N
-Dimethylamino) propyl] amidino] pyrrole-2
-Yl] benzimidazole-5- [N- [4- [N,
N-bis (2-chloroethyl) amino] phenyl]] carboxamide trihydrochloride (Compound No. 4) 1H-2- (1-methyl-4-cyanopyrrol-2-yl) benzimidazole-5- [N- [4 − [N, N−
Bis (2-chloroethyl) amino] phenyl]] carboxamide (0.30 g, 0.62 mmol) was suspended in ethanol (15 mL), and hydrochloric acid gas was blown into the mixture over 30 minutes while stirring in an ice bath containing sodium chloride until saturation. (Internal temperature -5 to 10 ° C). The ice bath was removed, and the mixture was further stirred for 3 hours and concentrated under reduced pressure.
5 mL was added and the solid was collected by filtration. Filter the residue with ethanol 15
suspended in N, N-dimethyl-1,3 under a nitrogen atmosphere.
-0.39 mL of propanediamine (3.12 mmol,
5.0 eq) was added at room temperature.

After standing overnight, the mixture was concentrated under reduced pressure, and the residue was subjected to gel filtration column chromatography (Sephdex LH-20, methanol). The eluted fraction was concentrated under reduced pressure, the residue was dissolved in methanol, 4N hydrochloric acid-dioxane was added, and the mixture was concentrated to dryness under reduced pressure. The residue was subjected to gel filtration column chromatography again to remove excess hydrochloric acid, and the residue was solidified with diethyl ether to give the title compound (0.127 g, 0.18 g).
mmol, 29.0%) as a hygroscopic powder. NMR (DMSO-d ₆ ) δ: 10.14 (s, 1H), 9.80 (m, 1H),
9.39 (s, 1H), 9.02 (s, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 7.95
(d, 1H), 7.73 (d, 1H), 7.65 (d, 2H), 7.64 (s, 1H), 6.77 (d, 2
H), 4.18 (s, 3H), 3.74 (s, 8H), 3.54 (m, 2H), 3.17 (m, 2H), 2.7
7 (d, 6H), 2.06 (m, 2H) IR (KBr) cm ^-1 : 3395,3104,161
8, 1595, 1518, 1458, 1331, 118
2,1147,817

Example 5 1H-2- (1-methyl-4-guanidinopyrrole-2
-Yl) benzimidazole-5- [N- [4- [N,
N-bis (2-chloroethyl) amino] phenyl]] carboxamide dihydrochloride (Compound No. 5) 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4 − [N, N−
Bis (2-chloroethyl) amino] phenyl]] carboxamide 0.32 g (0.64 mmol) in DMF5
Dissolve in mL-methanol 4 mL, 4N hydrochloric acid 0.16m
L was added thereto, and the mixture was hydrogenated under normal pressure using 0.19 g of 10% Pd / C (wet) as a catalyst to lead to the corresponding amino compound.

A DMF solution of this was stirred under ice-cooling under a nitrogen stream, and triethylamine (0.11 mL, 0.79 mmol) was added.
1,1,2 eq), 3,5-dimethylpyrazole-1-
0.4 g of carboxamide (1.93 mmol, 3.0e)
q) was added in order, the mixture was returned to room temperature, stirred for 6 hours, and left overnight. The resulting solid was separated by filtration, concentrated under reduced pressure, dissolved in methanol, and added with 4N hydrochloric acid-dioxane and evaporated. The residue was subjected to silica gel column chromatography (Kiesel
gel60, chloroform / methanol = 16%)
Subsequently, gel filtration column chromatography (Sephadex L)
H-20, methanol) and solidified from diethyl ether to give the title compound (93 mg, 0.16 mmol, 2
9.8%) as a yellow solid. NMR (DMSO-d ₆ ) δ: 10.17 (s, 1H), 9.57 (s, 1H),
8.29 (s, 1H), 7.97 (d, 1H), 7.75 (m, 1H), 7.64 (d, 1H), 7.64
(d, 2H), 7.41 (bs, 3H), 7.30 (s, 1H), 7.10 (s, 1H), 6.77 (d, 2
H), 4.13 (s, 3H ), 3.74 (s, 8H) Elemental analysis: Calculated _{(C 24 H 36 Cl 3 N} 8 O · 2HCl · 3
_{H 2 O) C: 45.07,} H: 5.35, N: 17.5
0, Cl: 22.14, analytical value C: 45.07, H:
5.03, N: 17.20, Cl: 22.24

Test Examples The antitumor activity of these compounds will be described. The test method is as follows. Mouse B16 melanoma cells were seeded on a 96-well culture plate, the compound was added one day later, and the cells were further cultured for 3 days at 37 ° C. in 5% CO ₂ . Ca
ncer. Res. According to the method described in 1988, 48, 589-601, the compound concentration required to cause 50% growth inhibition was determined. The results are shown in Table 1 [Table 1].

[0045]

TABLE 1 Antitumor activity Compound No. Drug concentration showing 50% inhibitory action (μg / mL) ─────── 1 3.7 5 3.5

Formulation Example 1 (tablets) Compound 1 30 g Lactose 68 g Crystalline cellulose 20 g Magnesium stearate 2 g According to the above formulation, compound 1 of the present invention (active ingredient)
Lactose, crystalline cellulose and magnesium stearate were weighed out and mixed well. This was tableted with a tableting machine to obtain a round plain tablet having a diameter of 7 mg and a tablet weight of 120 mg (containing 30 mg of compound). Further, tablets having uniform gloss were obtained through steps such as coating, coloring and polishing.

Formulation Example 2 (Injection) Compound 1 1 g Propylene glycol 1,000 mL According to the above formulation, the compound of the present invention was weighed, dissolved in propylene glycol, and sterilized. This is 5
Each 5 mL was sealed in an ampoule to produce a 5 mg injection.

[0048]

The compound of the present invention acts on DNA and can be used as an anticancer agent.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Yasuhiro Matsuba 1900-1 Togo, Mobara-shi, Chiba Mitsui Pharmaceutical Industry Co., Ltd.

Claims (4)

[Claims] 1. A compound represented by the general formula 1 or 2 and a pharmacologically acceptable salt. (Wherein, R ₁ represents a straight-chain or branched alkyl group having 1 to 8 carbon atoms, or a carbon atom having 1 to 8 carbon atoms substituted with a dialkylamino group)
And R ₁ N represents piperidine, N-methylpiperazine or morpholine, and n represents an integer of 0 to 3. R ₂ is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl chain having 1 to 3 carbon atoms substituted by a dialkylamino group, a halogen atom, a cyano atom, Group, trifluoromethyl group,
Indicates an amidino group. ). 2. 1H-2- (1-Methyl-4-amidinopyrrol-2-yl) benzimidazole-5- [N-
[4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide and pharmaceutically acceptable salts. 3. 1H-2- (1-methyl-4-guanidinopyrrol-2-yl) benzimidazole-5- [N
-[4- [N, N-bis (2-chloroethyl) amino]
Phenyl]] carboxamide and pharmacologically acceptable salts. 4. An anticancer agent comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.