JPH11302173A - Histone deacetylase inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor having histone deacetylase inhibitory action and improved in problems associated with safety, toxicity, pharmacokinetics, activity intensity and the like, by including a specific benzamide derivative (salt) as active ingredient. SOLUTION: This inhibitor is obtained by including, as active ingredient, a benzamide derivative (salt) of formula I A is a (substituted) pyridine ring or condensed pyridine ring; X is a directed bond, a group of formula II, formula III ((e) is 1-4; (g) is 0-4) or the like; (n) is 1-4; Q is a group of formula IV [R7 is H or a (substituted) 1-4C alkyl] or the like; R1 and R2 are each H, a halogen, amino, a 1-4C alkyl or the like; R3 is amino or OH}. The compound of formula I is obtained, for example, by condensation reaction between a compound of the formula A-X-R9 [R9 is NH2 or C(=G)OH (G is O or S)] and a compound of formula V [R10 is NH2 when R9 is C(=G)OH, while being C(=G)OH when R9 is NH2 ; R11 is a (protected) amino or (protected) OH].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a benzamide derivative having an inhibitory activity on histone deacetylase. More specifically, the present invention relates to the use of a histone deacetylase inhibitory activity for an anticancer drug and other drugs.

[0002]

BACKGROUND OF THE INVENTION In the nucleus of a cell, DNA forms a complex with histones, maintains a highly folded chromatin structure, and is kept in an inactive state (Knezetic et al., Cel.
1, 45 : 95-104, 1986). In order for gene transcription to take place in the nucleus, it is necessary to bring the structure into an unfolded state so that various transcription factors can come into contact with DNA (Felsenfeld et al., Cel.
1, 86 : 13-19, 1996). Although the relationship between histone acetylation and transcriptional activation has been reported for a long time, one of the actions that induces structural changes leading to transcriptional activation is one.
One was found to be histone acetylation (Hong et al., J. Biol. Chem., 268 :
305-314, 1993, etc.). The acetylation is controlled by histone acetyltransferase.
e) and histone deacetylase (histone d)
eAcetylase; HDA), and its importance has been recently recognized (A. Corders, Bioch).
em. J. 265 : 23, 1990). Sodium butyrate, which has long been confirmed to induce cell cycle arrest and differentiation, is a representative HDA inhibitor (LS Cou).
sens et al. Biol. Chem. , 254 : 17
16, 1979), and clinical use was also attempted (N
ovogrodsky et al., Cancer, 51 : 9-1.
4, 1983 and Miller et al., Eur. J. Ca
ncer Clin. Oncl. , 23 : 1283-1
287, 1987). However, since its basic inhibitory activity is low and its persistence in vivo is short, a high dose was required to show the effect. Therefore, a prodrug of butyric acid has been improved in sustainability (Zi-Xing et al., Can.
cer Res. 54 : 3494-3499,199.
4 and Kasukabe et al., British J. et al. C
ancer, 75 (6): 850-854, 1997, etc.).

In addition, trichostatin A (TS), a natural product,
A) Cell cycle arrest (Yoshida et al., Exp. Cell R).
es. 177 : 122-131, 1988), growth arrest, induction of differentiation (Yoshida et al., Cancer Res., 4) .
7 : 3688-3691, 1987), cell morphology change,
It was found to guide the induction of apoptosis. As a mechanism, TSA was confirmed to be a highly active HDA inhibitor in vitro (Yoshida et al., J. Am.
Biol. Chem. , 265 : 17174, 199
0).

[0004] In addition, research on other HDA inhibitors has been continued and trapoxins (Itazaki et al., J. Anti.
biot. 43 (12): 1544-1534,19
90), phenylbutyric acid (Carducci et al., Cl
in. Cancer Res. , 2 (2): 379, 1
996, etc.). Since these HDA inhibitors have cell cycle arrest and differentiation inducing effects, they are firstly expected to be applied to anticancer drugs. HDA inhibitors are also expected to be applied to various other drugs.

[0005] That is, treatment of diseases related to cell proliferation
As ameliorating agents, for example, autoimmune diseases, skin diseases, infectious diseases (Darkin-Rattray et al., Proc. Nat.
l. Acad. Sci. USA, 93 : 13143-1.
3147, 1996) as well as efficient vector introduction in gene therapy (Dion et al.,
Virology, 231 : 201-209, 199
7), enhanced transgene expression (Chen et al., Proc.
Natl. Acad. Sci. USA, 94 : 5798.
-5803, 1997). However, none of the conventional inhibitors has reached a sufficiently satisfactory level as a pharmaceutical product in consideration of stability, toxicity, pharmacokinetics and active strength. Therefore, there is a strong demand for the development of drugs that solve these problems.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a therapeutic and / or ameliorating agent for diseases related to cell proliferation and a drug for enhancing the effect of gene therapy, which have solved the problems of the conventional HDA inhibitors. It is to provide a compound useful as a pharmaceutical.

[0007]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that they have already reported that they have a differentiation-inducing action (Japanese Patent Application No. 09-1990).
260277) was confirmed to have a strong HDA inhibitory effect, thereby completing the present invention.

That is, the present invention relates to the following [1]:

[0009]

Embedded image [In the formula, A represents an optionally substituted pyridine ring or a condensed pyridine ring (as a substituent, a halogen atom, a hydroxyl group,
Amino group, nitro group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, aminoalkyl group having 1 to 4 carbon atoms, alkylamino group having 1 to 4 carbon atoms, 1 carbon atom Acyl group having 1 to 4 carbon atoms, acylamino group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyloxy group having 1 to 4 carbon atoms, carboxyl group, A group selected from the group consisting of alkoxycarbonyl groups having 1 to 4 carbon atoms,
Number). X is a direct bond or a compound of the formula (2)

[0010]

Embedded image 中 In the formula, e represents an integer of 1 to 4. g and m each independently represent an integer of 0-4. R4 is a hydrogen atom, an optionally substituted alkyl group having 1 to 4 carbon atoms or a group represented by the formula (3):

[0011]

Embedded image (Wherein, R 6 represents an alkyl group having 1 to 4 carbon atoms which may be substituted, a perfluoroalkyl group having 1 to 4 carbon atoms, a phenyl group or a pyridine ring). R5 represents any of the structures represented by｝ representing a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms. n represents an integer of 1 to 4.

Q is the formula (4)

[0013]

Embedded image (Wherein, R 7 and R 8 each independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms).

R1 and R2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a C1-4
Alkyl group, alkoxy group having 1 to 4 carbon atoms, 1 carbon atom
1 to 4 aminoalkyl groups, C1 to C4 alkylamino groups, C1 to C4 acyl groups, C1 to C4 acylamino groups, C1 to C4 alkylthio groups, C1 to C1
4 perfluoroalkyl group, C 1-4 perfluoroalkyloxy group, carboxyl group or 1 carbon atom
Represents an alkoxycarbonyl group of 1 to 4.

R3 represents an amino group or a hydroxyl group. ]
And a histone deacetylase inhibitor comprising, as an active ingredient, a benzamide derivative represented by the formula: or a pharmacologically acceptable salt thereof.

[0016]

Embedded image A histone deacetylase inhibitor comprising, as an active ingredient, a benzamide derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, and [3]:

[0017]

Embedded image And a histone deacetylase inhibitor comprising, as an active ingredient, a benzamide derivative represented by the formula: or a pharmacologically acceptable salt thereof.

[0018]

Embedded image A histone deacetylase inhibitor comprising, as an active ingredient, a benzamide derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, and [5] [1] to [4], It is an anticancer drug containing at least one as an active ingredient, and [6] treatment and / or amelioration of a dermatological disease containing at least one of the items described in any one of [1] to [4] as an active ingredient. [7] In any one of [1] to [4],
A therapeutic and / or ameliorating agent for infectious diseases containing at least one as an active ingredient, and [8] [1] to
It is a therapeutic and / or ameliorating agent for allergic diseases, comprising at least one of the active ingredients described in any one of [4] and [9], in any of [1] to [4]. Among them, a therapeutic and / or ameliorating agent for an autoimmune disease containing at least one as an active ingredient, and [10] at least one of the items according to any one of [1] to [4]. A gene therapy effect enhancer contained as an active ingredient, and [11] [1] to
The agent for treating and / or ameliorating a vascular disease, which comprises at least one of the components described in any one of [4] and [12], and is described in any one of [1] to [4]. Are pharmaceuticals containing at least one as an active ingredient.

[0019]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
The term "C1-4" as used herein refers to the number of carbon atoms per unit substituent. That is, for example, in the case of dialkyl substitution, it means having 2 to 8 carbon atoms.

The fused pyridine ring in the compound represented by the formula (1) means quinoline, isoquinoline, naphthyridine, furopyridine, thienopyridine, pyrrolopyridine,
Bicyclic fused pyridine rings such as oxazolopyridine, imidazolopyridine, thiazolopyridine and the like can be mentioned. The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The alkyl group having 1 to 4 carbon atoms includes, for example, methyl group, ethyl group, n-propyl group, isopropyl group,
n-butyl group, isobutyl group, sec-butyl group, te
An rt-butyl group and the like can be mentioned. Carbon number 1
Examples of the alkoxy group 4 include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an allyloxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. Examples of the aminoalkyl group having 1 to 4 carbon atoms include an aminomethyl group, a 1-aminoethyl group, and a 2-aminopropyl group.

The alkylamino group having 1 to 4 carbon atoms includes, for example, N-methylamino group, N, N-dimethylamino group,
N, N-diethylamino group, N-methyl-N-ethylamino group, N, N-diisopropylamino group and the like can be mentioned. Examples of the acyl group having 1 to 4 carbon atoms include an acetyl group, a propanoyl group, and a butanoyl group.

The acylamino group having 1 to 4 carbon atoms includes, for example, an acetylamino group, a propanoylamino group and a butanoylamino group.

The alkylthio group having 1 to 4 carbon atoms includes a methylthio group, an ethylthio group and a propylthio group. Examples of the perfluoroalkyl group having 1 to 4 carbon atoms include a trifluoromethyl group and a pentafluoroethyl group.

The perfluoroalkyloxy group having 1 to 4 carbon atoms includes, for example, a trifluoromethoxy group and a pentafluoroethoxy group. Carbon number 1
Examples of the alkoxycarbonyl group 4 include a methoxycarbonyl group and an ethoxycarbonyl group.

The optionally substituted alkyl group having 1 to 4 carbon atoms includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s
ec-butyl group, tert-butyl group and the like, and as its substituent, 1 to 4 groups selected from the group consisting of halogen atom, hydroxyl group, amino group, nitro group, cyano group, phenyl group and pyridine ring Can be mentioned. Salts of pharmacologically acceptable compounds include inorganic acids commonly used in this field, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, fumaric acid, Examples thereof include salts with organic acids such as maleic acid, citric acid, benzoic acid, trifluoroacetic acid, p-toluenesulfonic acid, and methanesulfonic acid.

Pharmaceuticals include anticancer drugs, skin diseases, infectious diseases,
It refers to a drug for treating and / or ameliorating an allergic disease, an autoimmune disease, a vascular disease and the like, or a gene therapy effect enhancer. When the compound represented by the formula (1) has an asymmetric carbon, it can exist in the form of a mixture of different stereoisomeric forms or stereoisomeric forms including racemic forms. That is, the present invention also includes various forms defined as described above, and these can be similarly used as the active ingredient compound.

The typical compounds of the present invention represented by the formula (1) are shown in Table 1 [Table 1 to Table 14]. Note that the present invention is not limited to these examples.

[0029]

[Table 1]

[0030]

[Table 2]

[0031]

[Table 3]

[0032]

[Table 4]

[0033]

[Table 5]

[0034]

[Table 6]

[0035]

[Table 7]

[0036]

[Table 8]

[0037]

[Table 9]

[0038]

[Table 10]

[0039]

[Table 11]

[0040]

[Table 12]

[0041]

[Table 13]

[0042]

[Table 14] The compound of the present invention represented by the formula (1) or a pharmacologically acceptable salt thereof can be produced by the method described in Japanese Patent Application No. 09-260277, for example, by the following method. can do. (A) Formula (8)

[0043]

Embedded image [Wherein, A and X are as defined above. R9 is -C (= G)
OH (G represents an oxygen atom or a sulfur atom) or-
Represents NH2. And a compound represented by the formula (9)
6]

[0044]

Embedded image [Wherein, R1, R2 and n are as defined above. R10 is R
When 9 is -C (= G) OH (G is as defined above)
It represents H _2, when R9 is -NH ₂ -C (= G) OH
(G is as defined above). R11 represents an amino group protected with a protecting group such as a tert-butoxycarbonyl group used in a usual peptide forming reaction or a hydroxyl group protected with a protecting group such as a benzyl group used in a usual peptide forming reaction. Or a compound represented by the formula (10):

[0045]

Embedded image Compound represented by (wherein, A and X are defined as above .R12 represents -OH or -NH _2.) And the formula (11)
[Formula 18]

[0046]

Embedded image (Wherein, R1, R2, R11 and n are as defined above. R
13 represents -OH or -NH _2. ) Is converted to N, N'-carbonyldiimidazole, N, N '
Formula (1) obtained by subjecting to condensation reaction using thiocarbonyldiimidazole, phosgene or thiophosgene, etc.
2) [Chemical Formula 19]

[0047]

Embedded image (Wherein A, X, Q, n, R1, R2 and R11 have the same meanings as described above), whereby the compound of the present invention can be obtained by removing the protective group. (C) a compound represented by the formula (8) and a compound represented by the formula (13):
0]

[0048]

Embedded image (Wherein, R1, R10 and n are as defined above. R14
Represents a methyl group, an ethyl group or a tert-butyl group. (D) is subjected to a condensation reaction, or (d) a compound represented by the formula (10) and a compound represented by the formula (14)

[0049]

Embedded image (Wherein R1, R13, R14 and n have the same meanings as described above), and condensed with N, N′-carbonyldiimidazole, N, N′-thiocarbonyldiimidazole, phosgene or thiophosgene, etc. Formula (15) obtained by the reaction

[0050]

Embedded image (Wherein, A, X, Q, n, R1 and R14 have the same meanings as described above).
6) [Formula 23]

[0051]

Embedded image (Wherein, A, X, Q, n and R1 have the same meanings as described above).

[0052]

Embedded image (Wherein R2 and R11 have the same meanings as described above). The compound of the present invention can also be obtained by removing the protecting group of the compound represented by the formula (12) obtained by subjecting the compound to a condensation reaction. Can be. (E) a compound represented by the formula (16) and a compound represented by the formula (18):

[0053]

Embedded image (Wherein R2 and R3 have the same meanings as described above). The compound of the present invention can also be obtained by subjecting the compound to a condensation reaction.

The synthesis of a typical intermediate will be described. The compound represented by the formula (8) is represented by the formula (19)

[0055]

Embedded image (Wherein R1, R10 and n are as defined above), after introducing a suitable protecting group into the benzoic acid derivative represented by the formula (17), subjecting it to a condensation reaction with the compound represented by the formula (17) and further deprotection. Can be obtained.

The compound represented by the formula (11) is represented by the formula (2)
0) [Formula 27]

[0057]

Embedded image (Wherein R1, R13 and n have the same meanings as described above), and after introducing a suitable protecting group into the benzoic acid derivative represented by the formula (17), the compound is subjected to a condensation reaction with the compound represented by the formula (17) to further deprotect. Can be obtained. The compound represented by the formula (17) can be obtained by introducing a protecting group into the compound represented by the formula (18).

Next, the reaction will be described. The condensation reaction (a) is carried out by an amide bond in an ordinary peptide.
Coupling reactions, such as active esters or mixed anhydrides
Or by the method of acid chlorides. An example
For example, a carboxylic acid component [in the formula (8), R9 is -C
(= G) OH (G is as defined above).
Or, in the formula (9), R10 is -C (= G) OH (G is
A compound represented by the same definition as above)] and 2,4,5-tric
Lorophenol, pentachlorophenol or 4-
Phenols such as nitrophenol, or N-hydrido
Roxysuccinimide, N-hydroxybenztriazole
N-hydroxy compounds such as dicyclohexylcar
Condensation in the presence of bodimide, converted to active ester form
After the reaction, an amine component [in the formula (8), R9 is -NH _Two
In the compound represented by the formula or formula (9), R10 is -N
H_TwoAnd a compound represented by the formula:
be able to.

Further, a carboxylic acid component [a compound represented by formula (8) wherein R9 is -C (= G) OH (G is as defined above) or R10 is -C (= G) O in formula (9)
H (G is as defined above)] with oxalyl chloride, thionyl chloride, phosphorus oxychloride, etc.
After converting to the acid chloride can be carried out by condensation with the amine component [R10 a compound represented by -NH2 in a compound R9 is represented by -NH ₂ in the formula (14) or formula (9)].

Further, a carboxylic acid component [a compound represented by the formula (8) wherein R9 is -C (= G) OH (G is as defined above) or R10 is -C (= G) O in the formula (9)
After H (G is said synonymous) to obtain a mixed acid anhydride by reacting such a compound] isobutyl chlorocarbonate or methanesulfonyl chloride represented by, R9 is In -NH ₂ in the amine component [formula (8) R10 in a compound or the formula (9) shown can be carried out by condensation with compound represented by -NH _2.

Furthermore, the condensation reaction is carried out by a peptide condensation such as dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, diphenylphosphate azide, diethylphosphate cyanide, 2-chloro-1,3-dimethylimidazolonium chloride. It can also be performed using the reagent alone.

The reaction is usually carried out at -20 to + 50 ° C. for 0.5 to
Perform for 48 hours. Examples of the solvent used include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and diethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, and N, N-dimethylformamide. Examples thereof include alcohols such as methanol and ethanol, and mixtures thereof. If necessary, an organic base such as triethylamine or pyridine is added to react.

In the condensation reaction (b), one of the compounds represented by the formulas (10) and (11) is converted to phosgene,
It can be carried out by activating with thiophosgene, N, N'-carbonyldiimidazole, N, N'-thiocarbonyldiimidazole or the like, followed by reacting with another compound. The reaction is usually performed at −20 to + 50 ° C.
For 0.5 to 48 hours. As the solvent used, for example, benzene, aromatic hydrocarbons such as toluene,
Ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as methylene chloride and chloroform; N, N-dimethylformamide;
Or a mixture thereof. If necessary, an organic base such as triethylamine or pyridine is added to carry out the reaction.

The condensation reaction (c) can be carried out in the same manner as the condensation reaction (a).

The condensation reaction of (d) can be carried out by the same method as the condensation reaction of (b). The removal of the protecting group of the compound represented by the formula (11) is performed under the conditions used for a general peptide formation reaction. For example, when R11 in the formula (12) is an amino group protected with a tert-butoxycarbonyl group, the deprotection reaction can be performed by treating with an acid such as hydrochloric acid or trifluoroacetic acid.

The salt of the compound represented by the formula (1) can be obtained by a reaction for producing the compound represented by the formula (1), but can easily form a salt with a pharmaceutically acceptable acid. Examples of the acid include hydrochloric acid, hydrobromic acid, sulfuric acid,
Examples thereof include inorganic acids such as phosphoric acid, and organic acids such as acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, and p-toluenesulfonic acid.
These salts can also be used as the active ingredient compound of the present invention similarly to the free form of the compound of the formula (1).

The compound represented by the formula (1) can be isolated and purified from the reaction mixture by a usual separation means, for example, an extraction method, a recrystallization method, a column chromatography and the like.

The benzamide derivative of the present invention having an inhibitory effect on histone deacetylase is useful as a therapeutic and / or ameliorating agent for diseases related to cell proliferation, an agent for enhancing the effect of gene therapy or an immunosuppressant. Here, the disease relating to cell proliferation includes malignant tumor, autoimmune disease, skin disease, infectious disease, vascular disease, allergic disease, gastrointestinal tract injury, hormonal disease, diabetes and the like.

Malignant tumors include hematopoietic tumors such as acute leukemia, chronic leukemia, malignant lymphoma, multiple myeloma, and macroglobulinemia, as well as colorectal cancer, brain tumor, head and neck cancer, breast cancer,
Lung, esophagus, gastric, liver, gallbladder, bile duct, pancreatic, islet cell, renal cell, adrenal cortical, bladder, prostate,
Solid tumors such as testicular tumor, ovarian cancer, uterine cancer, choriocarcinoma, thyroid cancer, malignant carcinoid tumor, skin cancer, malignant melanoma, osteosarcoma, soft tissue sarcoma, neuroblastoma, Wilms tumor, retinoblastoma No. Autoimmune diseases include rheumatism, nephritis, diabetes, systemic lupus erythematosus, human autoimmune lymphoproliferative lymphadenopathy, immunoblastic lymphadenopathy, Crohn's disease, ulcerative colitis and the like.
Skin diseases are psoriasis, acne, eczema, atopic dermatitis,
Examples include parasitic skin diseases, alopecia, purulent skin diseases, and skin sclerosis. Infectious diseases refer to diseases caused by infections such as various bacteria, viruses or parasites. The vascular disease includes arteriosclerosis and the like. The enhancement of the effect of the gene therapy includes, for example, increasing the efficiency of introduction of a gene vector and enhancing the expression of a transgene. The target disease of the present invention is not limited to these.

The active ingredient compounds of the present invention are useful as pharmaceuticals, and they are used in the form of general medical preparations. The formulation contains commonly used fillers, extenders, binders,
It is prepared using diluents or excipients such as humectants, disintegrants, surfactants and lubricants. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections (solutions, suspensions). And suppositories.

In molding into tablets, various carriers well known in the art can be widely used as carriers. Examples include lactose, glucose, starch, calcium carbonate, kaolin,
Excipients such as crystalline cellulose and silicic acid, water, ethanol,
Binders such as propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, polyvinylpyrrolidone, disintegrators such as dried starch, sodium alginate, agar powder, carmellose calcium, starch, lactose, etc. Disintegration inhibitors such as sucrose, cocoa butter, hydrogenated oils, etc., absorption promoters such as quaternary ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. And a lubricant such as talc, stearate and polyethylene glycol. Furthermore, tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets.

For molding into a pill form, a wide variety of carriers conventionally known in this field can be used. Examples include crystalline cellulose, lactose, starch,
Excipients such as hardened vegetable oil, kaolin, talc, etc., binders such as gum arabic powder, tragacanth powder, gelatin and the like, disintegrants such as carmellose calcium, agar and the like can be mentioned.

Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the resulting mixture into hard gelatin capsules, soft capsules, and the like, according to a conventional method.

When prepared as an injection, the liquid preparation, emulsion and suspension are preferably sterilized and isotonic with blood. In forming these forms, they are commonly used as diluents in this field. Things, such as water,
Ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, an amount of salt, glucose or glycerin necessary for preparing an isotonic solution may be contained in the pharmaceutical preparation,
Further, ordinary solubilizers, buffers, soothing agents and the like may be added.

In molding into suppository form, conventionally known carriers can be widely used. Examples thereof include semi-synthetic glycerides, cocoa butter, higher alcohols, esters of higher alcohols, polyethylene glycol and the like.

Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals can be contained in the pharmaceutical preparation.

The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight, preferably about 1 to 70% by weight in the preparation composition. Is preferably about 5 to 50% by weight.

The method of administering these pharmaceutical preparations of the present invention is not particularly limited, and the pharmaceutical preparations are administered according to various preparation forms, the age, sex, degree of disease and other conditions of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally, and injections are
It is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acids, and if necessary, intramuscularly, subcutaneously or intraperitoneally. Suppositories are administered rectally.

The dose of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, the age, sex, degree of disease and other conditions of the patient. Usually, the amount of the active ingredient compound is one per kg of body weight. It is preferable to use about 0.0001 to 100 mg per day. It is desirable that the active ingredient compound be contained in a dosage unit form in a range of about 0.001 to 1,000 mg.

The compound represented by the formula (1) and a salt thereof of the present invention do not show toxicity at a dose that is pharmacologically effective.

[0081]

The present invention will be described below in detail with reference to examples.
The present invention is not limited to these. Test Example 1 (Histone deacetylase inhibitory action) (1) [^ThreeH] Preparation of acetyl histone K562 cells (10⁸) To [^ThreeH] Sodium n-butyrate
And the method of Yoshida et al. (J. Biol. Chem.,
265: 17174, 1990)
Issued. (2) Partial purification of histone deacetylase K562 cells (2.5 × 10⁸Nucleus collected from
Tada et al.'S method (J. Biol. Chem., 265: 17).
174, 1990).
Using oQ HR5 / 5 (Pharmacia), 0-1M
Histone deacetylase by NaCl concentration gradient
Was partially purified. (3) Measurement of histone deacetylase inhibitory activity Prepared in (1) [^ThreeH] acetyl histone 100μ
g / ml and histone deacetylase prepared in (2)
Buffer A containing 2 μl of fraction [Composition: 5 mM potassium phosphate
(PH 7.5), 5% glycerol, 13 mM ED
TA] in 50 μl for 10 minutes at 37 ° C.
Was. After stopping the reaction by adding 2.5N hydrochloric acid, acetic acid was added.
Add 550 μl of ethyl, vortex and centrifuge.
Add 400 μl of ethyl acetate layer to scintillation via
And add 2 ml of scintillator to allow reaction.
Released^Three[H] acetic acid radioactivity was measured. Histo
For the measurement of deacetylase inhibitory activity, the test compound
After dissolving in MSO, appropriately dilute with buffer A and add to the reaction system
The concentration of the drug that causes 50% enzyme inhibition (I
C ₅₀: ΜM). The experimental results are shown in Table 2 below.
The results are shown in [Table 15 to Table 17].

[0082]

Table 15 Table 2 Histone deacetylase inhibitory activity 活性 Activity value for detailed description Compound number (IC in Table 1) ₅₀ : μM) ───────────────────── 1 2.01 4 9.13 5 4.20 8 4.23 9 7.01 11 18.50 12 6.89 13 0.87 14 3.22 15 3.72 16 2.88 17 2.66 18 2.43 19 1.94 20 5.12 22.46 ──────────

[0083]

[Table 16] Continuation (1) 活性 Activity value for detailed description Compound number in Table 1 (IC ₅₀ : μM) ) ２３ 23 3.30 24 1.69 25 4.53 26 7.07 27 8.77 28 1.80 29 4.85 30 5.04 31 10.43 32 24.30 33 3.01 34 4.11 36 6.89 38 12.25 39 1.42 40 1.75 41 3.72 42 2.99 43 3.27 44 5 .40 ─────────────────────

[0084]

[Table 17] Continuation (2) 活性 Activity value for detailed description Compound number in Table 1 (IC ₅₀ : μM) ) ４５ 45 3.90 46 4.17 47 2.50 48 2.30 50 4.86 51 2.12 52 3.86 53 2.52 54 1.22 55 2.63 57 2.22 58 3.48 59 1.00 60 1.92 61 3.14 62 3.17 63 4.76 64 0.53 65 4.36 66 3 .59 67 2.20 Sodium butyrate 190─────────────────────

Reference Example 1 N- (2-aminophenyl) -4- [N- (pyridine-
Synthesis of 3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 14) (1-1) 21 g of 4-aminomethylbenzoic acid (140
mmol) in dichloromethane (450 ml).
42 ml (300 mmol) of triethylamine were added. Under ice-cooling, a solution of 60 g (287 mmol) of trifluoroacetic anhydride in dichloromethane (50 ml) was added dropwise while maintaining the internal temperature at 3 to 8 ° C, and the mixture was stirred for 3 hours. After the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate, the solution was further acidified with a 10% aqueous hydrochloric acid solution. The precipitated gel precipitate was collected by filtration and dried to obtain 30 g (yield 87%) of 4- (N-trifluoroacetylaminomethyl) benzoic acid as a milky white solid. 1H NMR (270MHz, DMSO-d6) δppm: 4.47 (2H, d, J = 5.8Hz),
7.39 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 10.08 (1H,
t, J = 5.8Hz), 12.95 (1H, br.s).

(1-2) o-phenylenediamine 10
To a solution of 8 g (1.0 mol) of dioxane (1000 ml) was added a 1 N aqueous solution of sodium hydroxide (500 ml), and ditert-butoxydicarbonate 218 was added under ice cooling.
g (1.1 mol) in dioxane (500 ml) was added. After stirring at room temperature for 6 hours, the mixture was left overnight. Solvent 1
After concentrating to ２ volume, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform). The obtained solid was washed with ethyl ether to give N-tert-butoxy. Carbonyl-o-
68.4 g (32% yield) of phenylenediamine were obtained as a white solid. 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 3.75 (2H,
s), 6.26 (1H, s), 6.77 (1H, d, J = 8.1Hz), 6.79 (1H, dd, J =
7.3,8.1Hz), 7.00 (1H, dd, J = 7.3,8.1Hz), 7.27 (1H, d, J =
8.1Hz).

(1-3) 30 g (121 mmol) of the compound obtained in the step (1-1) was added to dichloromethane (20
0 ml) to the suspension while cooling with ice (internal temperature 10 to 15 ° C.)
21 g (165 mmol) of oxalyl chloride was gradually added dropwise. At that time, DMF was added occasionally (approximately 0.1 ml for every 2 ml added). After dropping the whole amount, the mixture was stirred until foaming stopped, and then stirred at 40 ° C. for 1 hour. After the solvent was distilled off, excess oxalyl chloride was azeotropically distilled with toluene, and dissolved again in dichloromethane (100 ml). 22 g of the compound obtained in the step (1-2) (110
(mmol) in a dichloromethane (100 ml) -pyridine (200 ml) solution under ice cooling (internal temperature 7 to 9 ° C). After the completion of the dropping, the temperature was raised to room temperature, and then left overnight. After adding saturated aqueous sodium hydrogen carbonate to the reaction mixture, the mixture was extracted with chloroform, washed with saturated saline, dried, and the solvent was distilled off. Methanol-diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to give N- [2- (N-tert).
-Butoxycarbonyl) aminophenyl] -4- (N-
Trifluoroacetylaminomethyl) benzamide 28
g (58% yield) as a pale yellow solid. 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.48 (2H,
d, J = 5.9Hz), 7.12-7.23 (2H, m), 7.44 (2H, d, J = 8.1Hz),
7.54 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.68 (1H, b
rs), 9.83 (1H, s), 10.10 (1H, br.t, J = 5.9Hz).

(1-4) Compound 13 of Step (1-3)
To a suspension of g (30 mmol) in methanol (120 ml) -water (180 ml) was added 4.7 g of potassium carbonate (34 m
mol), and the mixture was heated and stirred at 70 ° C. for 4 hours. Extract with chloroform, wash the organic layer with saturated saline, dry,
The solvent was distilled off and dried to obtain 10.3 g (quantitative) of 4-aminomethyl-N- [2- (N-tert-butoxycarbonyl) aminophenyl] benzamide as a pale yellow amorphous solid. 1H NMR (270MHz, DMSO-d6) δppm: 3.80 (2H, s), 7.13-7.2
3 (2H, m), 7.48-7.58 (4H, m), 7.90 (2H, d, J = 8.1Hz), 8.69
(1H, br.s), 9.77 (1H, br.s).

(1-5) 3-pyridinemethanol 38
4 mg (3.5 mmol) was dissolved in 5 ml of dry THF, and 523 mg of N, N'-carbonyldiimidazole was dissolved.
(3.2 mmol) was added at room temperature. After stirring for 1 hour, 1.0 g (2.9 mmol) of the compound of step (1-4)
6 ml of the dry THF solution of l) was added. After standing at room temperature overnight, 100 ml of chloroform was added, and the mixture was washed three times with 20 ml of water. Then, the mixture was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, silica gel column chromatography (chloroform: methanol = 3)
0: 1), and 1.2 g of N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide was converted to an amorphous solid. (Quantitative). 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 4.45 (2H, d,
J = 5.9Hz), 5.16 (1H, s), 7.10-7.50 (7H, m), 7.70 (1H, d, J =
8.1Hz), 7.80 (1H, d, J = 7.3Hz), 7.93 (1H, d, J = 8.1Hz), 8.
57 (1H, d, J = 4.4Hz), 8.63 (1H, s), 9.17 (1H, s).

(1-6) Compound of Step (1-5)
2 g (2.8 mmol) was dissolved in 10 ml of methanol. 20 ml of a 4N hydrochloric acid-dioxane solution was added, and the mixture was stirred at room temperature for 1.5 hours. After pouring into a dilute aqueous sodium hydroxide solution, the mixture was extracted three times with 60 ml of chloroform. After washing twice with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated to obtain 0.88 g of crystals. Then ethanol 16
recrystallized with N- (2-aminophenyl) -4.
668 mg (73% yield) of-[N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide were obtained. mp. 159-160 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz),
4.86 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.78 (1H
H, d, J = 7Hz), 6.97 (1H, t, J = 7Hz), 7.17 (1H, d, J = 8Hz), 7.
3-7.5 (3H, m), 7.78 (1H, d, J = 8Hz), 7.93 (2H, d, J = 8Hz),
8.53 (1H, d, J = 3.7Hz), 8.59 (1H, s), 9.61 (1H, s) .IR (KBr) cm ^-1 : 3295,1648,1541,1508,1457,1309,1183,74
2.

[0091]

The benzamide derivative of the present invention having an inhibitory effect on histone deacetylase is useful as a therapeutic and / or ameliorating agent for diseases related to cell proliferation, an effect-enhancing agent for gene therapy or an immunosuppressant. In particular, it is highly effective as an anticancer agent and is effective against hematopoietic tumors and solid cancers.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/44 ADA A61K 31/44 ADA ADU ADU ADZ ADZ AGZ AGZ // A61K 48/00 48/00 (72) Inventor Osamu Nakanishi Mitsui Pharmaceutical Industries Co., Ltd., 1900, Togo, Mobara City, Chiba Prefecture (72) Inventor Akiko Saito 1900, Togo, Togo, Mobara City, Chiba Prefecture, Japan Mitsui Pharmaceutical Industry Co., Ltd. House number 1 Mitsui Pharmaceutical Co., Ltd.

Claims (12)

[Claims] 1. A compound represented by the formula (1): [In the formula, A represents an optionally substituted pyridine ring or a condensed pyridine ring (as a substituent, a halogen atom, a hydroxyl group,
Amino group, nitro group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, aminoalkyl group having 1 to 4 carbon atoms, alkylamino group having 1 to 4 carbon atoms, 1 carbon atom Acyl group having 1 to 4 carbon atoms, acylamino group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyloxy group having 1 to 4 carbon atoms, carboxyl group, A group selected from the group consisting of alkoxycarbonyl groups having 1 to 4 carbon atoms,
Number). X is a direct bond or a compound of the formula (2) 中 In the formula, e represents an integer of 1 to 4. g and m each independently represent an integer of 0-4. R4 is a hydrogen atom, an optionally substituted alkyl group having 1 to 4 carbon atoms or a group represented by the formula (3): (Wherein, R 6 represents an optionally substituted alkyl group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, a phenyl group or a pyridine ring). R5 represents any of the structures represented by｝ representing a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms. n represents an integer of 1 to 4. Q is the equation (4)
[Formula 4] [Formula 4] (Wherein, R 7 and R 8 each independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms). R1 and R2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, an alkyl group having 1 to 4 carbon atoms,
C4 to C4 alkoxyamino group, C1 to C4 aminoalkyl group, C1 to C4 alkylamino group, C1 to C4 acyl group, C1 to C4 acylamino group, C1 to C1
4 represents an alkylthio group, a perfluoroalkyl group having 1 to 4 carbon atoms, a perfluoroalkyloxy group having 1 to 4 carbon atoms, a carboxyl group, or an alkoxycarbonyl group having 1 to 4 carbon atoms. R3 represents an amino group or a hydroxyl group. ] A histone deacetylase inhibitor comprising, as an active ingredient, a benzamide derivative or a pharmacologically acceptable salt thereof. 2. A compound of the formula (5) A histone deacetylase inhibitor comprising, as an active ingredient, a benzamide derivative represented by the formula or a pharmacologically acceptable salt thereof. 3. A compound of the formula (6) A histone deacetylase inhibitor comprising, as an active ingredient, a benzamide derivative represented by the formula or a pharmacologically acceptable salt thereof. 4. A compound of the formula (7) A histone deacetylase inhibitor comprising, as an active ingredient, a benzamide derivative represented by the formula or a pharmacologically acceptable salt thereof. 5. An anticancer agent comprising at least one of the inhibitors according to claim 1 as an active ingredient. 6. A therapeutic and / or ameliorating agent for dermatosis, comprising at least one of the inhibitors according to claim 1 as an active ingredient. 7. An agent for treating and / or ameliorating an infectious disease, comprising at least one of the inhibitors according to claim 1 as an active ingredient. 8. An agent for treating and / or ameliorating an allergic disease, comprising at least one of the inhibitors according to claim 1 as an active ingredient. 9. An agent for treating and / or ameliorating an autoimmune disease, comprising at least one of the inhibitors according to claim 1 as an active ingredient. 10. A gene therapy effect enhancer comprising at least one of the inhibitors according to claim 1 as an active ingredient. 11. An agent for treating and / or ameliorating a vascular disease, comprising at least one of the inhibitors according to claim 1 as an active ingredient. 12. A drug containing at least one inhibitor according to claim 1 as an active ingredient.