WO1999012884A1 - 4-substituted benzoic acid derivatives and carcinostatics containing the same as the active ingredient - Google Patents

Abstract

Novel compounds represented by general formula (I) which do not act on normal cells but detransform specifically cells transformed by various oncogenes, salts thereof, or hydrates of the same, wherein G1 represents OR?1 or NR2R3¿ (wherein R?2 and R3¿ are the same or different and each represents hydrogen, lower alkyl or hydroxy, or R?2 and R3¿ may form together with the nitrogen atom adjacent thereto a nitrogen-containing heterocycle); G¿2? represents hydrogen or halogeno; when G3 is hydrogen, hydroxy or lower alkylcarbonyloxy, then G4 represents lower alkyl, or G3 and G4 may form together -O-CH2-; and G5 represents OR?4 or NR5R6¿ (wherein R5 represents hydroxy or an optionally substituted cyclic group; and R6 represents hydrogen or lower alkyl).

Description

 Specification

(4) Monosubstituted benzoic acid derivatives and anticancer agents containing the same as an active ingredient

 TECHNICAL FIELD The present invention relates to a novel 4-substituted benzoic acid derivative and an anticancer agent containing the same. Background art

 In recent years, the development of anticancer drugs has made remarkable progress with the discovery of oncogenes. However, conventional anticancer drugs have been searched for as an index to inhibit the activity of factors involved in DNA synthesis, RNA synthesis, protein synthesis, or cell growth, and thus often inhibit the growth of normal cells at the same time. Was.

 Therefore, development has been promoted with the discovery of a substance that inhibits the growth of cancer cells but does not suppress the growth of normal cells.6 Ras was activated by mutating the first amino acid from glutamine to leucine. It was found that administration of azathicin to NIH 3 T 3 cells and normal NIH 3 T 3 cells transformed by introducing an oncogene specifically inhibited the growth of the transformed cells. At the same time, it was observed that about 85% of the transformed cells were converted into flat repartant cells resembling the morphology of normal cells after azachi oral treatment. In revertant cells, it is thought that the expression of genes involved in conversion to normal cells was activated (cancer and chemotherapy 17 (3): part-II, 500-501, 1990). If a drug that does not act on normal cells and specifically detransforms cells transformed with an oncogene is found, it is considered that it can be an excellent anticancer drug, and the development of such compounds is expected. It is rare.

By the way, some oncogenes are represented by dar, src, ras, myc, etc. Group. However, many of these oncogenes were found to transduce a single oncogenic signal pathway rather than transmitting cancer signals in parallel (LevitzkiA. & Gazit A. , Science, 261, 1782, (1995)). Specifically, it is a pathway such as growth factor (PDGF: platelet-derived growth factor) → receptor tyrosine kinase → …… → ras → raf → …… → fos → --- → canceration. And, no matter what factor is inhibited, this signaling pathway is inhibited, so each factor in this pathway can be a target for anticancer drugs. The sis oncogene targeted this time is a mutant of a growth factor, and its signal is thought to lead to canceration through the above pathway (Bishop, JM Cell, il, 23, (1985) )). Substances that inhibit the signal from the sis oncogene include not only those that directly act on the sis oncogene product, but also those that act on downstream factors. It is thought that these inhibitors specific for canceration signals will lead to anticancer drugs with high specificity for cancer.

 Trichostatins A, B, and C were isolated from the culture of actinomycetes (streptmyces hygro scopicus) in 1976-78, and their structure was determined and acted on molds such as Trichophyton and Epidermophyton. (N. Tsuj i, M. Kobayash i, K. Nagashima, Y. Waki saka, K. Koizumi, J. Antibiot., 29, 1 (1976), N. Tsuj i, M. Kobayashi, ibid., 31, 939 (1978)).

However, around 1985, it was discovered that trichostin C had a Friend leukemia cell differentiation-inducing activity (M. Yoshida, Y. Iwamoto, T. Uozumi, T. Beppu, Agric. Biol. Chem., 49, 563 (1985), Japanese Patent Application Laid-Open No. 61-17653, and the differentiation-inducing activity of trichostatin acid and trichostatin A has been found (H Morioka, M. Ishihara, M. Takezawa, K. Hi rayama, E. Suzuki, Y. Komada, H. Shibai, ibid., 49, 1365 (1985), Japanese Unexamined Patent Publication No. 60-14995 20). Furthermore, it is also known to inhibit the growth of NIH3T3 cells transformed by the sis gene (K. Sugita, K. Koizumi, H. Yoshida, Cancer Research., 52, 168-172). , January 1, 1992). As an analog of trichostatin, the following formula (A)

It is known that the dimethylaniline derivative represented by (1) has a cancer cell differentiation-inducing activity (Japanese Patent Laid-Open Publication No. 3-291256).

 Equation (B):

It has been known that the dimethylaniline derivative represented by the formula (1) has a cancer cell differentiation-inducing activity (Japanese Patent Laid-Open No. 3-291256).

 Further, Japanese Patent Application Laid-Open No. 2-124883 discloses an isoflavone derivative having an antioxidant effect. Disclosure of the invention

 An object of the present invention is to provide a novel compound that does not act on normal cells and specifically detransforms cells transformed with various oncogenes, and an anticancer agent containing the same.

The present inventors have conducted intensive studies in view of the above, and as a result, have found that the novel compound has an activity of specifically detransforming cells transformed with a cancer gene, and have completed the present invention. Reached. That is, the present invention

 (1) General formula (I)

[Wherein, is OR ¹ (where R ¹ represents hydrogen or lower alkyl) or NR ² R ³ (where R ² and R ³ are the same or different and are hydrogen, lower alkyl or hydroxyl group) Or R ² and R ³ may together form a nitrogen-containing heterocyclic ring with an adjacent nitrogen atom); G ₂ is hydrogen or halogen; G ₃ and G ₄ are such that G ₃ is hydrogen or a hydroxyl group. Or G ₄ is a lower alkylcarbonyloxy and G ₄ is lower alkyl, or G ₃ and G ₄ may together form one O—CH ₂ —; G ₅ is OR ⁴ ( Here, R ⁴ represents hydrogen or lower alkyl) or NR ⁵ R ⁶ (where R ⁵ represents a hydroxyl group or an optionally substituted cyclic group, and R ⁶ represents hydrogen or lower alkyl). (However, but is and G ₅ is oR ¹ unless an oR ⁴⁾ compound or a salt thereof] the Hydrates thereof,

 (2) The compound of (1), wherein Gi is methoxy, dimethylamino or pyrrolidine-1-yl, a salt thereof, or a hydrate thereof,

(3) G ₅ is a hydroxyl group or NR ⁵ R ⁶ (where R ⁵ represents a hydroxyl group or a cyclic group optionally substituted with a hydroxyl group); the compound according to (1), a salt thereof, or a salt thereof; Hydrate,

(4) The compound according to (1), wherein G ₄ is methyl, a salt thereof, or a hydrate thereof,

(5) is NR ² R ³ and G ₃ and G ₄ together form —O—CH ₂ —, or the compound according to (1), or a salt or hydrate thereof, and

(6) General formula (I):

[Wherein, G QR ¹ (where R ¹ represents hydrogen or lower alkyl) or NR ² R ³ (where R ² and R ³ are the same or different and are hydrogen, lower alkyl or hydroxyl group) Or R ² and R ³ may together form a nitrogen-containing heterocyclic ring with an adjacent nitrogen atom): G ₂ is hydrogen or halogen; G ₃ and G ₄ are such that G ₃ is hydrogen, hydroxyl Or G ₄ is a lower alkylcarbonyloxy and G ₄ is a lower alkyl, or G ₃ and G ₄ may together form one O—CH ₂ —; G ₅ is 〇R ⁴ (Where R ⁴ represents hydrogen or lower alkyl) or NR 5 R ⁶ (where R ⁵ represents a hydroxyl group or an optionally substituted cyclic group, and R ⁶ represents hydrogen or lower alkyl). And a salt thereof or a hydrate thereof.

 The term “lower” as used herein, unless otherwise specified, refers to a straight-chain or branched group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Represents

Specific examples of the "halogen" represented by G _2, fluorine, chlorine, bromine and the like. Particularly, fluorine and chlorine are preferred.

Specific examples of “lower alkyl” used herein, for example, “lower alkyl” represented by G ₄ , R ¹ > R ² , R ³ , R ⁴ and R ⁶ include methyl, ethyl, propyl Isopropyl, n-butyl, t-butyl and the like. Of these, methyl is particularly preferred.

Examples of the cyclic group of the “optionally substituted cyclic group” for R ⁵ include an aryl group, a heterocyclic group and an alicyclic hydrocarbon ring group.

The above aryl group is a heteroatom (oxygen, nitrogen, (Sulfur). Among them, an aryl group having 6 to 20 carbon atoms is preferable, and specific examples thereof include, for example, phenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl, etc.), anthryl, phenanthryl, acenafurenyl, Fluorenyl (9-fluorenyl, 1-fluorenyl) and the like. Of these, phenyl is particularly preferred.

The above heterocyclic group means a heterocyclic group containing at least one heteroatom of oxygen, sulfur and nitrogen as atoms constituting a ring system, and is preferably an aromatic heterocyclic group, Examples include an aromatic monocyclic heterocyclic group, a bicyclic or tricyclic fused aromatic heterocyclic group, and the like. Specific examples of the monocyclic heterocyclic group include, for example, furyl, phenyl, pyronyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 1,3,4,1-oxadiazolyl , Frazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3—triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyridyl Midinyl, pyrazinyl, triazinyl, quinolyl and the like. Specific examples of the bicyclic or tricyclic fused aromatic heterocyclic group include, for example, benzofuranyl, isobenzofuranyl, benzo [b] thenyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, and benzoxoxa. Zolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzozotriazolyl, quinolyl, isoquinolyl, cinnonyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pterizinyl, carbazolinyl , Α_carbolinyl, / 3-carbolinyl, r-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, fenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, Pyridazinyl, pyrazodine [1,5—a] pyridyl, imidazo [1,2—a] pyridyl, imidazo [1,5—a] pyridyl, imidazo [1,2— b] Pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-a] pyridazinyl and the like.

 The above-mentioned alicyclic hydrocarbon ring group means a saturated or unsaturated cyclic hydrocarbon group having no aromaticity, and includes, for example, a cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). Xyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [ 3, 3.1] nonyl, bicyclo [4.2.1] noel, bicyclo [4.3.1] decyl, adamantyl, etc., cycloalkenyl group (eg, 2-cyclopentyl-1-yl, 3-cyclopentyl) — 1 —yl, 2-cyclohexene-1-yl, 3-cyclohexene-1-yl, etc., cycloalkadienyl group (eg, 2,4-cyclopentadiene-1-yl, 2, To 4-cyclo Xadiene 11-yl, 2,5-cyclohexadiene 1-yl, etc.).

The substituent of the “optionally substituted cyclic group” for R ⁵ is preferably an acyclic group (a group other than the above-mentioned cyclic groups), and specific examples thereof include, for example, a halogen, a hydroxyl group , Lower alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), lower alkylcarbonyloxy (eg, acetyloxy, etc.), lower alkyl, carbonyl group, lower alkyloxycarbonyl, lower alkylcarbonylamino Group, N-mono-lower alkyl carbamoyl group, N-di-lower alkylcarbamoyl group, N-hydroxycarbamoyl group, N-hydroxy-N-lower-alkyl rubamoyl group, N-phenylcarbamoyl group, N- Substituted phenyl carbamoyl, cyano, amino, mono-lower alkylamino, di-lower alkyl Arylamino group, an amidino group, an azide group, a nitro group, a nitroso group, a mercapto group, a lower alkylthio group, etc. sulfo group. Among them, particularly, hydroxyl group, lower alkyloxy group, rubamoyl group, N-mono-lower alkyl group, rubamoyl group, N- Di-lower alkyl rubamoyl, N-hydroxycarbamoyl, N-hydroxy-N-lower alkyl rubamoyl, N-phenylcarbamoyl, N-substituted phenylcarbamoyl, amino, mono-lower alkylamino And di-lower alkylamino groups are preferred. If there are substituents, the number is 1 to 3, preferably 1. Depending on the type of cyclic group, there is a preferred substituent position (for example, para position for phenyl), but it is not particularly limited.

Specific examples of the substituted cyclic group represented by R ^5, for example, 4-hydroxy-phenylene le, 4- main Tokishifue sulfonyl, 4 one ethoxy-phenylalanine, 4 one n- propoxy-phenylalanine, 4 one n- Butokishifueniru 4-Acetyloxyphenyl, 4-methylphenyl, 4-ethylphenyl, 4-n-propylphenyl, 4-n-butylphenyl, 4-potoxyphenyl, 4-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl , 4 rubamoylphenyl, 4-N-monomethylcarbamoylphenyl, 4-N-monoethylcarbamoylphenyl, 4-N-mono-n-propylcarbamoylphenyl, 4-N-mono-n- Butylcarbamoylphenyl, 4-N-dimethylcarbamoylphenyl, 4-N-Jetylcarbamoylphenyl, 4-N-di-n-propyl-propylbamoylphenyl , 4-N-di-n-butylcarbamoylphenyl, 4-N-hydroxycarbamoylphenyl, 4-N-hydroxy-1-N-methylcarbamoylphenyl, 4-N-hydroxy-N-ethylcarbamoylphenyl Phenyl, 4-N-hydroxy-N-n-propyl-propyl-rubamoylphenyl, 4-N-hydroxy-N-n-butylcarbamoylphenyl, 4-aminophenyl, 4-monomethylaminophenyl, 4-mono 4-ethyl-aminophenyl, 4-mono-n-propylaminophenyl, 4-mono-n-butylphenyl, 4-dimethylaminophenyl, 4-dimethylaminophenyl, 4-di-n-propylaminophenyl, 4 Di-n-butylaminophenyl, 4-methylcarbonylaminophenyl, 4-ethylcarbonylaminoaminophenyl, 4-n-propylcarbonylaminophenyl, 4 n- butyl force Lupo sulfonyl § Minofu enyl, 4-N- (4- arsenate Dorokishifueniru) force Rubamoiru 4-monosubstituted phenyl such as phenyl.

Examples of the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” formed by those represented by NR ² R ³ include, for example, pyrroyl 11-yl, indole-11-yl, Power basazole—9—yl, imidazole—1—yl, pyrazol—1—yl, benz [d] Imidazole—1—yl, benz [b] pyrazole-1—yl, triazole — 1-yl, benztriazole— 1-yl, purine— 1—yl, pyrrolidine-1—yl, pyrroline—1—yl, imidazolidin— 1—yl, imidazoline-1—yl, Examples include virazolidine-11-yl, pyrazoline-1-1-yl, piperidine-1-1-yl, indolin-1-1-yl, piperazine-111-yl, and morpholin-4-yl. Among them, in particular, pyrroyl-1-yl, imidazole-1-yl, pyrazol-11-yl, triazol-11-yl, pyrrolidine_1-yl, pyrroline-1-yl , Imidazolidin-1 -yl, imidazoline-1 -yl, virazolidin-1-yl, pyrazoline-1 -yl, pyridin-1 -yl, piperazine-1-yl, morpholine — A monocyclic nitrogen-containing heterocyclic group such as —yl is preferred.

The substituent of the `` optionally substituted nitrogen-containing heterocyclic group '' formed by NR ² R ³ is preferably an acyclic group, and specific examples thereof include, for example, halogen, hydroxyl, Lower alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), lower alkylcarbonyloxy (eg, acetyloxy, etc.), lower alkyl, carboxyl group, lower alkoxycarbonyl group, lower alkylcarbonyloxyamino group, carbamoyl group, N —Mono-lower alkyl rubamoyl group, N-di lower alkyl rubamoyl group, N-hydroxycarbamoyl group, N-hydroxy-1-N-lower alkyl rubamoyl group, N-phenylcarbamoyl group, N-substituted phenylcarbamoyl group, Cyano group, amino group, mono-lower alkylamino group, di-lower amino group Examples thereof include a fluoramino group, an amidino group, an azide group, a nitro group, a nitroso group, a mercapto group, a lower alkylthio group, and a sulfo group. Among them, hydroxyl group, Lower alkyloxy, rubamoyl group, N-mono lower alkyl rubamoyl group, N-di-lower alkyl rubamoyl group, N—hydroxycarbamoyl group, N—hydroxyl N-lower alkyl rubamoyl group, N-phenyl Preferred are a rucarbamoyl group, an N-substituted phenylcarbamoyl group, an amino group, a mono-lower alkylamino group, and a di-lower alkylamino group. The number of substituents, if any, is one to three, preferably one. The position of the substituent is not particularly limited.

Specific examples of the substituted nitrogen-containing heterocyclic group formed by them represented by NR ² R ³ include, for example, 3 -methyl-pyrrole- 1 -yl, 3 -methyl-imidazo- 1 -yl, 3- Methyl-pyrazole — 1-yl, 4-methyl-triazole — 1-yl, 3-methyl-piperidine 1-yl, 3-methyl-piperyl — 1-yl, 3-methylimid Dazolidine-1-yl, 2-methyl-imidazoline-1-yl, 3-methyl-birazolidine-1-yl, 3-methyl-pyrazoline-1-yl, 4-methyl-piperidine-1--1 4-yl, 4-methyl-piperazine- 1-yl, 2-methyl-morpholine- 4-yl, 3-amino-pyrrol- 1-yl, 4-amino-imidazoyl- 1-yl, 4-Amino-pyrazole-1-yl, 4-Amino-triazole-1-yl, 3- Amino-pyrrolidine- 1-yl, 3-amino-pyrroline-l-yl, 4-amino-imidazoline-l-l-yl, 2-amino-imidazoline-l-yl, 3-amino-pyrazolidine — 1-yl, 4-amino-pyrazoline-1 1-yl, 4-amino-1 piperidine-1 1-yl, 2—amino-1-piperazine-1 1-yl, 2—amino-morpholine-4—yl, etc. Is mentioned.

The “salt” of the target compound (I) of the present invention is preferably a pharmacologically acceptable salt, for example, a salt with a base (a salt with an inorganic base, a salt with an organic base) or a salt with an acid Salts (salts with inorganic acids, salts with organic acids), salts with basic or acidic amino acids, and the like are included. Examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt, a magnesium salt, and a barium salt, and an aluminum salt and an ammonium salt. As a salt with an organic base, Salts with trimethylamine, triedulamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N 'dibenzylethylenediamine, and the like are included. Examples of salts with inorganic acids include salts with hydrochloric acid, hydrofluoric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, perchloric acid, hydroiodic acid, and the like. Salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, cunic acid, succinic acid, malic acid, mandelic acid, ascorbic acid, lactic acid, dalconic acid, methanesulfonic acid, Salts with p-toluenesulfonic acid, benzenesulfonic acid and the like can be mentioned. Salts with basic amino acids include salts with arginine, lysine, orditin, and salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

 The "hydrate" of the target compound (I) of the present invention is preferably a pharmacologically acceptable hydrate, and also includes a hydrate. Specific examples include monohydrate, dihydrate, hexahydrate and the like.

 In addition, the compound group especially preferable as a compound of this invention is shown below.

 General formula (C):

[Wherein, NR ² R ³ (where R ² and R ³ are the same or different and are hydrogen, lower alkyl or hydroxyl group); G ₅ is OR ⁴ (where R ⁴ is hydrogen or lower) Or NR ⁵ R ⁶ (where R ⁵ represents a hydroxyl group and R ⁶ represents hydrogen or lower alkyl)], a salt thereof, or a hydrate thereof.

General formula (D):

Wherein, in the formula, OR ¹ (where R ¹ represents hydrogen or lower alkyl) or NR ² R ³ (where R ² and R ³ are the same or different and are hydrogen, methyl or hydroxyl, or R ² and R ³ may together form a monocyclic nitrogen-containing heterocycle with adjacent nitrogen atoms); G ₂ is hydrogen or halogen; G ₅ is 〇R ⁴ (where R ⁴ represents hydrogen or lower alkyl) or NR ⁵ R ⁶ (where R ⁵ represents a hydroxyl group or a phenyl group which may be substituted, and R ⁶ represents hydrogen or lower alkyl). Its salts or their hydrates. BEST MODE FOR CARRYING OUT THE INVENTION

 The compound represented by the general formula (I) is a novel compound. Preferred examples of the compound represented by the general formula (I) or the following compounds as preferred examples for inclusion in the anticancer agent of the present invention include the following compounds. .

 4- [1- (4-dimethylaminobenzoyl) ethyl] ethyl benzoate (Compound No. 12: Example 1),

 4- [1- (4-Methoxybenzoyl) ethyl] ethyl benzoate (Compound No. 13: Example 2), 4- [1- (3-Fluoro mouth-4-pyrrolidinobenzoyl) ethyl] benzoic acid Ethyl (Compound No. 14: Example 3),

 Sodium 4- [1- (4-dimethylaminobenzoyl) ethyl] benzoate (Compound No. 15: Example 4),

4- [1- (4-Dimethylaminobenzoyl) ethyl] benzoic acid (Compound No. 16: Example 5), 4- [1- (4-Methoxybenzoyl) ethyl] benzoic acid (Compound No. 17: Example) 6) 4- [1- (3-Fluoro-4-pyrrolidinobenzoyl) ethyl] benzoic acid (Compound No. 18: real Example 7),

 4- [1- (4-Dimethylaminobenzoyl) ethyl] benzoic acid (Compound No. 19: Example 8) N-methyl-4- [1- (4-dimethylaminobenzoyl) ethyl] benzohydroxamic acid ( Compound number 20: Example 9),

4- [1- (4-methoxybenzoyl) ethyl] benzohydroxamic acid (Compound No. 21: Example 10),

 N-methyl-4-[(4-methoxybenzoyl) ethyl] benzohydroxamic acid (Compound No. 22: Example 11),

 4- [1- (3-Fluoro mouth-4-pyrrolidinobenzoyl) ethyl] benzohydroxamic acid 84-0276 (Compound No. 23: Example 12),

 N-methyl-4-[((3-fluoro-4--4-pyrrolidinobenzoyl) ethyl] benzohydroxamic acid 84-0277 (Compound No. 24: Example 13);

 4- [1- (4-dimethylaminobenzoyl) ethyl] (4-hydroxy) phenylpenzamide (Compound No. 26: Example 14),

4- [1- (4-methoxybenzoyl) ethyl] -N- (4-hydroxy) phenylbenzoamide ({conjugation compound number 27: Example 15);

 4- [1- (4-dimethylamino-2-hydroxybenzoyl) ethyl] ethyl benzoate (Compound No. 32: Example 16),

 4- [1- (2-acetoxy-4-dimethylaminobenzoyl) ethyl] ethyl benzoate (Compound No. 33: Example 17),

 4- (7-dimethylamino-4-oxo-chroman-3-yl) ethyl benzoate (Compound No. 36: Example 18),

 4- (7-dimethylamino-4-oxo-chroman-3-yl) benzoic acid (Compound No. 37: Example 19),

4- (7-Dimethylamino-2,3-dihydrochroman-3-yl) benzohydroxamic acid (Compound No. 38: Example 20). The compound (I) of the present invention can be produced by known methods, for example, by the methods described below and specifically shown in Examples.

Hereinafter, the compound (I) (1) G ₃ is hydrogen, compound G ₄ is lower alkyl (I one A;), (2) G 3 is hydroxy, compound G ₄ is lower alkyl (I one B), (3) a compound in which G ₃ is a lower alkyl group, ponylonoxy, and G ₄ is a lower alkyl (I—C), (4) When G ₃ and G ₄ come together — O— CH ₂ — to form a compound (I _ D), (5 ) G 5 is hydroxy compound (I one E) and (6) compound G ₅ is NR ⁵ R ⁶ - broken down by (I F), i.e. The manufacturing methods 1 to 6 will be described.

Here, depending on the types of the substituents G and G 3> G ₅ in these production methods 1 to 6, if the production methods described below have reactivity, the protection of the substituents G, G ₃ and G ₅ is appropriate. Introduce a group. As the protecting group, generally known types can be used, and the same applies to the removal method and the like.

(1) Preparation of compound (I-A) wherein G ₃ is hydrogen and G ₄ is lower alkyl

 (Production method 1)

[Wherein, G ₂ , G ₅ and X are as defined above, X is halogen, and R is lower alkyl]

The target compound (I-A) is, for example, as described in a publicly known document (Japanese Patent Application Laid-Open No. 3-291264), in the form of an aldehyde (II) in the form of trimethylsilyl cyanide or the like. It can be produced by an alkylation reaction with a halide (III) through a step of reacting a reaction activator.

 The above-mentioned production method 1 includes, for example, a step 1 for activating the aldehyde compound (II), a step 2 for reacting with the octogenide (III), and a step 3 for removing a group corresponding to the reaction activator. Can be manufactured.

 Examples of the activator for the aldehyde compound (II) include, for example, an O-silylation group having a trimethylsilyl group (TMS :), t-butyldimethylsilyl group, t-butyldiphenylsilyl group or triisopropyl group. Examples of such a reagent include a reagent having a t-butyl group, a trityl group, a benzyl group, a P-methoxybenzyl group, or the like.

 Hereinafter, a method for producing the compound (I) of the present invention using trimethylsilyl cyanide as a reagent will be described.

 (step 1 )

[Where G! And G ₂ are as defined above.]

The cyanide compound (IV) can be obtained, for example, from known literature (MHayashi, TMatsuda, NOguni, J. Chem Soc, Chem Commun 1990 (19), pl364, 1990, Torii S, Inokuchi T, Takagishi S, Horike H, Kuroda H, Undeyama K, B Chem Soc JPN 60 (6), 2173-2188 (1987), DA Evans, LK Truesdale, and GL Carroll, JCS Chem. Comm., 55-57 (1973)) The compound (II) is reacted with trimethylsilyl cyanide to produce the compound as described above, or as described in a known literature (R Yoneda, T Kurihara, et al, Synthesis (12), pl054, 1986). It can be produced by reacting both trimethylsilyl halide and cyanide such as lithium cyanide, sodium cyanide, lithium cyanide, etc. it can.

 Examples of the catalyst include anhydrous zinc iodide, zinc chloride, tetramethoxyaluminum potassium, zinc cyanide and the like.

 The reaction temperature is −78 ° C. to 70 °, preferably 0 ° (: to 25 ° C.).

 The reaction time varies depending on the compound, but is from 0.03 hours to 48 hours, preferably from 2 hours to 6 hours.

 Solvents that can be used include ether solvents (eg, tetrahydrofuran, getyl ether, dioxane, etc.), halogenated hydrocarbons (eg, tetrachloromethane, dichloromethane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.) ), Saturated hydrocarbons (eg, heptane, hexane, etc.), etc., or a mixed solvent thereof.

 Trimethylsilyl cyanide is used in an amount of 1.0 relative to the aldehyde (II).

To 2.0 equivalents, preferably 1.1 to 1.2 equivalents.

 The reaction is preferably performed in an argon or nitrogen atmosphere.

 The obtained cyanide compound (IV) can be used in the next step after purifying it as a reaction solution or in a crude form, or by a conventional method (eg, column chromatography, recrystallization, etc.).

 (Step 2)

[Wherein G, G ₂ , G ₅ , X and R are as defined above]

Compound (V) can be obtained, for example, from known literature (Fischer K, Hunig S, Tetrahedron 42 (19), 5337-5340 (1986), Delera AR, Saa JM, Suau R, Castedo L, J Heterocyclic chem 24 (1) , 95-100 (1987), Fischer K, Hunig S, J Org Chem 52 (4), 564-569 (1987), As described in Ian Fleming and Javed Iqbal, Tetrahedron 39 (6), 841-846 (1983)), it can be produced by an alkylation reaction of a cyanide compound (IV) and an octalogenide (III). .

 Examples of the reagent include lithium p-trimethylsilyl amide, sodium hydride, lithium diisopropyl amide (LDA), sodium ethoxide, potassium t-butoxide, 1,8-diazabicyclo [5.4.0] pendeck_7 — (BU).

 The reaction temperature is from 1 78 ° (: to 110 T :, preferably from 120 to 25 ° C. The reaction time varies depending on the compound, but is from 0.1 to 13 hours, preferably from 1 to 13 hours. 2 hours to 4 hours.

 Solvents that can be used include ether solvents (eg, tetrahydrofuran, getyl ether, dioxane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), saturated hydrocarbons (eg, heptane, hexane, etc.) ) Or a mixed solvent thereof.

 The amount of the reagent used is 1.0 equivalent to 2.0 equivalents, preferably 1.0 equivalent to 1 based on the cyanide form (IV). 2 equivalents.

 It is preferable to carry out the reaction under a nitrogen or argon atmosphere.

 The amount of the halide (III) to be used is 1.0 equivalent to 1.2 equivalents relative to the cyanide form (IV).

 The obtained compound (V) can be used in the next step after purification as a reaction solution or a crude product, or by a conventional method (eg, column chromatography, recrystallization, etc.).

(Step 3)

[Wherein, G ₁ G ₂ , G ₅ and R are as defined above]

 The target compound (I-A) can be produced by removing the group (TMS) corresponding to the reaction activator from the compound (V).

As the reaction conditions, for example, an excess of fluoride tetra - as tetrahydrofuran solution of n- Petit Ruan monitor © beam (nB u ₄ NF), as tetrahydrofuran / Sakusan'nosui (1: 1: 1) mixture of fluorinated Examples include conditions such as a pyridine salt of hydrogen, a mixed solution of 48% hydrogenacetonoacetonitrile (1: 7), and an aqueous hydrochloric acid solution.

 The obtained target compound (I-A) may be used as a reaction mixture or in crude form, or purified by a conventional method (eg, column chromatography, recrystallization, etc.) and used for the production of other target compounds. Can be.

(2) Preparation of the target compound (I-B) wherein G ₃ is a hydroxyl group and G ₄ is a lower alkyl

 (Production method 2)

 The compound (I-B) of the present invention can be produced by using known methods, for example, the methods described below and specifically shown in Examples.

In the following, shows almost the same method as in Production Method 1, preparation was used as a protecting group of t- heptyl dimethylsilyl (TB DMS) groups due to the presence of substituents (G ₃₎ to (Step 1-3) sequentially Is shown later.

 (step 1 )

[Wherein, G i and G ₂ are as defined above] The aldehyde (VII) can be produced from the compound (VI) by a known simple method, Vilsmeier reaction.

 The reaction temperature is 130 to 25 ° C.

 The reaction time varies depending on the compound, but is 2 hours to 30 hours.

 The amount of phosphorus oxychloride to be used is preferably 1.0 equivalent to 1.2 equivalent based on compound (VI).

 It is preferable to carry out the reaction under a nitrogen or argon atmosphere.

 The obtained aldehyde compound (VII) can be used in the next step after purifying it as a reaction solution or a crude product, or by a conventional method (eg, column chromatography, recrystallization, etc.).

 (Step 2)

[Wherein, G i and G ₂ are as defined above]

 The compound (VII) is produced by protecting the hydroxyl group of the compound (VII) with a t-butyldimethylsilyl (TBDMS) group.

 The reaction temperature is -20 to 8080.

 The reaction time varies depending on the compound, but is 0.2 to 60 hours.

The solvent that can be used is not particularly limited as long as it does not inhibit the reaction, in addition to N, N-dimethylformamide (DMF) described above. For example, halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), ethers (eg, ethyl ether, tetrahydrofuran, dioxane, dimethoxetane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), etc. Or a mixed solvent thereof. The obtained target compound (I-B) can be used as a reaction solution or in a crude form, or by a conventional method (eg, It can be purified by column chromatography, recrystallization, etc. and used in the next step.

 (Step 3)

[Wherein G or G ₂ , G 5, X and R are as defined above]

 The target compound (I-I-B) can be produced by a method similar to the method described in Production method 1 for reacting the compound (VIII) with the halide (III).

 The t-butyldimethylsilyl (TBDMS) group present in the compound (VIII) can be simultaneously removed by the same method as described in the production method 1 for the trimethylsilyl group.

 The obtained target compound (I-B) can be used as a reaction mixture or in crude form, or purified by a conventional method (eg, column chromatography, recrystallization, etc.) and used for the production of other target compounds. it can.

(3) Method for producing the target compound (I_C) wherein G ₃ is lower alkylcarbonyloxy and G ₄ is lower alkyl

 The compound (I-C) of the present invention can be produced using a known method, for example, a method described below or specifically shown in Examples.

(Production method 3)

[Wherein G ₂ , G ₅ and R have the same meanings as above, and Ra represents lower alkyl.] The target compound (IC) is produced by subjecting the compound (IB) to, for example, an acylation reaction. be able to.

 The acylation may be carried out by a known method. Examples of the acylating agent include an acyl halide or an alkylsulfonyl halide or an anhydride thereof (eg, acetic anhydride, 3-acetoxy-1,5,5-trimethylhydantoin, etc.). ) Or mixtures thereof.

 The reaction temperature is —10 ° (: 〜100).

 The reaction time varies depending on the compound, but is from 0.5 hours to 100 hours.

 The solvent that can be used is not particularly limited as long as it is a nonpolar solvent. Pyridine is particularly preferred, but others include 1,4-dioxane, dichloromethane, getyl ether, benzene and the like.

 The obtained target compound (I_C) can be used as is in the reaction solution or in crude form, or purified by a conventional method (eg, column chromatography, recrystallization, etc.) and used for the production of other target compounds. it can.

(4) G ₃ and G ₄ becomes within time cane one O-CH ₂ - target compound to form the (I - D) Preparation of

 (Production method 4)

 The compounds (ID) of the present invention are produced by known methods, for example, by using the methods described below (Steps 1 to 3) and specifically shown in Examples.

The following are the halogenation reaction (Step 1), the dehydrohalogenation reaction (Step 2), An example of the case of producing via deacetylation reaction and ring closure reaction (step 3) will be described. (step 1 )

[Wherein G, G ₂ , G ₅ , X and R are as defined above]

 The halide (X) is produced by halogenating the compound (IX). The octalogenation is preferably performed under strong acid conditions, for example, under the condition of a mixed solvent of acetic acid and sulfuric acid.

 The reaction temperature is O: 1100 ° C., preferably around room temperature.

 The reaction time varies depending on the compound, but is from 0.3 hours to 72 hours.

 The obtained halide (X) can be used in the next step after purification as a reaction solution or a crude product, or by a conventional method (eg, column chromatography, recrystallization, etc.).

 (Step 2)

[Wherein, G ₂ , G ₅ , X and R are as defined above]

Compound (XI) is produced by subjecting halide (X) to a dehydrohalogenation reaction. The method of the dehydrohalogenation reaction may be a known method, for example, a salt of an organic acid (e.g., a silver salt of an organic acid such as silver methanesulfonate, silver P-toluenesulfonate, silver acetate, Reaction in the presence of a copper salt of an organic acid).

 The reaction temperature is 0 to 100.

 The reaction time varies depending on the compound, but is from 0.3 hours to 50 hours.

 As a solvent that can be used, a polar solvent is preferable. For example, acid amides (eg, N,

N-dimethylformamide, etc.), acetonitrile, etc., or a mixed solvent thereof and the like.

 The obtained compound (XI) can be used in the next step after purifying it as a reaction solution or in a crude form, or by a conventional method (eg, column chromatography, recrystallization, etc.).

 (Step 3)

Wherein G, G ₂ , G ₅ and R are as defined above.

 The target compound (ID) can be produced by subjecting compound (XI) to deacylation and ring closure. The method may be a known method, for example, the addition of a metal salt of an alcohol (eg, sodium methoxide / methanol or the like) with an alcohol-based solvent.

 The reaction temperature is between 40 ° C and 80 :.

 The reaction time varies depending on the compound, but is from 0.3 hours to 50 hours.

 The obtained target compound (ID) can be purified by a conventional method (eg, column chromatography, recrystallization, etc.).

(5) Method for producing compound (I-E) or a salt thereof in which G ₅ is hydroxy

(Production method 5) The compounds (I-E) of the present invention are produced by known methods, for example, by the methods described below or specifically shown in Examples.

[Wherein, G, G ₂ , G ₃ , G ₄ and R are as defined above, and A represents hydrogen or metal]

 The target compound (IE) can be produced by hydrolysis using the ester (XII) as a raw material. When the target compound is a metal salt, for example, a sodium salt, it is produced by reacting sodium hydroxide. When the target compound is a carboxylic acid, the compound is produced, for example, by adding hydrochloric acid or the like to the above-mentioned metal salt to make it acidic.

 The obtained target compound (IE) can be used as is in the reaction solution or in crude form, or purified by a conventional method (eg, column chromatography, recrystallization, etc.) and used for the production of other target compounds. it can.

(6) Compound G ₅ is ^{NR 5 R 6 (I - F} ) Preparation of

 (Production method 6)

 The compound (IF) of the present invention can be produced using a known method, for example, a method described below or specifically shown in Examples.

 (ΧΠΙ) (I-F)

[Wherein, G ₂ , G ₃ , G ₄ , R ⁵ and R ⁶ are as defined above] The target compound (IF) is obtained by reacting a carboxylic acid form (XIII) with a carboxylic acid activator to produce a reactive derivative at the carbonyl group, and then reacting the hydroxylamine or substituted aniline derivative corresponding to the target compound. (XIV).

 In the reaction between the carboxylic acid compound (XIII) and the carboxylic acid activator, examples of the carboxylic acid activator include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, and chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate). Etc.), oxalyl chloride, carbonyldiimidazole, carbodiimides (for example, N, N-dicyclohexylcarboimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimid hydrochloride , N, N-di-isopropylcarbodiimide, N, N-di-p-tolyl carbodiimide, etc.) and hydroxyamino derivatives (eg, N-hydroxybenzotriazole, N-hydroxysuccinimide etc.) No. This reaction is usually carried out in the presence of halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran, dioxane, dimethyl ether, dimethyl ether and isopropyl ether, or a mixed solvent thereof. Is done. This reaction is carried out at a reaction temperature of 0 to 50 ° C., preferably around room temperature, for 0.5 to 10 hours, preferably 1 to 3 hours, depending on the compound.

 The acid anhydride, acid halide or active ester obtained by reacting with a carboxylic acid activator in this reaction is then reacted with a hydroxyamine or a substituted aniline derivative (XIV). This reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, dioxane, or acetone, in the presence of a deoxidizing agent such as pyridine, triethylamine, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, or sodium hydrogencarbonate. It is carried out under the condition of containing water. Further, this reaction is carried out at a reaction temperature of 0 to 50 ° C., preferably around room temperature for 0.1 to 10 hours, preferably 0.5 to 2 hours.

Hydroxamines and substituted aniline derivatives (XIV) are defined as Mine, N-methylhydroxylamine and their hydrochlorides, sulfates and the like, or P-hydroxyaniline, P-methoxyaniline and their hydrochlorides and the like. The obtained target compound (IF) can be isolated and purified by a conventional method (eg, column chromatography, recrystallization, etc.).

 The compound (I) of the present invention is compounded with a pharmacologically acceptable carrier to prepare a solid preparation such as tablets, capsules, granules, powders, powders, and suppositories, or a syrup, injection, suspension, or the like. It can be administered orally or parenterally as liquid preparations such as preparations, solutions and sprays. Pharmaceutically acceptable carriers include excipients, lubricants, binders, disintegrants, disintegration inhibitors, absorption enhancers, adsorbents, humectants, solubilizing agents, stabilizing agents, Solvents, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents and the like in liquid preparations. In addition, if necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can be used. Further, a substance having an anticancer effect other than the compound represented by the general formula (I), a salt thereof or a hydrate thereof may be added to the anticancer agent of the present invention. Parenteral routes of administration include intravenous injection, intramuscular injection, nasal, rectal, vaginal and transdermal.

 Excipients in solid preparations include, for example, glucose, lactose, sucrose, D-mannitol, crystalline cellulose, starch, calcium carbonate, light anhydrous caffeic acid, sodium chloride, kaolin and urea. Can be

 As the lubricant in the solid preparation, for example, magnesium stearate, calcium stearate, powdered boric acid, colloidal citric acid, talc, polyethylene dalicol and the like can be mentioned.

Examples of the binder in the solid preparation include water, ethanol, propanol, sucrose, D-mannitol, crystalline cellulose, dextrin, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, starch solution, gelatin solution, and poly (polyester). Vinylpyrrolidone, calcium phosphate, potassium phosphate, shellac and the like. Examples of disintegrants in solid preparations include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, agar powder, laminaran powder, croscarmellose sodium, carboxymethyl starch sodium, sodium alginate, sodium hydrogen carbonate, calcium carbonate, Examples include polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, starch, monosalicylate monostearate, lactose, and calcium calcium dalicholate.

 Preferred examples of the disintegration inhibitor in the solid preparation include hydrogenated oil, sucrose, stearin, cocoa butter, and hardened oil.

 Examples of the absorption enhancer in a solid preparation include quaternary ammonium bases and sodium lauryl sulfate.

 Examples of the adsorbent in the solid preparation include starch, lactose, kaolin, bentonite, and colloidal keic acid.

 Examples of the humectant in the solid preparation include glycerin, starch and the like.

 Examples of the solubilizer in the solid preparation include arginine, glutamic acid, and aspartic acid.

 Examples of the stabilizer in the solid preparation include human serum albumin, lactose and the like.

When preparing tablets, pills and the like as solid preparations, they may be coated with a film of a gastric or enteric substance (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.) as necessary. Tablets include tablets coated with ordinary skin as required, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets, and multilayer tablets. Capsules include hard capsules and soft capsules. When molding into suppository form, besides the additives listed above, for example, higher alcohols, higher alcohols Esters and semi-synthetic glycerides can be added.

 Preferable examples of the solvent in the liquid preparation include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferred examples of solubilizers in liquid preparations include polyethylene dalicol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Is mentioned.

 Preferable examples of the suspending agent in the liquid preparation include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate. And hydrophilic polymers such as polypinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyshethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.

 Preferable examples of the tonicity agent in the liquid preparation include sodium chloride, glycerin, D-mannitol and the like.

 Preferred examples of the buffer in the liquid preparation include buffers such as phosphate, acetate, carbonate, and citrate.

 Preferable examples of the soothing agent in the liquid preparation include benzyl alcohol, benzalkonium chloride and procaine hydrochloride.

 Preferable examples of the preservative in the liquid preparation include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

 Preferred examples of the antioxidant in the liquid preparation include sulfite, ascorbic acid, -tocopherol and cysteine.

When prepared as an injection, solutions and suspensions are sterilized and isotonic with blood. It is preferable that Usually, these are sterilized by filtration using a bacteria-retaining filter or the like, blending of a bactericide or irradiation. Further, after these treatments, solidified by freeze-drying and other methods, and sterile water or sterile injectable diluent (lidocaine hydrochloride aqueous solution, physiological saline solution, glucose aqueous solution, ethanol or a mixture thereof, etc.) immediately before use. ) May be added.

 In addition, if desired, the pharmaceutical preparations may contain coloring agents, preservatives, flavorings, flavors, sweeteners and the like, as well as other agents.

The proportion of the active ingredient in the anticancer agent of the present invention may vary depending on the dosage form, but is usually 0.1 to 70% by weight irrespective of the administration form. Dosage will, of course, the patient's age, sex, symptom, the desired therapeutic effect, but is to be determined in consideration of the administration period and the like, usually, per day per adult 0.01～1000M _g based on the (active ingredient amount) These can be administered as 1 to 4 times a day.

 (Example)

 Hereinafter, the present invention will be described in more detail with reference to Examples (Synthesis Examples and Formulation Examples) and Test Examples, but the present invention is not limited thereto. What is described as a reference example is a step not described in the above-mentioned production method, and is an example of the synthesis of a starting material in the production method and examples.

NMR spectrum was measured using CDCls or CDC1 ₃ + CD ₃ 0D as solvent. All δ values are given in ppm. In addition, the meaning of the symbol in NMR is shown below. s Singlet, d: doublet, t: triplet, dd: double doublet, m: multiplet, q: quaternary carbon.

 (Synthesis Example)

 (Reference example 1)

 3-Fluoro mouth-4-Pyrrolidinobenzaldehyde (Compound No. 4)

To a solution of 3,4-difluorobenzaldehyde (Compound No. 1, 6.62 ml, 60 mmol) in acetonitrile (40 ml), add pyrrolidine (7.51 ml, 90 mmol), and heat to reflux for 1 hour. did. The reaction solution was poured into a mixture of ethyl acetate and ice water, the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate: 9/1) and crystallized from a mixture of dichloromethane and n-hexane to give the title compound (7.78 g, yield: 67.1%) ).

 NMR (CDCh) δ: 1.88-2.10 (4H, m), 3.44-3.65 (4H, m), 6.62 (lH, t, J = 8.2 Hz), 7.45 (lH, dd, J = 7.0 and 1.6Hz), 7.51 (lH, s), 9.70 (lH, d, J = 2.4Hz)

 (Example 1)

 4- [l- (4-Dimethylaminobenzoyl) ethyl] ethyl benzoate (Compound No. 12) P-dimethylaminobenzaldehyde (Compound No. 2, 7.46 g, 50 mmol) and trimethylsilyl cyanide (6.70 ml, 50 mmol) ) Was added with anhydrous zinc iodide (10 mg), and the mixture was stirred at room temperature for 1 hour. Tetrahydrofuran (100 ml) was added to the reaction solution, and the mixture was cooled to -78 ° C. Then, a 1 M / L solution of lithium bistrimethylsilylamide in tetrahydrofuran (50 ml, 50 mmol) was added, and the mixture was stirred for 10 minutes. A solution of ethyl 4- (1-bromoethyl) benzoic acid (12.90 g, 50 mmol) in tetrahydrofuran (15 ml) was added dropwise to the reaction mixture. The reaction solution was stirred at -78 for 1 hour and then warmed to room temperature, 1N hydrochloric acid (120 ml) and ethyl acetate (150 ml) were added, and the mixture was stirred at room temperature for 15 hours. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (n-hexane / ethyl acetate: 9/1) to give the title compound (7.20 g). , 44.3%) as a colorless oil. mp62- 63 ° C

_{NMR (CDC1 3) d: 1.36} (3H, t, J = 7.2Hz), 1.53 (3H, d, J = 7.0Hz), 3.02 (6H, s), 4.34 (2 H, q, J = 7.2Hz) , 4.70 (1H, q, J = 7.0 Hz), 6.59 (2H, d, J = 9.4 Hz), 7.38 (2H, d, J = 8.2 Hz), 7.87 (2H, d, J = 9.4 Hz), 7.96 (2H, d, J = 8.2Hz)

 (Example 2)

4- [l- (4-Methoxybenzoyl) ethyl] ethyl benzoate (Compound No. 13) anisaldehyde (Compound No. 3, 6.1 ml, 50 mmol) was prepared in the same manner as in Example 1. The title compound (13.87 g, yield: 88.2%) was obtained as a yellow oil by similar reaction and treatment.

 NMR (CDClg) δ: 1.36 (3H, t, J = 7.2Hz), 1.53 (3H, d, J = 7.0Hz), 3.82 (3H, s), 4.34 (2H, q J = 7.2Hz), 4.70 ( lH, q, J = 7.0Hz), 6.86 (2H, d, J = 9.0Hz), 7.35 (2H, d, J = 8.2Hz), 7.92 (2H, d, J = 9.0Hz), 7.97 (2H, d, J = 8.2Hz)

 (Example 3)

 4- [l- (3-Fluoro mouth-4-pyrrolidinobenzoyl) ethyl] ethyl benzoate (Compound No. 14)

 The title compound (yield: 40.2%) was obtained as a foam by reacting and treating in the same manner as in the synthesis of Example 1.

 NMR (CDC) (5: 1.37 (3H, t, J = 7.2Hz), 1.51 (3H, d, J = 6.6Hz), 1.88-1.97 (4H, m), 3.41-3.52 (4H, m), 4.34 (2H, q, J = 7.2Hz), 4.63 (lH, q, J = 6.6Hz), 6.46 (lH, t, J = 8.4Hz), 7.36 (2H, d, J = 6.6Hz), 7.56 (lH , dd, J = 6.2 and 2.4Hz), 7.62 (lH, s), 7.96 (2H, d, J = 6.6Hz)

 (Example 4)

 Sodium 4- [l- (4-dimethylaminobenzoyl) ethyl] benzoate (Compound No. 15)

To a solution of 4- [1- (4-dimethylaminobenzoyl) ethyl] ethyl benzoate (Compound No. 12, 16.2 g, 49.7 mmol) in methanol (110 ml), add a 1N aqueous solution of caustic soda (49.7 ml) and heat to reflux for 3 hours. did. After the reaction solution was cooled on ice, the precipitated crystals were collected by filtration and washed with ether to give the title compound (15.46 _g ) as white crystals. (Example 5)

4-[(4-Dimethylaminobenzoyl) ethyl] benzoic acid (Compound No. 16) Methanol of 4- [1- (4-dimethylaminobenzoyl) ethyl] ethyl benzoate (Compound No. 12, 428mg, 1.32mmol) (4 ml) 1N aqueous sodium hydroxide solution was added to the solution, and the mixture was heated under reflux for 3 hours. The residue obtained after concentration of the reaction solution under reduced pressure Then, ice-cold 1N aqueous hydrochloric acid (1.32 ml) was added. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was crystallized from tetrahydrofuran and ether to give the title compound (186 mg, yield: 47.4%). mp l89-193

_{NMR (CDC1 3 + CD 3 0D} ) δ: 1.52 (3H, d, J = 6.8Hz), 3.0.3 (6H, s), 4.72 (lH, q, J = 6.8Hz), 6.63 (2H, d, J = 9.1Hz), 7.38 (2H, d, J = 8.3Hz), 7.88 (2H, d, J = 9.1Hz), 7.97 (2H, d, J = 8.3Hz)

 (Example 6)

 4- [l- (4-Methoxybenzoyl) ethyl] benzoic acid (Compound No. 17)

 To a solution of ethyl 4- [1- (4-methoxybenzoyl) ethyl] benzoyl benzoate (Compound No. 13, 2.09 g, 6.69 mmol) in methanol (21 ml) was added a 1N aqueous sodium hydroxide solution (6.70 ml), and the mixture was heated for 3 hours. Refluxed. The reaction solution was concentrated under reduced pressure, and to the residue obtained, ethyl acetate and a 2N aqueous hydrochloric acid solution (20 ml) in ice water were added. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crystalline crude product was recrystallized from ethyl acetate and n-hexane to give the title compound (1.52 g, yield: 80.0%) as white crystals.

 NMR (CDCls + CDsOD) δ: 1.52 (3H, d, J = 6.6Hz), 4.70 (lH, q, J = 6.6Hz), 6.87 (2H, d, J = 9.0Hz), 7.37 (2H, d, J = 8.2Hz), 7.69 (2H, d, J = 8.2Hz), 7.92 (2H, d, J = 9.0Hz)

 (Example 7)

 4- [l- (3-Fluoro-4-pyrrolidinobenzoyl) ethyl] benzoic acid (Compound No. 18) The title compound (Yield) was obtained by reacting and treating in the same manner as in the synthesis of Example 5. 65%) as colorless crystals.

NMR (CDCls + CDsOD) δ: 1.52 (3H, d, J = 7.0Hz), 1.92-1.99 (4H, m), 3.40-3.53 (4H, m), 4.65 (lH, q, J = 7.0Hz) ), 6.52 (lH, t, J = 8.2Hz), 7.37 (2H, d, J = 8.4Hz), 7.57 (lH, dd, J = 8.2 and 2.0Hz), 7.63 (lH, s), 7.98 (2H , d, J = 8.4Hz) (Example 8)

 4- [l- (4-Dimethylaminobenzoyl) ethyl] benzohydroxamic acid (Compound No. 19)

Ogizaryl chloride (87 l, 1.05 mmol) was added to a suspension of sodium 4- [1- (4-dimethylaminobenzoyl) ethyl] benzoate (compound No. 15, 319 mg, lmmol) in anhydrous benzene (22 ml). Was added and reacted at room temperature for 5 hours. The resulting reaction solution was prepared by reacting hydroxylamine hydrochloride (286 mg, 2 mmol) and caustic soda (188 _mg , 4.58 mmol) in methanol (22 ml) at 0 ° C for 30 minutes and then at room temperature for 1 hour. The hydroxylamine solution was added to the solution under ice-cooling, and reacted at 0 for 1 hour and then at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in a mixture of chloroform and methanol and washed with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained crude product was triturated with ether, filtered, and then washed with a small amount of ethyl acetate to obtain the title compound (286 mg, yield 91.6%). mp l89-190 ° C

 NMR (CDCls) δ: 1.53 (3H, d, J = 6.6Hz), 3.02 (6H, s), 4.72 (lH, q, J = 6.6Hz), 6.59 (2H, d, J = 9.4Hz), 7.41 (2H, d, J = 8.2Hz), 7.87 (2H, d, J = 9.4Hz), 8.01 (2H, d, J = 8.2Hz)

 (Example 9)

 N-methyl 4- [l- (4-dimethylaminobenzoyl) ethyl] benzohydroxamic acid (Compound No. 20)

 The crude product obtained by reacting acid chloride with N-methylhydroxylamine in the same manner as in the synthesis of Example 8 was subjected to silica gel column chromatography (n-hexane / ethyl acetate: 1/2). Then, the residue was crystallized from ether to give the title compound (48 mg, yield: 29.4%). mp77-81 ° C

NMR (CDCh) δ: 1.52 (3H, d, J = 7.0Hz), 3.03 (6H, s), 3.38 (3H, s), 4.69 (1H, q, J = 7.0Hz), 6.67 (2H, d , J = 8.8Hz), 7.38 (2H, d, J = 8.4Hz), 7.42 (2H, d, J = 8.4Hz), 7.89 (2H, dJ = 8.8)

(Example 13)

 N-methyl 4- [l- (3-fluoro-4-pyrrolidinobenzoyl) ethyl] benzohydroxamic acid (Compound No. 24)

The reaction and treatment were conducted in the same manner as in the synthesis of Example 10, and the mixture was triturated with petroleum ether and then with _n- hexane to give the title compound (yield: 82.3%) as a powder.

_{NMR (CDC1 3) δ: 1.51} (3H, d, J = 6.8Hz), 1.90 ~ 1.98 (4H, m), 3.39 (3H, s), 3. 43-3.55 (4H, m), 4.63 (lH, q, J = 6.8Hz), 6.50 (lH, t, J = 8.6Hz), 7.37 (2H, d, J = 8.4Hz), 7.47 (2H, d, J = 8.4Hz), 7.57 (lH, dd , J = 7.8 and 1.8Hz), 7.63 (lH's) (Example 14)

 4- [l- (4-Dimethylaminobenzoyl) ethyl] -N- (4-hydroxy) phenylbenzamide (Compound No. 26)

4- [1- (4-Dimethylaminobenzoyl) ethyl] benzoic acid (Compound No. 16, 50 mg, 0.2 mmol) in a solution of tetrahydrofuran (3 ml) and dichloromethane (6 ml) was added to a solution of 4-hydroxycarboxylic acid under ice cooling. (24 mg, 0.22 mmol) and water-soluble carbodiimide hydrochloride (42 _mg , 0.22 mmol) were added. The mixture was stirred for 30 minutes at room temperature and 3 hours at room temperature. After adding ethyl acetate and ice water to the reaction solution and stirring, the ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (n-hexane / ethyl acetate: 2/1) and crystallized from dichloromethane to give the title compound (49 _mg , yield: 63.1 _mg ) as white crystals. %). mp l49-159 t :.

_{NMR (CDC1 3) δ: 1.51} (lH, d, J = 7.0Hz), 3.01 (6H, s) 4.70 (lH, q, J = 7.0Hz), 6.59 (2H, d, J = 9.4Hz), 6.75 (2H, d, J = 8.4Hz), 7.32-7.38 (4H, m) 7.75 (2H, d, J = 8.4Hz), 7.88 (2H, d, J = 9.4Hz), 7.97 (lH, s)

 (Example 15)

4- [l- (4-Methoxybenzoyl) ethyl] -N- (4-hydroxy) phenylpenzamide (Compound No. 27) Acid chloride derived from 4- [1- (4-methoxybenzoyl) ethyl] benzoic acid (Compound No. 17, 190 mg, 0.67 mmol) by the method described earlier in the synthesis of Example 10. P-Aminophenol (88 mg, 0.80 mmol) and triedilamine (120 l, 0.8 mmol) were added to a solution of the benzene (10 ml) in the form of the amide, and the mixture was stirred at 0 for 1 hour and then at room temperature for 3 hours. The reaction solution was poured into ethyl acetate and ice water, the ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was crystallized from dichloromethane to give the title compound (142 _mg , yield: 56.4%) as white crystals.

 NMR (CDCls) δ: 1.54 (3H, d, J = 6.9Hz), 3.83 (3H's), 4.72 (lH, q, J = 6.9Hz), 6.78 (2H, d, J = 8.9Hz), 6.87 ( 2H, d, J = 9.0Hz), 7.36 (2H, s), 7.40 (2H, s), 7.77 (2H, dJ = 9.0), 7.93 (2H, d, J = 9.0Hz)

 (Example 16)

 4--(4-Dimethylamino-2-hydroxybenzoyl) ethyl] ethyl benzoate (Compound No. 32)

 Crude 4- [obtained by reacting and treating 2-t-butyldimethylsilyloxy-4-dimethylaminobenzaldehyde (Compound No. 29, 38.2 g, 137 mM) in the same manner as described in the synthesis of Example 1 1- (2-butyldimethylsilyloxy-4-dimethylaminobenzoyl) ethyl] ethyl benzoate (Compound No. 31) in tetrahydrofuran (270 ml) solution and 1M / L tetrabutylammonium fluoride in tetrahydrofuran (206 ml, 206 mmol) was added under ice cooling, and the mixture was stirred at 0 for 2 hours. The reaction solution was poured into a mixture of ethyl acetate and ice water. The organic layer was washed with water (three times), dried over magnesium sulfate, and concentrated under reduced pressure to obtain the crude title compound (29.3 g) as yellow crystals.

NMR (CDCla) <5: 1.36 (3H, t, J = 7.0Hz), 1.53 (3H, d, J = 6.8Hz), 3.00 (6H, s), 4.35 (2H, q, J = 7,0Hz) , 4.66 (lH, q, J = 6.8Hz), 6.06 (lH, d, J = 2.6Hz) _> 6.13 (lH, d, d, J = 9.2 and 2.6Hz), 7.39 (2H, d, J = 8.4 Hz), 7.55 (lH, d, J = 9.2Hz) _; 7.98 (2H, d, J = 8.4Hz) (Example 17)

 4- [l- (2-Acetoxy-4-dimethylaminobenzoyl) ethyl] ethyl benzoate (Compound 33)

 A solution of the previously obtained crude 4- [1- (4-dimethylamino-2-hydroxybenzoyl) ethyl] ethyl benzoate (Compound No. 32, 29.3 g) in pyridine (150 ml) was ice-cooled. After acetic anhydride (75 ml) was added thereto, the mixture was left at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate and washed with water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the obtained residue was recrystallized from dichloromethane-isopropyl ether to obtain the crude title compound (28.77 g) as yellow crystals.

 NMR (CDCls) δ: 1.38 (3H, t, J = 7.0Hz), 2.31 (3H, s), 3.04 (6H, s), 4.37 (2H, q, J = 7.0Hz), 5.63 (lH, s) , 6.01 (lH, s), 6.32 (lH, d, J = 2.6Hz), 6.41 (lH, d, d, J = 9.0 and 2.6Hz), 7.48 (2H, d, J = 8.4Hz), 7.58 ( 2H, d, J = 9.0Hz), 8.00 (2H, d, J = 8.4Hz)

 (Reference example 2)

 4- [l-Bromo-l- (2-acetoxy-4-dimethylaminobenzoyl) ethyl] ethyl benzoate (Compound 34)

The previously obtained crude 4- [1- (2-acetoxy-4-dimethylaminobenzoyl) ethyl) j ethyl benzoate (Compound No. 33, 28.77 g, 75 mmol) in acetic acid (735 ml) and concentrated To a mixture of sulfuric acid (147 ml) was added pyridinium bromide propyl bromide (28.7 g, 90 mmol) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was poured into a mixture of form and ice water, and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane / ethyl acetate: 4/1) to give the crude title compound (23.5 _g ) as an oil.

 NMR (CDCls) δ: 1.38 (3H, t, J = 7.0Hz), 2.13 (3H, s), 2.42 (3H, s), 2.96 (6H, s), 4.36 (2H, q, J = 7.0Hz) , 6.12 (lH, d, d, J = 9.0 and 2.6 Hz), 6.24 (lH'd, J = 2, 6 Hz), 7.33

(lH, d, J = 9.0Hz), 7.59 (2H, d, J = 8.6Hz), 7.98 (2H, d, J = 8.6Hz) (Example 18)

 4- (7-Dimethylamino-4-oxo-chroman-3-yl) ethyl benzoate (Compound No. 36)

 A solution of the previously obtained crude 4- [1-promole (2-acetoxy-4-dimethylaminobenzoyl) ethyl] ethyl benzoate (Compound No. 34, 23.5 g) in acetonitrile (300 ml) was added to methane. Silver sulfonate (8.1 g, 40 mmol) was added, and the mixture was heated at 50 ° C for 30 minutes. Ethyl acetate was added to the reaction solution, followed by filtration. The filtrate was concentrated under reduced pressure to give crude 4- [1- (2-acetoxy-4-dimethylaminobenzoyl) ethenyl] ethyl benzoate (Compound No. 35) ). To a solution of the compound obtained above in methanol (150 ml) was added 1 N sodium methoxide nomethanol solution (23 ml) under ice-cooling, and the mixture was stirred at 0 ° C for 1 hour. The reaction solution was poured into dichloromethane and ice water, the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane / ethyl acetate: 4/1) to give the title compound (6.25 g) as white crystals.

 NMR (CDCls) 6: 1.38 (3H, t, J = 7.0Hz), 3.07 (6H, s), 3.92 (lH, t, J = 6.4Hz), 4.36 (2H, q, J = 7.0Hz), 4.61 (lH, d, J = 2Hz), 4.64 (lH, s), 6.12 (lH, d, J = 2.4Hz), 6.42 (lH, d, d, J = 9.0 and 2Hz), 7.38 (2H, d, J = 8.2Hz), 7.83 (lH, d, J = 9.0Hz), 8.00 (2H, J = 8.2Hz)

 (Example 19)

 4- (7-dimethylamino-4-oxo-chroman-3-yl) benzoic acid (compound 37)

A 1N sodium methoxide methanol solution (18.4) was added to a solution of 4- (7-dimethylamino-4-oxo-chroman-3-yl) ethyl benzoate (Compound No. 36, 6.25 g) in methanol (122 ml). ml, 18.4 mmol), distilled water (18.4 ml) and tetrahydrofuran (18.4 ml), and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue obtained, ethyl acetate, water and 20 ml of 1N hydrochloric acid were added. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crystalline residue is washed with tetrahydrofuran The title compound (1.64 g, yield: 7.3% from compound 29) was obtained as white crystals by recrystallization from methanol.

 NMR (CDCls) δ: 3.07 (6H, s), 3.92 (lH, t, J = 5.0 Hz), 4.61-4.65 (2H, m), 6.11 (lH, d, J = 2.6 Hz), 6.42 (lH, dd, J = 9.0 and 2.6Hz), 7.39 (2H, d, J = 8.4Hz), 7.82 (lH, d, J = 9.0Hz), 8.02 (2H, d, J = 8.4Hz)

 (Example 20)

 4- (7-Dimethylamino-2,3-dihydrochroman-3-yl) benzohydroxamic acid compound (38)

To a solution of 4- (7-dimethylamino-4-oxo-chroman-3-yl) benzoic acid (Compound No. 37, 1.07 g, 3.44 mmol) in tetrahydrofuran (10 ml) was added oxalyl chloride (325 1, 3.78 mmol) and dimethylformamide (21) were added, and the mixture was stirred at 0 ° C for 1 hour and then at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a solution of tetrahydrofuran (20 ml). A solution of hydroxylamine hydrochloride (956 _mg , 13.76 mmol) in methanol (20 ml) and a 1 N solution of methanol were added. To a methanol solution of free hydroxyylamine prepared from a ethanol solution (15.72 ml, 15.72 mmol) was added dropwise under ice-cooling, and the mixture was stirred at 0 ° C for 2 hours. After concentration under reduced pressure, the reaction solution was dissolved in a mixed solvent of chloroform-methanol and distilled water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crystalline residue was triturated with ether and recrystallized from chloroform-methanol to give the title compound (740 mg, yield: 68.6%) as yellow crystals.

 NMR (CDCI3 + CD3OD) δ: 3.08 (6H, s), 3.92 (lH, dd, J = 8.0 and 5.8Hz), 4.56-4.64 (2H, m), 6.11 (lH, d, J = 2.6Hz), 6.42 (lH, dd, J = 9 and 2.6Hz), 7.35 (2H, d, J = 8.4Hz), 7.70 (2H, d, J = 8.4Hz), 7.80 (lH, d, J = 9.0Hz)

 (Example of formulation)

 Preparation of formulation

(Example 1) 2.5 mg of the compound of the invention was dissolved in a mixture of purified sesame oil lg and aluminum stearate gel lOOmg. 0.5 ml of the resulting solution was dispensed into capsules to give oral capsules.

 (Example 2)

 5.0 mg of the compound of the invention was dissolved in a mixture of purified sesame oil lg and aluminum stearate gel lOOmg. 0.5 ml of the resulting solution was dispensed into capsules to make oral capsules.

 Next, test methods for confirming the pharmacological action of the compound (I) of the present invention or a salt thereof and the results thereof will be described.

 (Test example)

 Assay for Detransformation Activity of NIH3T3 Cells Transformed with v-sis Gene First, a culture solution was prepared as follows. Dulbecco Eagle MEM medium (Nissui Pharmaceutical) 9.5 g and 7% sodium bicarbonate were added to 20 ml and 1 L of distilled water, and then fetal bovine serum (Flow Laboratories, Inc.) was added to a final concentration of 10% by volume. Added.

Then, NIH3T3 cells transformed with the v-sis gene (100 L) were inoculated into a 96-well plastic dish manufactured by Sumitomo Bei-Client Co., Ltd. in a 5 × 10 ³ cell well, and then incubated at 37 ° C. In a 5% CO 2 incubator. Next, test samples were added in a two-fold dilution series, and after 24 hours, the cell morphology was observed to determine the detransformation activity. The results are shown in Table 1 below.

Minimum transformation inhibitory activity (MIC) of NIH3T3 cells transformed with v-sis gene

 As can be seen from the above table, the compounds of the present invention exhibited a detransformation activity at MIC of 0.03 / ig / ml at 10 g / ml. Industrial applicability

 According to the present invention, a novel compound that specifically detransforms cells transformed with various oncogenes and a carcinostatic agent containing the same are provided.

Claims

The scope of the claims 'General formula (I)

[Wherein, is OR ¹ (where R ¹ represents hydrogen or lower alkyl) or NR ² R ³ (where R ² and R ³ are the same or different and are hydrogen, lower alkyl or hydroxyl group) Or R ² and R ³ may together form a nitrogen-containing heterocyclic ring with an adjacent nitrogen atom); G ₂ is hydrogen or halogen; G ₃ and G ₄ are such that G ₃ is hydrogen or a hydroxyl group. Or G ₄ is a lower alkylcarbonyloxy and G ₄ is lower alkyl, or G ₃ and G ₄ may together form one O—CH ₂ —: G ₅ is OR ⁴ ( Here, R ⁴ represents hydrogen or lower alkyl) or NR ⁵ R ⁶ (where R ⁵ represents a hydroxyl group or an optionally substituted cyclic group, and R ⁶ represents hydrogen or lower alkyl). (except when G is is and G ₅ is oR ¹ is oR ^4)] compound or a salt thereof or These hydrates. 2. The compound according to claim 1, wherein is a methoxy, dimethylamino group or a pyrrolidine-1-yl group, a salt thereof, or a hydrate thereof. 3. The compound according to claim 1, wherein G ₅ is a hydroxyl group or NR ⁵ R ⁶ (where R ⁵ represents a hydroxyl group or a cyclic group which may be substituted with a hydroxyl group), or a salt thereof or a salt thereof. Hydrate. 4. The compound according to claim 1, wherein G ₄ is methyl, a salt thereof, or a hydrate thereof. 5. The compound according to claim 1, wherein NR ² R ³ and G ₃ and G ₄ together form one O—CH ₂ —, a salt thereof, or a hydrate thereof. -General formula (I):

[Wherein, is OR ¹ (where R ¹ represents hydrogen or lower alkyl) or NR ² R ³ (where R ² and R ³ are the same or different and are hydrogen, lower alkyl or hydroxyl group) Or R ² and R ³ may together form a nitrogen-containing heterocyclic ring with an adjacent nitrogen atom); G ₂ is hydrogen or halogen; G ₃ and G ₄ are such that G ₃ is hydrogen or a hydroxyl group. Or G ₄ is lower alkyl, or G ₄ is lower alkyl, or G ₃ and G ₄ may together form —O—CH ₂ —; G ₅ is OR ⁴ ( Wherein R ⁴ represents hydrogen or lower alkyl) or NR ⁵ R ⁶ (Where R ⁵ represents a hydroxyl group or a cyclic group which may be substituted, and R ⁶ represents hydrogen or lower alkyl).] Or a salt thereof or a hydrate thereof. .