JP2001181279A - Benzofuranylpyrrolecarboxamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a compound which is a new compound having an action on DNA or a new compound having a partial structure acting on DNA and is useful as an anticancer agent, an antimicrobial agent and an antiviral agent. SOLUTION: This anticancer agent comprises a new benzofuranylpyrrolecarboxamide derivative of the general formula. Consequently the new anticancer agent acting on DNA is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a benzofuranylpyrrolecarboxamide derivative which suppresses the growth of cancer cells and a pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient, particularly an anticancer agent.

[0002]

2. Description of the Related Art Cancer has become DNA due to recent medical advances.
It was revealed that the disease was caused by abnormalities. If the anticancer drug to be administered can distinguish the difference in DNA,
It has become possible to develop anticancer drugs with few side effects. Anticancer drugs that have been used so far,
DNA damaging drugs such as adriamycin and cisplatin and nitrogen mustards such as chlorambucil are known to directly react with DNA, but their selectivity is relatively low. .

[0003] On the other hand, netropsin and distamicin (Dist) found in nature are known.
amycin) is known to exhibit anticancer activity by selectively binding to a partial sequence of DNA (Nature, Vol. 2).
03 1064-65 1964). Therefore, an attempt was made to design an anticancer drug using this skeleton (J. Am. Chem. Soc., Vo
l. 107 8266 1985, EP246868, WO93-13739, J. Med.Chem.,
Vol.32 774 1989). In addition, there has been reported an example of designing using a dye that exhibits selective binding to DNA (J. Med. Chem., Vol. 37 4338 1994).

[0004] However, since it is necessary to design using natural products and known dyes, there is little room for selecting a structure as a skeleton, and a compound which is considered to be clinically useful has not been obtained.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a DN.
An object of the present invention is to provide a novel compound acting on A or a novel compound having a partial structure acting on DNA and useful as an anticancer agent.

[0006]

Means for Solving the Problems In order to solve these problems, the present inventors first studied the binding selectivity of compounds having various backbone structures to DNA. As a result, they have found that a compound having a benzofuranylpyrrole carboxamide skeleton, which is not known at all as an anticancer agent, is effective. Further investigations to enhance the function as anticancer agents have led to the discovery of benzofuranylpyrrole carboxamide derivatives that exhibit much higher anticancer activity than distamycin or chlorambucil. That is, the present invention relates to [1] the general formula (1)

[0007]

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Wherein m and n are each independently 0-5
R1 and R2 each independently represent an amidino
Group, guanidyl group, alkyl group having 1 to 5 carbon atoms
Amino group, substituted with an alkyl group having 1 to 5 carbon atoms
Sulfo substituted with a thio group or an alkyl group having 1 to 5 carbon atoms
-N-((CH_Two)_Two−
Y) _Two(Where Y is a chlorine atom)
, A bromine atom and a methanesulfonyl group. )
You. The benzofuranylpyrrole carboxyl represented by
A amide derivative or a pharmacologically acceptable salt thereof,
Also, [2] Formula (2) [Formula 8]

[0009]

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A benzofuranylpyrrolecarboxamide derivative represented by the formula or a pharmacologically acceptable salt thereof, and [3] a compound represented by the formula (3):

[0011]

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A benzofuranylpyrrolecarboxamide derivative represented by the formula or a pharmacologically acceptable salt thereof, and [4] a compound of the formula (4)

[0013]

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A benzofuranylpyrrolecarboxamide derivative represented by the formula or a pharmacologically acceptable salt thereof, and [5] a compound of the formula (5)

[0015]

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A benzofuranylpyrrole carboxamide derivative represented by the formula or a pharmacologically acceptable salt thereof, and [6] a compound of the formula (6)

[0017]

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A benzofuranylpyrrole carboxamide derivative or a pharmacologically acceptable salt thereof represented by the formula: [7] An anticancer agent containing the compound described in [1] to [6] as an active ingredient. is there.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the formula (1), m and n each represent an integer of 0 to 5;
~ 3 is desirable. As the alkyl group having 1 to 5 carbon atoms,
Methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, n-
A pentyl group can be exemplified, and a methyl group is desirable.

Examples of the amino group substituted with an alkyl group having 1 to 5 carbon atoms include a methylamino group, a dimethylamino group,
Ethylamino group, ethylmethylamino group, diethylamino group, n-propylamino group, Nn-propylmethylamino group, dipropylamino group, isopropylamino group, N-isopropylmethylamino group, diisopropylamino group, n-butyl Examples thereof include an amino group, a Nn-butylmethylamino group, a dibutylamino group, and an n-pentylamino group, and a dimethylamino group is particularly preferred.

The thio group substituted by an alkyl group having 1 to 5 carbon atoms includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,
Examples thereof include an isobutylthio group, a t-butylthio group and an n-pentylthio group, and a methylthio group is particularly preferred.

Examples of the sulfonium group substituted by an alkyl group having 1 to 5 carbon atoms include a dimethylsulfonium group,
Ethylmethylsulfonium group, diethylsulfonium group, Sn-propylmethylsulfonium group, S-
Examples thereof include an isopropylmethylsulfonium group, a Sn-butylmethylsulfonium group, and a Sn-pentylmethylsulfonium group, and a dimethylsulfonium group is particularly preferred.

Y represents a chlorine atom, a bromine atom or a methanesulfonyl group, and a chlorine atom is particularly preferred.

-N ((CH ₂ ) _2-
As the phenyl group substituted by Y) _2, 2- [bis (2-chloroethyl) amino] phenyl group, 3- [bis (2-chloroethyl) amino] phenyl group, 4- [bis (2-chloroethyl) amino ] Phenyl group, 2- [bis (2-bromoethyl) amino] phenyl group, 3- [bis (2-bromoethyl) amino] phenyl group, 4- [bis (2-bromoethyl) amino] phenyl group, 2- [bis A (2-methanesulfonylethyl) amino] phenyl group, a 3- [bis (2-methanesulfonylethyl) amino] phenyl group, and a 4- [bis (2-methanesulfonylethyl) amino] phenyl group, 4
A-[bis (2-chloroethyl) amino] phenyl group is particularly preferred.

The pharmacologically acceptable salt is not particularly limited as long as it can be used as a medicament, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate. Inorganic acid salts such as salts or organic acid salts such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, acetate, fumarate, maleate, citrate, oxalate and tartrate. can give.

The synthesis of these compounds will be described.
In the following description or embodiments, DCC is N, N '
-Dicyclohexylcarbodiimide, CDI is N, N '
-Carbonyldiimidazole, DECP is diethyl cyanophosphate, HOSu is N-hydroxysuccinimide,
HOBt is 1-hydroxybenzotriazole, DMA
P represents 4-dimethylaminopyridine, and DMF represents N, N-dimethylformamide. Pd / C indicates palladium on activated carbon, and the palladium is usually 5 to 10% by weight based on activated carbon.

The amide bond at the 5-position of the benzofuranyl ring present in the compound of the present invention can be formed by introducing a carboxylic acid moiety to an acid chloride and reacting it with an amino group, or converting a carboxylic acid and an amino group into a suitable condensing agent such as DCC, CDI, EDCI, DE
It can be condensed using CP or the like. Further, HOBt, HOSu, or the like can be added to DCC.

The amide bond at the 2-position of the pyrrole ring present in the compound of the present invention can be synthesized by reducing the nitro group of the pyrrole ring to an amino group and then condensing with a compound having a carboxylic acid moiety. The condensing agent used at this time is DC
C, CDI, EDCI, DECP and the like. Further, HOBt, HOSu, or the like can be added to DCC. At this time, the amide bond at the 5-position of the benzofuranyl ring and the amide bond at the 2-position of the pyrrole ring can be synthesized in any order.

The compound of the present invention uses ethyl 5-nitro-1-benzofuran-2-carboxylate as a starting material,
This substance is Proc.Indian.Acad.Sci., Sect.A, VoL.58 (6)
It can be synthesized by the method shown in 3361963. The synthesis method of 5-{[(1-methyl-4-nitro-1H-pyrrol-2-yl) carbonyl] amino} -1-benzofuran-2-carboxylic acid [intermediate 1], which is a reaction intermediate, is represented by the following reaction scheme. (1)
A description will be given along [Formula 13].

[0030]

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Ethyl 5-nitro-1-benzofuran-2-carboxylate can be hydrogenated at room temperature and normal pressure using Pd-C as a catalyst to lead to the corresponding amino group.
At this time, a normal solvent is used, but ethanol, methanol, ethyl acetate, and DMF are used alone or in two
Two or more can be used in combination. Good results can be obtained by using 0.1 to 50% by weight of Pd-C with respect to the nitro compound.

The amino compound obtained here was added to Tetrahedron, Vol.
34 2389-2391 1-Methyl-4-nitropyrrole-2-carboxylic acid chloride synthesized by the method shown in 1978 is dissolved in a suitable solvent such as chloroform, methylene chloride, DM
The reaction is carried out at -10 to 50 ° C in one or more mixed solvents selected from F, and 5-{[(1-methyl-4-nitro-1H-pyrrol-2-yl) carbonyl] This gives ethyl amino｝ -1-benzofuran-2-carboxylate.

This condensation reaction can also be obtained by using the above amino compound and 1-methyl-4-nitropyrrole-2-carboxylic acid with a suitable condensing agent, for example, DCC, CDI, EDCI, DECP and the like. HOBt, HOSu, DMAP, etc. can also be added to the reaction. As the solvent, methylene chloride, chloroform, and DMF may be used alone or as a mixture of two or more. The ethyl ester of the carboxylic acid obtained here is hydrolyzed using sodium hydroxide or potassium hydroxide to obtain [intermediate 1] shown in the reaction formula (1). At this time, it is preferable to use ethanol or methanol containing 5 to 90% of water. The reaction time is usually from room temperature to reflux temperature. [Intermediate 1] can be used as all intermediates of the compound of the present invention.

The amide bond can be introduced into the carbonyl moiety at the 2-position of the benzofuranyl ring by a condensation reaction between the carboxyl group of [Intermediate 1] and an amino group-containing compound.
For example, N- [2- (3- (dimethylamino) propyl)
Amino] carboni) -1-benzofuran-5-yl)-
The synthesis method of 1-methyl-4-nitro-1H-pyrrole-2-carboxamide [intermediate 2] is represented by the reaction formula (2)
4].

[0035]

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With respect to the carboxylic acid of [intermediate 1] obtained in the reaction formula (1), N, N
And reacting dimethyl-1,3-propanediamine.
At this time, a common condensing agent such as DCC, CD
I, EDCI, DECP or the like may be used. Also HOB
t, HOSu, DMAP, etc. can also be added to the reaction. In addition, an ordinary solvent is used as the solvent, but DMF is used.
Or a mixed solvent containing the same gives good results. The reaction temperature may be selected between -10 and 50C.

Here, the amino compound is 1,4-propanediamine instead of N, N-dimethyl-1,3-propanediamine.
Phenylenediamine derivatives, for example, N-bis (2-
[Intermediate 3] can be synthesized by reacting (chloroethyl) -1,4-phenylenediamine (reaction formula (3) [Formula 15]).

[0038]

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Further, a nitrile group can be introduced by reacting 3-aminopropionitrile instead of N, N-dimethyl-1,3-propanediamine. (Reaction formula (4) [Formula 16]).

[0040]

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Further, [intermediate 4] in which a nitrile group is converted into a corresponding amidino group can be synthesized. (Reaction formula (5) [Formula 17]).

[0042]

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That is, the product of the reaction formula (4) is suspended in ethanol, and the resulting crystals are filtered through hydrogen chloride gas. This is dissolved or suspended in a solvent and further passed with ammonia gas to obtain the desired [Intermediate 4]. The solvent at this time is desirably ethanol or a mixed solvent of ethanol and methanol. The ratio of ethanol can be freely selected from 10 to 100%.

Next, a method for introducing an amide bond at the 5-position of the pyrrole ring will be described with reference to Reaction Formula (6) [Formula 18].

[0045]

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[Intermediate 2] was prepared by using Pd-C as a catalyst
Hydrogenation at room temperature and normal pressure can lead to the corresponding amino group. As the solvent at this time, an ordinary solvent is used, but ethanol, methanol, ethyl acetate, and DMF can be used alone or as a mixture of two or more. Further, 0.1 to 50% by weight of Pd-C based on the nitro compound
Is used to obtain good results. An amide bond can be introduced into the obtained amino compound by a condensation reaction with a compound having a carboxylic acid moiety.

For example, commercially available chlorambucil is condensed using a suitable condensing agent, and the compound of the formula (5) 4-[(4
-{4- [bis (2-chloroethyl) amino] phenyl} butanoyl) amino] -n- [2-({[3- (dimethylamino) propyl] amino} carbonyl) -1-
[Benzofuran-5-yl] -1-methyl-1H-pyrrole-2-carboxamide can be obtained. At this time, a common condensing agent such as DCC, CDI, or EDC is used.
I, DECP or the like may be used. HOBt, HOS
u, DMAP, etc. can be added to the reaction. As the solvent, methylene chloride, chloroform, and DMF may be used alone or as a mixture of two or more. Further, it can also be synthesized by a method using a corresponding carboxylic acid chloride.

The carboxylic acid derivative is 2
-When guanidinoacetic acid acts, an amide bond having a guanidino group is generated. For example, from [Intermediate 3], the compound of formula (3), 4-[(2-{[amino (imino) methyl] amino} acetyl) amino] -N-
｛2-[(｛4- [bis (2-chloroethyl) amino]
Phenyl {amino) carbonyl] -1-benzofuran-
5-yl} -1-methyl-1H-pyrrole-2-carboxamide can be synthesized.

Further, when 3-methylpropionic acid is reacted as a carboxylic acid derivative, an amino group having an alkylthio group can be introduced. For example, [Intermediate 3]
From N- {2-[({4
-[Bis (2-chloroethyl) amino] phenyl {amino) carbonyl] -1-benzofuran-5-yl} -1
-Methyl-4-{[3- (methylthio) propanoyl]
Amino 1H-pyrrole-2-carboxamide can be synthesized.

Further alkylation using a suitable alkylating agent enables introduction of sulfonium. This general synthesis method will be described as an example. The compound of formula (4) is methylated using a suitable methylating agent, for example, methyl iodide, dimethyl sulfate, methyl fluorosulfate, diazomethane, methyl toluenesulfonate, etc. to obtain a compound of formula (2) [3- ({5-[({2-[({4- [bis (2-chloroethyl) amino] phenyl} amino) carbonyl] -1-benzofuran-5-yl} amino) carbonyl] -1-methyl-1H-pyrrole -3-yl｝
Amino) -3-oxopropyl] (dimethyl) sulfonium iodide can be obtained. The solvent at this time is a common solvent, for example, methanol, ethanol, 2-
In addition to propanol, dioxane, ethyl acetate, acetone, chloroform, methylene chloride and the like, organic acids such as acetic acid and formic acid can be used as the solvent. Reaction is -5 to 50
It is desirable to carry out at ℃. (Reaction formula (7) [Formula 19]).

[0051]

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Other compounds can be synthesized by changing the raw materials in the same reaction as described above.

The compounds of the present invention can be used as anticancer agents having excellent activity. The cancer types used are leukemia, osteosarcoma, breast cancer, ovarian cancer, stomach cancer, colon cancer, lung cancer, head and neck cancer and the like. These compounds can also be used as antibacterial agents and antiviral agents.

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

In molding into tablets, various carriers well known in the art can be widely used as carriers. Examples include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin. Solution, shellac solution,
Binders such as methylcellulose solution, hydroxypropylcellulose solution, polyvinylpyrrolidone solution, carboxymethylcellulose solution, dried starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid Disintegrators such as monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearic acid, cocoa butter, and hydrogenated oil; quaternary ammonium salts, absorption enhancers such as sodium lauryl sulfate; humectants such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, crystalline cellulose, light anhydrous silicic acid, and lubricants such as talc, stearates, boric acid powder, and polyethylene glycol; 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.

In molding into the form of pills, a wide variety of carriers conventionally known in this field can be used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, binders such as gum arabic, powder tragacanth, gelatin, disintegrants such as carmellose calcium, agar and the like. Can be mentioned.

Capsules are prepared according to a conventional method, usually 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. When it is prepared as an injection, it is generally used in the art as a diluent, for example, water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol when it is formed into a solution, emulsion or suspension. , 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, and an aqueous suspension, and an emulsion using a surfactant such as polyoxyethylene hydrogenated castor oil 60 (HCO-60) in the presence of a suitable surfactant. Used as 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.

For shaping in the form of suppositories, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

Further, if necessary, coloring agents, preservatives, fragrances, flavors, sweeteners and other pharmaceuticals can be contained in the pharmaceutical preparation.

The method of administration of the pharmaceutical preparations of the present invention is not particularly limited, and the pharmaceutical preparations are administered in accordance with various preparation forms, the age, sex and other conditions of the patient, and the degree of the 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 as a mixture with a normal replenisher such as glucose or amino acid, and if necessary, intramuscularly, subcutaneously or intraperitoneally.
Suppositories are administered rectally. Dosage of these pharmaceutical preparations of the present invention, dosage, age of patient, gender and other conditions,
Although it is appropriately selected depending on the degree of the disease, the amount of the active ingredient compound is usually 0.001 to 1,000 mg per adult day.
It is good to be about. It is desirable that the active ingredient compound be contained in a dosage unit form in the range of about 0.001 to 1,000 mg.

[0061]

The present invention will be described below with reference to examples, but the present invention is not limited to these examples. Example 1 Synthesis of [Intermediate 1] 5-{[(1-Methyl-4-nitro-1H-pyrrole-
2-yl) carbonyl] amino} -1-benzofuran-
2-carboxylic acid

[0062]

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(Reaction 1) Synthesis of ethyl 5-{[(1-methyl-4-nitro-1H-pyrrol-2-yl) carbonyl] amino} -1-benzofuran-2-carboxylate Ethyl benzofurancarboxylate (1.
41 g, 6.0 mmol) of DMF-methanol (1:
1) 10% Pd-C (200 mg) in (20 mL) solution
, And a hydrogenation reaction was carried out at room temperature for 3 hours under a hydrogen stream. The reaction solution was filtered, and the filtrate was concentrated. D for concentrated residue
Dissolve in MF (20 mL) and add 1-methyl-4-nitro-
Pyrrole 2-carboxylic acid and DCC (1.36 g, 6.6)
mmol) and HOBt (900 mg, 6.6 mmol)
l) was added and reacted at room temperature overnight. The insolubles were removed by filtration, the filtrate was concentrated, and the residue was crystallized from methanol. After filtration and drying, the desired product (1.82 g, 85%) was obtained as a colorless solid. IR (KBr) νmax 3114, 2991, 1725, 1619, 1568, 1523,
1374, 1347, 1263 cm-1; 1H NMR (DMSO-d6) δ10.3 (s, 1H), 8.28 (d, J = 2.2
Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.78 (s, 1H), 7.
73-7.65 (m, 3H), 4.37 (q, J = 7.4 Hz, 2H), 3.98
(s, 3H), 1.35 (t, J = 7.4 Hz, 3H); MS (APCI) m / z 356 (MH).

(Reaction 2) Synthesis of 5-{[(1-methyl-4-nitro-1H-pyrrol-2-yl) carbonyl] amino} -1-benzofuran-2-carboxylic acid obtained in Reaction 1 5-{[(1-methyl-4-nitro-
1H-pyrrol-2-yl) carbonyl] amino} -1
Ethyl benzofuran-2-carboxylate (2.0 g,
5.6 mmol) in 5N sodium hydroxide (3 mL),
The mixture was suspended in a mixed solution of ethanol (150 mL) and water (20 mL) and stirred at room temperature for 2 hours. The mixture was acidified with concentrated hydrochloric acid, and the precipitate was collected by filtration, washed with water, and dried to obtain the desired product (1.7).
8g, 97%) as a colorless solid. IR (KBr) νmax 3390, 3123, 1697, 1671, 1528, 1312,
1236, 1116 cm-1; 1H NMR (DMSO-d6) δ? 10.3 (s, 1H), 8.26 (d, J = 2.2
Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.75-7.64 (m,
4H), 3.98 (s, 3H); MS (APCI) m / z 284 (M-CO2).

Example 2 Synthesis of [Intermediate 2] N- [2-({[3- (dimethylamino) propyl] amino} carbonyl) -1-benzofuran-5-yl]-
1-methyl-4-nitro-1H-pyrrole-2-carboxamide

[0066]

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[Intermediate 1] (221 mg, 0.671 m
mol) in DMF (6.6 mL).
mg, 0.878 mmol) and stirred at room temperature for 30 minutes. Further, 3- (dimethylamino) propylamine (75.4 mg, 0.738 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and ethanol was added to the residue for crystallization. The crystals were collected by filtration, washed with ethanol, and dried to give the desired product (148 mg, 53%) as a colorless solid. IR (KBr) νmax 3360, 3142, 2946, 2361, 2543, 1649,
1594, 1535, 1315 cm-1; 1H NMR (DMSO-d6) δ10.2 (s, 1H), 8.79 (t, J = 5.9
Hz, 1H), 8.24 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 1.5
Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.68 (dd, J =
2.2, 8.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.52
(s, 1H), 3.98 (s, 3H), 3.31 (m, 2H), 2.27 (t, J =
6.6 Hz, 2H), 2.25 (m, 6H), 1.67 (m, 2H); MS (ESI) m / z 414 (M + H).

Example 3 4-[(2-{[amino (imino) methyl] amino} acetyl) amino] -N- [2-({[3- (dimethylamino) propyl] amino} carbonyl) -1- Benzofuran-5-yl] -1-methyl-1H-pyrrole-2-
Carboxamide [Formula 22]

[0069]

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[Intermediate 2] (200 mg, 0.484 m
mol) of DMF-methanol (1: 1) (10 mL)
10% Pd-C (92 mg) was added to the mixed solution, and a hydrogenation reaction was performed for 1 hour at room temperature under a hydrogen stream. The reaction solution was filtered, and the filtrate was concentrated. The concentrated residue was washed with DMF (3.4 m
L) and DCC (309 mg, 150 mmol)
And 2-guanidinoacetic acid hydrochloride prepared from 2-guanidinoacetic acid and 4N hydrochloric acid-2-propanol (223 mg,
(1.45 mmol) and reacted at room temperature for 30 minutes.
The insoluble material was removed by filtration, the filtrate was concentrated, and the residue was purified by reversed-phase column chromatography (C-18 ODS; water-methanol (1:10)) to give the desired product (202 mg, 80 mg).
%) As a colorless solid. mp 210-229 ℃ dec; IR (KBr) 3363, 2726, 1655, 1592, 1530, 1469, 1444,
1240, 1161 cm-1; 1H NMR (DMSO-d6)? 10.3 (s, 1H), 10.0 (s, 1H), 8.9
1 (t, J = 5.9 Hz, 1H), 8.22 (m, 1H), 7.71 (m, 1H),
7.60 (m, 1H), 7.6-7.1 (br m, 4H), 7.56 (s, 1H),
7.25 (d, J = 1.5 Hz, 1H), 7.06 (d, J = 1.5 Hz, 1
H), 4.03 (m, 2H), 3.86 (s, 3H), 3.07 (m, 2H), 3.34
(m, 2H), 2.74 (m, 6H), 1.93 (m, 2H); MS (ESI) m / z 483 (M + H); Stability analysis (C23H30N8O4-3HCl-4H2O) Calculated: C, 41.61; H, 6.22; N, 16.88; Found: C, 41.
23; H, 5.84; N, 16.62.

Example 4 Synthesis of the compound of claim 5 4-[(4- {4- [bis (2-chloroethyl) amino] phenyl} butanoyl) amino] -n- [2-
({[3- (dimethylamino) propyl] amino} carbonyl) -1-benzofuran-5-yl] -1-methyl-1H-pyrrole-2-carboxamide

[0072]

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[Intermediate 2] (140 mg, 0.339 m
mol) of DMF-methanol (1: 1) (7 mL) was added with 10% Pd-C (53 mg), and a hydrogenation reaction was performed at room temperature for 3 hours under a hydrogen stream. The reaction solution was filtered, and the filtrate was concentrated. Concentrate residue to DMF (3.4 mL)
Dissolved in DCC (85 mg, 0.414 mmol),
HOSu (47.6 mg, 0.414 mmol) and chlorambucil (114 mg, 0.376 mmol) were added and reacted at room temperature for 6 hours. The insoluble material was removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methanol-chloroform (1:10)).
After treatment with 4N hydrochloric acid-2-propanol, the desired product (94.
(5 mg, 36%) as a colorless solid. mp 250-261 ℃ dec; IR (KBr) 3422, 3284, 2953, 1654, 1590, 1519, 1468,
1442, 1238 cm-1; 1H NMR (DMSO-d6)? 10.5 (br, 1H), 9.97 (s, 1H), 9.
89 (s, 1H), 8.91 (t, J = 5.8 Hz, 1H), 8.22 (d, J =
2.2 Hz, 1H), 7.69 (dd, J = 2.2, 8.8 Hz, 1H), 7.59
(d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.23 (d, J = 1.
5 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 7.01 (d, J =
1.5 Hz, 1H), 6.68 (d, J = 8.1 Hz, 2H), 3.84 (s, 3
H), 3.70 (m, 8H), 3.36 (m, 2H), 3.09 (m, 2H), 2.75
(s, 3H), 2.74 (s, 3H), 2.50 (m, 2H), 2.25 (m, 2H),
1.93 (m, 2H), 1.82 (m, 2H); Elemental analysis (C34H42N6O4Cl2-HCl-H2O) Calculated: C, 56.34; H, 6.26; N, 11.61. Found: C, 56.
42; H, 5.96; N, 11.23.

Example 5 Synthesis of [Intermediate 4] N- (2-{[(3-amino-3-iminopropyl) amino] carbonyl} -1-benzofuran-5-yl)-
1-methyl-4-nitro-1H-pyrrole-2-carboxamide

[0075]

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(Reaction 1) N- (2-{[(2-cyanoethyl) amino] carbonyl} -1-benzofuran-5
Yl) -1-methyl-4-nitro-1H-pyrrole-2
Synthesis of Carboxamide [Intermediate 1] (1.0 g, 3.04 mmol) in DMF
(30 mL) solution was charged with CDI (739 mg, 4.56 mm).
ol) and stirred at room temperature for 30 minutes. Furthermore, 3-aminopropionitrile (639 mg, 9.11 mmol
l) was added and the mixture was stirred at room temperature for 1 hour. Concentrate the reaction,
The residue was crystallized by adding 2-propanol. After filtering,
After washing with 2-propanol and drying, the desired product (1.16
g, 100%) as a colorless solid. IR (KBr) νmax 3335, 3138, 2364, 2248, 1656, 1591,
1534, 1498, 1314 cm-1; 1H NMR (DMSO-d6) δ10.3 (s, 1H),), 9.05 (t, J = 5.
9 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.235 (d, J =
2.2 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.66 (bd, J
= 6.9 Hz, 1H), 7.64 (d, J = 6.9 Hz, 1H), 7.59 (s,
1H), 3.98 (s, 3H), 3.53 (m, 2H), 2.80 (t, J = 6.6
Hz, 2H).

(Reaction 2) N- (2-{[(3-amino-
3-Iminopropyl) amino] carbonyl {-1-benzofuran-5-yl) -1-methyl-4-nitro-1H
Synthesis of -pyrrole-2-carboxamide N- (2-｛[(2-cyanoethyl) obtained in Reaction 1)
Amino] carbonyl} -1-benzofuran-5-yl)
-1-Methyl-4-nitro-1H-pyrrole-2-carboxamide (1.20 g, 3.15 mmol) was suspended in ethanol (60 mL), and hydrochloric acid gas was blown at 0 ° C. After completion of the reaction, the mixture was concentrated, and the residue was washed twice with diethyl ether. The crystals obtained here were suspended in methanol-ethanol (1: 1) (36 mL), and ammonia gas was blown at 0 ° C. After completion of the reaction, the precipitate was collected by filtration, and 2
-Washing with propanol and drying to give the desired product (1.30 g,
95%) as a colorless solid. IR (KBr) νmax 3394, 3111, 1697, 1648 1592, 1546, 1
313, 1238 cm-1; 1H NMR (DMSO-d6) δ 10.3 (bs, 1H), 8.97 (bs, 1H), 8.
8 (br, 2H), 8.243 (s, 1H), 8.239 (s, 1H), 7.74 (d,
J = 2.2 Hz, 1H), 7.70 (dd, J = 2.2, 8.8 Hz, 1H), 7.
64 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 3.98 (s, 3
H), 3.62 (m, 2H), 2.66 (t, J = 6.9 Hz, 2H); MS (ESI) m / z 399 (M + H).

Example 6 Synthesis of the compound of claim 6 N- (2-{[3-amino-3-iminopropyl] amino} carbonyl) -1-benzofuran-5) -4-
[(4- {4- [bis (2-chloroethyl) amino] phenyl} butanoyl) amino] -1-methyl-1H-pyrrole-2-carboxamide

[0079]

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[Intermediate 4] (218 mg, 0.501 mm
ol) in a mixed solution of DMF-methanol (1: 1) (16 mL) was added with 10% Pd-C (95 mg), and a hydrogenation reaction was performed at room temperature for 1 hour under a hydrogen stream. The reaction solution was filtered, and the filtrate was concentrated. The concentrated residue was dissolved in DMF (5 mL), DCC (134 mg, 0.652 mmol), D
MAP (catalytic amount) and chlorambucil (168 mg,
0.551 mmol) and reacted at room temperature overnight. The insoluble material was removed by filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate-2-propanol-).
Water (6: 2: 1)) to give the desired product (78.6 mg,
23%) as a colorless solid. mp 95-100 ° C; IR (KBr) 3278, 3103, 1648, 1590, 1519, 1468, 1443,
1351, 1238 cm-1; 1H NMR (DMSO-d6)? 9.95 (s, 1H), 9.84 (s, 1H), 9.0
4 (s, 1H), 8.93 (t, J = 5.9 Hz, 1H), 8.65 (s, 2H),
8.22 (bs, 1H), 7.70 (dd, J = 2.2, 8.8 Hz, 1H), 7.5
9 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.21 (d, J =
1.5 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 7.01 (bs, 1
H), 6.67 (d, J = 8.1 Hz, 2H), 3.84 (s, 3H), 3.70
(m, 8H), 3.62 (m, 2H), 2.68 (m, 2H), 2.51 (m, 2H),
2.25 (m, 2H), 1.82 (m, 2H); Elemental analysis (C32H37N7O4Cl2-HCl-0.5H2O) Calculated C, 54.90; H, 5.61; N, 14.01. Found: C, 54.
59; H, 5.84; N, 13.67.

Example 7 Synthesis of [Intermediate 3] N- {2-[({4- [bis (2-chloroethyl) amino] phenyl} amino) carbonyl] -1-benzofuran-5-yl} -1- Methyl-4-nitro-1H-pyrrole-2-carboxamide

[0082]

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[Intermediate 1] (494 mg, 1.5 mmol
1), N-bis (2-chloroethyl) -1,4-phenylenediamine hydrochloride (404 mg, 1.5 mmol) and triethylamine (0.62 mL, 4.5 mmol)
DECP was added to a solution of the mixture in DMF (5 mL) at 0 ° C.
(0.34 mL, 2.25 mmol) was added. After stirring at room temperature for 30 minutes, the mixture was concentrated, and methanol was added to the residue for crystallization. After each treatment of filtration, washing with methanol, and drying, the desired product (690 mg, 85%) was obtained as dark yellow amorphous crystals. IR (KBr) 3431, 1663, 1655, 1519, 1310, 1247, 816 c
m-1; 1H NMR (DMSO-d6) δ 10.32 (s, 1H), 10.28 (s, 1H),
8.25 (s, 2H), 7.74-7.68 (m, 4H), 7.64 (d, J = 8.
8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 3.98 (s, 3H),
3.74 (m, 8H); MS (ESI) m / z 544 (M +).

Example 8 Synthesis of the compound of claim 3 4-[(2-{[amino (imino) methyl] amino} acetyl) amino] -N- {2-[({4- [bis (2-
Chloroethyl) amino] phenyl {amino) carbonyl] -1-benzofuran-5-yl} -1-methyl-1
H-pyrrole-2-carboxamide (formula (3)
7])

[0085]

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[Intermediate 3] (200 mg, 0.367 mm
ol) in a mixed solution of DMF-methanol (1: 1) (10 mL) was added with 10% Pd-C (200 mg), and a hydrogenation reaction was performed for 1 hour at room temperature under a stream of hydrogen. The reaction solution was filtered, and the filtrate was concentrated. The concentrated residue was dissolved in DMF (6 mL), and DCC (227 mg, 1.1 mmol) and 2
-2-guanidinoacetic acid hydrochloride prepared from guanidinoacetic acid and 4N hydrochloric acid-2-propanol (169 mg, 1.1
mmol) and reacted at room temperature for 30 minutes. The insoluble material was removed by filtration, the filtrate was concentrated, and the residue was purified by gel chromatography (Sephadex LH-20; methanol) to obtain the desired product (130 mg, 55%) as a pale yellow solid. IR (KBr) 3309, 1675, 1644, 1598, 1520, 1446, 1327,
1241, 1158 cm-1; 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 10.2 (bs, 1H), 9.
99 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.75-7.6
(m, 3H), 7.64 (d, J = 8.8 Hz, 2H), 7.55-7.2 (br,
4H), 7.25 (d, J = 1.5 Hz, 1H), 7.05 (d, J = 1.5 H
z, 1H), 6.77 (d, J = 8.8 Hz, 2H), 4.02 (s, 2H), 3.8
7 (s, 3H), 3.74 (m, 8H); MS (ESI) m / z 613 (M + H).

Example 9 Synthesis of the compound of claim 4 N- {2-[({4- [bis (2-chloroethyl) amino] phenyl} amino) carbonyl] -1-benzofuran-5-yl} -1- Methyl-4-{[3- (methylthio) propanoyl] amino} -1H-pyrrole-2-carboxamide (Formula (4)

[0088]

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[Intermediate 3] (270 mg, 0.5 mmol
10% Pd-C (200 mg) was added to a mixed solution of 1) in DMF-methanol (1: 1) (10 mL), and a hydrogenation reaction was performed for 1 hour at room temperature under a hydrogen stream. The reaction solution was filtered, and the filtrate was concentrated. After dissolving the concentrated residue in DMF (6 mL) and adding triethylamine (0.084 mL), CDI (243 mg, 1.5 mmol) and 3-methylthiopropionic acid (180 mg, 1.5 mmol)
Of DMF (3 mL) was added and reacted at room temperature for 3 hours. After concentrating the reaction solution, the residue was purified by silica gel chromatography (methanol-chloroform (1:20)) to obtain the desired product (215 mg, 70%) as a pale yellow solid. IR (KBr) 3414, 1655, 1595, 1519, 1442, 1246 cm-1; 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 9.96 (s, 1H), 9.9
3 (s, 1H), 8.23 (d, J = 1.5 Hz, 1H), 7.75-7.6 (m,
3H), 7.64 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 2.2 Hz,
1H), 7.00 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 8.8 H
z, 2H), 3.85 (s, 3H), 3.74 (m, 8H), 2.74 (m, 2H),
2.55 (m, 2H), 2.09 (s, 3H); MS (ESI) m / z 616 (M + H).

Example 10 Synthesis of the compound of claim 2 [3-({5-[({2-[({4- [bis (2-chloroethyl) amino] phenyl} amino) carbonyl] -carbonyl]-
1-benzofuran-5-yl {amino) carbonyl]-
1-methyl-1H-pyrrol-3-yl {amino) -3
-Oxopropyl] (dimethyl) sulfonium iodide (Formula (2) [Formula 29])

[0091]

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Compound (4), that is, the compound of Example 9 (N- ｛2-[(｛4- [bis (2-chloroethyl)
Amino] phenyl {amino) carbonyl] -1-benzofuran-5-yl} -1-methyl-4-{[3- (methylthio) propanoyl] amino} -1H-pyrrole-2
-Carboxamide) (95 mg, 0.154 mmol)
Of methyl iodide (0.8 mL, 12.9 mmol) in a mixed solution of 80% formic acid (1 mL) -acetic acid (0.5 mL)
l) was added and stirred for 3 days. The reaction solution was concentrated, and ethanol was added to the residue for crystallization. After each treatment of filtration, washing with ethanol, and drying, the target product (60 mg, 51%) was obtained as dark red amorphous crystals. IR (KBr) 3450, 3273, 1656, 1596, 1519, 1443, 1326,
1248 cm-1; 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 10.2 (s, 1H), 9.9
7 (s, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.73-7.6 (m,
5H), 7.25 (d, J = 1.5 Hz, 1H), 7.02 (d, J = 1.5 H
z, 1H), 6.77 (d, J = 9.5 Hz, 2H), 3.87 (s, 3H), 3.
74 (m, 8H), 3.52 (m, 2H), 2.94 (s, 6H), 2.91 (m, 2
H); MS (ESI) m / z 631 (M + H).

Test Example 1 The antitumor activity of these compounds will be described. The method is the measurement of an in vitro tumor cell inhibitory effect. 96
Sow mouse B16 melanoma cells on a well culture plate,
One day later the drug is added and for another 3 days at 37 ° C. in 5% CO 2
And cultured. Cancer Res. According to the method described in 1988, 48, 589-601, the concentration of drug required to cause 50% growth inhibition was determined. Table-1
Table 1 shows the antitumor activity of representative compounds. The unit is microgram / milliliter. As a comparative example, the results of distamycin are also shown.

[0094]

[Table 1]

[0095]

The compound of the present invention is a new compound acting on DNA or a new compound having a partial structure acting on DNA and is useful as an anticancer agent.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Kazue Etsuji 1900-1 Togo, Mobara City, Chiba Prefecture Mitsui Pharmaceutical Co., Ltd. F-term (reference) 4B024 AA01 GA23 4C063 AA01 BB09 CC76 DD04 EE01 4C084 AA02 AA07 BA01 BA10 BA32 CA59 DA27 DA42 MA17 MA22 MA23 MA31 MA35 MA37 MA41 MA66 NA14 ZA592 ZA662 ZA812 ZB261 ZB262 ZB271 ZB272 ZB332 ZB352 4C086 AA01 AA02 AA03 BC05 GA02 GA07 MA01 MA04 NA14 ZA59 ZA66 ZA81 ZA96 ZB26 ZB35 ZB33

Claims (7)

[Claims] 1. A compound of the general formula (1)[Wherein, m and n each independently represent an integer of 0 to 5,
R1 and R2 each independently represent an amidino group, guanidyl
A group, an amino group substituted with an alkyl group having 1 to 5 carbon atoms,
A thio group substituted with an alkyl group having 1 to 5 carbon atoms,
A sulfonium group substituted with 1 to 5 alkyl groups,
-N ((CH_Two)_Two-Y) _TwoReplaced by
Phenyl group (where Y is chlorine atom, bromine atom,
Represents a tansulfonyl group. ). ]
Nzofuranylpyrrole carboxamide derivative or its
Pharmacologically acceptable salts. 2. A compound of the formula (2) Or a pharmacologically acceptable salt thereof. 3. A compound of the formula (3) Or a pharmacologically acceptable salt thereof. 4. A compound of the formula (4) Or a pharmacologically acceptable salt thereof. 5. A compound of the formula (5) Or a pharmacologically acceptable salt thereof. 6. A compound of the formula (6) Or a pharmacologically acceptable salt thereof. 7. An anticancer agent comprising the benzofuranylpyrrole carboxamide derivative according to claim 1 as an active ingredient.