JPH06122684A - Pyrroloindoledicarboxylic acid diester derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an antitumor agent having low toxicity, having high selectivity for a cancerous cell, effective for solid tumor. CONSTITUTION:Compounds of formula I and formula II [R is 1-4C alkyl; R<1> is alpha-amino acid residue, group of formula III(X<1> to X<3> are H, OH, etc.; Z<1> is O, S, etc.; (n) is 0-2), etc.; R<2> is H, hydroxyl-protecting group, etc.; Y is halogen, azido, etc.), its optically active compound, such as methyl 3-(3-acetoxymethyl-6- benzyloxy-1-t-butoxycarbonylindolin-5-yl) amino-3-methoxycarbonylacrylate. The compound is obtained by deprotecting a compound of formula IV (R<9> is amino-protecting group) by a well-known method, converting the deprotected compound into an imidoyl compound by reaction with a compound of the formula R<1>-V (V is halogen, 1-imidazolyl, etc.) or acylating the deprotected compound by condensation with a carboxylic acid of the formula R<1>-OH in the presence of a condensation agent and a base.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel 1,2,3,6-tetrahydropyrrolo [3,2-] having antibacterial and antitumor activity.
e] indole-7,8-dicarboxylic acid diester derivative and 1,2,8,8a-tetrahydrocyclopropa [c] pyrrolo [3,2-e] indole-4 (5H)-
The present invention relates to an on-6,7-dicarboxylic acid diester derivative, an optically active substance thereof, and a pharmacologically acceptable salt thereof.

[0002]

2. Description of the Related Art As an antibiotic having antibacterial activity and antitumor activity, CC-1065 is disclosed in "J. Antibiotics", Vol. 31, p. 1211 (1.
978), ibid. 34, p. 1119 (1981), USP.
No. 4169888, and Duocarmycin A and its analogs having a similar structure are disclosed in WO87 / 06265.
No., EP0318056, "Journal of Antibiotics," 42, 1229 (1989).
Year), and is disclosed in JP-A-4-99774.

Further, a derivative of CC-1065 is disclosed in Japanese Patent Laid-Open No.
No. 0-193989 and Japanese Patent Publication No. 2-502005, and derivatives of duocarmycins are disclosed in JP-A-3-7287.
No. 3-128379, EP 0354583.
No. EP 0406749. Do all of these use the basic skeleton of natural products as they are,
It is derived from chemical modification from natural products.

[0004]

Surgical resection, radiotherapy with X-rays, drug therapy with chemotherapeutic agents, and the like 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. This drug therapy, which originally 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 chemotherapeutic agents are effective against leukemia with fast cell growth, but are low against many solid tumors with slow growth. For this reason, cancer treatment with chemotherapeutic agents is not always first-line treatment.

Based on the current situation of such chemotherapeutic agents, the present inventors sought to find compounds that are highly selective for cancer cells, are effective against solid tumors, and have low toxicity.

[0006]

Means for Solving the Problems The present inventors have the following general formulas (1) and (2).

[0007]

[Chemical 79]

[Wherein R represents a C ₁ -C ₄ lower alkyl group, R ¹ represents an α-amino acid residue, and

[0009]

[Chemical 80]

(X ¹ , X ² and X ³ are independently of each other a hydrogen atom, OH, OR ³ (R ³ is a linear or branched C ₁ -C ₆ lower alkyl which may be substituted) Group, an optionally substituted aryl group), OCOR ³ (R ³ is the same as the above),
CHO, NO ₂ ,

[0011]

[Chemical 81]

(R ⁴ and R ⁵ are each independently a hydrogen atom, an optionally substituted linear or branched C ₁ -C ₆ lower alkyl group, or an optionally substituted aryl group. Shown (R ³ is the same as above).

[0013]

[Chemical formula 82]

(X ⁴ , X ⁵ and X ⁶ are independently of each other a hydrogen atom, OR ³ or

[0015]

[Chemical 83]

(Where R ³ , R ⁴ and R ⁵ are the same as above)),

[0017]

[Chemical 84]

(R ⁴ and R ⁵ are the same as above),

[0019]

[Chemical 85]

(R ⁴ and R ⁵ are the same as above), Z ¹ is O,
S, NR ⁴ (R ⁴ is the same as above), and n is 0 to 2. ),

[0021]

[Chemical 86]

(X ⁷ represents O, S or NH, X ⁸ represents C
H or N is shown (X ¹ , X ² , X ³ and Z ¹ are the same as above). ),

[0023]

[Chemical 87]

(X ⁹ and X ¹⁰ independently represent CH or N (X ¹ , X ² , X ³ , X ⁸ and Z ¹ are the same as above)),

[0025]

[Chemical 88]

X ¹¹ and X ¹² are independently CH or N.
(X ¹ , X ² , X ³ and Z ¹ are the same as the above)),

[0027]

[Chemical 89]

(R ⁶ represents formula a, b, c or d (X ₁ , X ₂ , X ₇ , X ₈ and Z ¹ are the same as above)),

[0029]

[Chemical 90]

(X ¹³ represents O, S or NH, X ¹⁴ represents CH or N (X ¹ , X ² , X ⁴ , X ⁵ , X ⁶ , X ⁷ ,
X ⁸ and Z ¹ are the same as above))

[0031]

[Chemical Formula 91]

[0032] (W _{is, - (CH 2) m -} , - (CH 2) m -
_{^{Z 2 - ((CH 2)}} n -, or

[0033]

[Chemical Formula 92]

(Z ¹ is the same as above). Here, Z ² represents S, O, NH, and m and n are independently 0 to 1
It is 6. ), 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 azide is shown. ] The pyrroloindole dicarboxylic acid diester derivative represented by the formula, its optically active substance, and pharmacologically acceptable salts thereof have excellent antibacterial action and antitumor action, and have high selectivity to cancer cells and low toxicity. I found that.

Here, the amino-protecting group is a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a t-butoxycarbonyl group or the like having 2 to 7 carbon atoms.
A linear or branched lower alkoxycarbonyl group of
2,2,2-trichloroethoxycarbonyloxy group,
It means a substituted or unsubstituted aralkyloxycarbonyl group such as a haloalkoxycarbonyl group such as a 2,2,2-trichloro-1,1-dimethylethoxycarbonyl group, a benzyloxycarbonyl group or a 4-methoxybenzyloxycarbonyl group. The hydroxyl-protecting group is a C ₁ -C ₄ lower alkyl group such as methyl group or ethyl group, benzyl group, 4
It means a substituted or unsubstituted aralkyl group such as -methoxybenzyl group, 2,4-dimethoxybenzyl group, benzhydryl group and trityl group. Further, the biodegradable substituent is a lower alkanoyl group, an aryloyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted aryloxycarbonyl group, α-amino acid acyl residue, an optionally substituted carbamoyl group, For example, an optionally substituted pyrrolidino group such as an N-lower alkylcarbamoyl group, an N, N-dilower alkylcarbamoyl group, an N-arylcarbamoyl group, a pyrrolidinocarbonyl group or a 3- (dimethylamino) pyrrolidinocarbonyl group. Optionally substituted piperidinocarbonyl group such as carbonyl group, 4- (dimethylamino) piperidinocarbonyl group or (4-piperidinopiperidino) 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
An optionally substituted 1-piperazinylcarbonyl group such as a-(dimethylamino) ethoxy] ethyl] -1-piperazinyl] carbonyl group or an optionally substituted 1
A morpholinocarbonyl group, a silyl group substituted with aryl or alkyl, and the like, and a substituent which gives a hydroxyl group when decomposed in vivo.

According to the present invention, the compounds represented by the above general formulas (1) and (2) can be produced, for example, by the method described below.

That is, the following general formula (3a)

[0038]

[Chemical formula 93]

(Wherein R ⁹ represents an amino-protecting group (R and Y are the same as above)), and the compound represented by the following general formula (3b) is deprotected.

[0040]

[Chemical 94]

(In the formula, R and Y are the same as above) or a salt thereof. This deprotection reaction is carried out by a conventional method, for example, “Protective Groups in Organic Synthesis”.
Second edition, p.315-348 (1990).

For example, when R ⁹ is a t-butoxycarbonyl group, it is 0 ° C. in an ethyl acetate solution containing 3N hydrogen chloride.
To 50 ° C., preferably at room temperature for 10 minutes to 2 hours, and then simply distilling off the solvent to give a compound of the general formula (3
The compound represented by b) is obtained as the hydrochloride salt.

Next, the compound represented by the general formula (3b) or a salt thereof and the following general formula (5a) R ¹ -V (5a) (wherein V is a halogen atom, 1-imidazolyl group, 4-
A reactive residue such as a nitrophenoxy group or a succinimidoyloxy group or OR ¹ (R ¹ is the same as above) is shown. )
Carboxylic acid or thiocarboxylic acid halide represented by, carboxylic acid or thiocarboxylic acid imidazolide,
Reaction with an active ester of carboxylic acid or thiocarboxylic acid, mixture of carboxylic acid or thiocarboxylic acid or symmetrical acid anhydride or imidoyl derivative such as imidoyl chloride, or the following general formula (5b) R ¹ —OH (5b) (R ¹ is the same as above) with dicarboxylic acid represented by dicyclohexylcarbodiimide (DCC) or 3-
By condensing with a condensing agent such as ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), the following general formula (3c)

[0044]

[Chemical 95]

A compound represented by the formula (wherein R, R ¹ and Y are the same as above) can be produced. This condensation 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, methylene chloride, toluene, acetonitrile, N, N-dimethylformamide. , Dimethyl sulfoxide, tetrahydrofuran, etc. or a mixed solvent thereof at -20 to 50 ° C. for 30 minutes to 4
It can be easily carried out by treating for 8 hours.

Further, the compound represented by the above general formula (3c) is a lower alkanoyl chloride, an aryloyl chloride, a lower alkoxycarbonyl chloride, an aryloxycarbonyl chloride, an α-amino acid chloride, or a carbamoyl which may be substituted. Chloride,
Alternatively, by treating with an active ester thereof, the following general formula (3d)

[0047]

[Chemical 96]

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

Further, the above general formula (3c)

[0050]

[Chemical 97]

(Wherein R, R ¹ and Y are the same as above), when the compound is closed in the presence of a base,
The following general formula (4a)

[0052]

[Chemical 98]

(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 (3c) 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 dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or a mixed solvent thereof, at −78 to 100 ° C., preferably 0 to 50 ° C. for 10 minutes to 24 hours, preferably 20 minutes to 5 It can be carried out by operating for a time. In addition, the above general formula (4
The compound represented by a) is converted into hydrogen chloride, hydrogen bromide, hydrochloric acid,
Inert solvent such as ethyl acetate, methylene chloride, alcohol, acetonitrile, dimethylformamide in the presence of acid such as hydrobromic acid, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydroazido acid In the reaction, the compound represented by the above general formula (3c) can be converted by treating at a temperature from −20 ° C. to the boiling point of the solvent, preferably 0 to 50 ° C. It is desirable to use an excess of acid for this reaction from the viewpoint of shortening the reaction time.

The following general formulas (3) and (4), which are the starting materials of the present invention,

[0055]

[Chemical 99]

A compound represented by the formula (wherein R ⁷ represents a hydrogen atom or an amino group protecting group, and R ⁸ represents a hydrogen atom or a hydroxyl group protecting group (R and Y are the same as above)) It is an important intermediate of the invention and is produced by the following method.

[0057]

[Chemical 100]

(Wherein R ¹¹ is a hydroxyl-protecting group, R ¹² is an amino-protecting group, and R ¹³ is a hydroxyl-protecting group (R and Y are the same as above).) When the optically active compound of the compound represented by 5) is used, the optically active compound of the compounds represented by the general formulas (1) and (2) is produced.
Further, the alcohol derivative represented by the above general formula (8) can be used as an intermediate for the production of an optically active substance after being made into a diastereoester with an optically active carboxylic acid. The compounds represented by the general formulas (1) and (2) can be used alone or in combination with one or more pharmaceutically acceptable adjuvants as an antibacterial or antitumor composition.

For example, a compound represented by the general formula (1) or (2), or a salt thereof is used in physiological saline or glucose,
It is dissolved in an aqueous solution of mannitol, lactose or the like to give a pharmaceutical composition suitable as an injection.

Alternatively, a salt of the compound represented by the general formula (1) or (2) is freeze-dried by a conventional method, and sodium chloride or the like is added thereto to give a powder injection. If necessary, the pharmaceutical composition may contain additives well known in the field of formulation, such as pharmaceutically acceptable salts.

Further, as oral preparations, tablets, capsules, powders, granules, ampoules and the like are included, and these include medicinal auxiliaries well known in the field of formulation. If desired, these can be administered intraarterially, intraperitoneally, intrathoracically, and the like.

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

Example 1

[0064]

[Chemical 101]

3-acetoxymethyl-5-amino-6-
Benzyloxy-1-t-butoxycarbonylindoline 435.7 mg (1.1 mmol) was dissolved in anhydrous methanol 2 ml, and dimethyl acetylenedicarboxylate 162.3 μl (1.32 mmol) was added dropwise under an ice atmosphere under ice cooling. And stirred for 1 hour. After stirring the reaction solution for 1 hour, the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
The target 3- (3-acetoxymethyl-6) attached to 2)
528.8 mg (87%) of methyl-benzyloxy-1-t-butoxycarbonylindoline-5-yl) amino-3-methoxycarbonylacrylate was obtained.

This product was recrystallized from ether hexane to obtain a pure yellow needle crystal product.

Mp. 98.5-99.5 ° C _{NMR (CDCl 3): 1.54 (} 9H, s), 2.11 (3H, s), 3.51~3.69 (2H,
m), 3.61 (3H, s), 3.72 (3H, s), 4.00 ~ 4.22 (3H, m), 5.12 (2
H, s), 5.33 (1H, s), 6.73 (1H, s), 7.22 ~ 7.60 (5H, m), 7.70 (1
H, br, s), 9.62 (1H, s) Example 2

[0068]

[Chemical 102]

3- (3-acetoxymethyl-6-benzyloxy-1-t-butoxycarbonylindoline-5
-Yl) Amino-3-methoxycarbonylmethyl acrylate 528.8 mg (0.953 mmol) and palladium acetate 428.1 mg (1.907 mmol) were dissolved in anhydrous dimethylacetamide 95 ml, and under argon atmosphere at 70 ° C. Stir for 5 hours. The reaction solution is water 200
After insoluble matter was removed by filtration through Celite, the methylene chloride layer was washed successively with water, diluted aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the resulting residue was subjected to column chromatography to give 1-acetoxymethyl-5-benzyloxy-3-t-butoxycarbonyl- as a pale yellow foamy substance.
Dimethyl 1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate is 257.5
mg (49%) was obtained.

NMR (CDCl ₃ ): 1.56 (9H, s), 2.03 (3H, s), 3.80
~ 4.07 (4H, m), 3.94 (3H, s), 3.95 (3H, s), 4.20 (1H, dd, J = 4
Hz, J = 11Hz), 5.22 (2H, s), 7.34 ~ 7.55 (5H, m), 7.90 (1H, b
r, s), 9.20 (1H, s) Example 3

[0071]

[Chemical 103]

1-acetoxymethyl-5-benzyloxy-3-t-butoxycarbonyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-
Dimethyl dicarboxylate 257.5 mg (0.466 mm
ol) was dissolved in 5 ml of anhydrous methanol, 77.3 mg (0.559 mmol) of potassium carbonate was added, and the mixture was stirred under an argon atmosphere under ice cooling for 3 hours and then at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride, neutralized with 10% citric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Ether was added to the obtained residue, and the crystals which were folded were collected by filtration and washed with ether.
Targeted pale yellow crystals of 5-benzyloxy-3-t-
Butoxycarbonyl-1-hydroxymethyl-1,2,
190.8 mg of dimethyl 3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate was obtained. The filtrate was concentrated, and the residue was subjected to preparative thin layer chromatography (hexane: ethyl acetate = 1: 2) to obtain 35.5 mg of the desired product. Total yield 99%.

Mp.98.5-99.5 ° C _{NMR (CDCl 3): 1.57 (} 9H, s), 1.86 (1H, br), 3.59 (1H, m), 3.69
(1H, m), 3.83 (1H, m), 3.93 (3H, s), 3.95 (3H, s), 4.03 (1H, d
d, J = 9Hz, J = 11Hz), 4.10 (1H, d, J = 13Hz), 5.22 (2H, s), 7.38
~ 7.49 (5H, m), 7.91 (1H, brs), 9.21 (1H, s) Example 4

[0074]

[Chemical 104]

102.1 mg (0) of dimethyl 5-benzyloxy-3-t-butoxycarbonyl-1-hydroxymethyl-1,2,3,6-tetohydropyrrolo [3,2-e] indole-7,8-dicarboxylate .2 mmol)
And triphenylphosphine 104.9 mg (0.4 mm
ol) was dissolved in 0.9 ml of anhydrous methylene chloride, and carbon tetrachloride (115.4 μl (1.2 mmo) was added under an argon atmosphere.
1) was added dropwise and the mixture was stirred overnight. The residue obtained by distilling off the solvent was subjected to column chromatography (hexane: ethyl acetate = 2: 1) to give 5-benzyloxy- as pale yellow crystals.
3-t-butoxycarbonyl-1-chloromethyl-1,
96.5 mg of dimethyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate
(91%) obtained.

NMR (CDCl ₃ ): 1.58 (9H, s), 3.31 (1H, t, J = 10H
z), 3.74 (1H, dd, J = 3Hz, J = 10Hz), 3.94 (3H, s), 3.99 (3H, s),
3.89 ~ 4.09 (2H, m), 4.17 (1H, br), 5.21 (2H, s), 7.37 ~ 7.57
(5H, m), 7.89 (1H, br), 9.27 (1H, s) Example 5

[0077]

[Chemical 105]

96.5 mg of dimethyl 5-benzyloxy-3-t-butoxycarbonyl-1-chloromethyl-1,2,3,6-tetohydropyrrolo [3,2-e] indole-7,8-dicarboxylate was added to tetrahydrofuran. 2.
Dissolved in 4 ml, 10% palladium on carbon 57.9 mg
(0.6 wt.eq.) was added. A 25% ammonium formate aqueous solution 0.6 was added to the reaction solution under argon cooling under an argon atmosphere.
ml was added and vigorously stirred for 1.5 hours. After extraction with ethyl acetate and drying over anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give pale yellow crystals of 3-t-butoxycarbonyl-1-chloromethyl-.
79.1 mg (99%) of dimethyl 5-hydroxy-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate was obtained.

NMR (CDCl ₃ ): 1.58 (9H, s), 3.30 (1H, t, J = 10H
z), 3.75 (1H, dd, J = 8Hz, J = 11Hz), 3.87-4.10 (2H, m), 3.96
(3H, s), 3.99 (3H, s), 4.17 (1H, d, J = 11Hz), 7.41 (1H, br, s),
7.73 (1H, s), 9.43 (1H, s) Example 6

[0080]

[Chemical formula 106]

10.1 mg (23 μmol) of dimethyl 3-t-butoxycarbonyl-1-chloromethyl-5-hydroxy-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate (3) Hydrogen chloride-ethyl acetate solution (0.34 ml) was added to the mixture (1) and the mixture was allowed to stand for 40 minutes and the solvent was distilled off. The resulting residue and 5.8 mg (23 μm) of 5,6,7-trimethoxyindole-2-carboxylic acid
mol) to 1- (3-dimethylaminopropyl) -3-
Ethylcarbodiimide hydrochloride 13.2 mg (69 μmo
0.23 ml of anhydrous dimethylformamide in the presence of 1)
The reaction was carried out in an argon atmosphere at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, 5% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was subjected to silica gel column chromatography (hexane: tetrahydrofuran = 1: 1) to give 1-chloromethyl-5-hydroxy-3- (5,6,7-trimethoxy) as pale yellow crystals. -1H-indol-2-ylcarbonyl) -1,2,
9.9 mg of dimethyl 3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate (75.
0%) was obtained.

NMR (CDCl ₃ ): 3.31 (1H, t, J = 11Hz), 3.72-3.
95 (2H, m), 3.84 (3H, s), 3.91 (3H, s), 3.97 (3H, s), 3.98 (3
H, s), 4.14 (3H, s), 4.55 (1H, t, J = 10Hz), 4.66 (1H, d, J = 11H
z), 6.78 (1H, s), 6.92 (1H, s), 8.38 (1H, s), 9.92 (2H, br), 1
0.43 (1H, br) Example 7

[0083]

[Chemical formula 107]

By the same method as in Example 6, 4.4 mg (23 μmo) of 5-methoxyindole-2-carboxylic acid was prepared.
1) to 1-chloromethyl-5-hydroxy-3- (5
-Methoxy-1H-indol-2-ylcarbonyl)
-1,2,3,6-Tetrahydropyrrolo [3,2-e]
Indole-7,8-dimethyl dimethyl 8.3m
g (71%) was obtained.

NMR (CDCl ₃ + DMSOd ₆ ) δ: 3.34 (1H, t, J = 10H
z), 3.75--4.14 (2H, m), 3.85 (3H, s), 3.97 (3H, s), 3.98 (3
H, s), 4.57 (1H, t, J = 10Hz), 4.69 (1H, d, J = 10Hz), 6.94 (1H,
dd, J = 2Hz, J = 9Hz), 6.97 (1H, s), 7.11 (1H, d, J = 2Hz), 7.42 (1
H, d, J = 9 Hz), 7.54 (1H, m), 7.93 (1H, s), 9.40 (1H, br) Example 8

[0086]

[Chemical 108]

In the same manner as in Example 6, 5- (1H-
Indole-2-ylcarbonyl) amino-1H-indole-2-carboxylic acid 7.3 mg (23 μmol) to 1-chloromethyl-5-hydroxy-3- [5-
[(1H-Indol-2-ylcarbonyl) amino]
-1H-indol-2-ylcarbonyl) -1,2,
Dimethyl 3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate was 11.2 mg (76
%) Obtained.

NMR (CDCl ₃ + DMSOd ₆ ) δ: 3.36 (1H, t, J = 10H
z), 3.83 (1H, dd, J = 2Hz, J = 10Hz), 3.97 (3H, s), 3.98 (3H, s),
4.10 (1H, m), 4.59 (1H, m), 4.70 (1H, d, J = 11Hz), 7.02 (1H,
s), 7.10 (1H, t, J = 8Hz), 7.24 (1H, t, J = 8Hz), 7.36 (1H, s),
7.50 (1H, s), 7.52 (1H, s), 7.53 ~ 7.60 (2H, m), 7.66 (1H, d,
J = 8Hz), 7.93 (1H, br), 8.23 (1H, s), 9.45 (1H, br), 9.69 (1H,
s) Example 9

[0089]

[Chemical 109]

In the same manner as in Example 6, 5- (benzofuran-2-ylcarbonyl) aminoindole-2-
Carboxylic acid 7.3 mg (23 μmol) to 1-chloromethyl-5-hydroxy-3- [5-[(benzofuran-2-ylcarbonyl) amino] -1H-indole-
9.9 mg (67%) of dimethyl 2-ylcarbonyl) -1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate was obtained.

NMR (CDCl ₃ + DMSOd ₆ ) δ: 3.36 (1H, t, J = 10H
z), 3.83 (1H, dd, J = 3Hz, J = 11Hz), 3.972 (3H, s), 3.974 (3H,
s), 4.09 (1H, m), 4.59 (1H, t, J = 11Hz), 4.69 (1H, d, J = 11H
z), 7.03 (1H, s), 7.34 (1H, t, J = 7Hz), 7.46 (1H, t, J = 7Hz),
7.51 ~ 7.68 (5H, m), 7.73 (1H, d, J = 8Hz), 7.92 (1H, br), 8.0
1 (1H, s), 8.23 (1H, s), 9.46 (1H, s), 9.47 (1H, br) Example 10

[0092]

[Chemical 110]

1-chloromethyl-5-hydroxy-3-
(5,6,7-trimethoxy-1H-indole-2-
Ylcarbonyl) -1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylic acid dimethyl 9.9 mg (17.3 μmol) was dissolved in anhydrous acetonitrile 2.8 ml to give 1, After adding 3.1 μl of 8-diazabicyclo [5,4,0] -7-undecene, the mixture was allowed to react for 2.5 hours under an argon atmosphere at room temperature while being shielded from light. A 0.5 mol dipotassium hydrogen phosphate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was subjected to silica gel column chromatography (hexane: tetrahydrofuran = 1: 2) to give 2- (5,6,7-trimethoxy-1H-indol-2-ylcarbonyl) as pale yellow crystals. ) -1,2,8,8a-Tetrahydrocyclopropa [c] pyrrolo [3,2-e] indole-4 (5H) -one-6,7-dicarboxylate dimethyl 8.1 mg (87.1%). Was obtained.

NMR (CDCl ₃ + DMSOd ₆ ) δ: 1.48 (1H, t, J = 4H
z), 2.13 (1H, q, J = 4Hz, J = 8Hz), 3.26-3.34 (1H, m), 3.85 (3
H, s), 3.89 (3H, s), 3.91 (3H, s), 3.92 (3H, s), 4.04 (3H, s),
4.38 (1H, d, J = 11Hz), 4.48 (1H, dd, J = 5Hz, J = 10Hz), 6.82 (1
H, s), 6.90 (1H, s), 6.95 (1H, d, J = 2Hz), 7.57 (1H, d, J = 2Hz),
7.59 (1H, s) Example 11

[0095]

[Chemical 111]

In the same manner as in Example 10, 1-chloromethyl-5-hydroxy-3- (5-methoxy-1H-)
Indole-2-ylcarbonyl) -1,2,3,6-
Tetrahydropyrrolo [3,2-e] indole-7,8
-Dimethyl dicarboxylate 6.9 mg (14 μmol) to 2- (5-methoxy-1H-indol-2-ylcarbonyl) -1,2,8,8a-tetrahydrocyclopropa [c] pyrrolo [3,2-e] Indore-4 (5
H) -one-6,7-dicarboxylate dimethyl was 4.0 m
g (62%) was obtained.

NMR (CDCl ₃ + DMSOd ₆ ) δ: 1.45 (1H, t, J = 4H
z), 2.13 (1H, dd, J = 4Hz, J = 8Hz), 3.31 (1H, m), 3.83 (3H, s),
3.85 (3H, s), 3.91 (3H, s), 4.44 (1H, d, J = 10Hz), 4.51 (1H, d
d, J = 5Hz, J = 10Hz), 6.90 ~ 6.98 (1H, m), 6.99 (1H, d, J = 2H
z), 7.04 (1H, d, J = 2Hz), 7.41 (1H, d, J = 9Hz), 7.54 ~ 7.60
(2H, m) Example 12

[0098]

[Chemical 112]

By the same method as in Example 10, 1-chloromethyl-5-hydroxy-3- [5-[(1H-indol-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -1. , 2,3,6-Tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate dimethyl 9.1 mg (14 μmol) to 2-
[5-[(1H-indol-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl]-
1,2,8,8a-Tetrahydrocyclopropa [c] pyrrolo [3,2-e] indole-4 (5H) -one-
6.1 mg (71%) of dimethyl 6,7-dicarboxylate
Was obtained.

NMR (CDCl ₃ + DMSO ₆ ) δ: 1.46 (1H, t, J = 4Hz),
2.14 (1H, dd, J = 4Hz, J = 8Hz), 3.30 ~ 3.37 (1H, m), 3.86 (3H,
s), 3.91 (3H, s), 4.47 (1H, d, J = 10Hz), 4.54 (1H, dd, J = 4Hz,
J = 10Hz), 7.03 (2H, m), 7.10 (1H, t, J = 7Hz), 7.25 (1H, t, J = 8
Hz), 7.35 (1H, s), 7.49 (1H, d, J = 9Hz), 7.50 (1H, d, J = 8Hz),
7.53 ~ 7.60 (2H, m), 7.66 (1H, d, J = 8Hz), 8.21 (1H, s), 9.68
(1H, s) Example 13

[0101]

[Chemical 113]

By a method similar to that in Example 10, 1-chloromethyl-5-hydroxy-3- [5-[(benzofuran-2-ylcarbonyl) amino] -1H-indole-
2-ylcarbonyl] -1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate dimethyl from 8.2 mg (13 μmol) to 2- [5-
[(Benzofuran-2-ylcarbonyl) amino] -1
H-indol-2-ylcarbonyl] -1,2,8,
8a-Tetrahydrocyclopropa [c] pyrrolo [3,2]
5.6 mg (72%) of dimethyl [e] indole-4 (5H) -one-6,7-dicarboxylate was obtained.

NMR (CDCl ₃ + DMSOd ₆ ) δ: 1.46 (1H, t, J = 4H
z), 2.14 (1H, dd, J = 4Hz, J = 8Hz), 3.30 ~ 3.36 (1H, m), 3.85
(3H, s), 3.91 (3H, s), 4.48 (1H, d, J = 10Hz), 4.55 (1H, dd, J =
5Hz, J = 10Hz), 7.02 (1H, s), 7.04 (1H, s), 7.33 (1H, t, J = 7H
z), 7.46 (1H, t, J = 8Hz), 7.51 (1H, d, J = 9Hz), 7.54 to 7.65
(5H, m), 7.73 (1H, d, J = 8Hz), 8.23 (1H, s), 9.59 (1H, br) Example 14

[0104]

[Chemical 114]

2- [5-[(benzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -1,2,8,8a-tetrahydrocyclopropa [c] pyrrolo [3,2- e] Indole-4 (5H)
Dimethyl-on-6,7-dicarboxylate 9.07 mg
(15 μmol) was suspended in 1.7 ml of acetonitrile, 0.85 ml of 1M hydrobromic acid was added, and the mixture was stirred for 1 hour. To the reaction solution was added 0.5 M potassium dihydrogenphosphate aqueous solution (1 ml), the mixture was extracted with chloroform-methanol (10: 1), dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue is subjected to silica gel chromatography (chloroform:
Purification with methanol = 10: 1) gives 3 as pale yellow crystals.
-[5-[(benzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -1-
8.3 mg (81%) of dimethyl bromomethyl-5-hydroxy-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate was obtained.

NMR (CDCl ₃ + DMSOd ₆ ) δ: 3.20 (1H, t, J = 10H
z), 3.70 (1H, J = 10Hz), 3.97 (3H, s), 4.02 (3H, s), 4.16 (1H,
m), 4.59 (1H, t, J = 10Hz), 4.70 (1H, d, J = 11Hz), 7.06 (1H, s),
7.32 ~ 7.35 (1H, m), 7.44 ~ 7.48 (1H, m), 7.50 (2H, m), 7.5
8 to 7.61 (2H, m), 7.72 (1H, d, J = 8Hz), 7.96 (1H, br), 8.24 (1
H, s), 8.69 (1H, br), 9.23 (1H, br), 10.03 (1H, br), 11.06 (1
H, br) Example 15

[0107]

[Chemical 115]

3- [5-[(benzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl] -1-chloromethyl-5-hydroxy-1,
5.0 mg of dimethyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate (7.
8 μmol), chloroformic acid-p-nitrophenyl 1.7
mg (8.6 μmol) was added to anhydrous tetrahydrofuran.
Dissolve in 4 ml and add 1.2 μl of triethylamine under ice cooling.
(8.0 μmol) was added dropwise and the mixture was stirred for 21 hours. 1.3 μl (12 μmol) of N-methylpiperazine in the reaction solution
Was added and the mixture was stirred overnight at room temperature. The reaction solution was diluted with chloroform, washed successively with 10% water sodium hydrogen carbonate and water, dried over colorless sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 6: 1) to give colorless crystals of 3- [5-[(benzofuran-2-ylcarbonyl) amino] -1H-indol-2-ylcarbonyl]-. 4.3 mg of dimethyl 1-chloromethyl-5- (4-methylpiperazin-1-ylcarbonyl) oxy-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate was obtained. (72%) was obtained.

NMR (CDCl ₃ ) δ: 2.37 (3H, s), 2.47 to 2.60 (4
H, m), 3.35 (1H, t, J = 10Hz), 3.60 ~ 3.74 (2H, m), 3.78 (1H, d
d, J = 3Hz, J = 11Hz), 3.83 (2H, br), 3.92 (3H, s), 4.02 (3H,
s), 4.20 (1H, m), 4.60 (1H, t, J = 11Hz), 4.69 (1H, d, J = 10Hz),
6.98 (1H, s), 7.31 ~ 7.42 (3H, m), 7.46 (1H, t, J = 7Hz), 7.57
(1H, d, J = 8Hz), 7.60 (1H, s), 7.71 (1H, d, J = 8Hz), 8.21 (1H,
br, s), 8.35 (1H, s), 8.42 (1H, s), 9.42 (1H, br, s), 9.53 (1H,
br, s) 2.7 mg (3.5 μmol) of the obtained crystal was added to 3M0.
The crystals were treated with 3 ml and the precipitated crystals were washed with ether to give 2.7 mg (95%) of colorless hydrochloride.

NMR (DMSO ₆ ) δ: 2.88 (3H, br, s), 3.13 to 3.3
6 (3H, m), 3.45-3.60 (3H, m), 3.65 (1H, dd, J = 8Hz, J = 11H
z), 3.83 ~ 3.97 (1H, m), 3.89 (3H, s), 3.95 (3H, s), 4.11 ~
4.27 (2H, m), 4.33 ~ 4.51 (1H, m), 4.59 (1H, d, J = 12Hz), 4.8
1 (1H, t, J = 10Hz), 7.19 (1H, s), 7.30 (1H, t, J = 8Hz), 7.48〜
7.52 (2H, m), 7.62 (1H, dd, J = 2Hz, J = 9Hz), 7.72 (1H, d, J = 8H
z), 7.76 (1H, s), 7.82 (1H, d, J = 8Hz), 8.15 (1H, br, s), 8.23
(1H, br, s), 8.29 (1H, s), 10.46 (1H, s), 11.63 (1H, s), 12.85
(1H, s) Example 16

[0111]

[Chemical formula 116]

In the same manner as in Example 15, 3- [5-
[(Benzofuran-2-ylcarbonyl) amino] -1
H-Indol-2-ylcarbonyl] -1-bromomethyl-5-hydroxy-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7,8-dicarboxylate dimethyl 11.8 mg (17 μmol) From 3- [5
-[(Benzofuran-2-ylcarbonyl) amino]-
1H-indol-2-ylcarbonyl] -1-bromomethyl-5- (4-methylpiperazin-1-ylcarbonyl) oxy-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7, Obtained 6.5 mg (47%) of dimethyl 8-dicarboxylate.

NMR (CDCl ₃ ) δ: 2.38 (3H, s), 2.47 to 2.58 (4
H, m), 3.22 (1H, t, J = 10Hz), 3.60〜3.73 (3H, m), 3.75〜3.8
8 (2H, m), 3.94 (3H, s), 4.04 (3H, s), 4.28 (1H, m), 4.63 (1H,
t, J = 10Hz), 4.71 (1H, d, J = 11Hz), 7.03 (1H, s), 7.33 (1H, t,
J = 7Hz), 7.43 (2H, br, s), 7.47 (1H, ddd, J = 2Hz, J = 7Hz, J = 8H
z), 7.58 (1H, J = 8Hz), 7.61 (1H, s), 7.72 (1H, d, J = 8Hz), 8.24
(1H, s), 8.34 (1H, s), 8.42 (1H, s), 9.37 (1H, br, s), 9.47 (1
H, br, s) 4.2 mg (5.2 μmol) of the obtained crystal was used as a hydrochloride to obtain 4.2 mg (94%).

NMR (DMSOd ₆ ) δ: 2.85 (3H, br, s), 3.10-3.
42 (3H, m), 3.45 ~ 3.65 (4H, m), 3.78 ~ 3.84 (1H, m), 3.89 (3
H, s), 3.95 (3H, s), 4.16 (1H, m), 4.26 (1H, m), 4.42 (1H, m),
4.55 (1H, d, J = 12Hz), 4.83 (1H, t, J = 11Hz), 7.20 (1H, s), 7.3
6 ~ 7.40 (1H, m), 7.49 ~ 7.53 (2H, m), 7.63 (1H, dd, J = 2Hz,
J = 9Hz), 7.74 (1H, d, J = 8Hz), 7.78 (1H, s), 7.84 (1H, d, J = 8H
z), 8.14 (1H, s), 8.23 (1H, s), 10.46 (1H, s), 10.50 (1H, br),
11.66 (1H, s), 12.91 (1H, s)

[0115]

【The invention's effect】

Experimental Example 1 Tumor cell growth inhibitory activity 10% Immobilized fetal bovine serum, 2 mM glutamine, 100 μ
P388 mouse leukemia cells were prepared at 1.5 × 10 ⁵ cells / ml using RPMI1640 medium (hereinafter referred to as medium) supplemented with g / ml kanamycin sulfate and 5 μM 2-hydroxyethyl disulfide, and then 96
60 μl was dispensed to each well multiplate. A test compound dissolved using dimethyl sulfoxide was appropriately diluted with a medium and added to the plate in an amount of 60 μl,
The cells were cultured in a carbon dioxide incubator (5% CO ₂ , 37 ° C) for 72 hours.

The method of Mosmann (J. Immun
ol. Meth. , 65 , 55-63, 1983), and the number of surviving cells was measured. That is, Dulbeccc
2.5 mg / m 2 using phosphate buffer solution (PBS)
1 prepared MTT (3- [4,5-Dimethyl
thiazol-2-yl] -2,5-dipheny
20 μl / well of the solution of letrazolium bromide) was added and the culture was continued for 3 hours.
0.04N hydrochloric acid-isopropanol solution 1 per well
MT produced by adding 60 μl and pipetting
The T-formazan was dissolved. The well containing no cells was used as a background, and the absorbance at 540 nm was measured. The 50% growth inhibitory concentration (IC ₅₀ ) was produced from the ratio of the absorbance of the treated group to the drug-free group and the drug concentration. The results are shown in Table 1 below.

[0117]

[Table 1]

Example 2 Antitumor Activity The test compound was dissolved using dimethyl sulfoxide,
10% Emulphor EL620 (made by Rhone Poulin)
Was appropriately diluted with to prepare a test drug solution. The antitumor activity was evaluated by the following test system.

[Evaluation in Mice Transplanted with P388 Cells Intraperitoneally] 1 × 10 ⁶ P388 cells were transplanted per individual into the abdominal cavity of female mice (CDF ₁ strain, 8-9 weeks old),
On the day after the transplantation, the test drug solution was intraperitoneally injected once. The solvent-administered control group used 5 to 8 mice and the drug-administered group 2 mice / group, and the ratio of the average survival time (T) of the administration group to the average survival time (C) of the solvent administration control group (T / C ,%) Was used to determine the antitumor effect, and 130% or more was considered effective. The results are shown in Table 2.

[0120]

[Table 2]

From the above-mentioned tests, the compounds of the present invention are clear to have antitumor activity and have high selectivity against cancer cells, and are useful.

Claims (7)

[Claims] 1. The following general formula (1): And the following general formula (2): [In the formula, R is a C ₁ -C ₄ lower alkyl group, and R ¹ is α-
Amino acid residues and (X ¹ , X ² and X ³ are each independently a hydrogen atom, OH, OR ³
(R ³ is an optionally substituted linear or branched C _1-
C ₆ lower alkyl group, optionally substituted aryl group), OCOR ³ (R ³ is the same as the above), CHO, N
O ₂ , embedded image (R ⁴ and R ⁵ are each independently a hydrogen atom, an optionally substituted linear or branched C _{1 to} C ₆ lower alkyl group,
The aryl group which may be substituted is shown (R ³ is the same as above). ), [Chemical 5] (X ⁴ , X ⁵ and X ⁶ are independently of each other a hydrogen atom, OR ³ or (Here, R ³ , R ⁴ , and R ⁵ are the same as the above)), (R ⁴ and R ⁵ are the same as above), (R ⁴ and R ⁵ are the same as above), Z ¹ is O, S and NR ⁴ (R ⁴
Is the same as the above), and n represents 0 to 2. ), (X ⁷ represents O, S or NH, X ⁸ represents CH or N (X ¹ , X ² , X ³ and Z ¹ are the same as above)), (X ⁹ and X ¹⁰ each independently represent CH or N (X ¹ , X ² , X ³ , X ⁸ and Z ¹ are the same as the above)), (X ¹¹ and X ¹² each independently represent CH or N (X
¹ , X ² , X ³ , X ⁷ and Z ¹ are the same as the above)), and (R ⁶ represents formula a, b, c or d (X ¹ , X ² , X ⁷ ,
X ⁸ and Z ¹ are the same as the above)), and (X ¹³ represents O, S or NH, X ¹⁴ represents CH or N
(X ¹ , X ² , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Z ¹
Is the same as above)) (W _{is, - (CH 2) m -} , - (CH 2) m -Z 2 - (C
H ₂ ) _n -or (Z ¹ is the same as above). Where Z ² is S, O, NH
And m and n are 0 to 16 independently of each other. )
R ² represents a hydrogen atom, a protective group for a hydroxyl group or a substituent degradable in vivo, and Y represents a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an azide. ] The pyrroloindole dicarboxylic acid diester derivative represented by these, those optically active substances, and its pharmacologically acceptable salt. 2. The following general formula (3): (In the formula, R is a C ₁ -C ₄ lower alkyl group, R ⁷ is a hydrogen atom or an amino group protecting group, R ⁸ is a hydrogen atom or a hydroxyl group protecting group, and Y is a hydroxyl group or a hydroxyl group protecting group. , A halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an azide), which is a pyrroloindole dicarboxylic acid diester intermediate. 3. The following general formula (4): (In the formula, R represents a C _{1 to} C ₄ lower alkyl group, and R ⁷ represents a hydrogen atom or an amino group-protecting group.) A cyclopropapyrroloindole dicarboxylic acid diester intermediate. 4. The following general formula (3a): (In the formula, R represents a C ₁ -C ₄ lower alkyl group, R ⁹ represents an amino-group protecting group, Y represents a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an azide. The compound of formula (3b) (Wherein R and Y are the same as above) or a salt thereof, and the compound is acylated or imidoylated to the following general formula (3c): (Wherein R ¹ is an α-amino acid residue and (X ¹ , X ² and X ³ are each independently a hydrogen atom, OH, OR ³
(R ³ is an optionally substituted linear or branched C _1-
C ₆ lower alkyl group, optionally substituted aryl group), OCOR ³ (R ³ is the same as the above), CHO, N
O ₂ , embedded image (R ⁴ and R ⁵ are each independently a hydrogen atom, an optionally substituted linear or branched C _{1 to} C ₆ lower alkyl group,
The aryl group which may be substituted is shown (R ³ is the same as above). ), [Chemical formula 23] (X ⁴ , X ⁵ and X ⁶ are independently of each other a hydrogen atom, OR ³ or (Here, R ³ , R ⁴ , and R ⁵ are the same as the above)), (R ⁴ and R ⁵ are the same as above), (R ⁴ and R ⁵ are the same as above), Z ¹ is O, S and NR ⁴ (R ⁴
Is the same as the above), and n represents 0 to 2. ), (X ⁷ represents O, S or NH, X ⁸ represents CH or N (X ¹ , X ² , X ³ and Z ¹ are the same as the above)), (X ⁹ and X ¹⁰ independently of each other represent CH or N (X ¹ , X ² , X ^3, X ⁸ and Z ¹ are the same as above)), (X ¹¹ and X ¹² each independently represent CH or N (X
¹ , X ² , X ³ , X ⁷ and Z ¹ are the same as the above)), and (R ⁶ represents formula a, b, c or d (X ¹ , X ² , X ⁷ ,
X ⁸ and Z ¹ are the same as above)), and (X ¹³ represents O, S or NH, X ¹⁴ represents CH or N
(X ¹ , X ² , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Z ¹
Is the same as above)) (W _{is, - (CH 2) m -} , - (CH 2) m -Z 2 - (C
H ₂ ) _n − or (Z ¹ is the same as above). Where Z ² is S, O, NH
And m and n are 0 to 16 independently of each other. )
And R and Y are the same as the above). 5. The following general formula (3c): (In the formula, R is a C ₁ -C ₄ lower alkyl group, and R ¹ is α-
Amino acid residues and (X ¹ , X ² and X ³ are each independently a hydrogen atom, OH, OR ³
(R ³ is an optionally substituted linear or branched C _1-
C ₆ lower alkyl group, optionally substituted aryl group), OCOR ³ (R ³ is the same as the above), CHO, N
O ₂ , embedded image (R ⁴ and R ⁵ are each independently a hydrogen atom, an optionally substituted linear or branched C _{1 to} C ₆ lower alkyl group,
The aryl group which may be substituted is shown (R ³ is the same as above). ), (X ⁴ , X ⁵ and X ⁶ are independently of each other a hydrogen atom, OR ³ or (Wherein R ³ , R ⁴ and R ⁵ are the same as above)), (R ⁴ and R ⁵ are the same as above), (R ⁴ and R ⁵ are the same as above), Z ¹ is O, S and NR ⁴ (R ⁴
Is the same as the above), and n represents 0 to 2. ), (X ⁷ represents O, S or NH, X ⁸ represents CH or N (X ¹ , X ² , X ³ and Z ¹ are the same as the above)), (X ⁹ and X ¹⁰ independently of each other represent CH or N (X ¹ , X ² , X ³ , X ⁸ and Z ¹ are the same as above)), (X ¹¹ and X ¹² each independently represent CH or N (X
¹ , X ² , X ³ , X ⁷ and Z ¹ are the same as the above)), (R ⁶ represents formula a, b, c or d (X ¹ , X ² , X ⁷ ,
X ⁸ and Z ¹ are the same as above). ), (X ¹³ represents O, S or NH, X ¹⁴ represents CH or N
(X ¹ , X ² , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Z ¹
Are the same as above)) (W _{is, - (CH 2) m -} , - (CH 2) m -Z 2 - (C
H ₂ ) _n -or (Z ¹ is the same as above). Where Z ² is S, O, NH
And m and n are 0 to 16 independently of each other. )
Y is a halogen atom, an arylsulfonyloxy group,
A lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an azide is shown. ) The hydroxyl group of the compound represented by the formula (3) is protected by a substituent decomposable in vivo, and the following general formula (3d): (In the formula, R ¹⁰ represents a protective group for a hydroxyl group that can be decomposed in vivo, and R, R ¹ and Y are the same as the above.). 6. The following general formula (3c): (In the formula, R is a C ₁ -C ₄ lower alkyl group, and R ¹ is α-
Amino acid residues and (X ¹ , X ² and X ³ are each independently a hydrogen atom, OH, OR ³
(R ³ is an optionally substituted linear or branched C _1-
C ₆ lower alkyl group, optionally substituted aryl group), OCOR ³ (R ³ is the same as the above), CHO, N
O ₂ , embedded image (R ⁴ and R ⁵ are each independently a hydrogen atom, an optionally substituted linear or branched C _{1 to} C ₆ lower alkyl group,
The aryl group which may be substituted is shown (R ³ is the same as above). ), (X ⁴ , X ⁵ and X ⁶ are independently of each other a hydrogen atom, OR ³ or (Where R ³ , R ⁴ and R ⁵ are the same as above)), (R ⁴ and R ⁵ are the same as above), (R ⁴ and R ⁵ are the same as above), Z ¹ is O, S and NR ⁴ (R ⁴
Is the same as the above), and n represents 0 to 2. ), (X ⁷ represents O, S or NH, X ⁸ represents CH or N (X ¹ , X ² , X ³ and Z ¹ are the same as above)), (X ⁹ and X ¹⁰ each independently represent CH or N (X ¹ , X ² , X ³ , X ⁸ and Z ¹ are the same as the above)), (X ¹¹ and X ¹² each independently represent CH or N (X
¹ , X ² , X ³ , X ⁷ and Z ¹ are the same as the above)), (R ⁶ represents formula a, b, c or d (X ¹ , X ² , X ⁷ ,
X ⁸ and Z ¹ are the same as the above)), (X ¹³ represents O, S or NH, X ¹⁴ represents CH or N
(X ¹ , X ² , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Z ¹
Are the same as above)) (W _{is, - (CH 2) m -} , - (CH 2) m -Z 2 - (C
H ₂ ) _n − or (Z ¹ is the same as above). Where Z ² is S, O, NH
And m and n are 0 to 16 independently of each other. )
Y is a halogen atom, an arylsulfonyloxy group,
A lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an azide is shown. ) A compound represented by the following general formula (4a) is characterized by ring-closing in the presence of a base catalyst. (In the formula, R and R ¹ are the same as the above). 7. The following general formula (4a): (In the formula, R is a C ₁ -C ₄ lower alkyl group, and R ¹ is α-
Amino acid residues and (X ¹ , X ² and X ³ are each independently a hydrogen atom, OH, OR ³
(R ³ is an optionally substituted linear or branched C _1-
C ₆ lower alkyl group, optionally substituted aryl group), OCOR ³ (R ³ is the same as the above), CHO, N
O ₂ , embedded image (R ⁴ and R ⁵ are each independently a hydrogen atom, an optionally substituted linear or branched C _{1 to} C ₆ lower alkyl group,
An aryl group which may be substituted (R ³ is the same as the above), (X ⁴ , X ⁵ and X ⁶ are independently of each other a hydrogen atom, OR ³ or (Wherein R ³ , R ⁴ and R ⁵ are the same as above)), (R ⁴ and R ⁵ are the same as above), (R ⁴ and R ⁵ are the same as above), Z ¹ is O, S and NR ⁴ (R ⁴
Is the same as the above), and n represents 0 to 2. ), (X ⁷ represents O, S or NH, X ⁸ represents CH or N (X ¹ , X ² , X ³ and Z ¹ are the same as the above)), (X ⁹ and X ¹⁰ each independently represent CH or N (X ¹ , X ² , X ³ , X ⁸ and Z ¹ are the same as the above)), (X ¹¹ and X ¹² each independently represent CH or N (X
¹ , X ² , X ³ , X ⁷ and Z ¹ are the same as the above)), (R ⁶ represents formula a, b, c or d (X ¹ , X ² , X ⁷ ,
X ⁸ and Z ¹ are the same as above)), and (X ¹³ represents O, S or NH, X ¹⁴ represents CH or N
(X ¹ , X ² , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Z ¹
Is the same as above)) (W _{is, - (CH 2) m -} , - (CH 2) m -Z 2 - (C
H ₂ ) _n − or embedded image (Z ¹ is the same as above). Where Z ² is S, O, NH
And m and n are 0 to 16 independently of each other. )
Indicates. ) An acid is added to the compound represented by the following general formula (3c): (In the formula, Y represents a halogen atom, an arylsulfonyloxy group, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an azide (R and R ¹ are the same as the above).).