JPH08269008A - Compound having distamycin-like structure and antitumor agent containing the compound - Google Patents

Abstract

PURPOSE: To obtain a new compound having suppressing activity against the growth of tumor cells and useful for treatment of leukemia, osteosarcoma, breast cancer, gastric cancer, etc., when used as an antitumor agent by modifying a partial structure of distamycin. CONSTITUTION: A compound of formula I [R1 is H, R3 (CH2 )r C0NH (R3 is H, amino, etc.; r:0-5), etc.; R2 is H, amidino, etc.; (m) and (n) are each 0,1; (m) and (n) can not be zero at the same time; t=0-5] or its salt, e.g. 4-benzoylamino- l-methyl-N-[3-(N,N-dimethylamino)propyl]-2-pyrrolecarboxamide. The compound is obtained e.g. by hydrogenating a nitro compound of formula II in the presence of a Pd/C catalyst in a solvent such as methanol to convert to an amino compound and subsequently subjecting the product to condensation reaction with chlorambucil of formula III. A nitro compound of formula II is obtained e.g. by starting from 4-(1-methyl-4-nitro-2-pyrrolecarboxamide)benzoic acid ethyl ester.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a compound having a distamycin-like structure which suppresses the growth of cancer cells, and a pharmaceutical composition containing the same.

[0002]

BACKGROUND OF THE INVENTION Distamycin or Netropsin is known as a substance having antitumor activity (Nature, 1964, 203).
Vol. 1064-65). It is known that these compounds have N-methylpyrrole as a constitutional unit, and are characterized by a structure in which the N-methylpyrrole is bound by 2 to 3 units by an amide bond. That is, it can be imagined that the repeating structure in which the N-methylpyrrole is bonded with an amide is one structural feature showing an anticancer effect.

A compound having a form in which a partial structure of an alkylating agent is bonded to distamycin has already been shown (J. Am. Chem. Soc. 1985, 107).
Volume, pages 8266-8268, or the same magazine, 1989.
111, 2700-2712). An example of an anticancer drug having such a structure is also shown (J. Med. Ch.
em. 1989, Vol. 32, pp. 774-778, JP-A-62-294653, JP-A-3-504863). It is possible that a part of the anticancer activity of such a compound is borne by the repeating structure of the ring structure linked by the amide bond. However, the few findings to date suggest that the ring structure connected by an amide bond may play a part in the anticancer activity, but which of these substructures is the structure that is really required, or It is completely impossible at this time to predict what other structures could be substituted. The fact that several different examples are given in particular predicts the presence of compounds with otherwise 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, regarding the alkylated partial structure for binding to the repeating structure of the ring structure, no example was found in which what kind of structure was optimal as an anticancer agent was not found. By the way, Chlorambucil (Chl
The same as anticancer agents such as nitrogen mustard, is an anticancer agent belonging to an alkylating agent having an N, N-bis (2-chloroethyl) amino group. The anticancer activity of chlorambucil is believed to be the result of alkylation to DNA, enzymes and the like. Although the anti-cancer activity of this compound is tentatively established, the activity is not necessarily higher than that of other anti-cancer agents.

[0004]

DISCLOSURE OF THE INVENTION The present inventors anticipate the existence of a group of compounds having a structure similar to distamycin and capable of being an important partial structure as an anticancer agent, and thus, they are newly required for anticancer activity. We searched for a partial structure. Moreover, since the anticancer activity of distamycin can be expected to be enhanced by the addition of an alkylating moiety, this was also investigated at the same time.

[0005]

[Means for Solving the Problems] In order to solve these problems, the present inventors synthesized a novel compound in which a partial structure of distamycin was converted, and searched for a skeleton showing a useful action as an anticancer agent. It was As a result, the inventors have found 4-benzoylamino-1-methyl-2-pyrrolecarboxamide derivatives or 1-methyl-N-phenyl-2-pyrrolecarboxamide derivatives as compounds useful as anticancer agents, and completed the present invention. These compounds are
At present, there is no knowledge as an anticancer drug. These compounds exhibited tumor cell growth inhibitory activity equivalent to that of distamycin. Further, as shown below, the compound to which chlorambucil or a compound having a similar structure to it was bound showed higher anticancer activity than distamycin or chlorambucil. From the above, the present inventors
The present invention has completed the invention of providing a new anticancer agent which is a novel substance that acts on. That is, the present invention is a compound represented by the following formula (1) [Chemical Formula 3] or a pharmaceutically acceptable salt thereof.

[0006]

Embedded image [However, R ₁ is hydrogen, R ₃ — (CH ₂ ) _r —CONH— or a group represented by the formula (2) [Chemical Formula 4]. R ₂ is hydrogen,
Amino group, aliphatic amino group, amidino group, guanidino group, trimethylammonium group, triethylammonium group, dimethylsulfonium group, diethylsulfonium group, phenyl group, substituted phenyl group, pyridyl group,
A group selected from an N-methylpyridyl group, a thienyl group, a furyl group, a pyrrolyl group, an N-methylpyrrolyl group or a group represented by the formula (2) [Chemical formula 4]. m and n represent 0 or 1. However, m and n are not 0 at the same time.
t represents an integer of 0 to 5. (However, R ₃ is hydrogen, amino group, dimethylamino group, aliphatic amino group, amidino group, guanidino group, trimethylammonium group, triethylammonium group, dimethylsulfonium group, diethylsulfonium group, pyridyl group, N-methylpyridyl group. , A thienyl group, a furyl group, a pyrrolyl group, and an N-methylpyrrolyl group, where r is an integer of 0 to 5.)

[0007]

[Chemical 4] (However, p is an integer of 0 to 5, and q is ₁ when the compound of the formula (2) represents R _1. The compound of the formula (2) is R ₂
Is 0 or 1. R ₄ is an alkyl group having 1 to 5 carbon atoms, an alkoxyl group having 1 to 5 carbon atoms, an amino group, a carboxyl group, a trifluoromethyl group, or a halogen atom. Further, X and Y are hydrogen or -N (CH ₂ C
H ₂ Cl) ₂ and both X and Y cannot be hydrogen at the same time. )] Hereinafter, the present invention will be described in more detail. In the compound of formula (1), the aliphatic amino group for R ₂ and R ₃ is a dimethylamino group, a diethylamino group, a dipropylamino group, a piperazinyl group, a 1-methylpiperazinyl group, a morpholino group, or a piperidino group. desirable. As the substituted phenyl group, 3-methoxyphenyl group, 4-
A methoxyphenyl group and a 3,4,5-methoxyphenyl group are desirable. Halogen atoms are F, Cl, Br.
The pharmacologically acceptable salt is, for example, an inorganic salt such as hydrochloride or sulfate, or an organic salt such as p-toluenesulfonate, acetate or oxalate.

Among the compounds represented by the formula (1), 4-benzoylamino-1-methyl-2-pyrrolecarboxamide derivative means 4- [4- [4- [N, N-bis (2
-Chloroethyl) amino] phenyl] butyrylamino]
Benzoylamino-1-methyl-2-pyrrolecarboxamide [N-substituted] derivative, 4- [4- [3- [N, N
-Bis (2-chloroethyl) amino] phenyl] butyrylamino] benzoylamino-1-methyl-2-pyrrolecarboxamide [N-substituted] derivative, 4- [4-
[N, N-bis (2-chloroethyl) amino] benzoylamino] benzoylamino-1-methyl-2-pyrrolecarboxamide [N-substituted] derivative, 4- [3-methyl-4- [4- [N, N -Bis (2-chloroethyl) amino]] benzoylamino] benzoylamino-1-methyl-2-pyrrolecarboxamide [N-substituted] derivative, 4- [3-chloro-4- [4- [N, N-bis ( Two
-Chloroethyl) amino]] benzoylamino] benzoylamino-1-methyl-2-pyrrolecarboxamide [N-substituted] derivative, 4- [substituted] benzoylamino-
1-methyl-2-pyrrolecarboxamide [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl]] derivative, 4- [substituted] benzoylamino-1-methyl-2-pyrrolecarboxamide [N-4- [3-
[N, N-bis (2-chloroethyl) amino] phenyl]] derivative.

The 1-methyl-N-phenyl-2-pyrrolecarboxamide derivative means 4- [4- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl] butyrylamino] -1-methyl-N- [substituted] phenyl-2-
Pyrrole carboxamide derivative, 4- [4- [3-
[N, N-bis (2-chloroethyl) amino] phenyl] butyrylamino] -1-methyl-N- [substituted] phenyl-2-pyrrolecarboxamide derivative, 4- [4-
[N, N-bis (2-chloroethyl) amino] benzoylamino] -1-methyl-N- [substituted] phenyl-2-
Pyrrole carboxamide derivative, 3- [N, N-bis (2-chloroethyl) amino] benzoylamino-1-
Methyl-N- [substituted] phenyl-2-pyrrolecarboxamide derivative, 4- [substituted] -1-methyl-N- [4-
[4- [N, N-bis (2-chloroethyl) amino] benzoylamino] phenyl] -2-pyrrolecarboxamide derivative, 4- [substituted] -1-methyl-N- [4-
[3-Methyl-4- [N, N-bis (2-chloroethyl) amino] benzoylamino] phenyl] -2-pyrrolecarboxamide derivative, 4- [substituted] -1-methyl-N- [4- [3- [3- Chloro-4- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] phenyl]
-2-Pyrrolecarboxamide derivative, 4- [substituted]-
1-methyl-N- [4- [3- [N, N-bis (2-chloroethyl) amino] benzoylamino] phenyl]-
A compound having any of 2-pyrrolecarboxamide derivatives.

Among these desirable examples are as follows:
There is. Each is pharmacologically similar to the corresponding hydrochloride salt
The salt form acceptable for the above is also a desirable form. (Compound 1) 4-benzoylamino-1-methyl-N-
[3- (N, N-dimethylamino) propyl] -2-pi
Roll carboxamide (Compound 2) 4-benzoylamino-1-methyl-N-
(2-amidinoethyl) -2-pyrrolecarboxamide (Compound 3) 4-benzoylamino-1-methyl-N-
(3,4,5-Trimethoxyphenyl) -2-pyrrole
Carboxamide (Compound 4) 4-[(3-formylamino) benzoyl
Amino] -1-methyl-N- [3- (N, N-dimethyl
Amino) propyl] -2-pyrrolecarboxamide (Compound 5) 4-[(4-formylamino) benzoyl
Amino] -1-methyl-N- [3- (N, N-dimethyl
Amino) propyl] -2-pyrrolecarboxamide (Compound 6) 4- [3- (4-formylamino-1-me
Cyl-2-pyrrolecarboxamido) benzoylami
No] -1-methyl-N- [3- (N, N-dimethylamido
No) propyl] -2-pyrrolecarboxamide (Compound 7) 4- [4- (4-formylamino-1-me
Cyl-2-pyrrolecarboxamido) benzoylami
No] -1-methyl-N- [3- (N, N-dimethylamido
No) propyl] -2-pyrrolecarboxamide (Compound 8) 3- (4-formylamino-1-methyl-
2-pyrrolecarboxamide) -N- [3- (N, N-
Dimethylamino) propyl] benzcarboxamide (Compound 9) 4- (4-formylamino-1-methyl-
2-pyrrolecarboxamide) -N- [3- (N, N-
Dimethylamino) propyl] benzcarboxamide (Compound 10) 4- [3- [4- [4- [N, N-bis
(2-Chloroethyl) amino] phenyl] butyrylamine
No] benzoylamino] -1-methyl-N- [3-
(N, N-Dimethylamino) propyl] -2-pyrrole
Carboxamide (Compound 11) 4- [4- [4- [4- [N, N-bis
(2-Chloroethyl) amino] phenyl] butyrylamine
No] benzoylamino] -1-methyl-N- [3-
(N, N-Dimethylamino) propyl] -2-pyrrole
Carboxamide (Compound 12) 4- [3- [4- [4- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl] butyri
Lumino] -1-methyl-2-pyrrolecarboxami
De] benzoylamino] -1-methyl-N- [3-
(N, N-Dimethylamino) propyl] -2-pyrrole
Carboxamide (Compound 13) 4- [4- [4- [4- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl] butyri
Lumino] -1-methyl-2-pyrrolecarboxami
De] benzoylamino] -1-methyl-N- [3-
(N, N-Dimethylamino) propyl] -2-pyrrole
Carboxamide (Compound 14) 4- [3- [4- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] benzoyl
Amino] -1-methyl-N- [3- (N, N-dimethyl
Amino) propyl)]-2-pyrrolecarboxamide (Compound 15) 4- [4- [4- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] benzoyl
Amino] -1-methyl-N- [3- (N, N-dimethyl
Amino) propyl] -2-pyrrolecarboxamide (Compound 16) 4- [3- [3- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] benzoyl
Amino] -1-methyl-N- [3- (N, N-dimethyl
Amino) propyl] -2-pyrrolecarboxamide (Compound 17) 4- [4- [3- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] benzoyl
Amino] -1-methyl-N- [3- (N, N-dimethyl
Amino) propyl] -2-pyrrolecarboxamide (Compound 18) 4- [4- [4- [3- [N, N-bis
(2-Chloroethyl) amino] benzoylamino] -1
-Methyl-2-pyrrolecarboxamide] benzoylurea
Mino] -1-methyl-N- [3- (N, N-dimethylacetate
Mino) propyl] -2-pyrrolecarboxamide (Compound 19) 4- [4- [3- [4- [N, N-bis
(2-Chloroethyl) amino] benzoylamino] -1
-Methyl-2-pyrrolecarboxamide] benzoylurea
Mino] -1-methyl-N- [3- (N, N-dimethylacetate
Mino) propyl] -2-pyrrolecarboxamide (Compound 20) 4- [3- (formylamino) benzoi
Lumino] -1-methyl-N- (2-amidinoethyl)
-2-Pyrrolecarboxamide (Compound 21) 4- [4- (formylamino) benzoi
Lumino] -1-methyl-N- (2-amidinoethyl)
-2-Pyrrolecarboxamide (Compound 22) 4- [3- (4-Formylamino-1-
Methyl-2-pyrrolecarboxamido) benzoylami
No] -1-methyl-N- (2-amidinoethyl) -2-
Pyrrolecarboxamide (Compound 23) 4- [4- (4-formylamino-1-)
Methyl-2-pyrrolecarboxamido) benzoylami
No] -1-methyl-N- (2-amidinoethyl) -2-
Pyrrolecarboxamide (Compound 24) 4- [4- [4- [4- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl] butyri
Lumino] -1-methyl-2-pyrrolecarboxami
De] benzoylamino] -1-methyl-N- (2-ami
(Dinoethyl) -2-pyrrolecarboxamide (Compound 25) 4- [3- [4- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] benzoyl
Amino] -1-methyl-N- (2-amidinoethyl)-
2-Pyrrolecarboxamide (Compound 26) 4- [4- [4- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] benzoyl
Amino] -1-methyl-N- (2-amidinoethyl)-
2-Pyrrolecarboxamide (Compound 27) 4- [3- [3- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] benzoyl
Amino] -1-methyl-N- (2-amidinoethyl)-
2-Pyrrolecarboxamide (Compound 28) 4- [4- [3- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] benzoyl
Amino] -1-methyl-N- (2-amidinoethyl)-
2-Pyrrolecarboxamide (Compound 29) 4- [4- [4- [3- [N, N-bis
(2-Chloroethyl) amino] benzoylamino] -1
-Methyl-2-pyrrolecarboxamide] benzoylurea
Mino] -1-methyl-N- (2-amidinoethyl) -2
-Pyrrolecarboxamide (Compound 30) 4- [4- [3- [4- [N, N-bis
(2-Chloroethyl) amino] benzoylamino] -1
-Methyl-2-pyrrolecarboxamide] benzoylurea
Mino] -1-methyl-N- (2-amidinoethyl) -2
-Pyrrole carboxamide (Compound 31) 4- [3- [4- [4- [N, N-bis
(2-Chloroethyl) amino] benzoylamino] -1
-Methyl-2-pyrrolecarboxamide] benzoylurea
Mino] -1-methyl-N- (2-amidinoethyl) -2
-Pyrrole carboxamide (Compound 32) 4- [4- [4- [4- [N, N-bis
(2-Chloroethyl) amino] benzoylamino] -1
-Methyl-2-pyrrolecarboxamide] benzoylurea
Mino] -1-methyl-N- (2-amidinoethyl) -2
-Pyrrole carboxamide (Compound 33) 4- [3- [4- [3- [N, N-bis
(2-Chloroethyl) amino] benzoylamino] -1
-Methyl-2-pyrrolecarboxamide] benzoylurea
Mino] -1-methyl-N- (2-amidinoethyl) -2
-Pyrrole carboxamide (Compound 34) 4- [4- [4- [3- [N, N-bis
(2-Bromoethyl) amino] benzoylamino] -1
-Methyl-2-pyrrolecarboxamide] benzoylurea
Mino] -1-methyl-N- (2-amidinoethyl) -2
-Pyrrolecarboxamide (Compound 35) 4- [3- [4- [4- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl] butyri
Lumino] -1-methyl-2-pyrrolecarboxami
Do] benzoylamino] -1-methyl-N- (3,4,
5-trimethoxyphenyl) -2-pyrrolecarboxa
Mido (Compound 36) 4- [4- [4- [4- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl] butyri
Lumino] -1-methyl-2-pyrrolecarboxami
Do] benzoylamino] -1-methyl-N- (3,4,
5-trimethoxyphenyl) -2-pyrrolecarboxa
Mido (Compound 37) 4- [3- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 38) 4- [4- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 39) 4- [3- (guanidinoacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
]]-2-Pyrrolecarboxamide (Compound 40) 4- [4- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 41) 4- [3- [4- [4- (N, N-dime
Cylamino) butyrylamino] -1-methyl-2-pyrro
Carboxamide] benzoylamino] -1-methyl
-N- [4- [N, N-bis (2-chloroethyl) ami]
No] phenyl] -2-pyrrolecarboxamide (Compound 42) 4- [4- [4- [4- (N, N-dime
Cylamino) butyrylamino] -1-methyl-2-pyrro
Carboxamide] benzoylamino] -1-methyl
-N- [4- [N, N-bis (2-chloroethyl) ami]
No] phenyl] -2-pyrrolecarboxamide (Compound 43) 4- [3- [4- (guanidinoacetyl
Amino) -1-methyl-2-pyrrolecarboxamide]
Benzoylamino] -1-methyl-N- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl] -2-
Pyrrolecarboxamide (Compound 44) 4- [4- [4- (guanidinoacetyl
Amino) -1-methyl-2-pyrrolecarboxamide]
Benzoylamino] -1-methyl-N- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl] -2-
Pyrrolecarboxamide (Compound 45) 4- [3- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-bromoethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 46) 4- [3- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [3-
[N, N-bis (2-chloroethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 47) 4- [3- [4- (N, N-diethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 48) 4- [3- (guanidinoacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-bromoethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 49) 4- [4- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [3- [N, N-bis (2-chloroethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 50) 4- [4- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-bromoethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 51) 4- [3- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [3- [N, N-bis (2-chloroethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 52) 4- [4- [4- (N, N-diethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 53) 4- [3- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [3-
[N, N-bis (2-bromoethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 54) 4- [3- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 55) 4- [3- [4- [4- (N, N-die
Cylamino) butyrylamino] -1-methyl-2-pyrro
Carboxamide] benzoylamino] -1-methyl
-N- [4- [N, N-bis (2-chloroethyl) ami]
No] phenyl] -2-pyrrolecarboxamide (Compound 56) 4- [4- [4- [4- (N, N-die
Cylamino) butyrylamino] -1-methyl-2-pyrro
Carboxamide] benzoylamino] -1-methyl
-N- [4- [N, N-bis (2-chloroethyl) ami]
No] phenyl] -2-pyrrolecarboxamide (Compound 57) 4- [3- [4- (piperidinoacetyl)
Amino) -1-methyl-2-pyrrolecarboxamide]
Benzoylamino] -1-methyl-N- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl] -2-
Pyrrolecarboxamide (Compound 58) 4- [4- [4- (guanidinoacetyl
Amino) -1-methyl-2-pyrrolecarboxamide]
Benzoylamino] -1-methyl-N- [4- [N, N
-Bis (2-bromoethyl) amino] phenyl] -2-
Pyrrolecarboxamide (Compound 59) 4- [3- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 60) 4- [3- (piperazinoacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 61) 4- [3- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-bromoethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 62) 4- [3- (3-pyridylacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 63) 4- [4- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [3- [N, N-bis (2-bromoethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 64) 4- [4- (piperazinoacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 65) 4- [3- [4- (N, N-diethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-bromoethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 66) 4- [4- [4- (N, N-dimethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-bromoethyl) a]
Mino] phenyl] -2-pyrrolecarboxamide (Compound 67) 4- [3- (4-pyridylacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 68) 4- [4- (3-pyridylacetylamid
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] -2-pyrrolecarboxamide (Compound 69) 4- [3- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino-3-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 70) 4- [4- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino-3-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 71) 4- [3- (guanidinoacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 72) 4- [4- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 73) 4- [3- [4- [4- (N, N-dime
Cylamino) butyrylamino] -1-methyl-2-pyrro
Carboxamide] benzoylamino] -1-methyl
-N- [4- [N, N-bis (2-chloroethyl) ami]
No-3-methyl] phenyl] -2-pyrrolecarboxa
Mido (Compound 74) 4- [4- [4- [4- (N, N-dim
Cylamino) butyrylamino] -1-methyl-2-pyrro
Carboxamide] benzoylamino] -1-methyl
-N- [4- [N, N-bis (2-chloroethyl) ami]
No-3-methyl] phenyl] -2-pyrrolecarboxa
Mido (Compound 75) 4- [3- [4- (guanidinoacetyl
Amino) -1-methyl-2-pyrrolecarboxamide]
Benzoylamino] -1-methyl-N- [4- [N, N
-Bis (2-chloroethyl) amino-3-methyl] phen
Nyl] -2-pyrrolecarboxamide (Compound 76) 4- [4- [4- (guanidinoacetyl
Amino) -1-methyl-2-pyrrolecarboxamide]
Benzoylamino] -1-methyl-N- [4- [N, N
-Bis (2-chloroethyl) amino-3-methyl] phen
Nyl] -2-pyrrolecarboxamide (Compound 77) 4- [3- [4- (N, N-diethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino-3-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 78) 4- [3- (1-Methylpiperazinyl aurea
Cetylamino) benzoylamino] -1-methyl-N-
[4- [N, N-bis (2-chloroethyl) amino-3
-Methyl] phenyl] -2-pyrrolecarboxamide (Compound 79) 4- [3- [4- (N, N-diethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-bromoethyl) a]
Mino-3-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 80) 4- [3- (piperidinoacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 81) 4- [4- [4- (N, N-diethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino-3-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 82) 4- [4- (4-pyridylacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 83) 4- [3- [4- (N, N-dimethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-bromoethyl) a]
Mino-3-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 84) 4- [4- [4- (N, N-dimethylacetate
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-bromoethyl) a]
Mino-3-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 85) 4- [3- (3-pyridylacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 86) 4- [4- (3-pyridylacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 87) 4- [3- [4- [4- (N, N-die
Cylamino) butyrylamino] -1-methyl-2-pyrro
Carboxamide] benzoylamino] -1-methyl
-N- [4- [N, N-bis (2-chloroethyl) ami]
No-3-methyl] phenyl] -2-pyrrolecarboxa
Mido (Compound 88) 4- [4- [4- [4- (N, N-die
Cylamino) butyrylamino] -1-methyl-2-pyrro
Carboxamide] benzoylamino] -1-methyl
-N- [4- [N, N-bis (2-chloroethyl) ami]
No-3-methyl] phenyl] -2-pyrrolecarboxa
Mido (Compound 89) 4- [3- (4-pyridylacetylamido)
No-1-methyl-2-pyrrolecarboxamido) benzo
Ilamino] -1-methyl-N- [4- [N, N-bis
(2-Chloroethyl) amino-3-methyl] phenyl]
-2-Pyrrolecarboxamide (Compound 90) 4- [4- (4-Pyridylacetylamido)
No-1-methyl-2-pyrrolecarboxamido) benzo
Ilamino] -1-methyl-N- [4- [N, N-bis
(2-Chloroethyl) amino-3-methyl] phenyl]
-2-Pyrrolecarboxamide (Compound 91) 4- (3-Piperazinoacetylaminobe
Nazoylamino) -1-methyl-N- [4- [N, N-
Bis (2-chloroethyl) amino-3-methyl] phenyl
]]-2-Pyrrolecarboxamide (Compound 92) 4- [3- (4-Pyridylacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 93) 4- [3- [4- (N, N-dimethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino-2-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 94) 4- [3- (guanidinoacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-2-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 95) 4- [4- [4- (N, N-dimethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino-2-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 96) 4- [4- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-2-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 97) 4- [3- [4- (N, N-diethyla
Mino) butyrylamino] benzoylamino] -1-methyl
Ru-N- [4- [N, N-bis (2-chloroethyl) a]
Mino-2-methyl] phenyl] -2-pyrrolecarboxy
Samide (Compound 98) 4- [4- (4- (pyridylacetylacea
Mino) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-2-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 99) 4- [3- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-methyl
Lu] phenyl] -2-pyrrolecarboxamide (Compound 100) 4- (4-piperidinoacetylamino)
Benzoylamino) -1-methyl-N- [4- [N, N
-Bis (2-chloroethyl) amino-3-methyl] phen
Nyl] -2-pyrrolecarboxamide (Compound 101) 4- [3- [3- (N, N-dimethyl
Amino) propylcarboxamide] benzoylamino]
-1-Methyl-N- [4- [N, N-bis (2-chloro
Ethyl) amino-3-chloro] phenyl] -2-pillo
Rucarboxamide (Compound 102) 4- [4- [3- (N, N-dimethyl
Amino) propylcarboxamide] benzoylamino]
-1-Methyl-N- [4- [N, N-bis (2-chloro
Ethyl) amino-3-chloro] phenyl] -2-pillo
Lucarboxamide (Compound 103) 4- [3- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-chloro
[] Phenyl] -2-pyrrolecarboxamide (Compound 104) 4- [4- (guanidinoacetylamido)
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-chloro
[] Phenyl] -2-pyrrolecarboxamide (Compound 105) 4- [3- [4- [3- (N, N-di
Methylamino) propylcarboxamide] -1-methyl
-2-Pyrrolecarboxamide] benzoylamino]-
1-methyl-N- [4- [N, N-bis (2-chloroe
Cyl) amino-3-chloro] phenyl] -2-pyrrole
Carboxamide (Compound 106) 4- [4- [4- [3- (N, N-di
Methylamino) propylcarboxamide] -1-methyl
-2-Pyrrolecarboxamide] benzoylamino]-
1-methyl-N- [4- [N, N-bis (2-chloroe
Cyl) amino-3-chloro] phenyl] -2-pyrrole
Carboxamide (Compound 107) 4- [3- [4- (guanidinoaceti
Lumino) -1-methyl-2-pyrrolecarboxami
De] benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-chloro
[] Phenyl] -2-pyrrolecarboxamide (Compound 108) 4- [4- [4- (guanidinoaceti)
Lumino) -1-methyl-2-pyrrolecarboxami
De] benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-chloro
[] Phenyl] -2-pyrrolecarboxamide (Compound 109) 4- [3- [3- (N, N-diethyl)
Amino) propylcarboxamide] benzoylamino]
-1-Methyl-N- [4- [N, N-bis (2-chloro
Ethyl) amino-3-chloro] phenyl] -2-pillo
Rucarboxamide (Compound 110) 4- [4- [3- (N, N-diethyl
Amino) propylcarboxamide] benzoylamino]
-1-Methyl-N- [4- [N, N-bis (2-chloro
Ethyl) amino-3-chloro] phenyl] -2-pillo
Rucarboxamide (Compound 111) 4- [3- [4- [3- (N, N-di
Ethylamino) propylcarboxamide] -1-methyl
-2-Pyrrolecarboxamide] benzoylamino]-
1-methyl-N- [4- [N, N-bis (2-chloroe
Cyl) amino-3-chloro] phenyl] -2-pyrrole
Carboxamide (Compound 112) 4- [4- [4- [3- (N, N-di
Ethylamino) propylcarboxamide] -1-methyl
-2-Pyrrolecarboxamide] benzoylamino]-
1-methyl-N- [4- [N, N-bis (2-chloroe
Cyl) amino-3-chloro] phenyl] -2-pyrrole
Carboxamide (Compound 113) 4- [3- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-chloro
[] Phenyl] -2-pyrrolecarboxamide (Compound 114) 4- [4- [3- (N, N-dimethyl
Amino) propylcarboxamide] benzoylamino]
-1-Methyl-N- [4- [N, N-bis (2-chloro
Ethyl) amino-3-chloro] phenyl] -2-pillo
Lecarboxamide (Compound 115) 4- [4- (guanidinoacetylami
No) benzoylamino] -1-methyl-N- [4-
[N, N-bis (2-chloroethyl) amino-3-chloro
[] Phenyl] -2-pyrrolecarboxamide (Compound 116) 4- [4- [3- (N, N-diethyl)
Amino) propylcarboxamide] benzoylamino]
-1-Methyl-N- [4- [N, N-bis (2-chloro
Ethyl) amino-3-chloro] phenyl] -2-pillo
Lecarboxamide

These compounds can be synthesized as follows. In this description, or in the examples,
DCC is N, N'-dicyclohexylcarbodiimide,
CDI is N, N'-carbonyldiimidazole, HOS
u is N-hydroxysuccinimide, EDCI is 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, DECP is diethyl cyanophosphonate, HOBt is 1-hydroxybenzotriazole, D
MF represents dimethylformamide. Pd / C is activated carbon with palladium, and usually palladium is 5 to 10
%. General synthetic methods of distamycin derivatives are described in the literature (eg, J. Org. Chem., 1981).
46, 3492-3497, J. Org. Ch
em. , 1985, 50, 3774-3779,
J. Am. Chem. Soc. , 1990, 112
Vol., Pages 838-845, etc.) and can be carried out according to these methods.

The synthesis of these compounds is carried out by reducing each nitro group to a corresponding amino group by using the nitro compound as a precursor, while the carbonyl group is converted to an acid chloride.
Alternatively, common condensing agents (eg DCC, CDI, E
DCI, DECP, etc.).
Of course, a method such as adding HOBt to DCC is also a commonly used method, and can be used in this case as well. The synthesis of these compounds involves two or more amidation reactions,
The order can be chosen freely.

Next, the synthesis method will be specifically described.
Each of these compounds is synthesized by using a nitro compound as a precursor to reduce the nitro group to a corresponding amino group, while the carbonyl group is used as an acid chloride, or a general condensing agent (eg, DCC, CDI). , EDCI, DE
CP or the like is used. A method such as adding HOBt to DCC is also a commonly used method and can be used in this case as well. It can be carried out by repeating the condensation reaction according to (1) and repeating the condensation reaction. When two or more amidation reactions are performed, the order can be freely selected and performed.

The major intermediate, 3- (1-methyl-4)
-Amino-2-pyrrolecarboxamide) -N- [3-
(N, N-Dimethylamino) propyl] phenylcarboxamide can be synthesized by the method represented by the following formula. [Chemical 5].

[0015]

Embedded image 1-Methyl-4-nitro-2-pyrrolecarboxylic acid was converted to chloride with thionyl chloride to give 3-amino-N- [3
-(N, N-Dimethylamino) propyl] phenylcarboxamide (3-nitro obtained by treating m-nitrobenzoic acid with thionyl chloride and reacting with 3- (N, N-dimethylamino) propylamine in the presence of triethylamine. −
Reduction of N- [3- (N, N-dimethylamino) propyl] phenylcarboxamide to the corresponding amino compound. ) Can be synthesized. The above reaction can be carried out in a general solvent such as chloroform, methylene chloride, benzene and toluene. In the reaction of converting carboxylic acid to chloride using thionyl chloride, the reaction temperature is
It can be carried out at room temperature to the reflux temperature of the solvent. The reaction is usually carried out for 30 minutes to 24 hours, but it is preferable to carry out while checking the progress of the reaction by TLC or the like. Also, 4-
Ethyl (1-methyl-4-nitro-2-pyrrolecarboxamide) benzoate can be synthesized according to the following formula [Chemical Formula 6].

[0016]

[Chemical 6] 1-Methyl-4-nitro-2-pyrrolecarboxylic acid is converted to the acid chloride using thionyl chloride or a mixture of thionyl chloride and DMF. At this time, a general solvent such as chloroform, methylene chloride, benzene, toluene or diethyl ether can be used as the solvent.
The reaction temperature at this time is preferably 0 ° C. to the reflux temperature. The reaction is usually carried out for 30 minutes to 24 hours, but it is preferable to carry out while checking the progress of the reaction by TLC or the like. The target product is obtained by reacting this acid chloride with ethyl 4-aminobenzoate in the presence of triethylamine. As the solvent, a general solvent such as chloroform, methylene chloride, benzene, toluene or diethyl ether can be used. The reaction temperature at this time is preferably 0 to 30 ° C. The reaction usually takes 30 to 24 hours, but TLC
It is advisable to perform the reaction while checking the progress of the reaction.

Further, 4- [4- (1-methyl-4-nitro-2-pyrrolecarboxamido) benzoylamino]
-1-Methyl-N- [3- (N, N-dimethylamino)
Propyl] -2-pyrrolecarboxamide can be synthesized by the method shown in the following formula [Chemical Formula 7].

[0018]

[Chemical 7] 4- (1-methyl-4-nitro-2-pyrrolecarboxamide) benzoic acid is 4- (1-methyl-4-nitro-
It is obtained by heating ethyl 2-pyrrolecarboxamide) benzoate in a mixed solvent of an aqueous sodium hydroxide solution and ethanol. At this time, ethanol is in the range of 5 to 90%, and the reaction temperature is from 80 ° C to the reflux temperature. The reaction can usually be performed in 30 minutes to 10 hours, but TLC
It is advisable to perform the reaction while checking the progress of the reaction. next,
4- (1-methyl-4-nitro-2-pyrrolecarboxamide) benzoic acid and 4-amino-methyl-N- [3-
The desired product is obtained by reacting (N, N-dimethylamino) propyl] -2-pyrrolecarboxamide with DCC in the presence of HOBt (or another general condensing agent may be used). As the solvent at this time, a general solvent is used, but DMF gives a relatively good result. Reaction temperature is 0 to 30
C gives relatively good results. The reaction is usually carried out for 30 minutes to 24 hours, but it is preferable to carry out while checking the progress of the reaction by TLC or the like. Furthermore, the synthesis method will be described with reference to Compound 13 (Example 9) [Chemical Formula 8].

[0019]

Embedded image 4- (1-Methyl-4-nitro-2-pyrrolecarboxamido) benzoylamino] -1-methyl-N- [3-
Catalytic hydrogenation of (N, N-dimethylamino) propyl] -2-pyrrolecarboxamide using Pd / C as a catalyst can be carried out to synthesize the corresponding amino compound. As the solvent at this time, a general solvent is used, but particularly methanol, ethanol or the like gives good results. Although not essential, the reaction system may be reduced by adding hydrochloric acid in an amount of 1 to 1.2 times the molar amount of the nitro compound. The reaction is usually carried out for 20 minutes to 5 hours. The amino compound obtained here is reacted with chlorambucil in the presence of DCC and HOBt (other general condensing agents can be used) to obtain the desired product. As the solvent at this time, a general solvent is used,
DMF gives relatively good results. Reaction temperature is 0 to 30
C gives relatively good results. The reaction is usually carried out for 30 minutes to 24 hours, but it is preferable to carry out while checking the progress of the reaction by TLC or the like. Similarly, other compounds can be synthesized. The conversion of the structure of the R ₁ or R ₂ portion can be performed according to the above method.

The method of administration of the compound of the present invention naturally varies depending on the symptoms of the administration subject, etc.
01-1000mg is divided into 1 time or divided into several times, and oral administration agents such as tablets, granules, powders, suspensions, capsules, syrups or injections, suppositories, isotonic solutions for blood transfusion, etc. It can be administered as a parenteral agent.

The formulation can be carried out by a known method.
For example, in the case of tablets, crystalline cellulose, light anhydrous silicic acid or the like is used as the adsorbent, and corn starch, lactose, calcium phosphate, magnesium stearate or the like is used as the excipient. Starch as a disintegrant,
Agar, calcium carbonate, etc. are used, and as a lubricant, magnesium stearate, talc, etc. are used. In the case of an injection, an aqueous solution of a compound or a non-aqueous solution using cottonseed oil, corn oil, peanut oil, olive oil, or the like,
Further, water is added to the compound of the present invention, and it is used as a suspension aqueous solution in the presence of a suitable surfactant, or as an emulsion using a surfactant such as HCO-60. The side effects of the compound of the present invention are at a level at which there is no problem in the degree of use as an anticancer agent.

[0022]

[Examples] As examples of the present invention, compound synthesis examples and anticancer activity test examples will be described in detail below, but the present invention is not limited thereto. Example 1 4-benzoylamino-1-methyl-N-
[3- (N, N-dimethylamino) propyl] -2-pi
Roll carboxamide [Chemical formula 9]

[0023]

[Chemical 9] 4-amino-1-methyl-N- [3- (N, N-dimethylamino) propyl] -2-pyrrolecarboxamide 0.07 g (0.31 mmol) was added to methylene chloride 5 mL.
Dissolved in ice-cold solution, and cooled under ice-cooling with 52 μL of triethylamine (0.3
9 mmol, 1.2 equimolar), benzoyl chloride
43 μL (0.37 mmol, 1.2 equimolar) was added,
The ice bath was removed, and the mixture was stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform and purified with a silica gel column (chloroform / methanol / aqueous ammonia 1
The elution fraction was concentrated and crystallized from methylene chloride-ether to obtain the title compound as yellowish white crystals. (70 mg, 69%) mp. _{130-134 ℃ NMR (CDCl 3) δ} : 8.16 (s, 1H), 7.
88 (d, 2H), 7.69 (bs, 1H), 7.50
(M, 3H), 7.32 (s, 1H), 6.61 (s,
1H), 3.93 (s, 3H), 3.44 (dd, 2)
H), 2.55 (t, 2H), 2.37 (s, 6H),
1.78 (ddd, 2H) IR (KBr); 3300, 2946, 2818, 16
51,1527 cm ^-1 Elemental analysis (including calculated value H ₂ O)
C: 62.41, H: 7.56, N: 16.17 (analytical value) C: 61.75, H: 7.37, N: 15.96

Example 2 4- [3- [4- [4- [N,
N-bis (2-chloroethyl) amino] phenyl] buty
Rylamino] benzoylamino] -1-methyl-N-
[3- (N, N-dimethylamino) propyl] -2-pi
Roll carboxamide [Chemical formula 10]

[0025]

[Chemical 10] (Reaction 1) 4-[(3-nitrobenzoyl) amino]-
1-methyl-N- [3- (N, N-dimethylamino) propyl
Ropyl] -2- pyrrolecarboxamide 3-nitrobenzoic acid 0.22 g (1.32 mmol) was dissolved in methylene chloride 8 mL (dissolved residue), and thionyl chloride 0.15 mL (2.1 mmol, 1.6 eq) was added, After dropping 10 drops of DMF, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent and unreacted thionyl chloride were distilled off under reduced pressure. The residue was dissolved in 20 mL of methylene chloride and stirred under ice cooling under a nitrogen atmosphere. Triethylamine 0.18mL
(1.3 mmol, 1.0 eq), 5 mL of a methylene chloride solution of 4-amino-1-methyl-N- [3- (N, N-dimethylamino) propyl] -2-pyrrolecarboxamide was sequentially added, and the ice bath was removed 1 Stir for hours. After confirming the completion of the reaction, methylene chloride and water were added for liquid separation, the aqueous layer was extracted with methylene chloride, and the methylene chloride layers were combined,
The extract was washed once with 0.5N sodium hydroxide and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting solid was washed with methanol and ether to give the title compound as pale yellowish white crystals. (0.25 g, 52%) mp. 173-176 ° C NMR (DMSO-d ₆ ) δ: 10.66 (s, 1
H), 8.78 (s, 1H), 8.42 (t, 2H),
8.14 (t, 1H), 7.82 (t, 1H), 7.3
1 (s, 1H), 6.89 (s, 1H), 3.84
(S, 3H), 3.20 (m, 2H), 2.25 (t,
2H), 2.14 (s, 6H), 1.62 (m, 2H) Elemental analysis (including calculated value 1 / 3H ₂ O) C: 56.9
8, H: 6.29, N: 18.54 (analytical value) C: 5
7.05, H: 6.17, N: 18.25

(Reaction 2) 4- [3- [4- [4- [N,
N-bis (2-chloroethyl) amino] phenyl] buty
Rylamino] benzoylamino] -1-methyl-N-
[3- (N, N-dimethylamino) propyl] -2-pi
Roll carboxamide chlorambucil 0.17 g (0.56 mmol) TH
Dissolve in F5mL, 0.12g CDI (0.74mmo
1, 1.3 eq) were added, and the mixture was stirred under a nitrogen stream at room temperature for 1.5 hours and at 40 ° C for 30 minutes. Ice-cooled 4- (3-aminobenzoyl) amino-1-methyl-N- [3- (N,
N-Dimethylamino) propyl] -2-pyrrolecarboxamide (0.54 mmol as 100%) / THF
The 4 mL solution was added dropwise from a syringe over 5 minutes. After removing the ice bath, the mixture was reacted at room temperature for 20 hours, concentrated under reduced pressure and purified by silica gel column (chloroform / methanol 8-12%).
And eluted with ether and crystallized from ethyl acetate to give the title compound as white crystals. (80 mg, 23
%) Mp. 147-152 ° C NMR (DMDO-d ₆ ) δ: 10.25 (s, 1
H), 10.05 (s, 1H), 8.12 (t, 1)
H), 8.06 (s, 1H), 7.80 (d, 1H),
7.56 (d, 1H) 7.40 (t, 1H), 7.25
(S, 1H), 7.05 (d, 2H), 6.85 (s,
1H), 6.67 (d, 2H), 3.82 (s, 3)
H), 3.70 (s, 8H), 3.20 (q, 2H),
2.52 (t, 2H), 2.33 (t, 2H), 2.2
7 (t, 2H), 2.16 (s, 6H) 1.86 (m,
2H) 1.62 (m, 2H) IR (KBr) 2946, 1633, 1520, 128
1,806 cm ⁻¹ Elemental analysis (including calculated value 1 / 2H ₂ O) C: 60.1
8, H: 6.79, N: 13.22, Cl: 11.10
(Analytical value) C: 60.37, H: 6.79, N: 12.
74, Cl: 11.09

Example 3 4-benzoylamino-1-me
Chill-N- (2-amidinoethyl) -2-pyrrocar
Voxamide [Chemical formula 11]

[0028]

[Chemical 11] 4-amino-1-methyl-N- (2-amidinomethyl)
-2-Pyrrole carboxamide 0.12 g (0.57 m
mol) 2 mL of methylene chloride, 1.5 mL of pyridine,
It was dissolved in 6 mL of DMF, and 0.1 mL (0.86 mmol) of benzoyl chloride was added dropwise under ice cooling and a nitrogen stream.
After completion of the dropping, the ice bath was removed and the mixture was stirred for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column (eluted with chloroform containing 15% methanol + acetic acid), and the eluted fraction was concentrated and crystallized from ethyl acetate-acetonitrile. (0.13 g, 73%) NMR (DMSO-d ₆ ) δ: 10.36 (s, 1
H), 9.03 (bs, 2H), 8.69 (bs, 2)
H), 8.29 (t, 1H), 7.94 (d, 2H),
7.50 (m, 3H), 7.30 (s, 1H), 6.9
8 (s, 1H), 3.83 (s, 3H), 3.66
(M, 2H), 2.64 (t, 2H)

Example 4 4-benzoylamino-1-me
Cyl-N- (3,4,5-trimethoxyphenyl) -2
-Pyrrole carboxamide [Chemical Formula 12]

[0030]

[Chemical 12] 4-Amino-1-methyl-N- (3,4,5-trimethoxyphenyl) -2-pyrrolecarboxamide (1.2
(8 mmol) was dissolved in 20 mL of pyridine, and the mixture was stirred under ice cooling under a nitrogen stream. Benzoyl chloride 0.18 mL (1.55
(mmol, 1.2 equimolar) was added, and the mixture was returned to room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the mixture was partitioned with methylene chloride-water and the solvent was distilled off. The residue was purified by silica gel column (eluted with chloroform / methanol 1-2%), and the eluted fraction was concentrated and crystallized from methylene chloride-ether to give the title compound as white crystals. (0.
34 g, 65%) mp. _{212-215 ℃ NMR (CDCl 3) δ} (dec.): 7.91 (s, 1H), 7.
85 (d, 2H), 7.64 (s, 1H), 7.53
(Q, 1H), 7.48 (q, 2H), 7.18 (s,
1H), 6.87 (m, 3H), 3.93 (s, 3
H), 3.86 (s, 6H), 3.82 (s, 3H) IR (KBr); 3353, 2935, 2863, 16
48,1510 cm ⁻¹ elemental analysis (including calculated value 3/4 H ₂ O) C: 62.48, H: 5.84, N: 9.98
(Analytical value) C: 62.65, H: 5.63, N: 9.8
5

Example 5 3- (4-formylamino-1)
-Methyl-2-pyrrolecarboxamide) -N- [3-
(N, N-Dimethylamino) propyl] benzcarboxy
Samide [Chemical 13]

[0032]

[Chemical 13] (Reaction 1) 3-nitro-N- [3- (N, N-dimethyl)
Luamino) propyl] phenylcarboxamide m-nitrobenzoic acid 10.0 g (60 mmol) and thionyl chloride 21.4 g (180 mmol) were mixed and heated under reflux for 3 hours. The solvent was distilled off, and methylene chloride 50m
Dissolve in L and mix with 3- (N, N-dimethylamino) propylamine 6.13 g (60 mmol) and triethylamine 6 g (60 mmol) (methylene chloride 50 mL).
(Middle) under ice cooling. Stir at room temperature and leave overnight. It was poured into ice water and extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate to obtain 8.0 mg (5
3.2%). Recrystallized from ether-hexane (pale yellow powder). NMR (CDCl ₃ ) δ: 9.55 (b, 1H), 8.
56 (s, 1H), 8.33 (d, 1H), 8.26
(D, 1H), 7.64 (t, 1H), 3.61 (m,
2H), 2.59 (m, 2H), 2.38 (s, 6)
H), 1.80 (m, 2H)

(Reaction 2) 3-amino-N- [3-
(N, N-Dimethylamino) propyl] phenylcarbo
Xamide 3-nitro-N- [3- (N, N-dimethylamino) propyl] phenylcarboxamide 2.3 g (9 mmo
l) is dissolved in 80 mL of methanol and 320 mg of 1
0% Pd / C was added and hydrogenated at room temperature. After the disappearance of the nitro form, the catalyst was removed and methanol was distilled off. It was purified by a silica gel column (chloroform containing 15-30% methanol). A clear liquid with a slight reddish tinge was obtained.
2.0 g (98.7%) NMR (CDCl ₃ ) δ: 7.19 (t, 1H), 7.
12 (s, 1H), 7.10 (d, 1H), 6.84
(D, 1H), 4.40 (s, 3H), 3.42 (m,
2H), 2.46 (m, 2H), 2.31 (s, 6)
H), 1.80 (t, 2H)

(Reaction 3) 3- (1-methyl-4-nit)
Ro-2-pyrrolecarboxamide) -N- [3- (N,
N-dimethylamino) propyl] phenylcarboxami
Do 1-methyl-4-nitro-2-pyrrolecarboxylic acid 42
5 mg (2.5 mmol) was made into an acid chloride by using thionyl chloride, and 5 mL of methylene chloride was added to the acid chloride.
-Amino-N- [3- (N, N-dimethylamino) propyl] phenylcarboxamide 553 mg (2.5 mm
ol) in methylene chloride (mostly dissolved) 3
It was added dropwise to a mixed solution of 0 mL and 1 mL of triethylamine. The temperature was returned to room temperature in 5 minutes, and the mixture was stirred as it was for 2 hours (solution became cloudy). A slightly yellowish white powder was collected by filtration.
Washing with methylene chloride gave 420 mg. This was recrystallized from methanol to obtain 376 mg (40.3%). Further, 670 mg of crystals were obtained from the filtrate (mixture). NMR (DMSO-d ₆ ) δ: 10.30 (s, 1
H), 10.15 (b, 1H), 8.64 (t, 1
H), 8.23 (d, 2H), 7.88 (d, 1H),
7.78 (s, 1H), 7.59 (d, 1H), 7.4
3 (t, 1H), 3.97 (s, 3H), 3.07
(M, 2H), 2.74 (s, 6H), 1.91 (m,
2H)

(Reaction 4) 3- (1-methyl-4-amido)
No-2-pyrrolecarboxamide) -N- [3- (N,
N-dimethylamino) propyl] phenylcarboxami
De 300mg of (0.80mmol) 3- (1- methyl -
4-nitro-2-pyrrolecarboxamide) -N- [3
-(N, N-Dimethylamino) propyl] phenylcarboxamide was dissolved in 150 mL of methanol to give 100
10 mg Pd / C (mg) was added, and the mixture was stirred at room temperature under a hydrogen stream or atmosphere. Pd / C was removed, and methanol was distilled off while replacing with THF. 200 mg (72.5
%). NMR (DMSO-d ₆ ) δ: 9.69 (s, 1H),
8.57 (t, 1H), 8.18 (s, 1H), 7.8
3 (d, 1H), 7.49 (d, 1H), 7.35
(T, 1H), 6.57 (s, 1H), 6.40 (s,
1H), 3.75 (s, 3H), 2.98 (m, 2)
H), 1.90 (m, 2H), 1.76 (m, 2H)

(Reaction 5) 3- (4-formylamino-
1-methyl-2-pyrrolecarboxamide) -N- [3
-(N, N-Dimethylamino) propyl] phenylcal
Dissolved Bokisamido formic acid 1.0mL to THF1.5mL, CDI4
71 mg (2.6 mmol) was added to what was dissolved in 3 mL of THF, and the mixture was stirred for 15 minutes. This is -40 ℃
(Dry ice + carbon tetrachloride + acetone) 3- (1-
Methyl-4-amino-2-pyrrolecarboxamide)-
200 mg (0.58 mmol) of N- [3- (N, N-dimethylamino) propyl] phenylcarboxamide was added dropwise to a solution of 7 mL of methanol. -40
The mixture was stirred at C for 15 minutes, the solvent was distilled off, and the residue was purified with a silica gel column (eluent: chloroform 85 + methanol 15 + ammonia water 6). It became a little yellow amorphous, but did not crystallize. 190 mg (87.8
%). This was dissolved in 2 mL of isopropyl alcohol, 2 mL of ethyl acetate was added, 0.1 mL of hydrochloric acid (4N) / dioxane was added, and the generated crystals were collected by filtration. It absorbed moisture and became a candy, and there was a loss during filtration. It was washed well in ether to give a powder. 100 mg (48%). mp.
Although a change was observed from 103 ° C, it decomposed at 140 ° C or higher. NMR (DMSO-d ₆ ) δ: 10.14 (s, 1
H), 10.05 (b, 1H), 9.99 (s, 1
H), 8.62 (t, 1H), 8.22 (s, 1H),
8.14 (s, 1H), 7.86 (d, 1H), 7.5
3 (d, 1H), 7.39 (t, 1H), 7.27
(S, 1H), 7.07 (s, 1H), 3.85 (s,
3H), 3.08 (m, 2H), 2.50 (s, 6
H), 1.93 (m, 2H) IR (KBr) 3405, 3082, 2961, 270
7, 1655, 1586, 1542, 1482, 140
2, 1304 cm ^-1 elemental analysis (including calculated value H ₂ O) C: 53.58, H:
6.63, N: 16.80, Cl: 8.32 (analytical value)
C: 54.50, H: 6.42, N: 15.31, C
1: 8.22

Example 6 4- [3- [4- [4- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] butyrylamino] -1-methyl-2-pyrrocar
Voxamide] benzoylamino] -1-methyl-N-
(3,4,5-Trimethoxyphenyl) -2-pyrrole
Carboxamide [Chemical formula 14]

[0038]

Embedded image (Reaction 1) 4- [N- (3-aminobenzoyl) ami
No] -1-methyl-N- (3,4,5-trimethoxyphenyl)
Phenyl) -2- pyrrolecarboxamide 1-methyl-4- [N- (3-nitrobenzoyl) amino] -N- (3,4,5-trimethoxyphenyl) -2
-Pyrrol carboxamide 0.16 g (0.36 mmo
l) was dissolved in 3 mL of DMF and 2 mL of methanol to obtain 10%
One cup of Pd / C was added to the spatula and catalytic hydrogenation was performed.
After completion of the reaction, the catalyst was filtered off and concentrated under reduced pressure to give the title compound as a light brown oil. This was directly used for the next reaction.

(Reaction 2) 4- [4- [bis (2-chloro)
0.13 g (0.43 mmol) of chloroethyl) amino] phenyl] butyryl chloride chlorambucil was dissolved in 2 mL of chloroform, 1.0 g of phosphorus oxychloride was added, and the mixture was stirred in a 60 ° C. oil bath for 4 hours. The mixture was concentrated under reduced pressure, and washed with a small amount of petroleum ether four times to remove unreacted phosphorus oxychloride, to obtain the title compound as a yellow oil. This was directly used for the next reaction.

(Reaction 3) 4- [3- [4- [4- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
L] butyrylamino] -1-methyl-2-pyrrocar
Voxamide] benzoylamino] -1-methyl-N-
(3,4,5-Trimethoxyphenyl) -2-pyrrole
Carboxamide 4-[(3-aminobenzoyl) amino] -1-methyl-N- (3,4,5-trimethoxyphenyl) -2-pyrrolecarboxamide (0.22 mmol as 100% from the nitro form) was added to 2 mL of pyridine. After dissolution, the mixture was stirred under ice cooling under a nitrogen stream. A solution of 4- [N, N-bis (2-chloroethyl) amino] phenylbutyryl chloride / methylene chloride (2.5 mL) was added dropwise, and the mixture was returned to room temperature and stirred for 2 hours. After concentration under reduced pressure, the residue was dissolved in acetone and adsorbed on silica gel, crude purification was performed by column chromatography (eluted with chloroform / methanol 6-10%), and further purified by TLC (chloroform / methanol 100 /
10) and crystallized from ether / acetone to give the title compound as pale yellow crystals. (26 mg, 1
1%) mp. 280 ° C or higher NMR (DMSO-d ₆ + CDCl ₃ ) δ: 9.97
(S, 1H), 9.69 (s, 1H), 9.37 (s,
1H), 8.11 (s, 1H), 7.88 (d, 1
H), 7.6 (d, 1H), 7.36 (t, 1H),
7.30 (s, 1H), 7.18 (s, 1H), 7.1
5 (s, 2H), 7.1 (d, 2H), 6.64 (d,
2H), 3.95 (s, 3H), 3.86 (s, 6)
H), 3.77 (s, 3H), 3.71 (m, 4H),
3.65 (m, 4H), 2.41 (t, 2H), 2.2
(T, 2H), 1.98 (m, 2H) IR (KBr); 3305, 2963, 1645, 15
19,1450 cm ⁻¹ elemental analysis (including calculated value 3/4 H ₂ O) C: 59.71, H: 5.92, N: 9.71,
(Analytical value) C: 59.53, H: 5.65, N: 9.7
5

Example 7 4- [3- [4- (N, N-di
Methylamino) butyrylamino] benzoylamino]-
1-methyl-N- [4- [N, N-bis (2-chloroe
Cyl) amino] phenyl] -2-pyrrolecarboxami
De [15]

[0042]

[Chemical 15] 4- [3- [4- (N, N-dimethylamino) butyrylamino] benzoylamino] -1-methyl-2-pyrrolecarboxylic acid 0.15 g (0.40 mmol), HOB
t60 mg (0.44 mmol) was placed in an eggplant-shaped flask and the atmosphere was replaced with nitrogen. There, 0.12 g of 4- [N, N-bis (2-chloroethyl)] aminoaniline hydrochloride (0.4
(5 mmol) was dissolved in 4 mL of DMF, and a solution containing 62 μL (0.44 mmol) of triethylamine was added, and the mixture was stirred under ice cooling. A solution of 93 mg (0.45 mmol) of DCC in DMF (2 mL) was added dropwise (2 minutes), the ice bath was removed, the mixture was stirred for 2 hours, and then left standing overnight at room temperature. The generated crystals were separated by filtration, concentrated, and the residue was purified by a silica gel column (eluted with chloroform / methanol 10 to 15%).
The product was further purified by TLC (chloroform: methanol: aqueous ammonia = 100: 20: 1) and crystallized from methylene chloride-ether to give the title compound as white crystals. (83 mg, 35%) mp. Decomposition started at 173 ° C and had no clear melting point. NMR (DMSO-d ₆ ) δ: 10.3 (s, 1H),
10.1 (s, 1H), 9.7 (s, 1H), 8.1
(S, 1H), 7.8 (d, 1H), 7.6 (d, 1)
H), 7.54 (d, 2H), 7.4 (t, 1H),
7.34 (s, 1H), 7.1 (s, 1H), 6.7
(D, 2H), 3.9 (s, 3H), 3.7 (s, 8)
H), 2.4 (t, 2H), 2.3 (t, 2H), 1.
7 (m, 2H) IR (KBr) 3304, 2953, 1642, 151
9,1436 cm ^-1 Elemental analysis (calculated value, including H ₂ O) C: 57.5
2, H: 6.32, N: 13.94, (analysis value) C: 5
7.53, H: 6.0, N: 14.25

Example 8 4- [3- [4- [4- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] butyrylamino] -1-methyl-2-pyrrocar
Voxamide] benzoylamino] -1-methyl-N-
[3- (N, N-dimethylamino) propyl] -2-pi
Roll carboxamide [Chemical 16]

[0044]

Embedded image (Reaction 1) 4- [3- (1-methyl-4-nitro-2)
-Pyrrolecarboxamido) benzoylamino] -1-
Methyl-N- [3- (N, N-dimethylamino) propyi
]]-2-Pyrrolecarboxamide 4- (3-nitrobenzoylamino) -1-methyl-N
-[3- (N, N-Dimethylamino) propyl] -2-
Pyrrolcarboxamide 0.50 g (1.34 mmo
1) was catalytically hydrogenated according to a conventional method to give a corresponding amino compound. This was dissolved in 6 mL of DMF and 0.23 g of 1-methyl-4-nitro-2-pyrrolecarboxylic acid
(1.35 mmol, 1.0 equimolar), HOBt0.2
0 g (1.48 mmol, 1.1 equimolar) were sequentially added,
Stir with ice cooling under a nitrogen atmosphere, and then 0.30 g of DCC (1.45
(mmol, 1.1 equimolar) was added, the mixture was returned to room temperature, stirred for 4 hours, and allowed to stand overnight. The white crystals formed on the next day were filtered off, the filtrate was concentrated, and methylene chloride-0.5N aqueous sodium hydroxide solution was added to the residue to precipitate crystals. The resulting crystals were collected by filtration, and combined with the methylene chloride layer concentrated residue and purified by silica gel column chromatography (eluted with methylene chloride / methanol (24%)). Crystallization from methylene chloride gave 0.50 g of the title compound as white crystals.
(1.01 mmol, 75.3%) was obtained. mp. 202-204 ° C NMR (DMSO-d ₆ ) δ: 10.31 (s, 1H)
10.29 (s, 1H) 8.24 (s, 1H) 8.23
(S, 1H) 8.1 (t, 1H) 7.9 (d, 1H)
7.77 (s, 1H) 7.65 (d, 1H) 7.47
(T, 1H) 7.27 (s, 1H) 6.85 (s, 1
H) 4.0 (s, 3H) 3.8 (s, 3H) 3.2
(Q, 2H) 2.25 (t, 2H) 2.1 (s, 6H)
1.6 (m, 2H)

(Reaction 2) 4- [3- [4- [4- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
L] butyrylamino] -1-methyl-2-pyrrocar
Voxamide] benzoylamino] -1-methyl-N-
[3- (N, N-dimethylamino) propyl] -2-pi
Roll carboxamide 4- [3- (1-methyl-4-nitro-2-pyrrolcarboxamido) benzoylamino] -1-methyl-N-
[3- (N, N-Dimethylamino) propyl] -2-pyrrolecarboxamide 0.35 g (0.71 mmol)
Was subjected to catalytic hydrogenation in the presence of 10% Pd / C to lead to the corresponding amino form. Dissolve this in 10 mL DMF,
Chlorambucil 246 mg (0.71 mmol, 1.0
Equimolar), HOBt 113 mg (0.84 mmol,
(1.2 equimolar) was added, and the mixture was stirred under ice cooling in a nitrogen atmosphere. D
CC 0.16 g (0.84 mmol, 1.2 equimolar) was added, the ice bath was removed, and stirring was continued for 6.5 hours. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, the residue was dissolved in methylene chloride, washed with 0.5N aqueous sodium hydroxide solution, extracted with methylene chloride, and the methylene chloride layer was combined and washed with saturated brine. After drying over sodium sulfate, concentrate and purify with silica gel column (methylene chloride / methanol (20%).
The crystals were eluted with hexane and crystallized from ether to give the title compound (0.34 g, 63%) as pale yellowish white crystals. mp. It turned brown from 220 ° C. but did not show a clear melting point. NMR (DMSO-d ₆ ) δ: 10.26 (s, 1
H), 10.0 (s, 1H), 9.8 (s, 1H),
8.2 (s, 1H), 8.13 (t, 1H), 7.9
(D, 1H), 7.6 (d, 1H), 7.4 (t, 1
H), 7.27 (s, 1H), 7.2 (s, 1H),
7.04 (d, 2H), 7.03 (s, 1H), 6.8
6 (s, 1H), 6.67 (d, 2H), 3.84
(S, 3H), 3.83 (s, 3H), 3.67 (s.
8H), 3.2 (q, 2H), 2.37 (t, 2H),
2.24 (s, 6H), 1.83 (m, 2H), 1.6
7 (m, 2H) IR (KBr) cm ^-1 ; 3287, 2950,164
7, 1519, 1439, 1284, 806, 745 Elemental analysis (calculated value) C: 59.29, H: 6.55,
N: 14.56, Cl: 9.21 (analytical value) C: 59.
57, H: 6.69, N: 14.07, Cl: 9.40.

Example 9 4- [4- [4- [4- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
L] butyrylamino] -1-methyl-2-pyrrocar
Voxamide] benzoylamino] -1-methyl-N-
[3- (N, N-dimethylamino) propyl] -2-pi
Roll carboxamide [Chemical formula 17]

[0047]

[Chemical 17] (Reaction 1) 4- (1-methyl-4-nitro-2-pyro)
Carboxamide) Ethyl benzoate 1-Methyl-4-nitro-2-pyrrolcarboxylic acid 0.
3 g (1.76 mmol) was suspended in 9 mL of ether,
Add DMF until dissolved, thionyl chloride 0.31 g
(2.6 mmol, 1.5 equimolar) was added and stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the residue was dissolved in 6 mL of methylene chloride, and 0.29 g (1.76 mmol, 1.0 equimolar) of ethyl 4-aminobenzoate under ice cooling and 0.24 mL (1.72 mmol, triethylamine). 0.9
8 equimolar) was added. After returning to room temperature and stirring for 2.5 hours, water and methylene chloride were added to carry out a liquid separation operation. Since the target substance was extracted into the aqueous layer, the aqueous layer was made alkaline with 5N aqueous sodium hydroxide solution and washed with methylene chloride. Extracted. After drying over sodium sulfate and concentration, the residue was purified by silica gel column chromatography (eluted with methylene chloride / methanol (8%)) and crystallized with ether to give the title compound as brown-white crystals. . (0.2g,
36%) mp. 210-212 ° C NMR (DMSO-d ₆ ) δ: 10.4 (s, 1H),
8.25 (s, 1H), 7.95 (d, 1H), 7.8
8 (d, 1H), 4.3 (q, 2H), 3.97 (s,
3H), 1.33 (t, 3H)

(Reaction 2) 4- (1-methyl-4-nit)
(2 -Pyrrolecarboxamide ) benzoic acid 4- (1-methyl-4-nitro-2-pyrrolcarboxamide) ethyl benzoate 0.21 g (0.66 mmo)
l) was suspended in 5 mL of ethanol, 5 mL of a 1N sodium hydroxide aqueous solution was added, and the mixture was heated with stirring at 90 ° C. for 1 hour. Ethanol was distilled off under reduced pressure, the remaining aqueous solution was acidified with 4N hydrochloric acid, and the resulting solid was filtered to obtain the title compound as brown-white crystals. (0.15 g, 79%) NMR (DMSO-d ₆ ) δ: 10.38 (s, 1
H), 8.25 (s, 1H), 7.9 (d, 1H),
7.86 (d, 1H), 7.77 (s, 1H), 3.9
7 (s, 3H)

(Reaction 3) 4- [4- (1-methyl-4)
-Nitro-2-pyrrolecarboxamido) benzoyla
Mino] -1-methyl-N- [3- (N, N-dimethylacetate
Mino) propyl] -2-pyrrolecarboxamide 4-amino-1-methyl-N- [3- (N, N-dimethylamino) propyl] -2-pyrrolecarboxamide (catalytic hydrogen from the corresponding nitro compound 0.55 mmol) (Synthesis by addition) was dissolved in 5 mL of DMF, and 0.15 g (0.52 mmol, 0.94 equimolar) of 4- (1-methyl-4-nitro-2-pyrrolecarboxamide) benzoic acid,
HOBt (82 mg, 1.1 equimolar) was added, and the mixture was ice-cooled and stirred under a nitrogen stream. DCC 0.12g (0.58mmo
1) was added, the mixture was returned to room temperature, stirred for 3.5 hours, and left overnight. The solid produced next day was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride (including methanol 16-20%)), and
Crystallization from tell gave the title compound as pale yellow crystals. (0.13 g, 47%) NMR (DMSO-d ₆ ) δ: 10.34 (s, 1
H), 10.3 (s, 1H), 8.25 (s, 1H),
8.13 (t, 1H), 7.94 (d, 2H), 7.8
5 (d, 2H), 7.76 (s, 1H), 7.27
(S, 1H), 6.9 (s, 1H), 4.0 (s, 3)
H), 3.8 (s, 3H), 3.2 (q, .2H) 2.
47 (t, 2H), 2.3 (t, 6H), 1.7 (m,
2H)

(Reaction 4) 4- [4- [4- [4- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
L] butyrylamino] -1-methyl-2-pyrrocar
Voxamide] benzoylamino] -1-methyl-N-
[3- (N, N-dimethylamino) propyl] -2-pi
Roll carboxamide 4- [4- (1-methyl-4-nitro-2-pyrrolecarboxamide) phenylcarboxamide] -1-methyl-N- [3- (N, N-dimethylamino) propyl]-
2-pyrrolcarboxamide 0.13 g (0.26 mm
was dissolved in methanol and catalytic hydrogenation was performed using 10% Pd / C to synthesize the corresponding amino compound. After the catalyst was filtered off, the solvent was evaporated under reduced pressure, and the residue was added with DMF (6 mL).
Dissolved in. Chlorambucil 85mg (0.28mmo
1, 1.1 equimolar), HOBt 45 mg (0.33 mm
ol, 1.3 equimolar), and stirred under ice cooling under a nitrogen stream.
61 mg (0.3 mmol, 1.15 equimolar) of DCC was added, the mixture was returned to room temperature, stirred for 4.5 hours, and then left as it was overnight. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, the residue was dissolved in methylene chloride, washed with 0.5N aqueous sodium hydroxide solution and saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. did. The residue was purified by silica gel column chromatography (methylene chloride / methanol (20
%) Eluted) and crystallized with ether to give the title compound as pale yellowish white crystals. (57mg, 29%) NMR ( DMSO-d 6) δ: 10.16 (s, 1
H), 10.0 (s, 1H), 9.8 (s, 1H),
8.1 (t, 1H), 7.9 (d, 1H), 7.84
(D, 1H), 7.26 (s, 1H), 7.23 (s,
1H), 7.04 (d, 2H), 7.03 (s, 1
H), 6.9 (s, 1H), 6.67 (d, 2H),
3.84 (s, 3H), 3.82 (s, 3H), 3.7
(S, 8H), 3.2 (q, 2H), 2.25 (t, 2)
H), 1.83 (m, 2H), 1.7 (m, 2H) IR (KBr) (cm ^-1 ); 3293, 2950, 16
44, 1519, 1438, 1247, 762 Elemental analysis (including calculated values 0.3 CH ₂ Cl ₂ , 2.2 H ₂ O) C: 56.31, H: 6.54, N: 13.72,
Cl: 11.20 (analytical value) C: 56.53, H: 6.
54, N: 13.96, Cl: 11.00

Example 10 (Anti-tumor activity test) The anti-cancer activity of these compounds will be described. (Table-
The antitumor activity of typical compounds is shown in 1). The method is the measurement of tumor cell growth inhibitory effect in vitro,
It was established as an assay. Cancer
Res., 1988, Vol. 48, pp. 589-601 was followed to determine the concentration required to cause 50% growth inhibition. The unit is microgram / milliliter. P-388 was used as a tumor cell (Table-
1) [Table 1].

[0052]

[Table 1] From the above results, it was shown that these compounds have high activity and are useful as anticancer agents. Therefore, the compound of the present invention is used as an anticancer agent having excellent activity. The cancer types used include leukemia, osteosarcoma, breast cancer, ovarian cancer, gastric cancer, colon cancer, lung cancer and head and neck cancer.

[0053]

INDUSTRIAL APPLICABILITY The compound according to the present invention exhibits tumor cell growth inhibitory activity and exhibits leukemia, osteosarcoma, breast cancer, ovarian cancer, gastric cancer,
It is useful for treating colorectal cancer, lung cancer, head and neck cancer and the like.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hajime Edashi 1900-1 Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd.

Claims (5)

[Claims] 1. A compound represented by the following formula (1) [Chemical formula 1], or a pharmaceutically acceptable salt thereof. Embedded image [However, R ₁ is hydrogen, R ₃ — (CH ₂ ) _r —CONH— or a group represented by the formula (2) [Chemical Formula 2]. R ₂ is hydrogen, amino group, aliphatic amino group, amidino group, guanidino group,
Trimethylammonium group, triethylammonium group, dimethylsulfonium group, diethylsulfonium group, phenyl group, substituted phenyl group, pyridyl group,
A group selected from an N-methylpyridyl group, a thienyl group, a furyl group, a pyrrolyl group, an N-methylpyrrolyl group or a group represented by the formula (2) [Chemical formula 2]. m and n represent 0 or 1. However, m and n are not 0 at the same time.
t represents an integer of 0 to 5. (However, R ₃ is hydrogen, amino group, dimethylamino group, aliphatic amino group, amidino group, guanidino group, trimethylammonium group, triethylammonium group, dimethylsulfonium group, diethylsulfonium group, pyridyl group, N-methylpyridyl group. , A thienyl group, a furyl group, a pyrrolyl group, and an N-methylpyrrolyl group, and r is an integer of 0 to 5.) (However, p is an integer of 0 to 5, and q is ₁ when the compound of the formula (2) represents R _1. The compound of the formula (2) is R ₂
Is 0 or 1. R ₄ is an alkyl group having 1 to 5 carbon atoms, an alkoxyl group having 1 to 5 carbon atoms, an amino group, a carboxyl group, a trifluoromethyl group, or a halogen atom. Further, X and Y are hydrogen or -N (CH ₂ C
H ₂ Cl) ₂ and both X and Y cannot be hydrogen at the same time. )] 2. The compound represented by the formula (1) is 4- [4
-[N, N-bis (2-chloroethyl) amino] phenyl] butyrylamino group, 4- [3- [N, N-bis (2
-Chloroethyl) amino] phenyl] butyrylamino group, 4- [N, N-bis (2-chloroethyl) amino]
Benzoylamino group, 3- [N, N-bis (2-chloroethyl) amino] benzoylamino group, or [4-
4-benzoylamino-1- having any of N, N-bis- (2-chloroethyl) amino] phenylamino group
The compound according to claim 1, which is a methyl-2-pyrrolecarboxamide derivative, or a pharmaceutically acceptable salt thereof. 3. The compound represented by the formula (1) is 4- [4
-[N, N-bis (2-chloroethyl) amino] phenyl] butyrylamino group, 4- [3- [N, N-bis (2
-Chloroethyl) amino] phenyl] butyrylamino group, 4- [N, N-bis (2-chloroethyl) amino]
Benzoylamino group, 3- [N, N-bis (2-chloroethyl) amino] benzoylamino group, or [4-
1-Methyl-N-phenyl-having any of N, N-bis- (2-chloroethyl) amino] phenylamino groups
The compound according to claim 1, which is a 2-pyrrolecarboxamide derivative, or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition containing the compound represented by claims 1 to 3 as an active ingredient. 5. An anticancer agent containing the compound represented by any one of claims 1 to 3 as an active ingredient.