JPH08151380A - Bis (trifluoromethylpyrroloindolecarboxylic acid ester) derivative and method for producing the same - Google Patents

Abstract

(57) [Summary] [Structure] A bis (trifluoromethylpyrroloindolecarboxylic acid ester) derivative represented by the following general formula (1) or (2). Embedded image As a specific example of the general formula (1), (S, S)-[3,3 '
-Carbonylbis (imino-1H-indole-5-diyl) -2-ylcarbonyl] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,
There is 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate methyl]. [Effect] It has high selectivity for cancer cells, low toxicity, and strong activity against solid tumors.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel bis (7-trifluoromethyl-1,2,3,6) having antibacterial and antitumor activity.
-Tetrahydropyrrolo [3,2-e] indole-8-
Carboxylic acid ester) derivative and bis (6-trifluoromethyl-1,2,8,8a-tetrahydrocyclopropa [c] pyrrolo [3,2-e] indole-4 (5H)
-On-7-carboxylic acid ester) derivative, an optically active substance thereof, and a pharmacologically acceptable salt thereof.

[0002]

2. Description of the Related Art CC-1065 as an antibiotic having antibacterial activity and antitumor activity is disclosed in "J. Antibiotics" 31: 1211 (1978), 34: 1119 (1981).
, U.S. Pat. No. 4,169,888, and duocarmycin A and its analogs having a similar structure are disclosed in WO87 /
06265, EP0318056, "Journal
Of Antibiotics "4
Volume 2, page 1229 (1989), JP-A-4-99977.
No. 4 is disclosed.

Further, a derivative of CC-1065 is EP03.
59454, Japanese Patent Laid-Open No. 60-193989, and Japanese Patent Publication No.
No. -502005, and derivatives of duocarmycins are disclosed in JP-A-3-7287 and JP-A-3-128379.
, EP0354583, EP0406749. These all utilize the basic skeleton of natural products as they are, or are derived from chemical modification of natural products.

A compound having two tetrahydropyrroloindole skeletons in one compound is disclosed in JP-A-60-19.
No. 3989 (EP0154445) and Tokuhyo 2-5
Although it is included in the scope of claims of 02005 (WO8804659), there is no specific description and there is no disclosure of applicable examples. Also, cross-linking moiety -R ₅ -T-R _'5 -
(R ₅ and R ′ ₅ are phenyl groups substituted with a carbonyl group,
Heterocyclic groups, benzene-fused heterocyclic groups, etc., T is aminocarbonyl, carbonylamino, carbonyloxy, oxycarbonyl, etc.)
No. 4 (WO90002746), wherein the bridging portion is a carbonylbis (imino-1H-indole-2-carbonyl) group, 5,5 ′-[(1,2-dioxo-1,2).
-Ethanediyl) diamino] bis-1H-indole-
Compounds having a 2-carbonyl group are disclosed as examples.

It has two 7-trifluoromethyl-8-methoxycarbonyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole rings, and the bridging moiety is carbonylbis (imino-1H-indole). The compound which is a (2-carbonyl) group has already been disclosed by the present applicants (JP-A-6-116269).

However, bis (trifluoromethylpyrroloindolecarboxylic acid ester) such as the compound of the present invention
Derivatives have not been previously known.

[0007]

Surgical resection, radiotherapy with X-rays, and drug therapy with chemotherapeutic agents are clinically used as therapeutic methods for cancer. Of these, drug therapy with chemotherapeutic agents is the only treatment for cancer that has spread to various parts of the body and end-stage cancer. Originally, this drug therapy, which seems to be the least burden on the patient, actually causes severe distress to the patient due to the strong side effects. In addition, many of the current chemotherapeutic agents are effective against leukemia with fast cell growth, but low against solid tumors with slow growth. For this reason, cancer treatment with chemotherapeutic agents is not always first-line treatment.

[0008] In view of the current state of such chemotherapy, the present invention aims to provide a compound which is highly selective for cancer cells, effective for solid tumors, and low in toxicity.

[0009]

As a result of intensive studies to solve the above problems, the present inventors have found that the novel compound of the present invention has high selectivity for cancer cells, low toxicity, and solid tumors. The inventors have found that they also have a strong activity against, and completed the invention.

That is, the present invention provides the following general formula (1) or (2)

[0011]

Embedded image

(In the formula, R is a linear or branched C1 to
A lower alkyl group of C6, R ¹ is a.

[0013]

[Chemical 38]

(X ¹ and X ² are each independently a hydrogen atom,
OH, OR ⁴ (R ⁴ is a linear or branched C1-C6 lower alkyl group, or an aryl group which may be substituted), OCOR ⁴ (R ⁴ is the same as the above), or a linear or branched group. A branched C1 to C6 lower alkyl group, X ³ is NH,
O or S, R ³ is

[0015]

[Chemical Formula 39]

(X ⁴ and X ⁵ are independently of each other a hydrogen atom, OH, OR ⁴ (R ⁴ is a linear or branched C1 to C
6 lower alkyl group, or an optionally substituted aryl group), OCOR ⁴ (R ⁴ is the same as the above), or a linear or branched C 1 to C ⁶ lower alkyl group). B.

[0017]

[Chemical 40]

C.

[0019]

Embedded image

(X ¹ and X ² are the same as above) or d.

[0021]

Embedded image

(X ¹ , X ² and X ³ are the same as above), R
² is a hydrogen atom, a protective group for a hydroxyl group, or a substituent decomposable in vivo, Y is a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an azido group. The present invention provides a bis (trifluoromethylpyrroloindolecarboxylic acid ester) derivative represented by the formula (1), an optically active substance thereof, a pharmacologically acceptable salt thereof, and a method for producing the salt.

Among the substituents defined here, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and an optionally substituted aryl group means a halogen atom, an alkyl group or an amino group. , An alkylamino group, an aminoalkyl group, an aryl group which may be substituted with a hydroxyl group and the like, for example, a chlorophenyl group, a methylphenyl group, an aminophenyl group, a methylaminophenyl group,
Examples thereof include aminomethylphenyl group and hydroxyphenyl group.

The term "biodegradable substituent" as used herein means a substituent which is decomposed in vivo to give a hydroxyl group, for example, a lower alkanoyl group, an aryloyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted group. Aryloxycarbonyl group, optionally substituted carbamoyl group, α-
Examples thereof include amino acid acyl residues.

Specific examples of the lower alkanoyl group include formyl group, acetyl group, propionyl group, butyryl group,
Examples thereof include pivaloyl group, valeryl group and caproyl group, and specific examples of the aryloyl group include benzoyl group, phenylacetyl group and naphthyl group. Specific examples of the lower alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a hexyloxycarbonyl group, and the like, and the substituted or unsubstituted aryloxycarbonyl group is a phenoxycarbonyl group. ,
p-chlorophenoxycarbonyl group, p-methoxyphenoxycarbonyl group, p-aminophenoxycarbonyl group, benzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-aminobenzyloxycarbonyl group, etc. Can be mentioned. Specific examples of the carbamoyl group which may be substituted are N-lower alkylcarbamoyl group, N, N-dilower alkylcarbamoyl group, N-arylcarbamoyl group, pyrrolidinylcarbonyl group, or 3- (dimethylamino). An optionally substituted pyrrolidinylcarbonyl group such as a pyrrolidinylcarbonyl group, 4
An optionally substituted piperidinylcarbonyl group such as a-(dimethylamino) piperidinylcarbonyl group or a (4-piperidinopiperidinyl) carbonyl group, (4-
Methyl-1-piperazinyl) carbonyl group, [4- [2
-(Dimethylamino) ethyl] -1-piperazinyl] carbonyl group, [4- (2- (hydroxyethyl) -1-
A piperazinyl] carbonyl group, or [4- [2- [2-
(Dimethylamino) ethoxy] ethyl] -1-piperazinyl] carbonyl group or the like, optionally substituted 1-piperazinylcarbonyl group, or optionally 1-
Examples thereof include a morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, and a silyl group substituted with an alkyl group. As the α-amino acid acyl residue, glycine, alanine, valine in which an amino group may be protected by a benzyloxycarbonyl group, a fluorenylmethyloxycarbonyl group, a t-butoxycarbonyl group or the like,
Leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, phenylalanine, tyrosine, histidine, tryptophan,
Mention may be made of amino acid acyl residues such as proline and hydroxyproline.

Specific examples of the arylsulfonyloxy group include a benzenesulfonyloxy group and a toluenesulfonyloxy group, and examples of the lower alkylsulfonyloxy group include a methanesulfonyloxy group, an ethanesulfonyloxy group, Examples thereof include a propanesulfonyloxy group and the like, and specific examples of the haloalkylsulfonyloxy group include a trifluoromethanesulfonyloxy group and a trichloromethanesulfonyloxy group.

The present invention further provides the compound represented by the above general formula (1) or (2) by the production method described below.

That is, the following general formula (3a)

[0029]

[Chemical 43]

(In the formula, R ⁷ represents a protecting group for an amino group (R, R ² and Y are the same as above)), and the compound represented by the following general formula (3) is deprotected.

[0031]

[Chemical 44]

(In the formula, R, R ² and Y are the same as above.)
Or convert to its salt. These compounds can be produced according to a known method (JP-A-6-116269).

Next, a compound represented by the above general formula (3),
Or a salt thereof and the following general formula (4a)

[0034]

Embedded image

(In the formula, V represents a halogen atom, a 1-imidazolyl group, a 4-nitrophenoxy group, a reactive residue such as a succinimidoyloxy group, or OR ¹ (R ¹ is the same as above). ) Represented by the formula (4b) HOOC-R ¹ -COOH represented by the following general formula (4b): carboxylic acid halide, carboxylic acid imidazolide, carboxylic acid active ester, carboxylic acid mixture, or symmetrical acid anhydride. (4b) Condensation with a carboxylic acid represented by (R ¹ is the same as above) using a condensing agent such as dicyclohexylcarbodiimide (DCC) or 3-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride. The following general formula (1)

[0036]

Embedded image

(In the formula, R, R ² and Y are the same as above.)
A compound represented by can be produced. This condensation reaction consists of triethylamine, diisopropylethylamine,
In a solvent such as dichloromethane, toluene, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, or tetrahydrofuran in the presence or absence of an organic base such as pyridine or dimethylaminopyridine, or an inorganic base such as sodium hydrogen carbonate or potassium carbonate. -20 to
It can be easily carried out by treating at 50 ° C. for 30 minutes to 48 hours.

[0038]

[Chemical 47]

(In the formula, R, R ¹ and Y are the same as above.) Further, the compound represented by the general formula (1a) is represented by the general formula (5) R ⁸ -Z (5) (in the formula, R ⁸ Is a substituent degradable in vivo, Z is a reactive residue), a lower alkanoyl chloride represented by
The following general formula (1c) is obtained by treating with allyloyl chloride, lower alkoxycarbonyl chloride, substituted or unsubstituted aryloxycarbonyl chloride, α-amino acid chloride, optionally substituted carbamoyl chloride, or their active ester.

[0040]

Embedded image

(In the formula, R ⁸ represents a substituent decomposable in vivo (R, R ¹ and Y are the same as the above)). This reaction is carried out in the presence or absence of an organic base such as triethylamine, diisopropylethylamine, pyridine or dimethylaminopyridine, or an inorganic base such as sodium hydrogen carbonate or potassium carbonate in an inert solvent at −20 to 100 ° C., preferably Is 0
It is carried out by treating at 50 ° C. for 30 minutes to 10 days.

Further, the following general formula (1a)

[0043]

[Chemical 49]

(In the formula, R, R ¹ and Y are the same as above.)
When the compound represented by the formula (1) is subjected to ring closure in the presence of a base,

[0045]

Embedded image

(In the formula, R and R ¹ are the same as the above.) And can be led to a compound. In this reaction, the compound of the general formula (1a) is used in an amount of 1 to 10 equivalent mol, preferably 1 to 5 equivalent mol of an organic base such as diazabicyclo base or triethylamine, or an inorganic substance such as sodium hydroxide, sodium hydride or potassium carbonate. In the presence of a base, in an inert solvent such as dichloromethane, toluene, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixed solvent thereof at -78 to 100 ° C, preferably 0 to 50 ° C for 10 minutes to 24 ° C. It can be carried out by treating for a time, preferably 20 minutes to 5 hours. Further, the compound represented by the above general formula (2) is converted into hydrogen chloride, hydrogen bromide, hydrochloric acid, hydrobromic acid, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid,
In the presence of an acid such as trifluoromethanesulfonic acid or hydrazoic acid, in an inert solvent such as ethyl acetate, dichloromethane, acetonitrile, N, N-dimethylformamide or tetrahydrofuran, a temperature from -20 ° C to the boiling point of the solvent, preferably Can be converted to the compound represented by the general formula (1a) by treating at a temperature of 0 to 50 ° C. It is preferable to use an excess of acid for this reaction from the viewpoint of shortening the reaction time.

When the optically active substance of the compound represented by the general formula (3) is used, the optically active substance of the compound represented by the general formulas (1) and (2) is produced. Here, the general formula (3)
The optically active isomer of the compound represented by can be produced according to a known method (JP-A-6-116269).

The compound represented by the general formula (1) or (2) can be used as an antibacterial or antitumor composition alone or in combination with one or more known pharmaceutically acceptable adjuvants, tablets, It can be provided as an oral or parenteral preparation such as a capsule, powder, granule, ampoule and the like.

When used parenterally, intravenous administration, intraarterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intrathoracic administration, local administration and the like are also possible.

For example, a compound represented by the general formula (1) or (2) or a salt thereof is dissolved in physiological saline or an aqueous solution of glucose, mannitol, lactose or the like to give a suitable pharmaceutical composition. Further, a salt of the compound represented by the general formula (1) or (2) is freeze-dried by a conventional method,
A powder injection can also be prepared by adding sodium chloride or the like to this. Further, the pharmaceutical composition may contain additives well known in the field of formulation, such as pharmaceutically acceptable salts, if necessary.

The dose varies depending on the age and symptoms of the patient, but is 0.00001 to 100 mg for mammals including humans.
/ Kg / day. The administration is, for example, once or several times a day, or intermittently, 1 to 5 times a week, and once every 2 to 4 weeks.

The following examples show the usefulness of the present invention, but the present invention is not limited to the examples.

[0053]

【Example】

 Example 1

[0054]

[Chemical 51]

(S) -3-t-butoxycarbonyl-1
-Chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-
e] Methyl indole-8-carboxylate 13.5 mg
(30 μmol) in 3 M hydrogen chloride-ethyl acetate 0.3 m
After adding 1 and stirring at room temperature for 40 minutes, the solvent was distilled off. To the obtained residue, 5,5 '-(carbonyldiimino) bisbenzofuran-2-carboxylic acid 5.7 mg (15 μmol)
1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (17.3 mg, 90 μmol) were added, and the mixture was stirred overnight at room temperature in 0.3 ml of dimethylformamide. The reaction solution was purified by silica gel column chromatography (tetrahydrofuran) and washed with methanol to give (S, S)-[3,3'-carbonylbis (imino-1H-indole-5-diyl) -2- as light yellow crystals.
6.6 mg of methylcarbonyl] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate] (42%) was obtained.

[Α] ²⁴ _D = + 18 ° (c = 0.2
0, dimethylformamide) NMR (DMSO d ₆ ) δ: 3.54 (2H, t, J = 10Hz), 3.85 (2
H, m), 3.88 (6H, s), 4.29 (2H, m), 4.54 (2H, d, J = 11Hz), 4.66
(2H, t, J = 9Hz), 7.49 (2H, dd, J = 2Hz, J = 9Hz), 7.65-7.67 (4
H, m), 7.93 (2H, brs), 8.04 (2H, d, J = 2Hz), 8.83 (2H, brs), 1
0.62 (2H, s), 13.11 (2H, s).

Example 2

[0058]

Embedded image

By the same method, 5,5 '-[(4,6-
Pyrimidinediyl) dicarbonyldiimino] bis-1H
-Indole-2-carboxylic acid 5.6 mg (11.5μ
mol) from (S, S) -3,3 '-[(4,6-pyrimidinediyldicarbonyl) bis [(imino-1H-
Indole-5-diyl) -2-ylcarbonyl]] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole- Methyl 8-carboxylate] was obtained in an amount of 6.2 mg (47%).

[Α] ²⁵ _d = + 107 ° (c = 0.28,
Tetrahydrofuran) NMR (DMSO d ₆ ) δ: 3.52 (2H, t, J = 9Hz), 3.87 (2
H, m) 3.89 (6H, s), 4.29 (2H, m), 4.55 (2H, d, J = 11Hz), 4.72 (2
H, t, J = 10Hz), 7.20 (2H, s) 7.52 (2H, d, J = 9Hz), 7.75 (2H, d,
J = 9Hz), 7.96 (2H, brs), 8.36 (2H, s), 8.72 (1H, s), 9.62 (1H,
s), 10.56 (2H, brs), 10.87 (2H, s), 11.77 (2H, s), 13.07 (2
H, brs).

Example 3

[0062]

Embedded image

By the same method, 5,5 '-[[3,3'
-(1,4-benzenediyl) diacryloyl] diimino] bis-1H-indole-2-carboxylic acid 8.0 m
From g (15 μmol), (S, S) -3,3′-
[3,3 ′-[(1,4-benzenediyl) diacryloyl] bis (imino-1H-indole-5-diyl)
-2-ylcarbonyl] bis- [1-chloromethyl-5
-Hydroxy-7-trifluoromethyl-1,2,3
6-Tetrahydropyrrolo [3,2-e] indole-8
-Methyl carboxylate] was obtained in an amount of 6.2 mg (47%).

[Α] ²⁴ _D = + 70 ° (c 0.20, dimethylformamide) NMR (DMSO d ₆ ) δ: 3.50 (2H, t, J = 10Hz), 3.86
(2H, m), 3.89 (6H, s), 4.29 (2H, m), 4.55 (2H, d, J = 11Hz), 4.7
0 (2H, t, J = 9Hz), 6.95 (2H, d, J = 16Hz), 7.15 (2H, s), 7.47 (4
H, s), 7.62 (2H, d, J = 16Hz), 7.71 (4H, s), 7.95 (2H, brs), 8.
24 (2H, s), 10.17 (2H, s), 10.51 (2H, s), 11.68 (2H, s), 13.03
(2H, brs).

Example 4

[0066]

[Chemical 54]

By the same method, 5,5'-bis-1H-
Indole-2-carboxylic acid 4.0 mg (12.5 μ
mol) from (S, S) -3,3 '-[5,5'-
Bis- (1H-indol-2-ylcarbonyl)] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole- Methyl 8-carboxylate] was obtained in an amount of 4.9 mg (40%).

[Α] ²³ _D = + 70 ° (c = 0.20, tetrahydrofuran) NMR (DMSO d ₆ ) δ: 3.53 (2H, t, J = 9Hz), 3.82-3.
94 (2H, m), 3.89 (6H, s) 4.25-4.34 (2H, m), 4.56 (2H, d, J = 11
Hz), 4.74 (2H, t, J = 9Hz), 7.21 (2H, s), 7.55-7.66 (4H, m), 7.
97 (4H, brs), 11.69 (2H, s), 11.76 (2H, s), 13.09 (2H, br
s).

Example 5

[0070]

[Chemical 55]

By the same method, 5,5 '-(methanediyl) bis-1H-indole-2-carboxylic acid 4.2 m
From g (12.5 μmol), (S, S) -3,3
′-[5,5 ′-(Methanediyl) bis- (1H-indol-2-ylcarbonyl)] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,
Methyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate] was 3.6 mg (29%).
Obtained.

[Α] ²⁴ _D = -29 ° (c = 0.20, tetrahydrofuran) NMR (DMSO d ₆ ) δ: 3.49 (2H, dd, J = 9Hz, J = 11H
z), 3.80-3.94 (2H m), 3.87 (6H, s), 4.11 (2H, brs), 4.22-4.
30 (2H, m), 4.51 (2H, d, J = 11Hz), 4.67 (2H, t, J = 11Hz), 7.09
(2H, d, J = 2Hz), 7.16 (2H, dd, J = 2Hz, J = 9Hz), 7.41 (2H, d, J = 8
Hz), 7.54 (2H, s), 7.94 (2H, brs), 10.56 (2H, s), 11.62 (2H, b
rs), 13.08 (2H, brs).

Example 6

[0074]

[Chemical 56]

By the same method, 5,5 '-(oxydiyl) bis-1H-indole-2-carboxylic acid 4.2 m
From g (12.5 μmol), (S, S) -3,3
′-[5,5 ′-(oxydiyl) bis- (1H-indol-2-ylcarbonyl)] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,
Methyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate] was 6.0 mg (48%).
Obtained.

[Α] ²⁴ _D = -25 ° (c = 0.20, tetrahydrofuran) NMR (DMSO d ₆ ) δ: 3.51 (2H, dd, J = 9Hz, J = 11H
z), 3.82-3.89 (2H, m), 3.87 (6H, s), 4.22-4.30 (2H, m), 4.50
(2H, d, J = 10Hz), 4.66 (2H, dd, J = 9Hz, J = 11Hz), 7.05 (2H, dd,
J = 3Hz, J = 9Hz), 7.09 (2H, brs), 7.24 (2H, d, J = 2Hz), 7.51 (2
H, d, J = 9Hz), 7.95 (2H, brs), 10.58 (2H, brs), 11.73 (2H, br
s), 13.10 (2H, brs).

Example 7

[0078]

[Chemical 57]

By the same method, 5,5 '-(ethyndiyl) bis-1H-indole-2-carboxylic acid 4.3
From mg (12.5 μmol) to (S, S) -3,3
′-[5,5 ′-(Ethindiyl) bis- (1H-indol-2-ylcarbonyl)] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,
Methyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate] was 4.6 mg (36%).
Obtained.

[Α] ²³ _D = + 94 ° (c = 0.20, tetrahydrofuran) NMR (DMSO d ₆ ) δ: 3.59 (2H, dd, J = 9Hz, J = 11H
z), 3.88-3.98 (2H, m), 3.94 (6H, s), 4.30-4.40 (2H, m), 4.59
(2H, d, J = 11Hz), 4.78 (2H, t, J = 11Hz), 7.25 (2H, s), 7.48 (2
H, d, J = 8Hz), 7.60 (2H, d, J = 9Hz), 7.96-8.06 (4H, m), 10.64
(2H, brs), 12.01 (2H, s), 13.16 (2H, brs).

Example 8

[0082]

Embedded image

In the same manner, 5,5 '-((Z)-
1,2-ethylenediyl) bis-1H-indole-2
-From 1.4 mg (4.0 μmol) of carboxylic acid,
(S, S) -3,3 '-[5,5'-((Z) -1,2
-Ethylenediyl) bis- (1H-indol-2-ylcarbonyl)] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2- e] indole-8-carboxylate] was obtained (2.0 mg, 51%).

[Α] ²³ _D = + 79 ° (c = 0.20, tetrahydrofuran) NMR (DMSO d ₆ ) δ: 3.53 (2H, dd, J = 9Hz, J = 11H
z), 3.83-3.97 (2H, m), 3.89 (6H, s), 4.23-4.34 (2H, m), 4.54
(2H, d, J = 11Hz), 4.73 (2H, dd, J = 9Hz, J = 11Hz), 7.17 (2H, d, J
= 2Hz), 7.29 (2H, s), 7.51 (2H, d, J = 8Hz), 7.63 (2H, d, J = 9H
z), 7.85 (2H, s), 7.95 (2H, s), 10.57 (2H, s), 11.78 (2H, s),
13.09 (2H, s).

Example 9

[0086]

Embedded image

In the same manner, from 5,5 '-(1,2-ethanediyl) bis-1H-indole-2-carboxylic acid 4.4 mg (12.5 μmol) to (S, S)
-3,3 '-[5,5'-(1,2-ethanediyl) bis- (1H-indol-2-ylcarbonyl)] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl- 4.2 mg (33%) of 1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate] was obtained.

[Α] ²⁴ _D = + 11 ° (c = 0.20, tetrahydrofuran) NMR (DMSO d ₆ ) δ: 3.02 (4H, brs), 3.50 (2H, t,
J = 11Hz), 3.80-3.94 (2H, m), 3.88 (6H, s), 4.22-4.32 (2H,
m), 4.51 (2H, d, J = 11Hz), 4.68 (2H, t, J = 10Hz), 7.06 (2H, d, J
= 1Hz), 7.17 (2H, dd, J = 1Hz, J = 9Hz), 7.41 (2H, d, J = 9Hz), 7.5
1 (2H, s), 7.95 (2H, brs), 10.55 (2H, brs), 11.60 (2H, brs),
13.07 (2H, brs).

Example 10

[0090]

Embedded image

By the same method, from 3.1 mg (12.5 μmol) of 1,6-dihydrobenzo [1,2-b: 3,4-b '] dipyrrole-2,7-dicarboxylic acid,
(S, S) -3,3 '-[1,6-dihydrobenzo [1,2-b: 3,4-b'] dipyrrole-2,7-diyldicarbonyl] bis- [1-chloromethyl- 5-hydroxy-7-trifluoromethyl-1,2,3,6-
4.4 mg (39%) of tetrahydropyrrolo [3,2-e] indole-8-carboxylate] was obtained.

[Α] ²³ _D = + 37 ° (c = 0.20, tetrahydrofuran) NMR (DMSO d ₆ ) δ: 3.48-3.57 (2H, m), 3.84-3.
94 (2H, m), 3.89 (3H, s), 3.90 (3H, s), 4.26-4.38 (2H, m), 4.5
8 (1H, d, J = 11Hz), 4.62-4.69 (2H, m), 4.73 (1H, dd, J = 9Hz, J =
11Hz), 7.26 (1H, d, J = 2Hz), 7.29 (1H, d, J = 9Hz), 7.54 (1H, d,
J = 9Hz), 7.77 (1H, brs), 8.00 (1H, s), 8.01 (1H, s), 10.56 (1
H, s), 10.58 (1H, S), 11.92 (1H, brs), 12.22 (1H, brs), 13.07
(1H, s), 13.09 (1H, s).

Example 11

[0094]

[Chemical formula 61]

In the same manner, from 3.1 mg (12.5 μmol) of 1,6-dihydrobenzo [1,2-b: 4,3-b '] dipyrrole-2,7-dicarboxylic acid,
(S, S) -3,3 '-[1,6-Dihydrobenzo [1,2-b: 4,3-b'] dipyrrole-2,7-diyldicarbonyl] bis- [1-chloromethyl- 5-hydroxy-7-trifluoromethyl-1,2,3,6-
5.0 mg (44%) of tetrahydropyrrolo [3,2-e] indole-8-carboxylate methyl] was obtained.

[Α] ²³ _D = + 206 ° (c = 0.20,
Tetrahydrofuran) NMR (DMSO d ₆ ) δ: 3.52 (2H, dd, J = 9Hz, J = 11H
z), 3.85-3.94 (2H, m), 3.88 (6H, s), 4.28-4.36 (2H, m), 4.62
(2H, d, J = 10Hz), 4.78 (2H, t, J = 11Hz), 7.45 (2H, s), 7.48 (2
H, brs), 7.99 (2H, s), 10.55 (2H, brs), 11.86 (2H, s), 13.07
(2H, brs).

Example 12

[0098]

Embedded image

(S, S) -3,3 '-[(4,6-pyrimidinediyldicarbonyl) bis [(imino-1H-indole-5-diyl) -2-ylcarbonyl]] bis- [1- Chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate methyl]
2.8 mg (2.4 μmol) of acetonitrile 1.0
ml and tetrahydrofuran 0.1 ml,
8-diazabicyclo [5.4.0] -7-undecene (1.5 [mu] l (4.9 [mu] mol) was added, and the mixture was added under an argon stream.
Stir at room temperature for 5 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography (tetrahydrofuran: hexane = 10: 1) to give yellow crystals of (S, S) -2,
2 '-[(4,6-pyrimidinediyldicarbonyl) bis [(imino-1H-indole-5-diyl) -2-
Ilcarbonyl]] bis- [6-trifluoromethyl-
1,2,8,8a-Tetrahydrocyclopropa [c] pyrrolo [3,2-e] indole-4 (5H) -one-7
-Methyl carboxylate] was obtained (2.5 mg, 94%).

[Α] ²⁵ _D = + 119 ° (c = 0.17,
Tetrahydrofuran) NMR (DMSO d ₆ ) δ: 1.55 (2H, t, J = 4Hz), 2.18 (2
H, q, J = 3Hz), 3.52 (2H, m), 3.81 (6H, s), 4.50 (2H, d, J = 10H
z), 4.62 (2H, dd, J = 5Hz, J = 11Hz), 6.92 (2H, s), 7.26 (2H, s),
7.50 (2H, d, J = 9Hz), 7.76 (2H, dd, J = 2Hz, J = 9Hz), 8.37 (2H,
s), 8.69 (1H, d, J = 2Hz), 9.61 (1H, d, J = 2Hz), 10.90 (2H, s), 1
1.89 (2H, s), 13.86 (2H, br).

Experimental Example 1 HeLa Cell Growth Inhibitory Activity: HeLa S ₃ cells were used in Eagle's Minimal Medium (Eagle's Minimal) containing 2 mM glutamine, 100 μg / ml kanamycin sulfate, and 10% inactivated fetal bovine serum. Mediu
m, Nissui Pharmaceutical Co., Ltd., Tokyo) and maintained at 37 ° C. in a carbon dioxide incubator as a monolayer medium. 1.8 × 10 ³ cells were seeded on a 96-well plate and contacted with a test compound for 72 hours from the next day. Method of Mosman et al.
Ann, T .; , J. et al. Immunol. Meth. , 6
5 , 55-63, 1983), and as the ability to reduce 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (MTT), live cells after compound treatment and culture. The number was measured. The cell growth inhibitory activity is shown in Table 1 as a 50% inhibitory concentration calculated from the relationship between the growth rate of compound-treated cells with respect to the growth of untreated cells and the compound concentration.

Experimental Example 2 Effect on colon cancer of colon 26 mouse: 1 × 10 ⁶ colon 26 cells were subcutaneously transplanted to the axillary region of an 8-week-old CDF ₁ female mouse (Nippon LSC Co., Ltd., Hamamatsu). Compounds were administered via the tail vein once 6 days after transplantation when tumors were confirmed by touch. Tumor growth inhibition obtained from the ratio (T / C) of the average tumor weight (T) of the compound-administered group to the control group (T / C) Rate (TGI% = (1−T / C) × 100)
Is shown in Table 1 as the antitumor effect.

[0103]

[Table 1]

From the above results, the compound of the present invention showed excellent antitumor activity.

[0105]

Industrial Applicability The compound of the present invention has excellent antibacterial activity and antitumor activity, and has high selectivity for cancer cells and low toxicity. Since the compound of the present invention has strong cytocidal activity and antitumor activity in a wide safety range, it is not only effective for tumors with reduced sensitivity to anticancer agents, but also reduces the burden of chemotherapy on cancer patients. Can be expected.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Hiroyuki Hu, 5932 Tomuma, Nogi-cho, Shimotsuga-gun, Tochigi Prefecture (72) Inventor, Keiro Terajima 2-27-4 Kyodo, Setagaya-ku, Tokyo

Claims (5)

[Claims] 1. The following general formula (1): Alternatively, the following general formula (2): (In the formula, R is a linear or branched C1 to C6 lower alkyl group, and R ¹ is a. (X ¹ and X ² are each independently a hydrogen atom, OH, OR ⁴
(R ⁴ is a linear or branched C1-C6 lower alkyl group, or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group, X ³ is NH, O or S, R ³
Is (X ⁴ and X ⁵ are each independently a hydrogen atom, OH, OR
⁴ (R ⁴ is a linear or branched C1-C6 lower alkyl group or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group). B. Embedded image c. [Chemical 6] (X ¹ and X ² are the same as above) or d. [Chemical 7] (X ¹ , X ² and X ³ are the same as above), R ² is a hydrogen atom, a protective group for a hydroxyl group or a substituent degradable in vivo, Y
Represents a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an azido group. ) (Bis (trifluoromethylpyrroloindolecarboxylic acid ester) represented by
Derivatives, optically active forms thereof, and pharmacologically acceptable salts thereof. 2. The following general formula (3): (In the formula, R is a linear or branched C1-C6 lower alkyl group, R ² is a hydrogen atom, a protective group for a hydroxyl group, or a biodegradable substituent, Y is a halogen atom, an arylsulfonyloxy group. A lower alkylsulfonyloxy group,
A haloalkylsulfonyloxy group or an azido group is shown. ) Or a salt thereof represented by the general formula (4): (R ⁶ represents OH or a reactive residue.) Acylation is performed with a compound represented by the following general formula (1): (In the formula, R is a linear or branched C1 to C6 lower alkyl group, and R ¹ is a. (X ¹ and X ² are each independently a hydrogen atom, OH, OR ⁴
(R ⁴ is a linear or branched C1-C6 lower alkyl group, or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group, X ³ is NH, O or S, R
³ is [Chemical 12] (X ⁴ and X ⁵ are each independently a hydrogen atom, OH, OR
⁴ (R ⁴ is a linear or branched C1-C6 lower alkyl group or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group). B. [Chemical 13] c. Embedded image (X ¹ and X ² are the same as above) or d. [Chemical 15] (X ¹ , X ² and X ³ are the same as above), R ² is a hydrogen atom, a protective group for a hydroxyl group, or a substituent degradable in vivo,
Y represents a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an azido group. The manufacturing method of the compound represented by these. 3. The following general formula (1a): (In the formula, R is a linear or branched C1 to C6 lower alkyl group, and R ¹ is a. (X ¹ and X ² are each independently a hydrogen atom, OH, OR ⁴
(R ⁴ is a linear or branched C1-C6 lower alkyl group, or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group, X ³ is NH, O or S,
R ³ is (X ⁴ and X ⁵ are each independently a hydrogen atom, OH, OR
⁴ (R ⁴ is a linear or branched C1-C6 lower alkyl group or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group). B. [Chemical 19] c. Embedded image (X ¹ and X ² are the same as above) or d. [Chemical 21] (X ¹ , X ² and X ³ are the same as above), Y represents a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an azido group. ) And a compound represented by the general formula (5) R ⁶ -Z (5) (in the formula, R ⁶ represents a substituent degradable in vivo, and Z represents a reactive residue). The following general formula (1b) is characterized by reacting with (In the formula, R, R ¹ , R ⁶ and Y are the same as the above.) A method for producing the compound. 4. The following general formula (1a): (Wherein R is a linear or branched C1-C6 lower alkyl group, and R ¹ is a. (X ¹ and X ² are each independently a hydrogen atom, OH, OR ⁴
(R ⁴ is a linear or branched C1-C6 lower alkyl group, or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group, X ³ is NH, O or S, R
³ is [Chemical 25] (X ⁴ and X ⁵ are each independently a hydrogen atom, OH, OR
⁴ (R ⁴ is a linear or branched C1-C6 lower alkyl group or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group). B. [Chemical formula 26] c. [Chemical 27] (X ¹ and X ² are the same as above) or d. [Chemical 28] (X ¹ , X ² and X ³ are the same as above), Y represents a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an azido group. ) The compound represented by the formula (2) is cyclized in the presence of a base catalyst. (In the formula, R and R ¹ are the same as above.) A method for producing a compound represented by the formula. 5. The following general formula (2): (In the formula, R is a linear or branched C1 to C6 lower alkyl group, and R ¹ is a. (X ¹ and X ² are each independently a hydrogen atom, OH, OR ⁴
(R ⁴ is a linear or branched C1-C6 lower alkyl group, or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group, X ³ is NH, O or S, R
³ is [Chemical 32] (X ⁴ and X ⁵ are each independently a hydrogen atom, OH, OR
⁴ (R ⁴ is a linear or branched C1-C6 lower alkyl group or an aryl group which may be substituted), OCO
R ⁴ (R ⁴ is the same as above), or straight-chain or branched C
1 to C6 lower alkyl group). ), B. [Chemical 33] c. Embedded image (X ¹ and X ² are the same as above) or d. Embedded image (Wherein X ¹ , X ² and X ³ are the same as the above), the following general formula (6) HY (6) (In the formula, Y is a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group) Group, a haloalkylsulfonyloxy group, or an azido group) is added to the compound represented by the following general formula (1a): (In the formula, R, R ¹ and Y are the same as above.) A method for producing the compound represented by the formula.