JPH11255744A - 2,4-bi-substituted and 2,3,5-tri-substituted pyrrole derivative and intermediate for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as an anticancer drug having strong cytotoxicity. SOLUTION: This compound is expressed by the formula (R<1> is H or a protective group for an amino group; R<2> is H or a protective group for a carboxylic acid; R<3> is a lower alkyl; X is H or a halogen), e.g. 13-(tert-butoxycarbonyl)-2-(1- methylethyl)-13-azabicyclo[10.2.1]pentadeca-12(15), 14-diene-3,3-dicarboxylic dimethyl ester. The compound of the formula is obtained by reacting 3- formylpyrrole with a malonic acid derivative, reacting the resulting derivative with a lower alkylmagnesium halide, then, reacting the resulting product with Vilsmeier reagent to effect hydrolysis to form the corresponding derivative followed by protecting the amino group of the derivative, reacting the protected derivative with a ylide, deprotecting the triphenylmethyl group of the derivative obtained, followed by methanesulfonylation, and then iodination of the resulting product, and subjecting the iodinated product to a reaction with a base to form a macrocyclic pyrrole derivative, followed by catalytic hydrogenation of the double bond in the macrocyclic pyrrole derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to novel 2,4-disubstituted and 2,3,5-trisubstituted pyrrole derivatives which exhibit strong cytotoxicity and are expected to be used as anticancer agents.

[0002]

2. Description of the Related Art There is a strong demand from society for the development of excellent anticancer drugs, and the creation of new compounds having strong cytotoxicity is very important in the development of excellent anticancer drugs. In general, since the anticancer activity and anticancer spectrum of a compound largely depend on its chemical structure, from a cytotoxic compound having a novel structure different from known ones,
There is a great possibility that an anticancer drug having characteristics superior to those of a currently used anticancer drug will be developed.

[0003]

An object of the present invention is to provide a novel anticancer agent having a novel chemical structure and having strong cytotoxicity.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that 2,4 represented by the following general formula [I] as a compound having a novel chemical structure and having strong cytotoxicity.
-Disubstituted pyrrole derivatives and 2,3,5-trisubstituted pyrrole derivatives represented by general formulas [II] and [III] have been found, and the present invention has been completed. That is, the present invention provides the following general formula [I]

[0005]

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(Wherein, R ¹ represents a hydrogen atom or an amino-protecting group, R ² represents a hydrogen atom or a carboxylic acid-protecting group, R ³ represents a lower alkyl group, and X represents a hydrogen atom. Or a halogen atom.)
Disubstituted pyrrole derivatives and general formula [II]

[0007]

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(Wherein R ² represents a hydrogen atom or a carboxylic acid protecting group, and R ³ represents a lower alkyl group), and a 2,3,5-trisubstituted pyrrole derivative represented by the following general formula: III]

Embedded image (Wherein, R ³ represents a lower alkyl group).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula [I], the protecting group for an amino group includes a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group and a methoxycarbonyl group; an aralkyloxycarbonyl group such as a benzyloxycarbonyl group; Aralkyl groups such as benzenesulfonyl group, p-toluenesulfonyl group, and substituted sulfonyl groups such as methanesulfonyl group; and general formulas [I] and [I
Examples of the carboxylic acid protecting group in [I] include a linear or branched lower alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group and an isobutyl group; And the like. Examples of the lower alkyl group represented by R ³ include a methyl group, an ethyl group,
1-6 carbon atoms such as propyl, butyl, isobutyl, etc.
And a lower alkyl group which is linear or branched.

The compound represented by the formula [I] of the present invention can be prepared by a method described in the literature [JMMuchowski et al., J. Org. Chem., 55,
6317-6328 (1990)].

[0011]

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Thus, it can be produced by the following synthesis process.

[0013]

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[0014]

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(Wherein, R ¹ represents a hydrogen atom or an amino-protecting group; R ^{1 ′} represents an amino-protecting group;
² represents a hydrogen atom or a carboxylic acid protecting group, R ³ represents a lower alkyl group, X represents a hydrogen atom or a halogen atom, and Tr represents a triphenylmethyl group. )

[First step] This step is performed using 3-formylpyrrole.
A malonic acid derivative is allowed to act on (IV) to produce a 2- (3-pyrrolyl) -1,1-ethylenedicarboxylic acid derivative represented by the general formula [V].

The reaction is usually performed in the presence of a base. Examples of the coexisting base include triethylamine, ethyldiisopropylamine, pyridine, pyrrolidine, piperidine,
Imidazole, 4- (dimethylamino) pyridine, N, N
-Diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate , Sodium carbonate, sodium hydrogen carbonate and the like.

The reaction is usually carried out in a solvent, and a neutral or basic solvent is used as the solvent. For example, pentane,
Hydrocarbon solvents such as hexane, cyclohexane, benzene, toluene and xylene, dichloromethane, 1,2-
Dichloroethane, chloroform, halogenated hydrocarbon solvents such as carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran (THF), ether solvents such as 1,4-dioxane, methanol, ethanol,
1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol,
Alcohol solvents such as 2-methyl-2-propanol, acetonitrile, propionitrile, acetone, nitromethane, nitroethane, aprotic polar solvents such as N, N-dimethylformamide (DMF) and dimethylsulfoxide (DMSO), pyridine and the like Is used. The reaction proceeds smoothly at 0 ° C to 100 ° C.

[Second Step] In this step, a lower alkylmagnesium halide such as isopropylmagnesium bromide is added to a 2- (3-pyrrolyl) -1,1-ethylenedicarboxylic acid derivative represented by the general formula [V]. 2-alkyl-2- (3-pyrrolyl) represented by the general formula [VI]
This is a step of producing a -1,1-ethanedicarboxylic acid derivative.

The reaction is usually carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but pentane, hexane, cyclohexane,
Hydrocarbon solvents such as benzene, toluene and xylene,
Ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane are preferably used. The reaction proceeds smoothly at -100 ° C to 50 ° C.

[Third Step] In this step, a 2-alkyl-2- (3-pyrrolyl) -1,1-ethanedicarboxylic acid derivative represented by the general formula [VI] is reacted with a Vilsmeier reagent. Is further hydrolyzed with a basic aqueous solution to selectively formylate the 5-position of the pyrrole ring to give a 2-alkyl-2- [4- (2
-Formylpyrrolyl]]-1,1-ethanedicarboxylic acid derivative.

The Vilsmeier reagent used is prepared by mixing phosphorus oxychloride, thionyl chloride, oxalyl chloride and the like with dimethylformamide and the like. The reaction is usually performed in a solvent, and any solvent can be used as long as it does not participate in the reaction, but pentane,
Hexane, cyclohexane, benzene, toluene, hydrocarbon solvents such as xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, ether solvents such as 1,4-dioxane, acetonitrile, propionitrile, acetone, nitromethane, nitroethane, N,
An aprotic polar solvent such as N-dimethylformamide and dimethyl sulfoxide is preferably used. As the basic aqueous solution at the time of hydrolysis, an aqueous solution of sodium carbonate,
An aqueous solution of potassium carbonate, an aqueous solution of potassium acetate, an aqueous solution of sodium acetate and the like are used. The reaction is performed at -20 ° C to 50
It proceeds smoothly at ° C.

[Fourth Step] In this step, an amino group of a 2-alkyl-2- [4- (2-formylpyrrolyl)]-1,1-ethanedicarboxylic acid derivative represented by the general formula [VII] is used. And a 2-alkyl-2- represented by the general formula [VIII]
[4- (2-formyl-1-substituted pyrrolyl)]-1,1-
This is a step of obtaining an ethanedicarboxylic acid derivative.

The protection is carried out under conditions usually applied to the protecting groups used [TWGreen and PGMWuts, "Protective groups".
in Organic Synthesis ", 2nd Ed., Wiley Interscience
Publication, John-Wiley & Sons, New York, 1991, p
p315-405].

[Fifth Step] This step comprises the step of preparing a 2-alkyl-2- [4- (2-formyl-1-substituted pyrrolyl)]-1,1-ethanedicarboxylic acid derivative represented by the general formula [VIII]: Was reacted with 7-triphenylmethyloxyheptyltriphenylphosphonium bromide and an ylide adjusted with a base to carry out a Wittig reaction to obtain a compound of the general formula [I
X] -Alkyl-2- [4- (8-triphenylmethyloxy-1-octenyl) -1-substituted pyrrolyl]
This is a step of producing a -1,1-ethanedicarboxylic acid derivative.

As the base to be used, n-butyllithium,
Lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and the like. The reaction is usually performed in a solvent, and any solvent can be used as long as it does not participate in the reaction.Pentane, hexane, cyclohexane, benzene, toluene, hydrocarbon solvents such as xylene, diethyl ether Aprotic polar solvents such as ether solvents such as diisopropyl ether, tetrahydrofuran and 1,4-dioxane, acetonitrile, propionitrile, acetone, nitromethane, nitroethane, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide A solvent or a mixed solvent thereof is suitably used. Reaction is from -100 ° C to 50 ° C
It progresses smoothly.

[Sixth Step] This step comprises the steps of 2-alkyl-2- [4- (8-triphenylmethyloxy-1-octenyl) -1-substituted pyrrolyl] -1 represented by the general formula [IX]. , 1-
The triphenylmethyl group at the terminal of the alkyl chain of the ethanedicarboxylic acid derivative is deprotected to give a hydroxyl group, and methanesulfonylation and iodination are successively performed to give a 2-alkyl-2- [4- represented by the general formula [X]. This is a step of producing a (8-iodo-1-octenyl) -1-substituted pyrrolyl] -1,1-ethanedicarboxylic acid derivative.

The deprotection of the triphenylmethyl group is carried out under the conditions usually applied [TWGreen and PGMWuts, "Protective
groups in Organic Synthesis ", 2nd Ed., Wiley Inte
rscience Publication, John-Wiley & Sons, New York,
1991, pp61-62]. The methanesulfonylation of the resulting hydroxyl groups is usually carried out under the conditions [TWGreen
and PGMWuts, "Protective groups in Organic Syn
thesis ", 2nd Ed., Wiley Interscience Publication,
John-Wiley & Sons, New York, 1991, pp 117-118]. Subsequent iodination is performed using sodium iodide, potassium iodide and the like. The reaction is usually performed in a solvent, and any solvent can be used as long as it does not participate in the reaction, but pentane, hexane, cyclohexane, benzene, toluene,
Hydrocarbon solvents such as xylene, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane, acetonitrile, propionitrile, acetone, nitromethane, nitroethane, N, N-dimethylformamide, dimethyl sulfoxide, hexa An aprotic polar solvent such as methylphosphoric triamide is preferably used. The reaction is performed at -100C to -100C.
It proceeds smoothly at ° C.

[Seventh Step] In this step, a 2-alkyl-2- [4- (8-iodo-1-octenyl) -1-substituted pyrrolyl] -1,1- represented by the general formula [X] is used. This is a step of producing a macrocyclic pyrrole derivative represented by the general formula [XI] by allowing a base to act on the ethanedicarboxylic acid derivative.

Examples of the base used include cesium carbonate, potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, potassium tert-butoxide and the like. The reaction is usually performed in a solvent, and any solvent can be used as long as it does not participate in the reaction.Pentane, hexane, cyclohexane, benzene, toluene, hydrocarbon solvents such as xylene, diethyl ether, Ether solvents such as diisopropyl ether, tetrahydrofuran and 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and 2-methyl-1
Alcoholic solvents such as -propanol and 2-methyl-2-propanol; aprotic polar solvents such as acetonitrile, propionitrile, acetone, nitromethane, nitroethane, N, N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide Is preferably used. The reaction proceeds smoothly at -100C to -100C.

[Eighth Step] In this step, the double bond in the macrocyclic pyrrole derivative represented by the general formula [XI] is catalytically hydrogenated to form a 2,2 compound represented by the general formula [Ia] of the present invention. This is a step of producing a 4-disubstituted pyrrole derivative. If necessary, the protecting group at the 1-position of the pyrrole ring can be deprotected. In this case, a compound represented by the general formula [Ia] in which R ¹ is a hydrogen atom is obtained as a product.

The catalytic hydrogenation is carried out in a solvent using a catalyst such as palladium carbon, Raney nickel, palladium hydroxide and rhodium-alumina. Any solvent can be used as long as it does not participate in the reaction, but pentane, hexane, cyclohexane, benzene,
Hydrocarbon solvents such as toluene and xylene, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, -Methyl-1
Alcohol solvents such as -propanol and 2-methyl-2-propanol are preferably used. The reaction proceeds smoothly at -100C to -100C.

Deprotection of the protecting group at the 1-position of the pyrrole ring can be carried out by using generally used conditions [TWGreen and PGMWuts, "Pr
otective groups in Organic Synthesis ", 2nd Ed., Wi
leyInterscience Publication, John-Wiley & Sons, Ne
w York, 1991, pp 315-405].

[Ninth Step] In this step, the 2-position of pyrrole of the 2,4-disubstituted pyrrole derivative represented by the general formula [Ia] in which the 1-position of the pyrrole ring is deprotected is halogenated, Ib]
This is a step of producing a macrocyclic halopyrrole derivative represented by

The halogenation of the 2-position of pyrrole is carried out using a halogenating agent. Examples of the halogenating agent for halogenation include N-bromosuccinimide, pyridinium hydrobromide perbromide, N-iodosuccinimide and the like. The reaction is usually performed in a solvent, and any solvent can be used as long as it does not participate in the reaction.Pentane, hexane, cyclohexane, benzene, toluene, hydrocarbon solvents such as xylene, diethyl ether And ether solvents such as diisopropyl ether, tetrahydrofuran, and 1,4-dioxane. The reaction proceeds smoothly from -100 ° C to 0 ° C.

Formula (Ib) wherein R ¹ is a protecting group for an amino group
The macrocyclic halopyrrole derivative represented by
Obtained by reprotecting the position. The introduction of protecting groups is subject to the conditions normally applied [TWGreen and PGMWuts, "
Protective groups in OrganicSynthesis ", 2nd Ed., W
iley Interscience Publication, John-Wiley & Sons, N
ew York, 1991, pp 315-405].

[Tenth Step] In this step, a lithiopyrrole derivative is prepared in a system by reacting an alkyllithium with a macrocyclic halopyrrole derivative represented by the general formula [Ib] in which the 1-position of the pyrrole ring is protected. In this step, the intramolecular cyclization reaction proceeds by nucleophilic attack on an ester group in the molecule to produce a 2,3,5-trisubstituted pyrrole derivative represented by the general formula [II] of the present invention.

Examples of the alkyl lithium used include methyl lithium, ethyl lithium, n-butyl lithium, s-butyl lithium and t-butyl lithium. The reaction is usually performed in a solvent, and any solvent can be used as long as it does not participate in the reaction.Pentane, hexane, cyclohexane, benzene, toluene, hydrocarbon solvents such as xylene, diethyl ether, Diisopropyl ether, tetrahydrofuran, 1,
An ether solvent such as 4-dioxane is preferably used. The reaction proceeds smoothly from -100 ° C to 0 ° C.

In this step, the intramolecular cyclization proceeds stereoselectively, and the desired (4RS, 5SR) -form is selectively obtained.

[Eleventh Step] In this step, the 2,3,5-trisubstituted pyrrole derivative represented by the general formula [II] is decarboxylated, and the decarboxylation of the 2,3 represented by the present invention [III] , A 3,5-trisubstituted pyrrole derivative.

The decarboxylation is carried out by heating in a solvent in the presence of sodium cyanide and water. As the solvent, an aprotic polar solvent such as acetonitrile, propionitrile, acetone, nitromethane, nitroethane, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide (HMPA) is used. The reaction proceeds smoothly from -50 ° C to 200 ° C.

When the compound of the present invention is used as an anticancer agent, the compound of the present invention is also used as a pharmaceutically acceptable salt. Typical examples of pharmaceutically acceptable salts include, for example, carbonic acid, phosphoric acid, hydrochloric acid, salts with inorganic acids such as sulfuric acid, acetic acid,
Examples thereof include salts with organic acids such as propionic acid, fumaric acid, citric acid, trifluoroacetic acid, paratoluenesulfonic acid, and trifluoromethanesulfonic acid.

The above general formula [I] obtained as described above
A 2,4-disubstituted pyrrole derivative represented by the formula:
A malignant tumor cell growth inhibitory activity test was conducted on 2,3,5-trisubstituted pyrrole derivatives represented by [II] and [III], and these compounds exhibited strong cytotoxicity and were used as anticancer agents. It was confirmed.

Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.

[0045]

[Example] Reference Example 1

[0046]

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3-formylpyrrole in an argon stream
(1.61 g, 16.9 mmol) and dimethyl malonate (4.47 g, 33.
8 mmol) in pyridine (16 ml), piperidine (1 ml)
And stirred at 65 ° C. for 10 hours. The reaction mixture was returned to room temperature and diluted with ether. This was washed sequentially with a 1 N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate 3: 1) to give dimethyl 2- (3-pyrrolyl) -1,1-ethylenedicarboxylate (2.47 g).
Was obtained as a white solid in 70% yield.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.81 (3H,
s), 3.90 (3H, s), 6.31-6.35 (1H, m), 6.78-6.82 (1
H, m), 7.13-7.17 (1H, m), 7.73 (1H, s), 8.51 (1H,
broad, NH).

Reference Example 2

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In an argon stream, dimethyl 2- (3-pyrrolyl) -1,1-ethylenedicarboxylate (1.05
g, 5.02 mmol) in THF (70 ml) was added to a THF solution of isopropylmagnesium bromide (0.67 mol / l, 30.0 ml, 2
0 mmol) was added dropwise over 20 minutes and stirred for 1 hour. Water was poured into the reaction mixture, extracted three times with ethyl acetate, and washed with a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate 5: 1) to give dimethyl 3-methyl-2- (3-pyrrolyl) -1,1-butanedicarboxylate (1.03 g) as a white solid in 81%. In a yield of

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.81 (3H,
d, J = 6 Hz), 0.84 (3H, d, J = 6 Hz), 1.78-1.92 (1
H, m), 3.34 (1H, dd, J = 11, 2 Hz), 3.50 (3H, s),
3.75 (3H, s), 3.85 (1H, d, J = 11 Hz), 6.01-6.07
(1H, m), 6.55-6.59 (1H, m), 6.65-6.69 (1H, m), 8.1
0 (1H, broad, NH).

Reference Example 3

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Phosphorus oxychloride (POCl ₃ , 190 ml, 2.04 mmol) was added dropwise to DMF (7 ml) at 0 ° C. in an argon stream to prepare a Vilsmeier reagent. On the other hand, a DMF (7 ml) solution of dimethyl 3-methyl-2- (3-pyrrolyl) -1,1-butanedicarboxylate (260.0 mg, 1.02 mmol) was added to 0 ml.
C. was added dropwise. After stirring at room temperature for 1 hour, an aqueous sodium acetate solution (5 mol / l, 13 ml) was added, and the mixture was heated to 60 ° C. and stirred for 1 hour. Water was poured into the reaction mixture, extracted three times with ethyl acetate, and washed with a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate 3: 1),
3-methyl-2- [4- (2-formylpyrrolyl)]-
Dimethyl 1,1-butanedicarboxylate (275.7 mg) was obtained as white crystals in a 96% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.81 (3H,
d, J = 6.7 Hz), 0.86 (3H, d, J = 6.7 Hz), 1.88-1.9
8 (1H, m), 3.34 (1H, dd, J = 4.9, 10.7 Hz), 3.54 (3
H, s), 3.75 (3H, s), 3.80 (1H, d, J = 10.7 Hz), 6.8
0-6.81 (1H, m), 6.95-6.96 (1H, m), 9.41 (1H, broa
d), 9.45-9.46 (1H, m); MS, m / e 281 (M ⁺ ).

Reference Example 4

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3-methyl-2- at room temperature in a stream of argon
[4- (2-Formylpyrrolyl)]-1,1-butanedicarboxylate dimethyl (271.8 mg, 0.97 mmol) and dititanium dicarbonate
To a solution of ert-butyl ((Boc) 2O, 424.8 mg, 1.95 mmol) in acetonitrile (10 ml) was added 4-dimethylaminopyridine (D
MAP, 119.5 mg, 0.98 mmol) and stirred for 2 hours.
After diluting the reaction mixture with diethyl ether, 1N hydrochloric acid,
The extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate 5: 1) to give 3-methyl-2- [4- (1-ter
t-butoxycarbonyl-2-formylpyrrolyl)]-
Dimethyl 1,1-butanedicarboxylate (343.8 mg) was obtained as white crystals in a 93% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 0.80 (3H,
d, J = 6.8 Hz), 0.87 (3H, d, J = 6.8 Hz), 1.64 (9
H, s), 1.83-1.93 (1H, m), 3.28 (1H, dd, 4.8, 10.7
Hz), 3.57 (3H, s), 3.76 (3H, s), 3.82 (1H, d, J =
10.7 Hz), 7.02 (1H, d, J = 1.9 Hz), 7.25 (1H, d, J
= 1.9 Hz), 10.27 (1H, s).

Reference Example 5

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At 0 ° C. in a stream of argon, a solution of sodium hexamethyldisilazide in THF (50 ml) was added to a solution of the phosphonium salt (4.76 g, 6.80 mmol) just dried in THF (1.
0M, 5.70 ml, 5.7 mmol) was added dropwise and stirred for 30 minutes. After cooling the reaction mixture to −78 ° C., 3-methyl-2- [4-
(1-tert-butoxycarbonyl-2-formylpyrrolyl)]-1,1-butanedicarboxylate dimethyl (434 mg,
A solution of 1.14 mmol) in THF (15 ml) was added dropwise, and the temperature was gradually raised while stirring overnight. A 10% aqueous ammonium chloride solution was poured into the obtained reaction mixture, extracted twice with ethyl acetate, and washed with a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel chromatography.
(Hexane / ethyl acetate 10: 1) to give 3-methyl-
2- [4- (8-triphenylmethyloxy-1-octenyl) -1-tert-butoxycarbonylpyrrolyl] -1,
Dimethyl 1-butanedicarboxylate (774 mg) was obtained as a mixture of geometric isomers of the olefin (cis: trans = 3: 1) in 94% yield.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.80 (3H,
d, J = 13.4 Hz), 0.87 (3H, d, J = 13.4 Hz), 1.21-
1.68 (8H, m), 1.77-1.89 (1H, m), 2.02-2.28 (2H, m
m), 3.04 (2H, t, J = 6.5 Hz), 3.25 (1H, dd, J = 4.
4, 10.9 Hz), 3.54 (2.25H, s), 3.56 (0.75H, s), 3.
75 (3H, s), 3.80 (0.25H, d, J = 11.1 Hz), 3.81 (0.
75H, d, J = 11.1 Hz), 5.50-5.63 (0.75H, m), 5.85-5.
98 (0.25H, m), 5.98 (0.75H, s), 6.12 (0.25H.s),
6.65 (0.75H, d, J = 11.3 Hz), 6.80 (0.25H, d, J = 1
6.1 Hz), 6.93 (0.25H, d, J = 1.8 Hz), 6.97 (0.75H,
d, J = 1.7 Hz), 7.17-7.33 (9H, m), 7.41-7.46 (6H,
m); MS, m / e 721 (M ⁺ ), 621 (M ⁺ -Boc + 1).

Reference Example 6

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In an argon stream, 3-methyl-2- [4-
(8-triphenylmethyloxy-1-octenyl) -1
-Tert-butoxycarbonylpyrrolyl] -1,1-butanedicarboxylate (189.2 mg, 0.262 mmol) in chloroform-methanol (CHCl ₃ : MeOH = 2: 1) solution
Toluenesulfonic acid monohydrate (p-TsOH H ₂ O, 7 mg) is added, and the mixture is stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, and washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product having an alcohol at the terminal. Next, methanesulfonyl chloride (MsCl, 40 ml, 0.517 mmol) and 4-dimethylaminopyridine (DMAP) (3.5 mg, 0.029 mmol) were sequentially added to a crude pyridine (6 ml) solution of the terminal alcohol at 0 ° C. In addition, the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed twice with 1N hydrochloric acid, and sequentially with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude methanesulfonyl compound. Subsequently, a solution of the crude terminal methanesulfonyl compound in acetone (10 ml) was added to a solution of sodium iodide (39
9.0 mg, 2.66 mmol) and stirred at 60 ° C. for 3 hours. A 5% aqueous sodium sulfite solution was poured into the reaction mixture, extracted three times with ether, and washed with a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate 15: 1) to give 3-methyl-2.
-Dimethyl [-(4- (8-iodo-1-octenyl) -1-tert-butoxycarbonylpyrrolyl] -1,1-butanedicarboxylate (98.8 mg) was obtained as a mixture of geometric isomers (cis: trans = 3: 1) was obtained in a yield of 64%.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.80 (3H,
d, J = 13.4 Hz), 0.87 (3H, d, J = 13.4 Hz), 1.21-
1.68 (8H, m), 1.77-1.89 (1H, m), 2.02-2.28 (2H, m
m), 3.19 (0.75H, t, J = 6.5 Hz), 3.21 (0.25H, t, J
= 6.5 Hz), 3.25 (1H, dd, J = 4.4, 10.9 Hz), 3.57
(3H, s), 3.75 (0.75 H, s), 3.76 (2.25H, s), 3.80
(0.25H, d, J = 11.1 Hz), 3.82 (0.75H, d, J = 11.1
Hz), 5.50-5.63 (0.75H, m), 5.85-5.98 (0.25H, m), 5.
98 (0.75H, s), 6.12 (0.25H.s), 6.65 (0.75H, d, J =
11.3 Hz), 6.80 (0.25H, d, J = 16.1 Hz), 6.93 (0.2
5H, d, J = 1.8 Hz), 6.97 (0.75H, d, J = 1.7 Hz); MS,
m / e 589 (M ⁺ ), 533 (M ⁺ -Bu ^t +1), 489 (M ⁺ -Boc + 1).

Reference Example 7

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Cesium carbonate (Cs ₂ CO ₃ , 9
20 mg, 2.82 mmol) in DMF (80 ml) at 90 ° C.
Methyl-2- [4- (8-iodo-1-octenyl) -1-
tert-Butoxycarbonylpyrrolyl] -1,1-butanedicarboxylate (289 mg, 0.490 mmol) in DMF (20
ml) solution was added dropwise over 1 hour and then stirred for 15 hours. A 10% aqueous ammonium chloride solution was added to the reaction mixture,
Extracted twice with ether and washed with a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography was performed.
(Hexane / ethyl acetate 15: 1) to give 13- (tert
-Butoxycarbonyl) -2- (1-methylethyl)-
13-Azabicyclo [10.2.1] pentadeca-10,12 (15), 14
-Diene-3,3-dicarboxylate (85.2 mg) was obtained as colorless crystals in a yield of 38%.

₁ H NMR (500 MHz, CDCl ₃ ) δ 0.66-0.76
(1H, m), 0.85 (3H, d, J = 6.7 Hz), 0.91 (3H, d, J =
6.7 Hz), 0.98-1.07 (1H, m), 1.21-1.49 (6H, m), 1.
54 (9H, s), 1.56-1.63 (1H, m), 1.73 (1H, dt, Jd =
3.1 Hz, Jt = 13.5 Hz), 1.92 (1H, dt, Jd = 4.9 Hz, J
t = 13.5 Hz), 1.95-2.02 (1H, m), 2.06-2.12 (1H,
m), 3.36 (1H, d, J = 4.1 Hz), 3.72 (3H, s), 3.76
(3H, s), 5.90 (1H, ddd, J = 6.8, 8.8, 10.7 Hz), 6.0
9 (1H, broad), 6.49 (1H, d, J = 10.7 Hz), 7.06 (1
H, d, J = 1.4 Hz); MS, m / e 461 (M ⁺ ), 405 (M ⁺ -Bu ^t +
1), 361 (M ⁺ -Boc + 1), 346 (M ⁺ -Bu ^t -CO ₂ Me + 1), 302 (M ⁺ -B
oc-CO ₂ Me + 1).

Embodiment 1

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13- (tert-butoxycarbonyl) -2- (1-methylethyl) -13 at room temperature in an argon stream
-Azabicyclo [10.2.1] pentadeca-10,12 (15), dimethyl 14-triene-3,3-dicarboxylate (85.2 mg, 0.18
4 mmol) in toluene (12 ml), 10% Pd-carbon powder (85 mg) was added, and the reaction system was replaced with a hydrogen atmosphere.
Stirred vigorously at room temperature for 10 hours. The reaction mixture was filtered through celite, and the resulting solution was evaporated under reduced pressure to give 13- (tert-
(Butoxycarbonyl) -2- (1-methylethyl) -1
Dimethyl 3-azabicyclo [10.2.1] pentadeca-12 (15), 14-diene-3,3-dicarboxylate (81.3 mg) was obtained in 95% yield as colorless crystals.

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.62 (3H,
d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 1.06-1.6
3 (13H, m), 1.60 (9H, s), 2.04-2.06 (1H, m), 2.16
(1H, dt, Jd = 2.4 Hz, Jt = 6.7 Hz), 2.72-3.04 (2H,
m), 3.30 (1H, d, J = 2.3 Hz), 3.73 (3H, s), 3.76
(3H, s), 6.03-6.09 (1H, m), 7.03 (1H, d, J = 1.9 H
z) .MS, m / e 463 (M ⁺ ), 407 (M ⁺ -Bu ^t +1), 363 (M ⁺ -Boc +
1), 320 (M ⁺ -Boc-Pr ⁱ +1).

Embodiment 2

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13- (tert-butoxycarbonyl) -2- (1-methylethyl) -13-azabicyclo [10.2.1] pentadeca-12 (15), 14-diene-3,3 in air at room temperature
-To a solution of dimethyl dicarboxylate (8.7 mg, 0.019 mmol) in dichloromethane (1 ml) was added 1 ml of trifluoroacetic acid,
Stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and purified by thin-layer silica gel chromatography (hexane / ethyl acetate 5: 1) to give 2- (1-methylethyl) -13. -Azabicyclo [10.2.1] pentadeca-12
(15) Dimethyl 14,14-diene-3,3-dicarboxylate (6.7 m
g) was obtained as colorless crystals in a yield of 99%.

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.63 (3H,
d, J = 6.7 Hz), 0.97 (3H, d, J = 6.7 Hz), 1.11-1.6
5 (12H, m), 2.08-2.20 (2H, m), 2.56-2.68 (2H, m),
3.37 (1H, d, J = 2.1 Hz), 3.72 (3H, s), 3.75 (3H,
s), 5.93 (1H, broad), 6.49 (1H, broad), 7.75 (1H,
broad); MS, m / e 363 (M ⁺ ), 348 (M ⁺ -CH ₃ ), 320 (M ⁺ -Pr
ⁱ ), 304 (M ⁺ -CO ₂ Me).

Embodiment 3

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13- (tert-butoxycarbonyl) -2- (1-methylethyl) -13-azabicyclo [10.2.1] pentadeca-12 (15), 14-diene-3,3 at room temperature in air
-To a solution of dimethyl dicarboxylate (39.6 mg, 0.0854 mmol) in dichloromethane (1 ml) was added 1 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. After the organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure to obtain a crude deprotected product. In a stream of argon, a solution of the crude deprotected product in tetrahydrofuran (1 ml) at -78 ° C was added to pyridinium hydrobromide perbromide (42.6 mg,
0.133 mmol) in tetrahydrofuran (1 ml).
Stirred for minutes. To the reaction mixture was added a 5% aqueous sodium sulfite solution, extracted twice with ether, and washed with a saturated aqueous sodium chloride solution. After drying the organic layer over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure to obtain a crude bromopyrrole derivative. In a stream of argon, at room temperature, the crude bromopyrrole derivative and acetonitrile of dibutyl dicarbonate (3 m
l) Dimethylaminopyridine (14.7 mg, 0.120 mmo
l) was added and stirred at room temperature for 30 minutes. The reaction mixture was diluted with ether and washed with a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting mixture was thin-layer silica gel chromatography.
(Hexane / ethyl acetate 5: 1) to give 14-bromo-1
3- (tert-butoxycarbonyl) -2- (1-methylethyl) -13-azabicyclo [10.2.1] pentadeca-12
(15) Dimethyl 14,14-diene-3,3-dicarboxylate (29.0
mg) as colorless crystals in 63% yield.

¹ H NMR (500 MHz, CDCl ₃ ) δ -0.29--0.22
(1H, m), 0.52-0.58 (1H, m), 0.59 (3H, d, J = 6.7 H
z), 0.73-0.80 (1H, m), 0.92-0.99 (1H, m), 1.04 (3
H, d, J = 6.7 Hz), 1.09-1.37 (6H, m), 1.49-1.58 (1
H, m), 1.62 (9H, s), 1.69-1.76 (1H, m), 2.07 (1H,
dt, Jd = 3.7 Hz, Jt = 13.8 Hz), 2.24 (1H, dt, Jd =
1.8 Hz, Jt = 6.8 Hz), 2.43 (1H, dt, Jd = 4.1 Hz, J
t = 13.2 Hz), 3.24 (1H, dt, Jd = 14.1 Hz, Jt = 3.5
Hz), 3.67 (1H, d, J = 2.0 Hz), 3.75 (3H, s), 3.77
(3H, s), 6.32 (1H, s).

Embodiment 4

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14-bromo-13 in an argon stream at -78 ° C
-(Tert-butoxycarbonyl) -2- (1-methylethyl) -13-azabicyclo [10.2.1] pentadeca-12 (1
5) Dimethyl 14,14-diene-3,3-dicarboxylate (12.6 m
g, 0.0232 mmol) in THF (2.0 ml) -HMPA (0.2 ml) solution, n-butyllithium hexane solution (1.61 M, 0.025 m
1,0.040 mmol) was added dropwise and stirred for 2 hours. A 10% aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was heated to room temperature, extracted twice with ether, and washed with a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is
Purification by thin layer silica gel chromatography (hexane / ethyl acetate 4: 1) gives 13- (tert-butoxycarbonyl) -2- (1-methylethyl) -13-azabicyclo [10.2.1] pentadeca-12 (15) Dimethyl 14,14-diene-3,3-dicarboxylate (6.8 mg) was 63%, which was the target (4RS,
(5SR) -4,5-dihydro-5-methoxycarbonyl-4-
(1-methylethyl) -2,5-octanocyclopenta [b]
Pyrrole-6 (1H) -one (2.4 mg) was obtained in 31% yield.

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.33-0.49
(2H, m), 0.72 (3H, d, J = 6.6 Hz), 0.80-1.37 (10H,
m), 1.03 (3H, d, J = 6.6 Hz), 1.83-1.90 (1H, m),
1.95-2.05 (2H, m), 2.47 (1H, ddd, J = 5.9, 11.0, 1
4.0 Hz), 2.86-2.93 (1H, m), 2.92 (1H, d, J = 4.7 H
z), 3.76 (3H, s), 6.00 (1H, d, J = 1.5 Hz), 9.47
(1H, broad); MS, m / e 331 (M ⁺ ), 288 (M ⁺ -Pr ⁱ ), 272
(M ⁺ -CO ₂ Me).

Embodiment 5

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(4RS, 5SR) -4,5 at room temperature in a stream of argon
-Dihydro-5-methoxycarbonyl-4- (1-methylethyl) -2,5-octanocyclopenta [b] pyrrole-6
(1H) -one (2.1 mg, 0.0063 mmol) in DMSO (1 ml) -H2
O (0.1 ml) solution was added sodium cyanide (NaCN, 2.2 mg,
0.045 mmol), and the mixture was stirred at 140 ° C for 20 hours. After the reaction mixture was brought to room temperature, water was added, extracted twice with ether, and washed with a saturated aqueous sodium chloride solution. About the organic layer,
After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by thin-layer silica gel chromatography (hexane / ethyl acetate 2: 1) to give (4RS, 5RS) -4,5-dihydro-
4- (1-methylethyl) -2,5-octanocyclopenta
[b] Pyrrole-6 (1H) -one (1.4 mg) was obtained in an 81% yield.

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.39-0.48
(2H, m), 0.83-1.32 (10H, m), 0.89 (3H, d, J = 6.6
Hz), 1.00 (3H, d, J = 6.6 Hz), 1.75-1.85 (2H, m),
1.90-1.97 (1H, m), 2.43 (1H, ddd, J = 5.8, 10.5, 1
4.0 Hz), 2.61 (1H, d, J = 6.7Hz), 2.75 (1H, dd, J
= 3.5, 4.8 Hz), 2.88 (1H, ddd, J = 5.0, 5.0, 14.0H
z), 5.99 (1H, d, J = 1.7 Hz), 8.90 (1H, broad); MS,
^{m / e 273 (M +)} , 258 (M + -CH 3), 230 (M + -Pr i).

Test Example 1 (Malignant Tumor Cell Growth Inhibition Test) Murine lymphocytic leukemia cells (P388) were added to 10% fetal bovine serum-containing RPMI-1640 medium supplemented with 5 ml of 2-hydroxyethyl disulfide and 100 mg / ml kanamycin sulfate. In addition, the cultured cells were adjusted to 1 × 10 ⁴ cells / ml. The compound of the present invention was added thereto to a predetermined concentration, and cultured in a CO ₂ incubator (CO ₂ 5%, humidity 100%, 37 ° C.) for 4 days. The number of surviving cells was counted by the MTT colorimetric method, and
The% cell growth inhibitory concentration (IC ₅₀ ) was determined. Table 1 shows the results.

Table 1. 50% growth inhibitory concentration on mouse lymphocytic leukemia cells (P388)

[0084]

[Table 1]

Claims (3)

[Claims] 1. A compound of the general formula (Wherein, R ¹ represents a hydrogen atom or an amino-protecting group, R ² represents a hydrogen atom or a carboxylic acid-protecting group, R ³ represents a lower alkyl group, X represents a hydrogen atom or a halogen atom. Represents a 2,4-disubstituted pyrrole derivative. 2. A compound of the general formula (Wherein, R ² represents a hydrogen atom or a carboxylic acid protecting group, and R ³ represents a lower alkyl group).
3,5-trisubstituted pyrrole derivatives. 3. A compound of the general formula (Wherein, R ³ represents a lower alkyl group).