JPH05148227A - Heterocyclic oligopeptide having antitumor activity - Google Patents

Abstract

PURPOSE: To obtain a novel heterocyclic oligopeptide which has a nature of cell proliferation suppression of cancer cells and is particularly effective for a mammary cancer, ovarian tumor, endometrial tumor, soft tissue tumor, osteosarcoma, malignant tumors of blood, such as leukemia, etc.

CONSTITUTION: Heterocyclic oligopeptide derivatives of formula I [A is H, -NHCOR₁ (R₁ is acryl, aziridinyl, cyclopropyl, etc., substd. in 2-position by halogen) B is H, -(CH₂)_m-NHCOR₁ ((m) is 0 or 3), when A is H, B is exclusive of H, when A is exclusive of H, B is H; Z, Z' are -CH=, CH-; X, X' are N, O, S; (n) is 0, 1] and their pharmaceutically acceptable salts; for example, 2'(α- promoacryloyl)5-(benzofuran2-carboxyamide)indole2-carbohydrazide. The compd. of formula I and, above all, the compd. in which A is H and B is (CH₂)_n-NHCOR₁ is obtd. by bringing a novel compd. of formula II and a compd. of formula III (L is a halogen, an eliminable group such as imidazolyl) into reaction.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

The present invention relates to a heterocyclic oligopeptide derivative having a cell growth inhibitory property against cancer cells, a process for producing them, an intermediate product and a pharmaceutical composition containing them.

The compounds of the present invention have the formula (I):

[0003]

[Chemical 7] [In the formula, A is hydrogen; -NHCOR ₁ (R ₁ is an acryl group substituted at the 2-position with halogen, unsubstituted or substituted at the 2-position or the 3-position with methyl, oxiranyl, aziridinyl, cyclo) Propyl, 4- [N, N-bis- (2-chloroethyl) amino] phenyl, which represents an alicyclic α, β-unsaturated ketone or lactone);
R ₂ R ₃ (R ₂ and R ₃ have the same meaning, and
Position is halogen or -OSO ₂ R ₄ group (R ₄ is C ₂ -
A C ₂ -C ₄ alkyl group substituted with a C ₄ alkyl or phenyl group), or R ₂ and R ₃
One of which is hydrogen and the other has the same meaning as defined above), B is hydrogen; or- (C
H ₂ ) _m NHCOR ₁ (R ₁ is the same as defined above and m is 0 or an integer of 1 to 3)
Is hydrogen, B is a group other than hydrogen, A is limited to hydrogen when A has any other meaning as defined above other than hydrogen, and each of Z and Z ′ is independently -C
H = or -CH = CH-, each of X and X'is independently N, O or S, and n represents 0 or 1.]
It is represented by.

The preferred meaning of the substituent in the compound of formula (I) is that R ₁ is 2-bromoacrylyl, oxiranyl or 4- [N, N-bis (2-chloroethyl).
Amino] phenyl, m is 0 or 2, R ₂ and R ₃ are 2-
C ₂ -C ₄ alkyl group or a -CH ₂ -CH ₂ 2-position is substituted by halogen such as chloroethyl -
-O such as OSO ₂ R ₄ (R ₄ is preferably methyl)
C ₂ -C the 2-position is substituted by SO ₂ R ₄ groups
₄ Alkyl group, Z ′ is —CH═, X and X ′ are each independently nitrogen or oxygen, and n is 1.

One group of preferred compounds according to the invention is represented by the symbol in formula (I): A is hydrogen and B is-(CH ₂ ) _m NH.
COR ₁ (R ₁ is 2-bromoacrylyl, oxiranyl or 4- [N, N-bis (2-chloroethyl) amino] phenyl, m is 0 or 2), Z is —CH═ when X is oxygen, and X is nitrogen. When -CH = CH-, Z '
Is a compound represented by -CH =, X'is nitrogen, and n is 0 or 1.

Another group of preferred compounds of the present invention is the symbol in formula (I) wherein A is --NHCOR ₁ (R ₁ is 2-bromoacrylyl, oxiranyl, 4- [N, N-bis (2-chloroethyl). ) Amino] phenyl) or-
NR ₂ R ₃ (R ₂ and R ₃ have the same meaning and when they are C ₂ -C ₄ alkyl groups in which the 2-position is substituted by halogen, it is preferably 2-chloroethyl) , Z and Z ′ are both —CH═, X and X ′ are both nitrogen, B is hydrogen, and n is 1.

Specific examples of preferred compounds of the present invention include:

2 '-(α-bromoacryloyl) -5-
(Benzofuran-2-carboxamido) indole-
2-Carbohydrazide, 2 '-(2,3-epoxypropionyl) -5- (benzofuran-2-carboxamido) indole-2-carbohydrazide, 2'-[4-
(N, N-Bis-2′-chloroethylamino) benzoyl] -5- (benzofuran-2-carboxamido) indole-2-carbohydrazide, 2 ′-(α-bromoacryloyl) -5- (quinoline-2) -Carboxamido) indole-2-carbohydrazide, 2 '-(2,
3-epoxypropionyl) -5- (quinoline-2-carboxamido) indole-2-carbohydrazide,
2 '-[4- (N, N-bis-2'-chloroethylamino) benzoyl] -5- (quinoline-2-carboxamido) indole-2-carbohydrazide, 5- [5-
[4-N, N-bis (2-chloroethyl) amino] benzoylamino] indole-2-carboxamide] indole-2-carboxamide, 5- [5- (2,3
-Epoxypropionylamino) indole-2-carboxamide] indole-2-carboxamide, 5
-[5- (α-Bromoacryloylamino) indole-2-carboxamide] indole-2-carboxamide, 5- [5- [N, N-bis (2-chloroethyl) amino] indole-2-carboxamide] Indole-2-carboxamide, N- [2- [4-
[N, N-bis (2-chloroethyl) amino] benzoylamino] ethyl) -5- [benzofuran-2-carboxamido] indole-2-carboxamide, N-
[2- (2,3-Epoxypropionylamino) ethyl] -5- [benzofuran-2-carboxamido] indole-2-carboxamide, N- [2- (α-bromoacryloylamino) ethyl] -5- [ Benzofuran-2-carboxamido] indole-2-carboxamide, N- [2- [4- [N, N-bis (2-chloroethyl) amino] benzoylamino] ethyl] -5-
[Quinoline-2-carboxamide] indole-2-
Carboxamide, N- [2- (2,3-epoxypropionylamino) ethyl] -5- [quinoline-2-carboxamido] indole-2-carboxamide, N
-[2- (α-Bromoacryloylamino) ethyl]-
5- [quinoline-2-carboxamido] indole-
2-carboxamide, N- [2- [4- [N, N-bis (2-chloroethyl) amino] benzoylamino] ethyl] quinoline-2-carboxamide, N- [2-
(2,3-Epoxypropionylamino) ethyl] quinoline-2-carboxamide, N- [2- (α-bromoacryloylamino) ethyl] quinoline-2-carboxamide.

The present invention includes the pharmaceutically acceptable salts of the compounds of formula (I) as well as the possible isomers, either alone or in the form of mixtures. The term "pharmaceutically acceptable salt" means a pharmaceutically acceptable acid, ie an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid or citric acid,
It includes salts with any of organic acids such as tartaric acid, maleic acid, fumaric acid, methanesulfonic acid and ethanesulfonic acid.

Another object of the invention relates to a process for preparing compounds of formula (I). In formula (I), A is hydrogen and B
There - (CH _{2) m} NHCOR ₁ compound (R ₁ and m are as defined above) is the formula (II):

[0011]

[Chemical 8] (Wherein X, X ', Z, Z', m and n are the same as defined above) and a compound of formula (III):

[0012]

[Chemical 9] By reacting with a compound of formula (wherein R ₁ is as defined above, L represents a halogen such as chlorine or bromine, a leaving group such as imidazolyl, pivaloyloxy or isobutyloxycarbonyloxy groups) It can be manufactured. In addition, the compound of formula (III) is replaced by the compound of formula (IV):

[0013]

[Chemical 10] (Wherein X, X ', Z, Z'and n are the same as defined above), B is hydrogen,
It is also possible to obtain compounds of formula (I) in which A is —NHCOR ₁ (R ₁ is as defined above), X, X ′, Z, Z ′ and n is as defined above. Furthermore, the compound of formula (IV) is replaced by formula (V):

[0014]

[Chemical 11] (Wherein Y is hydrogen or a C ₁ -C ₂ alkyl group) to react with a compound represented by the formula (VI)

[0015]

[Chemical 12] (Wherein X, X ', Z, Z'and n have the same meanings as defined above, and Y'has the same meaning as Y), and a compound of the formula (I) B is hydrogen, A is -NR ₂
R ₃ (R ₂ and R ₃ are the same as defined above), X,
It is also possible to convert compounds in which X ', Z, Z'and n are the same as defined above. Also, a compound of formula (I) may be optionally converted to another compound of the formula and further optionally converted to one of its pharmaceutically acceptable salts.

The reaction between the compound of formula (II) or formula (IV) and the compound of formula (III) is preferably carried out in the presence of a solvent per 1 mol of the compound of formula (II) or (IV). (III)
Of the compound of formula (III) in an excess of 1.1 to 2 mol.

The solvent is preferably an inert organic solvent selected from dialkyl sulfoxides such as dimethyl sulfoxide, fatty acids, dialkyl amides such as dimethylformamide, heterocyclic amines such as pyridine, aliphatic alcohols or water. .. A particularly preferred solvent is dimethylformamide. The reaction temperature may range from about 20-80 ° C. The time required for the reaction can be varied in the range of about 0.5-24 hours.

The reaction between the compound of formula (IV) and the compound of formula (V) is preferably in the presence of a solvent, 25 to 50 compounds of formula (V) per mole of compound of formula (IV). It is carried out in molar proportion with an excess of the compound of formula (V). The solvent is preferably water, an aliphatic alcohol such as methanol or ethanol, an aliphatic carboxylic acid such as acetic acid, a dialkylamide of a fatty acid such as dimethylformamide, a dialkylsulfoxide such as dimethylsulfoxide, dioxane or dimethoxyethane. A particularly preferred solvent is methanol. The reaction temperature may range from about -20 to 25 ° C. The time required for the reaction can be varied in the range of about 2-48 hours.

In the compound of formula (VI), A is --NR ₂ R
Formula (I) wherein ₃ (R ₂ and R ₃ are as defined above)
The conversion of to a compound is usually carried out by a reaction used in organic chemistry. For example, a compound of formula (VI) may be reacted with a halogenating agent such as chlorine, bromine, a thionyl halide such as thionyl chloride or a sulfonyl halide such as methanesulfonyl chloride to give a compound of formula (I). ..

Similarly, a compound of formula (VI) and a compound of formula R ₄ SO ₃
H (where R ₄ is as defined above) is reacted with a sulfonic acid of formula (I) or, more preferably, a corresponding sulfonyl halide such as the corresponding sulfonyl chloride or a reactive derivative of said sulfonic acid such as an anhydride. ) May be obtained.

In addition, a compound of formula (I) is optionally converted into another compound of formula (I), a compound of formula (I) is optionally salified, and a free compound is optionally prepared from a salt. It may be performed according to a known method. Formula (I)
The fractional crystallization and chromatography used to separate the mixture of isomers of ## STR1 ## into single isomers is carried out according to conventional methods.

Another aspect of the present invention is the formula (II),
It relates to intermediate products of (IV) and (VI). These compounds are new, and they are commercially available compounds or known methods (JACS, 1958, 80, 4621).
It can be prepared by carrying out a usual amidation reaction starting from the compound prepared in. The compound of formula (III) is a known compound, and can be produced by activating a compound based on carboxy by a commonly used method, and the compound of formula (V) is a commercially available compound. ..

The compounds of formula (I) according to the present invention have cytostatic properties against tumor cells and therefore are useful for the treatment of carcinomas such as breast cancer, lung cancer, bladder cancer; colon cancer, ovarian and endometrial tumors. It is useful for suppressing the growth of such various tumors. Other neoplasms to which the compounds of the invention may be applied include sarcomas such as soft tissue sarcomas and osteosarcomas, and hematological tumors such as leukemias.

Tables 1 and 2 explain the properties of the products of the present invention for inhibiting the growth of tumor cells.

Table 1 Antitumor activity of 2 '-(α-bromoacryloyl) -5- (benzofuran-2-carboxyamido) indole-2-carbohydrazide Tumor cells IC ₅₀ (γ / ml) L 1210 0.188 L 1210 / LPAM 0.188 LOVO 0.478 LOVO / D 0.500 Table 2 2 '-[4- (N, N-bis-2'-chloroethylamino) benzoyl] -5- [benzofuran-2-carboxamido] indole-2-carbohydrazide Antitumor activity of tumor cells IC ₅₀ (γ / ml) L 1210 1.45 L 1210 / LPAM 1.40 LOVO 42 The compound of the present invention is administered parenterally, intramuscularly or subcutaneously by conventional means, for example, intravenous injection or infusion. It can be administered topically or orally. The dose depends on the age, weight and condition of the patient and the means of administration. For example, a suitable dose for an adult is about 0.1 to 100 mg once a day.
It is a range of 4 times.

The pharmaceutical compositions according to the invention contain the compound of formula (I) as active substance together with one or more pharmaceutically acceptable excipients. The pharmaceutical composition of the present invention is usually prepared according to a general method and administered in a pharmaceutically suitable form. For example, solutions for intravenous injection or infusion contain, for example, sterile water as a carrier, and are preferably in the form of sterile isotonic saline solution. Suspensions or solutions for intramuscular injection may be combined with the active compound in a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and optionally a suitable amount of lidocaine hydrochloride. It may contain salt. In the form for topical application eg creams, lotions or pastes for dermatological treatment, the active ingredient may be mixed with common oily or emulsifying excipients. Solid oral forms such as tablets and capsules with the active compound together with diluents such as lactose, dextrose, saccharose, cellulose, corn starch and potato starch, for example silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol. Lubricants such as starches, gum arabic, gelatin,
Binders such as methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, e.g. starch, alginic acid, alginates, disintegrants such as sodium starch glycolate, effervescent mixtures, dyes, sweeteners such as lecithin, polysorbates, lauryl sulphates. Wetting agents and non-toxic and pharmacologically inactive substances generally used in the formulation of drugs may be included. The pharmaceutical preparation can be prepared by known methods such as mixing, granulating,
Manufactured by the process of tableting, sugar coating or film coating.

The present invention further provides a method for treating tumors which comprises administering the composition of the present invention to a patient in need thereof.

[0028]

EXAMPLES In the following examples, the terms DMSO, THF and DMF are respectively dimethylsulfoxide,
It represents tetrahydrofuran and dimethylformamide. The following examples illustrate the invention,
It does not impose any restrictions.

Example 1 2,3-Epoxypropionic acid (132 mg) in DMF (3 m
l) To a 80% stirred solution was added N, N-carbonyldiimidazole (194 mg) under a nitrogen atmosphere and the mixture was allowed to stand at room temperature for 45 minutes, then 5- (benzofuran-2-carboxamido) indole-2. -Carbohydrazide (200m
It was treated with a solution of g) in DMF (5 ml). After standing at room temperature for 1 hour, the solution was poured into water and a white solid was collected, washed with water and washed with 2 '
190 mg of-(2,3-epoxypropionyl) -5- (benzofuran-2-carboxamido) indole-2-carbohydrazide was obtained.

NMR (DMSO-d ₆ ) δ: 2.7-3.2
(2H, m); 3.53 (1H, dd); 7.21 (1H, b
s); 7.25-8.10 (7H, m); 8.13 (1H, bs);
10.38 (3H, s); 11.7 (1H, bs).

The following compound was obtained in a similar manner.

2 '-(2,3-epoxypropionyl)
-5- (quinolin-2-carboxamido) indole-2-carbohydrazide _{NMR (DMSO-d 6) δ} : 2.70-3.18 (2H,
m); 3.52 (1H, dd); 7.10-8.80 (10H, m);
10.15-10.55 (2H, br); 10.65 (1H, s); 11.
75 (1H, bs).

5- [5- (2,3-Epoxypropionylamino) indole-2-carboxamide] indole-2-carboxamide NMR (DMSO-d ₆ ) δ: 2.71-3.20 (2H,
m); 3.5 (1H, dd); 6.8-8.2 (10H, m); 1
0.31 (2H, s); 11.55 (1H, bs); 12.09 (1
H, bs).

N- [2- (2,3-epoxypropionylamino) ethyl] -5- [benzofuran-2-carboxamido] indole-2-carboxamide NMR (DMSO-d ₆ ) δ: 2.6-2.95 (2H , M);
3.0-3.7 (5H, m); 6.9-8.25 (10H, m); 8-8.45
(1H, br); 10.3 (1H, s); 11.5 (1H, b)
s). N- [2- (2,3-Epoxypropionylamino) ethyl] -5- [quinoline-2-carboxamido] indole-2-carboxamide.

N- [2- (2,3-epoxypropionylamino) ethyl] quinoline-2-carboxamide NMR (DMSO-d ₆ ) δ: 2.6-3.0 (2H, m);
3.05-3.80 (5H, m); 7.4-8.7 (7H, m); 8.95
(1H, bt).

[0036] Methanol (150ml) stirred solution of cooled to Example 2 -10 ℃ 5- [5- amino-indole-2-carboxamide] indole-2-carboxamide hydrochloride (1 g), cold ethylene oxide (15ml) Was added.

The reaction flask was sealed and allowed to stand overnight at room temperature. Methanol and excess ethylene oxide were removed under reduced pressure, the residue was washed with ethyl acetate, and 5- [5- [N,
N-bis (2-hydroxyethyl) amino] indole-2-carboxamido] indole-2-carboxamide (860 mg) was obtained.

NMR (DMSO-d ₆ ) δ: 2.90-3.80
(8H, m); 6.9-8.2 (10H, m); 10.28 (1H,
s); 11.54 (1H, bs); 12.09 (1H, bs).

Example 3 5- [5- [N, N-bis (2-hydroxyethyl) amino] indole-2-carboxamide] indole-2-carboxamide (860 mg) pyridine cooled to 0-5 ° C. The (10 ml) solution was treated with methanesulfonyl chloride (0.34 ml) in pyridine (3 ml) for 1 hour. After adding methanol (10 ml), the reaction mixture was warmed to room temperature.
The solvent was removed under vacuum, the residue was washed with acetone and collected to give 5- [5- [N, N-bis (2-chloroethyl) amino] indole-2-carboxamido] indole-
2-Carboxamide (470 mg) was obtained.

NMR (DMSO-d ₆ ) δ: 3.20-3.70
(8H, m); 6.9-8.25 (10H, m); 10.3 (1H,
s); 11.54 (1H, bs); 11.8 (1H, bs).

Example 4 5- (Benzofuran-2-carboxamido) indole-2-carbohydrazide (100 mg) in dry pyridine (1
To the stirred solution was added 4- [N, N-bis (2-chloroethyl) amino] benzoyl chloride (100 mg) and the solution was allowed to stand at room temperature for 30 minutes. The mixture was poured into 2N hydrochloric acid and the residue was collected, washed with acetone and 2 '-[4-
(N, N-Bis-2'-chloroethylamino) benzoyl] -5- (benzofuran-2-carboxamido) indole-2-carbohydrazide (150 mg) was obtained as a white solid.

NMR (DMSO-d ₆ ) δ: 3.4-4.1
(8H, m); 6.7-8.2 (13H, m); 10.2 (1H,
s); 10.42 (2H, s); 11.7 (1H, s).

The following compound was obtained by the same method.

2 '-[4- (N, N-bis-2'-chloroethylamino) benzoyl] -5- (quinoline-2-
Carboxamido) indole-2-carbohydrazide _{NMR (DMSO-d 6) δ} : 3.6-4.1 (8H, m);
6.7-8.75 (14H, m); 10.2 (1H, bs); 10.35
(1H, bs); 10.65 (1H, s); 11.7 (1H, b)
s).

5- [5- [4- [N, N-bis (2-chloroethyl) amino] benzoylamino] indole-
2-Carboxamide] indole-2-carboxamide.

N- [2- [4- [N, N-bis (2-chloroethyl) amino] benzoylamino] ethyl] -5
- [benzofuran-2-carboxamido] indole-2-carboxamide _{NMR (DMSO-d 6) δ} : 3.1-3.55 (4H, m);
3.55-4.0 (8H, m); 6.6-8.7 (15H, m) 10.35 (1
H, s); 11.55 (1H, bs).

N- [2- [4- [N, N-bis (2-chloroethyl) amino] benzoylamino] ethyl] -5
-[Quinoline-2-carboxamido] indole-2
-Carboxamide.

N- [2- [4- [N, N-bis (2-chloroethyl) amino] benzoylamino] ethyl] quinoline-2-carboxamide.

Example 5 α-Bromoacrylic acid (135 mg) and triethylamine
To a stirred solution of (0.125 ml) in dry THF (4 ml) was added pivaloyl chloride (0.098 ml) at -10 ° C. After 20 minutes the mixture was warmed to room temperature, the triethylammonium chloride was filtered off and then added dropwise to a solution of 5- (benzofuran-2-carboxamido) indole-2-carbohydrazide (150 mg) in dry DMF (5 ml).

The mixture is allowed to stand at room temperature for 1 hour, then 2N.
Poured into hydrochloric acid. The resulting residue is collected, washed with ethanol and 2 '-(α-bromoacryloyl) -5- (benzofuran-2-carboxamido) indole-2-.
75 mg of carbohydrazide was obtained.

NMR (DMSO-d ₆ ) δ: 6.3 (1
H, d); 6.77 (1H, d); 7.2 (1H, bs);
7.2-7.9 (7H, m); 8.12 (1H, bs); 10.3-10.
6 (3H, br); 11.7 (1H, bs).

The following compound was obtained in a similar manner: 2 '-(α-bromoacryloyl) -5- (quinoline-
2-carboxamido) indole-2-carbohydrazide _{NMR (DMSO-d 6) δ} : 6.32 (1H, d); 6.75
(1H, d); 7.10-8.82 (10H, m); 10.12-10.55
(2H, br); 10.6 (1H, s); 11.7 (1H, b
s).

5- [5- (α-bromoacryloylamino) indole-2-carboxamido] indole-
2-carboxamide.

N- [2- (α-bromoacryloylamino) ethyl] -5- [benzofuran-2-carboxamido] indole-2-carboxamide.

N- [2- (α-bromoacryloylamino) ethyl] -5- [quinoline-2-carboxamido] indole-2-carboxamide.

N- [2- (α-bromoacryloylamino) ethyl] quinoline-2-carboxamide NMR (DMSO-d ₆ ) δ: 3.0-3.65 (4H, m);
6.15 (1H, d); 6.65 (1H, d); 7.5-8.7 (7
H, m); 9.05 (1H, bt).

Example 6 To prepare an intramuscular injection solution of 1 mg / ml, 2 '-(α-
Bromoacryloyl) -5- (benzofuran-2-carboxamido) indole-2-carbohydrazide 1 g
Can be dissolved in water for injection (1000 ml) and sealed in an ampoule of 1 to 5 ml to prepare an injectable pharmaceutical composition.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/47 7252-4C C07D 215/48 307/85 311/66 6701-4C 333/68 401 / 12 209 8829-4C 405/12 209 8829-4C (72) Inventor Roberto Darrezcio Italy, 20092 Cinizeturo Balsamo Milan, Via San Paolo 5 (72) Inventor Maria Grande Italy , 20129, Milan, Piazza Cinque Giornate, 6 (72) Inventor Huedelico Spreahuico Italy, 20129, Milan, Via Sil Torri, 22

Claims (16)

[Claims] 1. The following formula (I): [In the formula, A is hydrogen; -NHCOR ₁ (R ₁ is an acryl group substituted at the 2-position with halogen, unsubstituted or substituted at the 2-position or the 3-position with methyl, oxiranyl, aziridinyl, cyclo) Propyl, 4- [N, N-bis- (2-chloroethyl) amino] phenyl, which represents an alicyclic α, β-unsaturated ketone or lactone);
R ₂ R ₃ (R ₂ and R ₃ have the same meaning, and
Position is halogen or -OSO ₂ R ₄ group (R ₄ is C ₂ -
A C ₂ -C ₄ alkyl group substituted with a C ₄ alkyl or phenyl group), or R ₂ and R
One ₃ is hydrogen and the other represents a) a defined above and the same meaning, B is hydrogen; or _{- (CH 2) m -NHCOR 1} (R 1 is the same as defined above, m Is 0 or an integer of 1 to 3), but when A is hydrogen, B is a group other than hydrogen, and when A has another meaning as defined above other than hydrogen, B Is limited to hydrogen, and each of Z and Z'is independently -CH = or -CH.
Is CH—, each of X and X ′ is independently N, O or S, and n represents 0 or 1, and these are represented by the following formulas, alone or in the form of a mixture. The isomers considered from the above and pharmaceutically acceptable salts thereof. 2. A heterocyclic oligopeptide derivative according to claim 1, wherein the symbols in formula (I) are as follows, isomers and pharmaceutically acceptable salts thereof, wherein A is hydrogen, the _{B - (CH 2) m -NHCOR} 1 (R 1 is 2-Buromoakuririru, oxiranyl or 4-[N, N-bis (2
-Chloroethyl) amino] phenyl, m is 0 or 2), Z is preferably -CH = when X is oxygen, or -CH = CH- when X is nitrogen, and Z'is Preferably -CH =, X'is nitrogen, and n is preferably 0 or 1. 3. The heterocyclic oligopeptide derivative according to claim 1, wherein the symbols in formula (I) are as follows, isomers and pharmaceutically acceptable salts considered from these: A is —NHCOR. ₁ (R ₁ is 2-bromoacrylyl, oxiranyl, 4- [N, N-bis (2-chloroethyl)
Amino] phenyl), or —NR ₂ R ₃ (R ₂ and R ₃
Are the same and C ₂ is substituted in the 2-position with halogen.
When an alkyl group -C ₄ is 2-chloroethyl), Z and Z 'are both -CH =, X and X' are preferably both nitrogen, B is hydrogen, n is 1. 4. 2 '-(α-bromoacryloyl) -5
-(Benzofuran-2-carboxamido) indole-2-carbohydrazide. 5. 2 '-[4- (N, N-bis-2'-chloroethylamino-benzoyl] -5- [benzofuran-2-carboxamido] indole-2-carbohydrazide. 6. The following formula (II): (Wherein X, X ', Z, Z', m and n are the same as defined above) and a compound of formula (III): (Wherein R ₁ is the same as defined above, L represents a halogen such as chlorine or bromine, a leaving group such as imidazolyl, pivaloyloxy or isobutyloxycarbonyloxy group) and a solvent In existence
A is hydrogen and B is (CH ₂ ) _n- NHCOR ₁ , consisting of reacting at a temperature of 20-80 ° C. and then optionally converting to one of their pharmaceutically acceptable salts. A method for producing the compound according to 1, 2, 4 and 5. 7. The following formula (IV): A compound represented by the formula (wherein X, X ', Z, Z'and n are the same as defined above) and the formula (III) according to claim 6.
Reacting in the presence of a solvent at a temperature of 20-80 ° C., and then optionally converting to one of their pharmaceutically acceptable salts, wherein A is —NHCOR ₁ and B is hydrogen. The method for producing the compound according to claim 1 or 3, wherein 8. The following formula (V): (Wherein Y represents hydrogen or a C ₁ -C ₂ alkyl group) and the compound of formula (IV) according to claim 7 in the presence of a solvent at a temperature of -20 to 25 ° C. After reaction, the following formula (VI): (Wherein X, X ', Z, Z', Y and n are the same as defined above, and Y'has the same meaning as Y), and a compound of formula (VI) The compound of formula (I) is converted to a compound of formula (I) by using a halogenating agent such as chlorine, bromine, thionyl halide such as thionyl chloride, sulfonyl halide such as methanesulfonyl chloride, and further, a pharmaceutical composition thereof. _2. A according to claim 1, wherein A is --NR ₂ R ₃ (R ₂ and R ₃ are as defined above) and B is hydrogen, which comprises conversion to one of the pharmaceutically acceptable salts. Method for producing compound. 9. A process for preparing a compound according to claims 1 to 5, which comprises converting a compound of formula (I) into another compound of formula (I). 10. An intermediate compound of formula (II) according to claim 6. 11. An intermediate compound of formula (IV) according to claim 7. 12. An intermediate compound of formula (VI) according to claim 8. 13. Process according to claims 6 and 7, wherein the solvent used is dimethylformamide. 14. The method according to claim 8, wherein the solvent used is methanol. 15. Useful against animal and mammalian tumors such as breast cancers, ovarian tumors and endometrial tumors, soft tissue sarcomas and hematological malignancies such as osteosarcoma and leukemias.
5. The compound according to any one of to 5. 16. A pharmaceutical composition comprising a heterocyclic oligopeptide derivative according to any one of claims 1 to 5, which is a mixture with a pharmaceutically acceptable diluent or carrier.