JP2011020992A - Dihydroquinoxaline derivative and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a dihydroquinoxalin-2-on derivative, which does not require many steps and is environmentally friendly, to provide a new dihydroquinoxalin-2-on derivative, and to provide a therapeutic agent for cancer. <P>SOLUTION: The method for producing the dihydroquinoxalin-2-on derivative comprises a one-pot cyclization reaction between a (heterocyclic) aromatic compound having a halogen and an amino group as neighboring substituents, e.g. a 2-haloaniline derivative, and an α-amino acid derivative. Preferably, a copper catalyst, a base and an aprotic polar solvent are used. The derivative may be an optically active substance. The therapeutic agent for cancer comprises the dihydroquinoxalin-2-on derivative as an active ingredient and is particularly effective for treating human uterine cervical cancer. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel method for producing a dihydroquinoxaline derivative, a novel dihydroquinoxaline derivative, and a therapeutic drug for cancer comprising a dihydroquinoxaline derivative as an active ingredient.

  The dihydroquinoxaline derivative is one of pharmacologically important nitrogen-containing heterocyclic compounds, and many of the derivatives are drug candidate compounds. Many of them are drug candidate compounds such as antiallergic agents and anti-inflammatory agents. For example, quinoxaline compound A exhibits norepinephrine reabsorption inhibitory activity and has been reported as a preventive and therapeutic agent for central nervous system disorders (Shelkun, RM et al., International Patent Application WO2006 / 016278), and quinoxaline compound B is It has an inhibitory activity on VEGF (vascular endothelial growth factor) involved in angiogenesis and angiogenesis, and its action as an anticancer agent has been reported (Koseki et al., JP 2007-099641 A).

  Quinoxaline is a bicyclic heterocyclic compound having a structure such as 1, and many derivatives thereof have useful pharmacological activity. Quinoxaline compound C has been reported to exhibit glutamate receptor antagonism (Sakamoto et al., JP-A-7-165756). Other than that, for example, anticancer agent 2 (Lakshmi, MV; Hsu, FF; Schut, AJ; Zenser, VT Chem. Res. Toxicol., 2006, 19, 325-333.) Drug 3 (Catarzi, D .; Colotta, V .; Varano, F .; Calabri, RF; Filacchioni, G .; Galli, A .; Costagli, C .; Carla, VJ Med. Chem., 2004, 47, 262 -272.) Is known.

  As a method for synthesizing a quinoxaline derivative, a reaction using a metal catalyst has been conventionally known. For example, Ma et al. Synthesized a quinoxaline derivative from 2-iodotrifluoroacetanilide and methyl pyrrolate using L-proline as a ligand and CN coupling reaction using cuprous iodide as a catalyst and hydrolysis domino type reaction. (Reaction Formula (1)) (Yuan, Q .; Ma, DJ Org. Chem., 2008, 73, 5159-5162).

  In addition, Zhao et al. Conducted CN coupling of α-amino acid and o-nitroiodobenzene using cuprous iodide as a catalyst, followed by a reduction reaction with tin (II) chloride, thereby converting the quinoxaline derivative. (Reaction Formula (2)) (Jiang, Q .; Jiang, D .; Jiang, Y .; Fu, H .; Zhao, Y. Synlett, 2007, 12, 1836-1842).

  Tamariz et al. Derived quinoxaline derivatives by CN coupling using palladium catalyst after introducing 3-nitrobenzeneamine and 2-methylpropanaldehyde to enamine (Reaction Formula (3)) (Soderberg CGB Wallace, MJ; Tamariz, J. Org. Lett., 2002, 4, 1339-1342).

  These conventional methods for synthesizing quinoxaline derivatives include problems such as a large load on the environment, such as using a multi-step process, using toxic reactants, or starting materials being expensive or difficult to obtain. It is out.

International Patent Application WO2006 / 016278 JP 2007-099641 A Japanese Patent Application Laid-Open No.7-165756

Lakshmi, M. V .; Hsu, F. F .; Schut, A. J .; Zenser, V. T. Chem. Res. Toxicol., 2006, 19, 325-333. Colotta, V .; Varano, F .; Calabri, R. F .; Filacchioni, G .; Galli, A .; Costagli, C .; Carla, V. J. Med. Chem., 2004, 47, 262-272. Yuan, Q .; Ma, D. J. Org. Chem., 2008, 73, 5159-5162. Jiang, Q .; Jiang, D .; Jiang, Y .; Fu, H .; Zhao, Y. Synlett, 2007, 12, 1836-1842. Soderberg C. G. B .; Wallace, M. J .; Tamariz, J. Org. Lett., 2002, 4, 1339-1342.

  The present invention provides a method for synthesizing a quinoxaline derivative that does not require many steps, has a low environmental burden, is inexpensive and easily available, and provides a novel dihydroquinoxaline derivative. The present invention also provides a novel cancer therapeutic agent comprising a dihydroquinoxaline derivative as an active ingredient.

  That is, the present invention relates to the general formula (I):

[Wherein X is a bromine, iodine or chlorine atom, Y ^{1 to} Y ⁴ are the same or different and are a carbon atom or a nitrogen atom (provided that at least two of Y ^{1 to} Y ⁴ are carbon atoms) ),
R ¹ is a hydrogen atom, an unsubstituted or substituted alkyl group, an alkylcarbonyl group, a haloalkylcarbonyl group, iodine, a halogen atom other than bromine, a cyano group, an alkoxy group, a haloalkoxy group, an aryloxy group, or a nitro group,
R ² is a hydrogen atom, an unsubstituted or substituted alkyl group, an acyl group, a sulfonyl group,
n is an integer of 1 to 4. ]
An aromatic compound represented by general formula (II):

[Wherein R ³ represents a hydrogen atom or an unsubstituted or substituted alkyl group;
R ⁴ is a hydrogen atom, an unsubstituted or substituted alkyl group or a cycloalkyl group,
R ³ and R ⁴ may be combined to form a ring. ]
Comprising reacting an α-amino acid derivative represented by:
General formula (III):

[Wherein, Y ^{1 to} Y ⁴ , R ^{1 to} R ⁴ and n are as defined above. ]
The present invention relates to a method for producing a dihydroquinoxalin-2-one derivative represented by the formula:
Here, the substituent when R ¹ and / or R ² is a substituted alkyl group is an aryl group or a nitrogen heterocycle.

  The present invention is directed to general formula (IV):

[Wherein R ¹² represents an unsubstituted or substituted alkyl group,
R ^{13 to} R ¹⁶ are the same or different and are each a hydrogen atom, an unsubstituted or substituted alkyl group, a cycloalkyl group, an alkylcarbonyl group, a haloalkylcarbonyl group, iodine, a halogen atom other than bromine, a cyano group, an alkoxy group, a haloalkoxy group , An aryloxy group or a nitro group. ]
It is related with the dihydroquinoxalin-2-one derivative represented by these.
Here, when R ¹² is a substituted alkyl group, the substituent is an aryl group, a hydroxy-substituted aryl group, an alkoxy-substituted aryl group, a nitrogen alicyclic group, or a nitrogen heterocycle, and R ^{13 to} R ¹⁶ are substituted alkyl groups. Sometimes the substituent is an aryl group or a nitrogen heterocycle.

  The present invention relates to a novel cancer therapeutic agent comprising a dihydroquinoxalin-2-one derivative represented by the general formula (III) as an active ingredient.

  The present invention provides a method for synthesizing a dihydroquinoxalin-2-one derivative that does not require multiple steps and has a low environmental impact, and provides a novel dihydroquinoxalin-2-one derivative (III). . The present invention also provides a novel cancer therapeutic agent comprising a dihydroquinoxalin-2-one derivative (III) as an active ingredient.

FIG. 1 shows (2S, 3S) -3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one [A-1c] and the optically active dihydroquinoxalin-2-one derivatives of the present invention. ¹ is a ¹ H-NMR chart of a diastereomeric mixture of (2S, 3R) -3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one [A-1a].

The present invention relates to a method for producing a dihydroquinoxalin-2-one derivative (III) comprising a step of reacting an aromatic compound (I) with an α-amino acid derivative (II).
Here, the substituent when R ¹ and / or R ² is a substituted alkyl group is an aryl group or a nitrogen heterocycle.

Hereinafter, Y ¹ to Y ⁴ , R ^{1 to} R ⁴ and n in the general formulas (I) to (III) will be specifically described using the product dihydroquinoxalin-2-one derivative (III). .

Y ^{1 to} Y ⁴ are the same or different and are a carbon atom or a nitrogen atom. However, at least two of Y ^{1 to} Y ⁴ are carbon atoms. Examples of the condensed heterocyclic ring in the formula (III) are shown in Table 1.

That is, examples of the aromatic ring of the compound represented by the general formula (I), which is an aromatic compound raw material, include a benzene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, and a pyridazine ring.
Examples of the condensed heterocyclic ring in the formula (III) include a dihydroquinoxaline ring, a pyrido [2,3-b] dihydropyrazine ring, a pyrido [3,4-b] dihydropyrazine ring, and a pyrazino [2,3-b]. Dihydropyrazine ring, pyrazino [2,3-b] dihydropyrazine ring, pyrimidino [4,5-b] dihydropyrazine ring, pyridazino [3,4-b] dihydropyrazine ring, pyridazino [4,5-b] dihydropyrazine A ring etc. are mentioned.

R ¹ is a hydrogen atom, an unsubstituted or substituted alkyl group, an alkylcarbonyl group, a haloalkylcarbonyl group, a halogen atom other than bromine, a cyano group, an alkoxy group, a haloalkoxy group, an aryloxy group, or a nitro group.
Examples of the alkyl group include linear or branched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an amyl group, an isoamyl group, a hexyl group, a pentyl group, an octyl group, a nonyl group, and a 2-ethylhexyl group.
The substituted alkyl group is an aryl group or an alkyl group having 1 to 10 carbon atoms substituted with a nitrogen heterocycle, for example, an aryl group having 6 to 18 carbon atoms or a pyrrole ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, or a pyridazine. A C1-C10 alkyl group substituted with a nitrogen heterocycle such as a ring, indole ring, carbazole ring, and more specifically, a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, a 3-methyl- Examples include 4-phenylbutyl group, 2-ethyl-6-phenylhexyl group, 3-pyridylpropyl group, and 3-indolylpropyl group.
Examples of the alkyl group of the alkylcarbonyl group include linear or branched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. Examples of the alkylcarbonyl group include an acetyl group, a propanoyl group, an octanoyl group, and a 7-methyloctanoyl group.
The halogen atom of the haloalkylcarbonyl group includes fluorine or chlorine, and the alkyl group is a linear or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Groups. Examples of the haloalkylcarbonyl group include trifluoroacetyl group, perfluoroethylcarbonyl group, 6-trifluoromethyloctanoyl group, trichloroacetyl group, perchloroethylcarbonyl group, 6-trichloromethyloctanoyl group and the like.
Examples of the halogen atom include fluorine and chlorine.
Examples of the alkoxy group include linear or branched alkoxy groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. Examples include methoxy group, ethoxy group, isopropoxy group, octyloxy group and the like.
Examples of the haloalkoxy group include linear or branched alkoxy groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, substituted with fluorine or chlorine. Examples include trifluoromethoxy group, pentafluoroethoxy group, hexafluoroisopropoxy group, 2-pentafluoroethylhexyloxy group, trichloromethoxy group, pentachloroethoxy group, hexachloroisopropoxy group, 2-pentachloroethylhexyloxy group, etc. Is mentioned.
Examples of the aryl group of the aryloxy group include an aryl group having 6 to 25 carbon atoms, preferably an aryl group having 6 to 15 carbon atoms, and more preferably an aryl group having 6 to 12 carbon atoms. Examples of the aryloxy group include phenyloxy group, 4-methylphenyloxy group, 4-octylphenyloxy group, 2-methylphenyloxy group, 4-methoxyphenyloxy group, naphthyl group and the like.

n is an integer of 2-4. Among Y ^{1 to} Y ⁴ , it is necessary to include two or more carbon atoms, and therefore the number n of substitutions is an integer of 2 to 4.

R ^{2 to} R ⁴ are a hydrogen atom or an unsubstituted or substituted alkyl group, and the substituent when the substituted alkyl group is an aryl group or a nitrogen heterocycle. Examples of the unsubstituted or substituted alkyl group include the same examples as those for R ¹ described above. R ³ and R ⁴ may be combined to form a ring, for example, a pyrrolidine ring or a piperidine ring. Illustratively, 1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] quinoxalin-4-one derivatives (IIIb), 1,2,3,3a-tetrahydro-5H-pyrrolo [1 , 2-a] -6-Azaquinoxalin-4-one derivative (IIIb-6N), 1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] -9-azaquinoxalin-4-one Derivative (IIIb-9N), 7,8,9,10-Tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one derivative (IIIc), 7,8,9,10-tetrahydro-5H , 6aH-pyrido [1,2-a] -4-azaquinoxalin-6-one derivative (IIIc-4N), 7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a]- And 1-azaquinoxalin-6-one derivative (IIIc-1N).

  The present invention relates to a novel dihydroquinoxalin-2-one derivative (IV).

In the formula, R ¹² is an unsubstituted or substituted alkyl group, and the substituent is an aryl group, a hydroxy-substituted aryl group, an alkoxy-substituted aryl group, a nitrogen alicyclic group, or a nitrogen heterocycle.
Examples of the alkyl group include linear or branched unsubstituted or substituted alkyl groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. Examples of the substituted alkyl group include a benzyl group, a p-hydroxybenzyl group, a 3,4-dihydroxybenzyl group, and a 3-indolyl group.
R ^{13 to} R ¹⁶ are the same or different and are a hydrogen atom, an unsubstituted or substituted alkyl group, an alkylcarbonyl group, a haloalkylcarbonyl group, a halogen atom other than iodine or bromine, a cyano group, an alkoxy group, a haloalkoxy group, an aryloxy group or a nitro group include the same examples as R ¹ above.

Next, the method for producing the dihydroquinoxalin-2-one derivative of the present invention will be described in more detail.
Preferred reaction raw materials used in the method of the present invention are as follows.
The aromatic compound (I) is preferably represented by the general formula (Ia):

[Wherein, X, R ¹ , R ² and n are as defined above. ]
It may be a 2-haloaniline derivative represented by:

  Examples of α-amino acid derivative (II), which is the other raw material, include amino groups such as glycine, alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, and tryptophan that form part of the heterocyclic ring. In addition to no amino acid, the amino acid whose amino group forms part of the heterocyclic ring (IIa):

[Wherein, R ^{5 to} R ⁷ are the same or different and each represents a hydrogen atom, an unsubstituted or substituted alkyl group, or a carbonyl group, and two adjacent groups thereof may form a ring. And a proline derivative represented by (IIb):

[Wherein, R ^{8 to} R ¹¹ are the same or different and each represents a hydrogen atom, an unsubstituted or substituted alkyl group, or a carbonyl group, and two adjacent groups thereof may form a ring. ], The pipecolic acid derivative represented by this.

R ^{5 to} R ¹¹ are the same or different and each represents a hydrogen atom, an unsubstituted or substituted alkyl group, or a carbonyl group. For example, the unsubstituted or substituted alkyl group of R ^{5 to} R ¹¹ preferably has 1 to 10 carbon atoms, preferably Is a linear or branched alkyl group having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Examples of the substituted alkyl group include an aryl group or an alkyl group having 1 to 10 carbon atoms substituted with a nitrogen heterocycle.
Examples of the carbonyl group include an acetyl group, a propanoyl group, an octanoyl group, and a 7-methyloctanoyl group as an alkylcarbonyl group. Examples of the haloalkylcarbonyl group include a trifluoroacetyl group, a perfluoroethylcarbonyl group, and a 6-trifluoromethyloctanoyl group.
Two of R ^{5 to} R ⁷ and R ^{8 to} R ¹¹ that are adjacent to each other may form a ring.

  Among the above raw materials, as a preferable combination of reactions, for example, a product obtained by reacting a 2-bromoaniline derivative (Ia) with an α-amino acid derivative (II) is represented by the general formula (IIIa):

[Wherein, R1 to R4 and n are as defined above. ],
In the case where the α-amino acid derivative is (IIa) or (IIb), the resulting products are respectively represented by the general formula (IIIb):

[Wherein, R ¹ , R ^{5 to} R ⁷ , and n are as defined above. ]
A tetrahydropyrrolo [1,2-a] quinoxalin-4-one derivative represented by the general formula (IIIc):

[Wherein R ¹ , R ^{8 to} R ¹¹ , and n are as defined above]
A pentahydropyrido [1,2-a] quinoxalin-5-one derivative represented by the formula:

  The present invention uses the α-amino acid derivative represented by the general formulas (II), (IIa), and (IIb), which is one of the raw materials, as an optically active substance, thereby producing a product dihydroquinoxalin-2-one derivative. The present invention relates to a method for producing an optically active substance. An optically active α-amino acid derivative can be easily derived from a natural optically active L-amino acid, and therefore can be obtained at a low cost. The optical purity of the product obtained depends on the degree of racemization during the reaction. If the degree of racemization is low, a product having high optical activity is obtained, and if the degree of racemization is high, the optical activity of the resulting product is low. Since the degree of racemization can vary depending on the strength of the base used, the reaction temperature, the reaction time, etc., those skilled in the art can appropriately set reaction conditions for producing a desired optically active substance.

  In the production method of the present invention, the use molar ratio of the aromatic compound (I) to the α-amino acid derivative (II) is not particularly limited, but the molar ratio of (I) to (II) is usually from 1:10 to 10: 1, preferably 1: 3 to 3: 1, particularly preferably 1: 2 to 2: 1. The yield of the product in the examples is expressed as the molar yield of the product dihydroquinoxaline derivative based on the aromatic compound used.

In the production method of the present invention, a catalyst may be used in the reaction step, and preferably a copper catalyst is used. More preferably, the copper catalyst is at least one cuprous halide selected from CuCl, CuBr and CuI. Of these, CuCl is particularly preferred.
A bidentate ligand such as BINOL (1,1′-binaphthol) may be used as a ligand for the catalyst.
The amount of the catalyst to be used is 0.001 to 0.5 mol, preferably 0.03 to 0.50 mol, particularly preferably 0.05 to 0.20 mol, per 1 mol of the aromatic compound represented by the general formula (I) of the raw material. The reaction rate depends on the amount of catalyst used, but if the amount of catalyst exceeds the above range, an effect commensurate with the amount of use cannot be obtained and it is not economical, while if the amount of catalyst is greatly below the above range, It becomes difficult to obtain a desired product without obtaining a sufficient reaction rate.

  In another embodiment of the present invention, a bidentate ligand such as DMEDA (N, N′-dimethylethylenediamine), TMEDA (N, N′-tetramethylethylenediamine), EDA (ethylenediamine) is used as a ligand for the catalyst. It may be used. Of these ligands, DMEDA is particularly preferable.

In a further embodiment of the present invention, the amount of the catalyst used is 0.001 to 0.5 mol, preferably 0.003 to 0.30 mol, more preferably 0.005, per 1 mol of the aromatic compound represented by the general formula (I) of the raw material. It may be ~ 0.20 mole. Although the reaction rate depends on the amount of catalyst used, it can naturally depend on factors such as the reaction temperature, the concentration of the reaction raw material, and the type of reaction solvent. Accordingly, the range of the catalyst usage can vary depending on factors such as the reaction temperature, the reaction raw material concentration, and the type of reaction solvent.
The reaction yield depends on the reaction rate and reaction time, but also depends on the reaction selectivity (the ratio of the reacted raw material added to the target product). The reaction selectivity can vary depending on factors such as reaction temperature, reaction raw material concentration, reaction solvent type, etc., in addition to the type and amount of catalyst used. The copper salt catalyst according to the present invention exhibits excellent reaction selectivity.

  The production method of the present invention is not limited by theory, but can be represented by the following reaction formula.

That is, the present invention is a cyclization reaction involving de-HX reaction and dehydration reaction. Therefore, in the present invention, the entire reaction can be promoted by neutralizing HX eliminated in the reaction step using a base.
The base used here is preferably an inorganic base, more preferably a phosphate or carbonate, and particularly preferably a phosphate. The carbonate is preferably at least one selected from cesium carbonate, potassium carbonate, and sodium carbonate, and the phosphate is at least selected from sodium phosphate, potassium phosphate, rubidium phosphate, and cesium phosphate. One is preferred. In particular, potassium phosphate is suitable as a base for this production method.
The amount of the base used is required to be equal to or greater than the amount that neutralizes the desorbed HX. According to the formula (V), the maximum amount of HX desorbed is equal to the lesser amount of the aromatic compound and α-amino acid derivative that are the reaction raw materials. For example, the use of the aromatic compound When the molar amount is less than the amount of the α-amino acid derivative used, it is preferable to use a molar amount of the aromatic compound and a base equal to or higher than the molar amount, and more preferably about 1 to 3 times the molar amount of the aromatic compound. If the amount of the base used is much higher than this range, for example, when trying to obtain an optically active form, it may cause undesirable results such as causing racemization of the other raw material α-amino acid. .

In the production method of the present invention, it is preferable to use an aprotic polar organic solvent in the reaction step. The aprotic polar organic solvent is not particularly limited, and is at least one selected from, for example, dimethyl sulfoxide, dimethylacetamide, and dimethylformamide.
The aprotic polar organic solvent is particularly suitable for dissolving the raw material α-amino acid derivative, and promotes the reaction to proceed efficiently in a homogeneous system. The aprotic polar organic solvent is preferably used in an amount that is equal to or higher than the amount that uniformly dissolves all raw materials at a predetermined reaction temperature. Usually, the total amount of the starting aromatic compound and α-amino acid is 100 weights. The range is 2000 to 3000 parts by weight, preferably 2500 to 3000 parts by weight, and more preferably 1000 to 3000 parts by weight.

In the production method of the present invention, an aprotic polar organic solvent is charged in a reaction vessel, and a reaction substrate (aromatic compound and α-amino acid derivative) is added and stirred and mixed with stirring. Next, the reaction vessel is replaced with an inert gas such as nitrogen, a base and a copper catalyst are added, and the reaction is continued while stirring. Here, there is no restriction | limiting in particular in the addition order of a solvent, a reaction substrate, a base, and a catalyst. The reaction temperature is usually 25 ° C to 250 ° C, preferably 50 ° C to 200 ° C, particularly preferably 100 ° C to 180 ° C.
The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 12 hours, and after completion of the reaction is confirmed by a thin layer chromatograph (TLC), gas chromatograph (GC), liquid chromatograph (LC) or the like. Then, distilled water or acidic water is poured into the reaction vessel to stop the reaction. The reaction mixture is extracted with an organic solvent such as ethyl acetate or chloroform, and the organic solvent layer is washed with distilled water, saturated aqueous ammonium chloride or the like, and dried over anhydrous sodium sulfate or the like. The desiccant is filtered and the solvent is distilled off to obtain the crude product.

The obtained crude reaction product is purified by a conventional method such as distillation, recrystallization, column chromatography or the like to obtain a purified product, dihydroquinoxalin-2-one derivative.
The obtained dihydroquinoxalin-2-one derivative can be analyzed by H-NMR, ¹³ C-NMR, MS, FAB-MASS, polarimeter, etc. to determine the chemical composition and chemical structure.
The optical purity when the dihydroquinoxalin-2-one derivative is an optically active substance can be determined by a polarimeter, H-NMR, ¹³ C-NMR, HPLC (high performance liquid chromatograph) using a chiral column, or the like.

The novel dihydroquinoxalin-2-one derivative (IV) of the present invention will be described in detail.
The dihydroquinoxalin-2-one derivative, which is a novel compound according to the present invention, has the general formula (IV):

[Wherein R ¹² represents an unsubstituted or substituted alkyl group,
R ^{13 to} R ¹⁶ are the same or different and each represents a hydrogen atom, an unsubstituted or substituted alkyl group, an alkylcarbonyl group, a haloalkylcarbonyl group, a halogen atom other than bromine, a cyano group, an alkoxy group, a haloalkoxy group, an aryloxy group, or a nitro group. It is a group. ]
A dihydroquinoxalin-2-one derivative represented by:

  Examples of the dihydroquinoxalin-2-one derivative represented by the general formula (IV) include

  3- (4-hydroxybenzyl) -3,4-dihydro-1H-quinoxalin-2-one (A-3), 3- (3,4-dihydroxybenzyl) -3,4-dihydro-1H-quinoxaline-2 -On (A-4),

3-sec-butyl-7-trifluoromethoxy-3,4-dihydro-1H-quinoxalin-2-one (A-5), 3-sec-butyl-6-methyl-3,4-dihydro-1H-quinoxaline -2-one (A-6),

Or 3-sec-butyl-2-oxo-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (A-7)

である、ジヒドロキノキサリン-2-オン誘導体が挙げられる。

And dihydroquinoxalin-2-one derivatives.

Next, the optically active dihydroquinoxalin-2-one derivative of the present invention will be described in detail.
That is, the 3-position carbon atom to which the substituent R ¹² is bonded in the dihydroquinoxalin-2-one derivative of the general formula (IV) is an asymmetric carbon, and can be an optically active dihydroquinoxalin-2-one derivative. To obtain an optically active dihydroquinoxalin-2-one derivative having a 3R or 3S configuration with respect to the carbon atom at position 3. For example, when R ¹² is a t-butyl group, the optically active 3R form: (3R) -dihydroquinoxalin-2-one derivative (IVa) or 3S form: (3S) -dihydroquinoxalin-2-one derivative (IVb )

  In addition, (3R) -3-tert-butyl-3,4-dihydro-1H-quinoxalin-2-one (A-2a), (3R) -3-p-hydroxybenzyl- 3,4-dihydro-1H-quinoxalin-2-one (A-3a) and (3R) -3-3,4-dihydroxybenzyl-3,4-dihydro-1H-quinoxalin-2-one (A- 4a), and (3S) -3-tert-butyl-3,4-dihydro-1H-quinoxalin-2-one (A-2b) as 3S form, (3S) -3-p-hydroxybenzyl-3, 4-dihydro-1H-quinoxalin-2-one (A-3b), and (3S) -3-3,4-dihydroxybenzyl-3,4-dihydro-1H-quinoxalin-2-one (A-4b) An optically active dihydroquinoxalin-2-one derivative represented by the above formula is included in the present invention.

  Especially when the 3-position substituent of dihydroquinoxalin-2-one itself contains an asymmetric carbon, for example, when an optically active sec-butyl group is substituted at the 3-position such as A-1, A5-A7 The dihydroquinoxalin-2-one derivative has a total of four optically active forms (A-1a, A-1b, A-1c, A-1d) as two R / S combinations for each asymmetric carbon. Can exist. This can be illustrated as follows for A-1. (2S, 3R) -3-Sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (A-1a), (2R, 3S) -3-Sec-butyl-3,4-dihydro-1H -Quinoxalin-2-one (A-1b), (2S, 3S) -3-Sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (A-1c), (2R, 3R) -3 -Sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (A-1d).

  Of these, A-1a and A-1b, and A-1c and A-1d are in the relationship of enantiomers (enantiomers), while A-1a, A-1c, and A-1d, for example, are There is a stereomer relationship.

  The optically active dihydroquinoxalin-2-one derivative can be produced from a racemate by an optical resolution method based on a conventional method. Or as already demonstrated, it can also manufacture from the aromatic compound shown by general formula (I), and optically active alpha-amino acid according to the manufacturing method of this invention.

Next, a cancer therapeutic agent containing a dihydroquinoxalin-2-one derivative represented by the general formula (III) as an active ingredient will be described.
It has been found that the dihydroquinoxalin-2-one derivative obtained in the present invention exhibits an inhibitory effect on the growth of human cancer cells. The dihydroquinoxaline derivative obtained in the present invention exhibits an excellent inhibitory effect particularly in a cell growth inhibition test against the human cervical cancer cell HeLa.S3 cell line. For example, the following dihydroquinoxalin-2-one derivatives show an excellent cancer cell growth inhibitory effect (the compound number is shown in parentheses):
3-iso-propyl-3,4-dihydro-1H-quinoxalin-2-one (32),
3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (4),
3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (6),
3-sec-butyl-6-cyano-3,4-dihydro-1H-quinoxalin-2-one (23),
3,4-dihydro-1H-quinoxalin-2-one (14),
3- (4-hydroxybenzyl) -3,4-dihydro-1H-quinoxalin-2-one (8),
3- (3,4-dihydroxybenzyl) -3,4-dihydro-1H-quinoxalin-2-one (9),
2-chloro-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (20),
2-methyl-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (24),
2-cyano-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (27),
3-trifluoromethoxy-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (25),
3-nitro-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (28),
4-hydro-1H-quinoxalin-2-one-3-spirocyclohexane (33),
7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] -4-azaquinoxalin-6-one (34),
1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] quinoxalin-4-one (11),
8-Trifluoromethoxy-1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] quinoxalin-4-one (35).

Of the above compounds,
3-iso-propyl-3,4-dihydro-1H-quinoxalin-2-one (32),
3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (4),
2-chloro-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (20),
2-methyl-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (24),
2-cyano-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (27),
1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] quinoxalin-4-one (11) and
8-Trifluoromethoxy-1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] quinoxalin-4-one (35) exhibits a particularly excellent cancer cell inhibitory effect.

  Considering that this test method is generally used as a general screening test for cell growth inhibitory effect on human cancer cells, the dihydroquinoxaline derivative obtained in the present invention may have a growth inhibitory effect on human cancer cells in general. Indicates.

EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
Example 1
Synthesis of 3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (4):

2-Bromoaniline (0.20 g, 1.16 mmol), L-isoleucine (0.31 g, 2.32 mmol), CuCl (11.5 mg, 0.12 mmol), K ₃ PO ₄ (0.49 g, 2.32 mmol) in a 20 ml eggplant-shaped flask Dry DMSO (5 ml) was added, and the mixture was reacted at 120 ° C. for 12 hours under a nitrogen stream. After confirming the completion of the reaction by TLC, distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated ammonium chloride, and dried over anhydrous sodium sulfate. The desiccant was filtered and the solvent was distilled off to give a yellow liquid. This was purified by a silica gel column (hexane: AcOEt = 5: 1) and dried to obtain 0.20 g (0.99 mmol) of quinoxaline derivative 4 as a yellow oily substance. The molar yield of 2-bromoaniline was 85%.

Examples 2-13
The experiment was conducted in the same manner as in Example 1 except that 2.32 mmol of the α-amino acid derivative shown in Tables 2 to 5 was used instead of 2.32 mmol of L-isoleucine in Example 1. The obtained results are shown in Tables 2-5.

Analytical data of melting point, optical rotation, ¹ H-NMR, ¹³ C-NMR, IR, and FAB-MS of the products obtained in Examples 1 to ¹³ are shown in Tables 6 to 11.

Regarding the 3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (4) obtained in the examples, the optical purity thereof was determined from the ¹ H-NMR chart shown in FIG. Were determined.
That is, L-isoleucine used as a raw material has an absolute configuration of (2S, 3S) -L-(+) and has two asymmetric carbon atoms. Therefore, if the α-position of L-isoleucine occurs in the reaction process, the product 3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (4) It becomes a diastereomeric mixture.

  In the chart of FIG. 1, triplet peaks considered to be diastereomeric pairs of methyl groups appeared at δ0.89 ppm and δ0.97 ppm, and the optical purity was determined to be 63% from the integration ratio.

Examples 14-20
Effect of catalyst, solvent, reaction temperature and reaction time on the synthesis of 3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (4):

According to Example 1, 2-haloaniline (1.16 mmol), L-isoleucine (0.31 g, 2.32 mmol), cuprous halide shown in Table 9 (CuX: 0.12 mmol (10 mol) in a 20 ml eggplant-shaped flask. % 2-bromoaniline)), K ₃ PO ₄ (0.49 g, 2.32 mmol) and an aprotic polar solvent (5 ml) were added, and the reaction was carried out at a temperature and time shown in Table 9 under a nitrogen stream. After confirming the completion of the reaction by TLC, distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated ammonium chloride, and dried over anhydrous sodium sulfate. The desiccant was filtered and the solvent was distilled off to obtain the crude product. This was purified by a silica gel column (hexane: ethyl acetate = 5: 1) and dried to obtain 3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (4). The obtained results are shown in Table 12 together with the results of Example 1.

  Examples 21-24

2-bromoaniline derivative (1.16 mmol), L-isoleucine (0.31 g, 2.32 mmol), CuCl (11.5 mg: 0.12 mmol (10 mol% vs. 2-bromoaniline derivative) shown in Table 10 in a 20 ml eggplant type flask ), K ₃ PO ₄ (0.49 g, 2.32 mmol) and dry DMSO (5 ml) were added, and the mixture was reacted under a nitrogen stream for 12 hours at 120 ° C. After confirming the completion of the reaction by TLC, distilled water was added. The reaction was then stopped, and the purified dihydroquinoxaline derivative was obtained in the same manner as in Example 1. The results are shown in Table 11. The yield was expressed based on the molar amount of the 2-bromoaniline derivative. The analytical values of the obtained products are shown in Tables 13-15.

Examples 25-29
For 2-haloaniline, 2 equivalents of picolinic acid, 10 mol% cuprous iodide (CuI) or cuprous bromide (CuBr) and 2 equivalents of bases (cesium carbonate (Cs ₂ CO ₃ ), carbonate In the presence of potassium (K ₂ CO ₃ )), the reaction is carried out in a solvent at 120 to 175 ° C. for 30 minutes to 15 hours, and tricyclic 7,8,9,10-tetrahydro-5H, 6aH-pyrido [1 , 2-a] quinoxalin-6-one (12) was synthesized. The results are shown in Table 16.

a) 2-ハロアニリンに対するmol収率

a) mol yield based on 2-haloaniline

Examples 30-41
For 2-haloaniline derivative or 2-bromo-3-aminopyridine, 2 equivalents of picolinic acid or benz [4,5] picolinic acid, 10 mol% cuprous iodide (CuI) and 2 equivalents of cesium carbonate The reaction was carried out in DMSO in the presence of (Cs ₂ CO ₃ ) at 125 ° C. for 5 hours to synthesize a tricyclic quinoxalin-2-one derivative. The results are shown in Table 17.

  The chemical formula of the obtained product is shown below.

Example 42
2-Bromoaniline (340.2 mg, 1.97 mmol), L-phenylalanine (646.4 mg, 3.94 mmol), CuCl (2.0 mg, 0.02 mmol, 1 mol%), K ₃ PO ₄ (836.3 mg) in a 30 ml eggplant-shaped flask , 3.94 mmol), DMEDA (N, N7-dimethylethylenediamine: 34.0 mg, 0.2 mmol, 20 mol%), dry DMSO (7 ml) were added, sealed with a septum, and reacted at 120 ° C. for 24 hours. After confirming the completion of the reaction by TLC, 5 ml of distilled water was added to stop the reaction. Next, the reaction mixture was extracted with 70 ml of ethyl acetate, and the organic layer was washed with distilled water (7.5 ml × 3) and saturated ammonium chloride (7.5 ml × 3) and dried over anhydrous sodium sulfate. The desiccant was filtered and the solvent was distilled off to obtain yellow crystals. When this was purified by silica gel column (hexane: AcOEt = 7: 3) and dried, 3-benzyl-3,4-dihydro-1H-quinoxalin-2-one (0.47 g, 1.95 mmol, yield) was obtained as white crystals. = 99%).
The analysis results of the product are shown below. The product had high optical activity with [α] _D = −45.90.
[α] _D = −45.90 (c = 0.5, CHCl ₃ );
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.10 (brs, 1H, NH), 7.39-7.20 (m, 6H, Ar), 6.93-6.89 (m, 1H, Ar), 6.86-6.85 (m, 2H , Ar), 6.60 (d, 1H, J = 7.8 Hz, Ar), 4.30 (brs, 1H, NH), 4.06 (dd, 1H, J = 3.2, 11.2 Hz, CH), 3.26 (dd, 1H, J = 2.9, 13.4 Hz, CH ₂ ), 2.85 (dd, 1H, J = 11.2, 13.2 Hz, CH ₂ );
¹³ C NMR (136 MHz, CDCl ₃ ): δ 168.8, 136.8, 132.4, 129.4 (2C), 128.9 (2C), 127.0, 125.4, 124.1, 119.5, 115.5, 114.6, 57.8, 37.5

Examples 43-50
In Example 42, the amount of the catalyst CuCl, the reaction temperature and the reaction time were changed as shown in Table 18, and the ligands shown in Table 18 were added if necessary. Bromoaniline (340.2 mg, 1.97 mmol) was reacted with L-phenylalanine (646.4 mg, 3.94 mmol). After completion of the reaction, the reaction mixture was treated in the same manner as in Example 42 to isolate and acquire 3-benzyl-3,4-dihydro-1H-quinoxalin-2-one. The obtained results are shown in Table 18 together with Example 42.

Examples 51-56
Using catalyst CuCl (1 mol% based on 2-haloaniline) in the same manner as in Example 47 except that the types of 2-haloaniline (1 equivalent) and α-amino acid (2 equivalents) were changed as shown in Table 19, anhydrous The reaction was performed in DMSO at 110 ° C. for 12 hours. After completion of the reaction, the reaction mixture was post-treated in the same manner as in Example 42 to obtain and obtain dihydro-1H-quinoxalin-2-one derivatives shown in Table 19. The obtained results are shown in Table 19.

Example 57
The human cervical cancer cell HeLa.S3 cell line was used to assay the cell growth inhibitory activity of dihydroquinoxaline derivatives. The obtained results are shown in Tables 20-22.

  The production method according to the present invention can be used for the production of dihydroquinoxalin-2-one derivatives that are useful as pharmaceuticals, agricultural chemicals, functional materials, etc., or as intermediates thereof. The novel dihydroquinoxalin-2-one derivatives according to the present invention can themselves be used as pharmaceuticals, agricultural chemicals or functional material substances, etc., or as intermediates thereof. The cancer therapeutic agent containing the dihydroquinoxalin-2-one derivative of the present invention as an active ingredient can contribute to the treatment of cancer such as human cervical cancer.

Claims (20)

Formula (I):

[Wherein X is a bromine, iodine or chlorine atom, Y ^{1 to} Y ⁴ are the same or different and are a carbon atom or a nitrogen atom (provided that at least two of Y ^{1 to} Y ⁴ are carbon atoms) ),
R ¹ is a hydrogen atom, an unsubstituted or substituted alkyl group, an alkylcarbonyl group, a haloalkylcarbonyl group, iodine, a halogen atom other than bromine, a cyano group, an alkoxy group, a haloalkoxy group, an aryloxy group, or a nitro group,
R ² is a hydrogen atom, an unsubstituted or substituted alkyl group, an acyl group, or a sulfonyl group, and n is an integer of 1 to 4. ]
An aromatic compound represented by
General formula (II):

[Wherein R ³ represents a hydrogen atom or an unsubstituted or substituted alkyl group;
R ⁴ is a hydrogen atom or an unsubstituted or substituted alkyl group,
R ³ and R ⁴ may be combined to form a ring. ]
A step of reacting an α-amino acid derivative represented by the following formula in the presence of a cuprous salt catalyst and a base:
General formula (III):

[Wherein, Y ^{1 to} Y ⁴ , R ^{1 to} R ⁴ and n are as defined above. ]
The manufacturing method of the dihydroquinoxalin-2-one derivative represented by these.   The manufacturing method of Claim 1 whose cuprous salt is cuprous chloride.   The manufacturing method of Claim 1 or 2 whose usage-amount of cuprous salt is 0.001-0.5 mol on the basis of 1 mol of aromatic compounds shown by general formula (I).   The production method according to claim 1, wherein the base is a phosphate.   5. The composition further comprises at least one bidentate ligand selected from DMEDA (N, N′-dimethylethylenediamine), TMEDA (N, N′-tetramethylethylenediamine) or EDA (ethylenediamine). The manufacturing method as described in any one of these.   The production method according to claim 5, wherein the bidentate ligand is DMEDA (N, N'-dimethylethylenediamine). Aromatic compounds
General formula (Ia):

[Wherein, X, R ¹ , R ² and n are as defined above. ]
The production method according to any one of claims 1 to 6, which is an α-bromoaniline derivative represented by the formula: Aromatic compounds
General formula (Ia-1):

[Wherein, X, R ¹ , R ² and n are as defined above. ]
The production method according to any one of claims 1 to 6, which is a 2-amino-3-bromopyridyl derivative represented by the formula: The aromatic compound is an α-bromoaniline derivative;
α-amino acid is
General formula (IIa):

[Wherein, R ^{5 to} R ⁷ are the same or different and each represents a hydrogen atom, an unsubstituted or substituted alkyl group, or a carbonyl group, and two adjacent groups thereof may form a ring. ]
The production method according to any one of claims 1 to 6, which is a proline derivative represented by the formula: The aromatic compound is an α-bromoaniline derivative;
α-amino acid is
Formula (IIb):

[Wherein, R ^{8 to} R ¹¹ are the same or different and each represents a hydrogen atom, an unsubstituted or substituted alkyl group, or a carbonyl group, and two adjacent groups thereof may form a ring. ]
The production method according to any one of claims 1 to 6, which is a pipecolic acid derivative represented by the formula:   The α-amino acid derivative represented by the general formulas (II), (IIa) and (IIb) is an optically active substance, and the product dihydroquinoxalin-2-one derivative is an optically active substance. The manufacturing method as described in any one of these.   The production method according to claim 1, wherein the reaction step uses an aprotic polar organic solvent.   The production method according to claim 12, wherein the aprotic polar organic solvent is at least one selected from dimethyl sulfoxide, dimethylacetamide and dimethylformamide, tetrahydrofuran and acetonitrile. Formula (IV):

[Wherein R ¹² represents an unsubstituted or substituted alkyl group,
R ^{13 to} R ¹⁶ are the same or different and are a hydrogen atom, an unsubstituted or substituted alkyl group, an alkylcarbonyl group, a haloalkylcarbonyl group, a halogen atom other than iodine or bromine, a cyano group, an alkoxy group, a haloalkoxy group, an aryloxy group Or it is a nitro group. ]
A dihydroquinoxalin-2-one derivative represented by: Dihydroquinoxalin-2-one derivatives include 3-tert-butyl-3,4-dihydro-1H-quinoxalin-2-one (A-1), tert-butyl-3,4-dihydro-1H-quinoxaline- 2-on (A-2),

3- (4-hydroxybenzyl) -3,4-dihydro-1H-quinoxalin-2-one (A-3), 3- (3,4-dihydroxybenzyl) -3,4-dihydro-1H-quinoxaline-2 -On (A-4),

3-2Butyl-7-trifluoromethoxy-3,4-dihydro-1H-quinoxalin-2-one (A-5), 3-2Butyl-6-methyl-3,4-dihydro-1H-quinoxaline -2-one (A-6),

Or 3-2 butyl-2-oxo-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (A-7)

The dihydroquinoxalin-2-one derivative according to claim 14, wherein   The dihydroquinoxalin-2-one derivative according to claim 14 or 15, wherein the dihydroquinoxalin-2-one derivative is an optically active substance. General formula (III):

[Wherein Y ^{1 to} Y ⁴ , R ^{1 to} R ⁴ and n are as defined above. ]
A therapeutic drug for cancer comprising a dihydroquinoxalin-2-one derivative (III) represented by the formula: The dihydroquinoxalin-2-one derivative (III) is
3-iso-propyl-3,4-dihydro-1H-quinoxalin-2-one (32),
3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (4),
3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (6),
3-sec-butyl-6-cyano-3,4-dihydro-1H-quinoxalin-2-one (23),
3,4-dihydro-1H-quinoxalin-2-one (14),
3- (4-hydroxybenzyl) -3,4-dihydro-1H-quinoxalin-2-one (8),
3- (3,4-dihydroxybenzyl) -3,4-dihydro-1H-quinoxalin-2-one (9),
2-chloro-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (20),
2-methyl-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (24),
2-cyano-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (27),
3-trifluoromethoxy-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (25),
3-nitro-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (28),
4-hydro-1H-quinoxalin-2-one-3-spirocyclohexane (33),
7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] -4-azaquinoxalin-6-one (34),
1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] quinoxalin-4-one (11) and
8-trifluoromethoxy-1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] quinoxalin-4-one (35) (the compound number is shown in parentheses)
The cancer therapeutic agent according to claim 17, which is at least one compound selected from the group consisting of: The dihydroquinoxalin-2-one derivative (III) is
3-iso-propyl-3,4-dihydro-1H-quinoxalin-2-one (32),
3-sec-butyl-3,4-dihydro-1H-quinoxalin-2-one (4),
2-chloro-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (20),
2-methyl-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (24),
2-cyano-7,8,9,10-tetrahydro-5H, 6aH-pyrido [1,2-a] quinoxalin-6-one (27),
1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] quinoxalin-4-one (11) and
8-trifluoromethoxy-1,2,3,3a-tetrahydro-5H-pyrrolo [1,2-a] quinoxalin-4-one (35) [in parentheses indicate compound numbers. ]
The cancer therapeutic agent according to claim 17, which is at least one compound selected from the group consisting of:   The cancer therapeutic agent according to any one of claims 17 to 19, wherein the cancer is human cervical cancer.

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