JP4528918B2 - Carboxamide derivatives - Google Patents

Description

  The present invention relates to carboxamide (carboxamide) derivatives. More specifically, the present invention has, for example, histone deacetylase (HDAC) inhibitory activity, and includes anticancer agents, anticancer agents, cardiac hypertrophy improving agents, immunosuppressive agents, gene therapy effect enhancing agents, neurodegenerative disease improving agents, etc. The present invention relates to a carboxamide derivative that can be used for the above-mentioned applications.

  In recent years, histone deacetylase (HDAC) has attracted attention as a new molecular target for cancer drug therapy. In eukaryotic nuclei, DNA has a nucleosome-based chromatin structure. It is considered that when a specific lysine residue of histone, which is a protein constituting a nucleosome, is acetylated, the positive charge of histone is neutralized, the nucleosome structure is relaxed, and transcription is activated. Acetylation of specific lysine residues in histone molecules is turned over by histone acetylase (HAT) and deacetylase (HDAC). In recent years, it has been reported that drugs that inhibit the latter enzyme HDAC exhibit cell cycle arrest, apoptosis-inducing activity and differentiation induction of tumor cells (Non-patent Document 1). From this, it was considered that the decrease in histone acetylation in a specific gene region is closely related to cancer. Therefore, there is an increasing expectation that an HDAC inhibitor that accumulates highly acetylated histones can be a new type of anticancer agent, and its application to anticancer agents is strongly desired.

As an HDAC inhibitor, trichostatin A (Non-patent document 2), trapoxin (Non-patent document 3) and the like have been found from natural resources. In addition, synthetic compounds such as MS-275 (Non-patent Document 4), SAHA (Non-patent Document 5) and the like are in clinical trials as compounds of the same system as these two agents. In addition, FK228 (Non-patent Document 6) having a depsipeptide structure is in clinical trials. Furthermore, as an HDAC inhibitor, a compound having a 2-aminophenylbenzamide group or a 2-hydroxyphenylbenzamide group (Non-Patent Document 4), a compound having a plurality of amide groups or ester groups in one molecule (Non-Patent Document 4). To 7), 3- (4-aroyl-1H-pyrrol-2-yl) -N-hydroxy-2-propenamide derivatives (Non-patent document 8), sulfonamide derivatives (Non-patent document 9) and the like are also known. ing. However, as a result of clinical trials, the above compounds are known to have problems in compound safety, physical properties (stability, solubility, etc.), drug pharmacokinetics, metabolic stability, etc. Therefore, the emergence of HDAC inhibitors with a new structure is awaited.
Exp. Cell Res., 177, 122-131 (1988); Cancer Res., 47, 3688-3691 (1987) J. Biol. Chem., 265, 17174-17179 (1990) J. Antibiot., 43 (12), 1524-1534 (1990) Proc. Natl. Acad. Sci. USA, 96, 4592-4597 (1999) Proc. Natl. Acad. Sci. USA, 95, 3003-3007 (1998) Exp. Cell Res., 241, 126-133 (1998) Oncogene, 13, 143-149 (1996) J. Med. Chem., 44, 2069-2072 (2001) Bioorg. & Med. Chem. Lett., 11, 2847-2850 (2001)

  Therefore, an object of the present invention is to provide a novel compound having strong cancer cell growth inhibitory activity and the like, and excellent in metabolic stability, solubility and the like.

  In order to solve the above problems, the compound of the present invention is a carboxamide derivative represented by the following general formula [I], a tautomer or stereoisomer thereof, or a salt thereof.

前記式［Ｉ］中、
Ｌ^１、Ｌ^２およびＬ^３は、同一であるかまたは異なり、それぞれ、直鎖もしくは分枝アルキレン基であるか、または存在せず、
［Ａ］は、ヒドロキシ基であるか、または１もしくは複数の電子供与基で置換された芳香環であり、
［Ｂ］は、飽和または不飽和の単環または縮合環であり、ヘテロ原子を含んでいても含んでいなくても良く、１または複数の置換基で置換されていても置換されていなくても良く、
［Ｃ］は、水素またはヒドロキシ基であり、
［Ｄ］は、飽和または不飽和の単環または縮合環であり、ヘテロ原子を含んでいても含んでいなくても良く、１または複数の置換基で置換されていても置換されていなくても良い。

In the formula [I],
L ¹ , L ² and L ³ are the same or different and are each a linear or branched alkylene group or absent,
[A] is a hydroxy group or an aromatic ring substituted with one or more electron donating groups;
[B] is a saturated or unsaturated monocyclic or condensed ring, which may or may not contain a hetero atom, and may be substituted with one or more substituents. Well,
[C] is hydrogen or a hydroxy group,
[D] is a saturated or unsaturated monocyclic or condensed ring, which may or may not contain a heteroatom, and may be substituted with one or more substituents. Also good.

  Since the compound of the present invention has the above structure, it has strong cancer cell growth inhibitory activity and the like, and is excellent in metabolic stability, solubility and the like. Further, the compound of the present invention has excellent histone deacetylase (HDAC) inhibitory activity, so that, in addition to anticancer agents or anticancer agents, for example, cardiac hypertrophy improving agents, immunosuppressive agents, gene therapy effect enhancing agents, nerves It can also be used for applications such as degenerative disease remedies.

  Hereinafter, the present invention will be described in more detail.

  Prior to the present invention, the present inventors obtained an N-hydroxycarboxamide derivative having a bicyclic aromatic hydrocarbon group at one end of the molecular structure and an N-hydroxybenzamide group at the other end. It was created as a histone deacetylase inhibitor [Bioorg. & Med. Chem. 12, 4351-4360 (2004), and WO 03/070691 (PCT / JP03 / 01681)]. And it discovered that the said N-hydroxy carboxamide derivative | guide_body has the proliferation inhibitory effect which exceeds MS-275 in the human colon cancer cell strain HCT116 cell proliferation inhibitory test. Furthermore, in an anti-cancer screening [Cancer and Chemotherapy, 25, Supplement II, 147-156 (1998)] using a panel of human cultured cancer cells (38 strains), the effective concentration was sufficiently low, and differential growth inhibition was observed, and compare negative: It was found that r <0.5 or high activity around 0.5. These numerical values suggested that the N-hydroxycarboxamide derivative had a tumor cell growth inhibitory action with a unique mechanism of action. In fact, some of the N-hydroxycarboxamide derivatives showed a high life-prolonging effect in a mouse model transplanted with P388 leukemia cells (T / C, up to 185%) [Bioorg. & Med. Chem. 12, 4351-4360 (2004)].

  At this time, the present inventors focused on the excellent structural features of the N-hydroxycarboxamide derivative and developed structural modifications aiming at further improvement in water solubility and metabolic stability. As a result of intensive studies, the carboxamide derivative represented by the above general formula [I], its tautomer or stereoisomer, or a salt thereof has excellent solubility (water solubility), metabolic stability, and the like. As a result, the present invention has been completed.

  The compound of the present invention has, for example, stronger HDAC inhibitory action, cancer cell growth inhibitory action and the like than conventional carboxamide derivatives, and improved physical properties such as water solubility and metabolic stability. . As a result, the compound of the present invention has, for example, higher histone deacetylase inhibitory activity while maintaining almost the same level of cancer cell growth inhibitory activity as SAHA and MS-275 currently in clinical trials, and It can be used as a histone deacetylation inhibitor that has improved physical properties.

  The compound of the present invention, for example, has a hydroxyalkylamino group or an alkylamino group as a partial structure of the molecule, so that the histone desorption of Non-Patent Documents 4 to 7 having a plurality of amide groups and ester groups in one molecule. Compared to acetylase inhibitors, it is excellent in water solubility and metabolic stability. In addition, among the compounds of the present invention, for example, a compound having a 2-aminophenylbenzamide group or a 2-hydroxyphenylbenzamide group as in the compound of Non-Patent Document 4 may be a drug with higher metabolic stability. Be expected. Furthermore, the compound of the present invention has an excellent HDAC inhibitory activity, so that, for example, a therapeutic and / or ameliorating agent for diseases related to cell proliferation, an effect enhancing agent for gene therapy, a cardiac hypertrophy improving agent, an immunosuppressive agent Also, it can be expected to be applied to various uses such as drugs that delay or prevent neurodegenerative diseases such as Huntington's disease caused by expansion of polyglutamine repeats.

  Next, the compound of the present invention will be described in more detail.

  When the carboxamide derivative represented by the formula [I] or a salt thereof has a tautomer or stereoisomer (eg, geometric isomer and conformer), each of the separated isomers and Mixtures are also included in the compounds of the present invention. In addition, when the carboxamide derivative represented by the formula [I] or a salt thereof has an asymmetric carbon in its structure, those optically active substances and racemic mixtures are also included in the compound of the present invention.

  The salt of the carboxamide derivative represented by the formula [I] may be an acid addition salt or a base addition salt. The acid forming the acid addition salt may be an inorganic acid or an organic acid. Although it does not specifically limit as an inorganic acid, For example, a sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid etc. are possible. The organic acid is not particularly limited, and examples thereof include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. The base forming the base addition salt may be an inorganic base or an organic base. Examples of the inorganic base include, but are not limited to, ammonium hydroxide, alkali metal hydroxide, alkaline earth metal hydroxide, carbonate, bicarbonate, and the like. More specifically, for example, Sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydroxide, calcium carbonate and the like are possible. The organic base is not particularly limited, and for example, ethanolamine, triethylamine, tris (hydroxymethyl) aminomethane and the like are possible.

In the formula [I], the atomic groups represented by [A], [B] and [D] preferably satisfy the following conditions, for example. That is, first, [A] is a hydroxy group, or a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, or other aromatic ring substituted with one or more substituents. It preferably contains at least one of an amino group and a hydroxy group. [B] is a cyclohexyl group, other cycloalkyl group, adamantyl group, or other bicyclic or tricyclic cycloalkyl group, phenyl group, naphthyl group, anthryl group, phenanthryl group, biphenylyl group, or other Monocyclic, bicyclic or tricyclic unsaturated ring, pyridyl group, quinolyl group, isoquinolyl group, indolyl group, 1,3-benzodioxolyl group, benzofuranyl group, benzothienyl group, morpholinyl group, or others A monocyclic, bicyclic or tricyclic saturated or unsaturated heterocyclic ring, which may or may not be substituted with one or more substituents, Each of the substituents is independently halogen, linear or branched alkyl group, phenyl group, benzyl group, hydroxy group, Or branched alkoxy group, phenoxy group, benzyloxy group, methylenedioxy group, mercapto group, linear or branched alkylthio group, phenylthio group, benzylthio group, formyl group, linear or branched alkanoyl group, benzoyl group, Benzylcarbonyl group, carboxy group, linear or branched alkoxycarbonyl group, linear or branched alkoxycarbonyloxy group, carbamoyl group, linear or branched alkylcarbamoyl group, —NR ^a R ^b (R ^a and R ^b are Each independently hydrogen, a linear or branched alkyl group, a formyl group, a linear or branched alkanoyl group, a carboxyl group, or a linear or branched alkoxycarbonyl group.), A sulfo group, a linear or branched group Branched alkylsulfo group, sulfino group, straight chain or branched Alkyl sulfino group, hydroxy-substituted linear or branched alkyl group, mono-di- or trihalogen-substituted linear or branched alkyl group, mono-di- or trihalogen-substituted linear or branched alkoxy group, hydra A dinocarbonyl group, amidino group, nitro group, cyano group, isocyano group, cyanato group, isocyanato group, thiocyanato group, isothiocyanato group, nitroso group, oxo group, imino group or thioxo group are preferred. [D] is a cyclohexylene group, or other cycloalkylene group, bicyclic or tricyclic cycloalkylene group, phenylene group, naphthylene group, anthrylene group, phenanthrylene group, or other monocyclic or bicyclic group Or a tricyclic unsaturated ring, a biphenylene group, or a monocyclic, bicyclic or tricyclic saturated or unsaturated heterocyclic ring, which is substituted even if substituted by one or more substituents In the case where it is substituted, each of the substituents is independently a halogen, a linear or branched alkyl group, a phenyl group, a benzyl group, a hydroxy group, a linear or branched alkoxy group, or a phenoxy group. , Benzyloxy group, methylenedioxy group, mercapto group, linear or branched alkylthio group, phenylthio group, benzylthio group, formi Group, straight-chain or branched alkanoyl group, benzoyl group, benzylcarbonyl group, carboxyl group, straight-chain or branched alkoxycarbonyl group, straight-chain or branched alkoxycarbonyloxy group, carbamoyl group, straight-chain or branched alkylcarbamoyl group -NR ^c R ^d (wherein R ^c and R ^d are each independently hydrogen, a linear or branched alkyl group, a formyl group, a linear or branched alkanoyl group, a carboxyl group, or a linear or branched alkoxycarbonyl group) A sulfo group, a linear or branched alkylsulfo group, a sulfino group, a linear or branched alkylsulfino group, a hydroxy-substituted linear or branched alkyl group, a mono-di- or trihalogen-substituted group. Straight or branched alkyl groups, mono-, di- or tri Gen-substituted linear or branched alkoxy group, hydrazinocarbonyl group, amidino group, nitro group, cyano group, isocyano group, cyanato group, isocyanato group, thiocyanato group, isothiocyanato group, nitroso group, oxo group, imino group or A thioxo group is preferred.

In the formula [I], L ¹ , L ² and L ³ are the same or different and are each preferably a linear or branched C _{1 to} C ₁₂ alkylene group or absent. . [B] is a cyclohexyl group, or another C _{3 to} C ₈ cycloalkyl group, an adamantyl group, or another bicyclic or tricyclic C _{5 to} C ₁₆ cycloalkyl group, a phenyl group, a naphthyl group, or an anthryl group. , Phenanthryl group, biphenylyl group, or other monocyclic, bicyclic or tricyclic unsaturated 5-16 membered ring, pyridyl group, quinolyl group, isoquinolyl group, indolyl group, 1,3-benzodioxolyl group , Benzofuranyl, benzothienyl, morpholinyl, or other monocyclic, bicyclic or tricyclic saturated or unsaturated 5- to 16-membered heterocycles, substituted with one or more substituents even if not also substituted in good, if it is substituted, the substituent are each independently halogen, linear or branched C ₁ -C Alkyl group, a phenyl group, a benzyl group, hydroxy group, a linear or branched C ₁ -C ₆ alkoxy group, a phenoxy group, a benzyloxy group, methylenedioxy group, a mercapto group, a linear or branched C ₁ -C ₆ alkylthio group, a phenylthio group, a benzylthio group, a formyl group, a linear or branched C ₁ -C ₆ alkanoyl group, a benzoyl group, a benzylcarbonyl group, a carboxy group, a linear or branched C ₁ -C ₆ alkoxycarbonyl group, a straight A chain or branched C ₁ -C ₆ alkoxycarbonyloxy group, a carbamoyl group, a straight chain or branched C ₁ -C ₆ alkylcarbamoyl group, —NR ^a R ^b (R ^a and R ^b are each independently hydrogen, linear or branched _C 1 -C ₆ alkyl group, a formyl group, a linear or branched _C 1 -C ₆ alkanol Group, a carboxyl group or a linear or branched C ₁ -C ₆ alkoxycarbonyl group.), A sulfo group, a linear or branched C ₁ -C ₆ alkylsulfonyl group, a sulfino group, a linear or branched C ₁ -C ₆ alkylsulfanyl Fino group, hydroxy-substituted straight or branched _C 1 -C ₆ alkyl group, a mono- di or tri halogen-substituted straight-chain or branched _C 1 -C ₆ alkyl group, mono di or tri halogen-substituted straight-chain or branched C ₁ -C ₆ alkoxy group, hydrazinocarbonyl group, an amidino group, a nitro group, a cyano group, isocyano group, cyanato group, isocyanato group, thiocyanato group, isothiocyanato group, More preferred is a nitroso group, an oxo group, an imino group or a thioxo group. [D] is a cyclohexylene group, or other C _{3 to} C ₈ cycloalkylene group, bicyclic or tricyclic C _{5 to} C ₁₆ cycloalkylene group, phenylene group, naphthylene group, anthrylene group, phenanthrylene group, Or other monocyclic, bicyclic or tricyclic unsaturated 5-16 membered ring, biphenylene group, or monocyclic, bicyclic or tricyclic saturated or unsaturated 5-16 membered heterocyclic ring Yes, it may or may not be substituted with one or more substituents, and when substituted, said substituents are each independently halogen, linear or branched C ₁ -C ₆ alkyl group, a phenyl group, a benzyl group, hydroxy group, a linear or branched C ₁ -C ₆ alkoxy group, a phenoxy group, a benzyloxy group, methylenedioxy group, a mercapto group, Or branched C ₁ -C ₆ alkylthio group, a phenylthio group, a benzylthio group, a formyl group, a linear or branched C ₁ -C ₆ alkanoyl group, a benzoyl group, a benzylcarbonyl group, a carboxyl group, a linear or branched C _{1 to} C ₆ alkoxycarbonyl group, linear or branched C _{1 to} C ₆ alkoxycarbonyloxy group, carbamoyl group, linear or branched C _{1 to} C ₆ alkylcarbamoyl group, —NR ^c R ^d (R ^c and R ^d is each independently hydrogen, linear or branched C ₁ -C ₆ alkyl group, formyl group, linear or branched C ₁ -C ₆ alkanoyl group, carboxyl group, or linear or branched C _1- a C ₆ alkoxycarbonyl group.), a sulfo group, a linear or branched _C 1 -C ₆ alkylsulfonyl group, a sulfino , Straight-chain or branched C ₁ -C ₆ alkylsulfanyl Fino group, hydroxy-substituted straight or branched C ₁ -C ₆ alkyl group, a mono- di or tri halogen-substituted straight-chain or branched C ₁ ~ C ₆ alkyl group, a mono- di or tri halogen-substituted straight-chain or branched C ₁ -C ₆ alkoxy group, hydrazinocarbonyl group, an amidino group, a nitro group, a cyano group, isocyano group, cyanato group, isocyanato group, It is more preferably a thiocyanate group, an isothiocyanate group, a nitroso group, an oxo group, an imino group or a thioxo group.

In the present invention, “halogen” refers to any halogen element, and examples thereof include fluorine, chlorine, bromine and iodine. The alkyl group is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. The same applies to a group containing an alkyl group in its structure (for example, an alkylcarbamoyl group, an alkoxycarbonyl group, etc.). Examples of the alkanoyl group is not particularly limited, for example, a formyl group, an acetyl group, a propionyl group, an isobutyryl group, a valeryl group and an isovaleryl group, and a formyl group and C ₁ alkanoyl group (alkanoyl group having 1 carbon atom) Shall be pointed to.

  In the formula [I], [A] is a hydroxy group, or a phenyl group, a naphthyl group, an anthryl group, or a phenanthryl group substituted with one or more substituents. More preferably, it contains at least one of an amino group and a hydroxy group. [B] is an atomic group represented by a structural formula obtained by removing any one hydrogen from the molecule represented by any of the following formulas (101) to (153), and one or more substituents May or may not be substituted,

置換されている場合は、前記置換基は、それぞれ独立に、ハロゲン、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキル基、フェニル基、ベンジル基、ヒドロキシ基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシ基、フェノキシ基、ベンジルオキシ基、メチレンジオキシ基、メルカプト基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキルチオ基、フェニルチオ基、ベンジルチオ基、ホルミル基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルカノイル基、ベンゾイル基、ベンジルカルボニル基、カルボキシ基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシカルボニル基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシカルボニルオキシ基、カルバモイル基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキルカルバモイル基、 −ＮＲ^ａＲ^ｂ（Ｒ^ａおよびＲ^ｂは、それぞれ独立に、水素、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキル基、ホルミル基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルカノイル基、カルボキシル基、または直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシカルボニル基である。）、スルホ基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキルスルホ基、スルフィノ基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキルスルフィノ基、ヒドロキシ置換された直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキル基、モノ・ジもしくはトリハロゲン置換された直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキル基、モノ・ジもしくはトリハロゲン置換された直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシ基、ヒドラジノカルボニル基、アミジノ基、ニトロ基、シアノ基、イソシアノ基、シアナト基、イソシアナト基、チオシアナト基、イソチオシアナト基、ニトロソ基、オキソ基、イミノ基またはチオキソ基であることがさらに好ましい。［Ｄ］は、前記式（１０１）〜（１５３）のいずれかで表される分子から任意の２個の水素を除いた構造式で表される原子団であり、１個または複数の置換基で置換されていても置換されていなくても良く、置換されている場合は、前記置換基は、それぞれ独立に、ハロゲン、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキル基、フェニル基、ベンジル基、ヒドロキシ基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシ基、フェノキシ基、ベンジルオキシ基、メチレンジオキシ基、メルカプト基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキルチオ基、フェニルチオ基、ベンジルチオ基、ホルミル基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルカノイル基、ベンゾイル基、ベンジルカルボニル基、カルボキシル基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシカルボニル基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシカルボニルオキシ基、カルバモイル基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキルカルバモイル基、 −ＮＲ^ｃＲ^ｄ（Ｒ^ｃおよびＲ^ｄは、それぞれ独立に、水素、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキル基、ホルミル基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルカノイル基、カルボキシル基、または直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシカルボニル基である。）、スルホ基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキルスルホ基、スルフィノ基、直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキルスルフィノ基、ヒドロキシ置換された直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキル基、モノ・ジもしくはトリハロゲン置換された直鎖もしくは分枝Ｃ_１〜Ｃ_６アルキル基、モノ・ジもしくはトリハロゲン置換された直鎖もしくは分枝Ｃ_１〜Ｃ_６アルコキシ基、ヒドラジノカルボニル基、アミジノ基、ニトロ基、シアノ基、イソシアノ基、シアナト基、イソシアナト基、チオシアナト基、イソチオシアナト基、ニトロソ基、オキソ基、イミノ基またはチオキソ基であることが、さらに好ましい。

When substituted, the substituents are each independently halogen, linear or branched C ₁ -C ₆ alkyl group, phenyl group, benzyl group, hydroxy group, linear or branched C ₁ -C _6. Alkoxy group, phenoxy group, benzyloxy group, methylenedioxy group, mercapto group, linear or branched C ₁ -C ₆ alkylthio group, phenylthio group, benzylthio group, formyl group, linear or branched C ₁ -C ₆ Alkanoyl group, benzoyl group, benzylcarbonyl group, carboxy group, linear or branched C ₁ -C ₆ alkoxycarbonyl group, linear or branched C ₁ -C ₆ alkoxycarbonyloxy group, carbamoyl group, linear or branched A C ₁ -C ₆ alkylcarbamoyl group, —NR ^a R ^b (R ^a and R ^b are each independently hydrogen, Linear or branched _C 1 -C ₆ alkyl group, a formyl group, a linear or branched _C 1 -C ₆ alkanoyl group, a carboxyl group or a linear or branched _C 1 -C ₆ alkoxycarbonyl group.) , a sulfo group, a linear or branched _C 1 -C ₆ alkylsulfonyl group, a sulfino group, a linear or branched _C 1 -C ₆ alkylsulfanyl Fino group, hydroxy-substituted straight or branched _C 1 -C ₆ alkyl group, mono di- or tri-halogen-substituted straight-chain or branched C ₁ -C ₆ alkyl group, a mono- di or tri halogen-substituted straight-chain or branched C ₁ -C ₆ alkoxy group, hydrazinocarbonyl Group, amidino group, nitro group, cyano group, isocyano group, cyanato group, isocyanato group, thiocyanato group, isothiocyanato group, nitroso group, o Seo group, more preferably an imino group or a thioxo group. [D] is an atomic group represented by a structural formula obtained by removing any two hydrogen atoms from the molecule represented by any one of the formulas (101) to (153), and one or more substituents in may be unsubstituted substituted, if substituted, the substituents are each independently halogen, linear or branched C ₁ -C ₆ alkyl group, a phenyl group, a benzyl group , hydroxy group, a linear or branched C ₁ -C ₆ alkoxy group, a phenoxy group, a benzyloxy group, methylenedioxy group, a mercapto group, a linear or branched C ₁ -C ₆ alkylthio group, a phenylthio group, a benzylthio group , formyl group, a linear or branched _C 1 -C ₆ alkanoyl group, a benzoyl group, a benzylcarbonyl group, a carboxyl group, a linear or branched _C 1 -C ₆ alkoxycarbonyl , Straight-chain or branched _C 1 -C ₆ alkoxycarbonyloxy group, a carbamoyl group, a linear or branched _C 1 -C ₆ alkylcarbamoyl group, ^-NR c ^R d ^{(R c} and ^{R d} are each independently Hydrogen, linear or branched C ₁ -C ₆ alkyl group, formyl group, linear or branched C ₁ -C ₆ alkanoyl group, carboxyl group, or linear or branched C ₁ -C ₆ alkoxycarbonyl group .), a sulfo group, a linear or branched _C 1 -C ₆ alkylsulfonyl group, a sulfino group, a linear or branched _C 1 -C ₆ alkylsulfanyl Fino group, hydroxy-substituted straight or branched _C 1 ~ C ₆ alkyl group, a mono- di or tri halogen-substituted straight-chain or branched C ₁ -C ₆ alkyl group, a mono- di or tri halogen substituted straight Or branched C ₁ -C ₆ alkoxy group, hydrazinocarbonyl group, an amidino group, a nitro group, a cyano group, isocyano group, cyanato group, isocyanato group, thiocyanato group, isothiocyanato group, nitroso group, oxo group, an imino group or thioxo More preferably, it is a group.

In the formula [I], L ¹ , L ² and L ³ are the same or different and each is a methylene group, an ethylene group (dimethylene group) or a trimethylene group, or is not present. preferable. [A] is a hydroxy group or a phenyl group substituted with one or more substituents, and the substituents are more preferably independently an amino group or a hydroxy group. [D] is more preferably an o-phenylene group, an m-phenylene group or a p-phenylene group. [B] is a group represented by any of the following formulas (154) to (161),

前記式（１５４）〜（１６１）中、
Ｒ^１およびＲ^２は、それぞれ独立に、水素、フッ素、塩素、臭素、ヨウ素、メチル基、エチル基、プロピル基、イソプロピル基、t−ブトキシカルボニル基、ヒドロキシ基、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、t−ブトキシカルボニルオキシ基、もしくは −ＮＲ^ａＲ^ｂ（Ｒ^ａおよびＲ^ｂは、それぞれ独立に、水素、メチル基、エチル基、プロピル基、イソプロピル基、またはt−ブトキシカルボニル基である。）であるか、またはＲ^１とＲ^２が一体となってメチレンジオキシ基を形成し、
Ｒ^３およびＲ^４は、それぞれ独立に、水素、フッ素、塩素、臭素、ヨウ素、もしくはメトキシ基であるか、またはＲ^３とＲ^４が一体となってメチレンジオキシ基を形成し、
Ｘは、ＮＨ、ＮＣＨ_３、ＯまたはＳであることが、一層好ましい。

In the above formulas (154) to (161),
R ¹ and R ² are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl group, ethyl group, propyl group, isopropyl group, t-butoxycarbonyl group, hydroxy group, methoxy group, ethoxy group, propoxy group , Isopropoxy group, t-butoxycarbonyloxy group, or —NR ^a R ^b (R ^a and R ^b are each independently hydrogen, methyl group, ethyl group, propyl group, isopropyl group, or t-butoxycarbonyl group Or R ¹ and R ² together form a methylenedioxy group,
R ³ and R ⁴ are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a methoxy group, or R ³ and R ⁴ together form a methylenedioxy group,
More preferably, X is NH, NCH ₃ , O or S.

Among the carboxamide derivatives represented by the formula [I], particularly preferable compounds include, for example,
N- (2-aminophenyl) -4-{[benzyl (2-hydroxyethyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-({(2-hydroxyethyl) [(1-methyl-1H-indol-3-yl) methyl] amino} methyl) benzamide,
N- (2-aminophenyl) -4-{[(1,3-benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-{[(3,4-difluorobenzyl) (2-hydroxyethyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (3-pyridinylmethyl) amino] methyl} benzamide,
N-hydroxy-4-{[(2-hydroxyethyl) (2-naphthylmethyl) amino] methyl} benzamide,
N-hydroxy-4-({(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] amino} methyl) benzamide,
4-{[(1,3-benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} -N-hydroxybenzamide,
N-hydroxy-4-{[methyl (2-naphthylmethyl) amino] methyl} benzamide,
N-hydroxy-4-{[(2-hydroxyethyl) (3-quinolinylmethyl) amino] methyl} benzamide,
N-hydroxy-4-{[(2-hydroxyethyl) (3-pyridinylmethyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (3-quinolinylmethyl) amino] methyl} benzamide,
2-{{4- [1- (2-aminoanilino) vinyl] benzyl} [(5-methoxy-1H-indol-3-yl) methyl] amino} ethanol,
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (2-naphthylmethyl) amino] methyl} benzamide,
2-{{4- [1- (2-aminoanilino) vinyl] benzyl} [(5-fluoro-1H-indol-3-yl) methyl] amino} ethanol,
N- (2-aminophenyl) -4-({(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] amino} methyl) benzamide,
2-[{4- [1- (2-aminoanilino) vinyl] benzyl} (1-benzofuran-2-ylmethyl) amino] ethanol,
N- (2-aminophenyl) -4-{[[4- (dimethylamino) benzyl] (2-hydroxyethyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (4-methoxybenzyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (4-morpholinylmethyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-{[(3,4-dimethoxybenzyl) (2-hydroxyethyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-{[(4-fluorobenzyl) (2-hydroxyethyl) amino] methyl} benzamide,
4-{[benzyl (2-hydroxyethyl) amino] methyl} -N- (2-hydroxyphenyl) benzamide,
4-{[(1,3-benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} -N- (2-hydroxyphenyl) benzamide,
N-hydroxy-4-({(2-hydroxyethyl) [(1H-indol-3-yl) methyl] amino} methyl) benzamide,
2-([(5-fluoro-1H-indol-3-yl) methyl] {4- [1- (methylamino) vinyl] benzyl} amino) ethanol,
N-hydroxy-4-({(2-hydroxyethyl) [(1-methyl1H-indol-3-yl) methyl] amino} methyl) benzamide,
2-((1-benzofuran-2-ylmethyl) {4- [1- (methylamino) vinyl] benzyl} amino) ethanol,
2-([(5-methoxy-1H-indol-3-yl) methyl] {4- [1- (methylamino) vinyl] benzyl} amino) ethanol,
and
1- (4-{[(1-benzofuran-2-ylmethyl) amino] methyl} phenyl) -N-methylethylenamine.

  Examples of the method of using the compound of the present invention include a carboxamide represented by the above formula [I] in order to treat or prevent a disease related to HDAC activity in a human or animal patient, or to reduce the symptoms thereof. An effective amount of at least one substance selected from the group consisting of derivatives, tautomers and stereoisomers thereof, and physiologically acceptable salts thereof may be administered to the patient.

  The administration form of the compound of the present invention is not particularly limited, and can be administered orally or parenterally depending on the purpose. The form when administered as an oral preparation is not particularly limited, and normal and enteric-coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solvents, suspensions, syrups, solid or liquid aerosols, The form normally used by those skilled in the art, such as an emulsion and the like, can be selected. Moreover, the form at the time of parenteral administration is not specifically limited, The form normally used by those skilled in the art, such as intravenous administration, intraperitoneal administration, subcutaneous administration, and intramuscular administration, can be selected.

  There are no particular limitations on the dose, administration interval, etc. of the compound of the present invention, and it can be appropriately selected according to the purpose. They include various factors including the patient's age, weight, sex, medical condition, medical condition, route of administration, patient's level of metabolic and excretory function, dosage form used, the particular compound being administered and its salts. It is selected by those skilled in the art in consideration.

  In addition, the method of using the compound of the present invention includes, for example, carboxamide derivatives represented by the above formula [I], their tautomers and stereoisomers, and physiologically acceptable At least one substance selected from the group consisting of these salts may be used. That is, the medicament of the present invention is at least one selected from the group consisting of the carboxamide derivatives represented by the formula [I], tautomers and stereoisomers thereof, and physiologically acceptable salts thereof. It is a medicine containing a substance as an active ingredient. The active ingredient preferably has a histone deacetylase (HDAC) inhibitory activity.

  The medicament of the present invention preferably further contains, for example, one or more kinds of pharmaceutically acceptable additives. That is, for example, the compound of the present invention is preferably formulated with one or more pharmaceutically acceptable additives prior to administration. The additive is not particularly limited, and examples thereof include inert substances such as carriers, diluents, fragrances, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents, and encapsulating materials. is there. Besides these, for example, any additive generally used in the field of medicine may be used as appropriate.

  Although the manufacturing method of the pharmaceutical of this invention is not specifically limited, For example, the said active ingredient may be mixed with a diluent and may be enclosed with a support | carrier. The carrier can be in the form of, for example, a capsule, a sachet, paper or other container. The carrier may also serve as a diluent and may be solid, semi-solid, or liquid that acts as a vehicle. The form of the medicament of the present invention is not particularly limited. For example, tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, soft / hard gelatin capsules, suppositories Various forms such as sterile injectable solutions and packaged sterile powders are possible.

  When the additive is orally administered, for example, the substances listed below can be used. As the carrier, for example, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methylcellulose and the like can be used. Examples of the disintegrant include corn flour, starch, methyl cellulose, agar, bentonite, xanthan gum, alginic acid and the like. As the binder, for example, gelatin, natural sugar, beta-lactose, corn sweetener, natural and synthetic rubber, gum arabic, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, wax and the like can be used. As the lubricant, for example, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc and the like can be used.

  The medicament of the present invention has, for example, at least one selected from the group consisting of treatment of diseases related to cell proliferation, reduction of symptoms, and prevention, because the active ingredient has histone deacetylase (HDAC) inhibitory activity. Can be used for one purpose. Diseases related to cell proliferation include, for example, brain tumor, head and neck cancer, neuroblastoma, sinus cancer, pharyngeal cancer, esophageal cancer, lung cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, biliary tract cancer, pancreatic cancer, prostate Cancer, bladder cancer, testicular cancer, breast cancer, uterine cancer, uterine fibroid, cervical cancer, ovarian cancer, acute leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, malignant lymphoma, erythrocytosis, true polycythemia, essential It is preferably at least one disease selected from the group consisting of thrombocytosis, myeloma, osteosarcoma, choriocarcinoma, Hodgkin's disease, non-Hodgkin's disease, glioblastoma, astrocytoma and soft tissue sarcoma.

  Moreover, the medicament of the present invention can be used for at least one of an anticancer agent and an anticancer agent, for example, because the active ingredient has strong cancer cell growth inhibitory activity.

  Furthermore, the medicament of the present invention can be used for at least one application selected from the group consisting of, for example, a cardiac hypertrophy ameliorating agent, an immunosuppressant, and a gene therapy effect enhancer. The medicament of the present invention can be used for at least one application selected from the group consisting of, for example, treatment of neurodegenerative diseases, reduction of symptoms, and prevention. The neurodegenerative disease is preferably a disease caused by expansion of a polyglutamic acid repeat sequence. Particularly preferred is at least one disease selected from the group consisting of -Joseph disease (SCA3) and spinocerebellar ataxia type 6 (SCA6).

  The HDAC inhibitor of the present invention is at least one selected from the group consisting of the carboxamide derivatives represented by the above formula [I], tautomers and stereoisomers thereof, and physiologically acceptable salts thereof. An HDAC inhibitor comprising the substance:

  Next, the manufacturing method of the compound of this invention is demonstrated. However, the production method of the compound of the present invention is not limited to the production method described below, and any production method may be used.

  Among the carboxamide derivatives represented by the formula [I], a compound in which the atomic group [A] is an amino-substituted aromatic ring can be produced, for example, by the production method described in the following flowchart A.

[Flowchart A]

In the flowchart A, the atomic groups [B], [D], L ¹ , L ² and L ³ are the same as those in the formula [I]. Ar is an aromatic ring. L ¹ ′ is an atomic group that becomes L ¹ by converting a formyl group (—CHO) added to the terminal to a methylene group. L ² ′ is an atomic group that becomes L ² by converting a formyl group (—CHO) added to the terminal to a methylene group. X is a halogen such as chlorine, bromine or iodine. [D] is preferably, for example, an o-phenylene group, an m-phenylene group or a p-phenylene group, but is not limited thereto, and may be another atomic group represented by the formula [I]. For example, it may be a naphthylene group or an anthrylene group. Ar is, for example, preferably an o-phenylene group, an m-phenylene group or a p-phenylene group, but is not limited thereto, and may be another atomic group represented by the formula [I], such as a naphthylene group, An anthrylene group or the like may be used.

  Hereinafter, each process in the flowchart A will be described in detail. In addition, various reaction conditions, such as reaction temperature, reaction time, a solvent, a reagent, are not limited to the conditions demonstrated below, You may change suitably as needed.

まず、上記式BocHN-L³-[D]-COOHで表される出発原料を準備する。この出発原料は、例えば、{[(tert-ブトキシカルボニル)アミノ]メチル}安息香酸等が好ましい。次に、前記出発原料を、非プロトン性溶媒に溶解または懸濁させる。前記非プロトン性溶媒としては、例えば、トルエン等の炭化水素、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル、クロロホルム、塩化メチレン等のハロゲン化炭素、ジメチルホルムアミド等のアミドが挙げられ、単独で用いても二種類以上併用しても良い。さらに、この溶液または懸濁液に、ピリジン、トリエチルアミン、DMAP、DBU、DBN、等の塩基存在下或いは非存在下、二塩化オギサリル、塩化チオニル、又は、三塩化リン、等を加え、0〜１００℃で、数時間攪拌する。反応液から沈殿物を濾過して除いた後、濾液を減圧濃縮し、酸塩化物(1A)を得る。 [Step 1A]

First, a starting material represented by the above formula BocHN-L ^3- [D] -COOH is prepared. The starting material is preferably, for example, {[(tert-butoxycarbonyl) amino] methyl} benzoic acid. Next, the starting material is dissolved or suspended in an aprotic solvent. Examples of the aprotic solvent include hydrocarbons such as toluene, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated carbons such as chloroform and methylene chloride, and amides such as dimethylformamide. Two or more types may be used in combination. Furthermore, oxalyl dichloride, thionyl chloride, or phosphorus trichloride is added to this solution or suspension in the presence or absence of a base such as pyridine, triethylamine, DMAP, DBU, DBN, etc., and 0 to 100 Stir at a temperature of several hours. After removing the precipitate from the reaction solution by filtration, the filtrate is concentrated under reduced pressure to obtain acid chloride (1A).

第一工程で得られた一般式(1A)で示される酸塩化物を、ピリジン、トリエチルアミン、DMAP、DBU、DBN、等の塩基存在下或いは非存在下、一般式H₂N-Ar-NO₂で表される化合物、例えばニトロ基置換アニリンを加え、-10〜１００℃で、数時間攪拌する。反応液を減圧濃縮後、残渣をトルエン、エーテル、酢酸エチル、クロロホルム、塩化メチレン、等の適宜な溶媒に溶解し、酸、重曹、飽和食塩水等で洗浄後、無水硫酸ナトリウム或いは硫酸マグネシウムで乾燥する。この溶液を減圧濃縮後、残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(2A)で示されるアミド体を得る。 [Step 2A]

The acid chloride represented by the general formula (1A) obtained in the first step is converted to the general formula H ₂ N—Ar—NO _{2 in the} presence or absence of a base such as pyridine, triethylamine, DMAP, DBU, DBN, etc. And a nitro group-substituted aniline is added and stirred at −10 to 100 ° C. for several hours. After concentrating the reaction solution under reduced pressure, the residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, etc., washed with acid, sodium bicarbonate, saturated saline, etc., and then dried over anhydrous sodium sulfate or magnesium sulfate. To do. The solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography as necessary to obtain an amide compound represented by the general formula (2A).

まず、アミド体(2A) を、水または水と親水性溶媒の混液に溶かし、溶液を調製する。前記親水性溶媒としては、特に限定されないが、テトラヒドロフラン、ジオキサン、アセトニトリル、メタノール、エタノール、等が挙げられ、単独でも二種類以上併用しても良い。次に、この溶液に塩酸、臭酸、硫酸等の酸を用いて脱Boc化反応を行う。反応溶液を減圧濃縮後、乾燥させ、一般式(3A)で示されるアミン体を得る。 [Step 3A]

First, the amide (2A) is dissolved in water or a mixture of water and a hydrophilic solvent to prepare a solution. Although it does not specifically limit as said hydrophilic solvent, Tetrahydrofuran, dioxane, acetonitrile, methanol, ethanol, etc. are mentioned, You may use individually or in combination of 2 or more types. Next, this solution is subjected to a de-Boc reaction using an acid such as hydrochloric acid, odorous acid or sulfuric acid. The reaction solution is concentrated under reduced pressure and then dried to obtain an amine compound represented by the general formula (3A).

まず、アミン体(3A)を溶媒に溶かし、溶液を調製する。前記溶媒としては、例えば、クロロホルム、塩化メチレン（ジクロロメタン）等のハロゲン化炭素、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコールが挙げられ、単独で用いても二種類以上併用しても良い。次に、この溶液に、ピリジン、トリエチルアミン、DMAP、DBU、DBN、等の塩基存在下、[B]-L²'CHOで表されるアルデヒド、例えばアリールアルデヒド又はアリール基置換アルカナール及び酢酸、シュウ酸或いはトリフルオロ酢酸等の酸を加える。さらに、シアノトリヒドロホウ酸ナトリウム、或いは、水素化ホウ素ナトリウム等の還元剤を加え、還元的アミノ化反応を行う。これを室温或いは25〜100℃で1〜１０時間撹拌後、反応液を減圧濃縮し、残渣をトルエン、エーテル、酢酸エチル、クロロホルム、塩化メチレン等の適宜な溶媒に溶解し、酸、重曹、飽和食塩水等で洗浄する。無水硫酸ナトリウム或いは硫酸マグネシウムで乾燥後、この溶液を減圧濃縮する。残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(4A)で示される二級アミン体を得る。 [Step 4A]

First, the amine body (3A) is dissolved in a solvent to prepare a solution. Examples of the solvent include halogenated carbons such as chloroform and methylene chloride (dichloromethane), ethers such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, and alcohols such as methanol and ethanol. Two or more types may be used in combination. Next, in this solution, in the presence of a base such as pyridine, triethylamine, DMAP, DBU, DBN, etc., an aldehyde represented by [B] -L ² 'CHO, for example, an aryl aldehyde or an aryl group-substituted alkanal and acetic acid, Add acid or acid such as trifluoroacetic acid. Furthermore, a reductive amination reaction is performed by adding a reducing agent such as sodium cyanotrihydroborate or sodium borohydride. After stirring at room temperature or 25 to 100 ° C. for 1 to 10 hours, the reaction solution is concentrated under reduced pressure, and the residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, acid, sodium bicarbonate, saturated Wash with saline solution. After drying over anhydrous sodium sulfate or magnesium sulfate, the solution is concentrated under reduced pressure. The residue is purified by silica gel column chromatography as necessary to obtain a secondary amine compound represented by the general formula (4A).

まず、二級アミン体(4A)を、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いはこれらの混液に溶かし、炭酸カリウム、炭酸ナトリウム、或いは、炭酸水素ナトリウムの存在下、X-L¹OHで表されるハロゲン化アルコール、例えば2-ブロモエタノールを加えて、室温または25〜100℃で撹拌する。反応液から沈殿物を濾過して除いた後、濾液を減圧濃縮する。残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(5A)で示される三級アミン体を得る。 [Step 5A]

First, the secondary amine (4A) is dissolved in an ether such as tetrahydrofuran or dioxane, a nitrile such as acetonitrile, an alcohol such as methanol or ethanol, or a mixture thereof, and the presence of potassium carbonate, sodium carbonate, or sodium bicarbonate. Then, a halogenated alcohol represented by XL ¹ OH, for example, 2-bromoethanol is added, and the mixture is stirred at room temperature or 25 to 100 ° C. After removing the precipitate from the reaction solution by filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography as necessary to obtain a tertiary amine compound represented by the general formula (5A).

三級アミン体(5A)を、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いは、これらの混液に溶かし、塩化スズ(II)第二水和物、亜鉛アマルガム或いは鉄粉を加え、さらに、酢酸アンモニウム或いは塩酸を加え、室温〜100℃で10分〜3時間撹拌する。反応液から沈殿物を濾過して除いた後、濾液を濃縮する。残渣を、トルエン、エーテル、酢酸エチル、クロロホルム、塩化メチレン等の適宜な溶媒に溶解し、酸、重曹、飽和食塩水等で洗浄後、無水硫酸ナトリウム或いは硫酸マグネシウムで乾燥する。溶媒を留去し、残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、目的化合物[I-1]を得る。 [Step 6A]

A tertiary amine compound (5A) is dissolved in an ether such as tetrahydrofuran or dioxane, a nitrile such as acetonitrile, an alcohol such as methanol or ethanol, or a mixture thereof, and tin (II) chloride dihydrate, zinc amalgam or Add iron powder, then add ammonium acetate or hydrochloric acid, and stir at room temperature to 100 ° C. for 10 minutes to 3 hours. The precipitate is filtered off from the reaction solution, and then the filtrate is concentrated. The residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, etc., washed with acid, sodium bicarbonate, saturated saline, etc., and dried over anhydrous sodium sulfate or magnesium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography as necessary to obtain the target compound [I-1].

まず、一般式(3A)で示されるアミン体を、ジクロロメタン、クロロホルム等のハロゲン化炭素、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いは、これらの混液に溶かす。次に、この容器に、ピリジン、トリエチルアミン、DMAP、DBU、DBN、等の塩基存在下、式OHC-L¹'-OTBSで表される(tert- ブチルジメチルシリルオキシ)アルカナール及び酢酸、シュウ酸或いはトリフルオロ酢酸等の酸を加え、さらに、シアノトリヒドロホウ酸ナトリウム、或いは、水素化ホウ素ナトリウム等の還元剤を加え、還元的アミノ化反応を行う。これを室温或いは25〜100℃で1〜１０時間撹拌後、反応液を減圧濃縮し、残渣をトルエン、エーテル、酢酸エチル、クロロホルム、塩化メチレン等の適宜な溶媒に溶解し、酸、重曹、飽和食塩水等で洗浄する。無水硫酸ナトリウム或いは硫酸マグネシウムで乾燥後、この溶液を減圧濃縮する。残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(4A’)で示される二級アミン体を得る。 [Step 4A ']

First, the amine compound represented by the general formula (3A) is dissolved in halogenated carbon such as dichloromethane and chloroform, ether such as tetrahydrofuran and dioxane, nitrile such as acetonitrile, alcohol such as methanol and ethanol, or a mixed solution thereof. Next to the vessel, pyridine, triethylamine, DMAP, DBU, DBN, the presence of a base like, represented by the formula OHC-L ¹ '-OTBS (tert- butyldimethylsilyloxy) alkanal and acetic acid, oxalic acid Alternatively, an acid such as trifluoroacetic acid is added, and further a reducing agent such as sodium cyanotrihydroborate or sodium borohydride is added to perform a reductive amination reaction. After stirring at room temperature or 25 to 100 ° C. for 1 to 10 hours, the reaction solution is concentrated under reduced pressure, and the residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, acid, sodium bicarbonate, saturated Wash with saline solution. After drying over anhydrous sodium sulfate or magnesium sulfate, the solution is concentrated under reduced pressure. The residue is purified by silica gel column chromatography as necessary to obtain a secondary amine compound represented by the general formula (4A ′).

一般式(4A’)で示される二級アミン体を、ジクロロメタン、クロロホルム等のハロゲン化炭素、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いは、これらの混液に溶かす。次に、この溶液に、ピリジン、トリエチルアミン、DMAP、DBU、DBN、等の塩基存在下、OHC-L²’-[B]で表されるアルデヒド、例えばアリールアルデヒド又はアリール基置換アルカナール及び酢酸、シュウ酸或いはトリフルオロ酢酸等の酸を加える。さらに、シアノトリヒドロホウ酸ナトリウム、或いは、水素化ホウ素ナトリウム等の還元剤を加え、還元的アミノ化反応を行う。これを室温或いは25〜100℃で1〜１０時間撹拌後、反応液を減圧濃縮し、残渣をトルエン、エーテル、酢酸エチル、クロロホルム、塩化メチレン等の適宜な溶媒に溶解し、酸、重曹、飽和食塩水等で洗浄する。無水硫酸ナトリウム或いは硫酸マグネシウムで乾燥後、この溶液を減圧濃縮する。残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(5A’)で示される三級アミン体を得る。 [Step 5A ']

Dissolve the secondary amine represented by the general formula (4A ') in a halogenated carbon such as dichloromethane and chloroform, an ether such as tetrahydrofuran and dioxane, a nitrile such as acetonitrile, an alcohol such as methanol and ethanol, or a mixture thereof. . Next, in this solution, in the presence of a base such as pyridine, triethylamine, DMAP, DBU, DBN, etc., an aldehyde represented by OHC-L ² ′-[B], for example, an aryl aldehyde or an aryl group-substituted alkanal and acetic acid, Add an acid such as oxalic acid or trifluoroacetic acid. Furthermore, a reductive amination reaction is performed by adding a reducing agent such as sodium cyanotrihydroborate or sodium borohydride. After stirring at room temperature or 25 to 100 ° C. for 1 to 10 hours, the reaction solution is concentrated under reduced pressure, and the residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, acid, sodium bicarbonate, saturated Wash with saline solution. After drying over anhydrous sodium sulfate or magnesium sulfate, the solution is concentrated under reduced pressure. The residue is purified by silica gel column chromatography as necessary to obtain a tertiary amine compound represented by the general formula (5A ′).

まず、三級アミン体(5A’)を、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いは、これらの混液に溶かし、塩化スズ(II)第二水和物、亜鉛アマルガム或いは鉄粉を加え、さらに、酢酸アンモニウム或いは塩酸を加え、室温〜100℃で10分〜5時間撹拌する。この反応液から沈殿物を濾過して除いた後、濾液を濃縮する。残渣を、トルエン、エーテル、酢酸エチル、クロロホルム、塩化メチレン等の適宜な溶媒に溶解し、酸、重曹、飽和食塩水等で洗浄後、無水硫酸ナトリウム或いは硫酸マグネシウムで乾燥する。溶液を減圧濃縮して得られる残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(6A’)で示される還元体を得る。 [Step 6A ']

First, the tertiary amine compound (5A ′) is dissolved in an ether such as tetrahydrofuran or dioxane, a nitrile such as acetonitrile, an alcohol such as methanol or ethanol, or a mixture thereof, tin (II) chloride dihydrate, Add zinc amalgam or iron powder, add ammonium acetate or hydrochloric acid, and stir at room temperature to 100 ° C. for 10 minutes to 5 hours. The precipitate is filtered off from the reaction solution, and then the filtrate is concentrated. The residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, etc., washed with acid, sodium bicarbonate, saturated saline, etc., and dried over anhydrous sodium sulfate or magnesium sulfate. The residue obtained by concentrating the solution under reduced pressure is purified by silica gel column chromatography as necessary to obtain a reduced product represented by the general formula (6A ′).

還元体(6A’)を、トリフルオロ酢酸、塩化水素酸、硫酸、臭化水素酸、ヨウ化水素酸等の酸の水溶液に溶かし、室温〜100℃で10分〜7時間撹拌する。この反応液を減圧濃縮し、残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、目的の化合物［I-1］を得る。 [Step 7A ']

The reductant (6A ′) is dissolved in an aqueous solution of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and the mixture is stirred at room temperature to 100 ° C. for 10 minutes to 7 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography as necessary to give the desired compound [I-1].

  The flowchart A has been described above.

  Next, among the carboxamide derivatives represented by the formula [I], a compound in which the atomic group [A] is a hydroxy group can be produced, for example, by the production method described in the following flowchart B.

[Flowchart B]

In the flowchart B, the atomic groups [B], [D], L ¹ , L ² and L ³ are the same as those in the formula [I]. L ¹ ′ is an atomic group that becomes L ¹ by converting a formyl group (—CHO) added to the terminal to a methylene group. L ² ′ is an atomic group that becomes L ² by converting a formyl group (—CHO) added to the terminal to a methylene group. L ³ ′ is an atomic group that becomes L ³ by converting a formyl group (—CHO) added to the terminal to a methylene group. X is a halogen such as chlorine, bromine or iodine. R is a substituent such as an alkyl group. [D] is preferably, for example, an o-phenylene group, an m-phenylene group or a p-phenylene group, but is not limited thereto, and may be another atomic group represented by the formula [I]. For example, it may be a naphthylene group or an anthrylene group.

  Hereinafter, each process in the flowchart B will be described in detail. In addition, various reaction conditions, such as reaction temperature, reaction time, a solvent, a reagent, are not limited to the conditions demonstrated below, You may change suitably as needed.

[B]-L²NH₂で表されるアミン、例えば置換アニリンまたはアリール基置換アルキルアミンの塩酸塩を、ジクロロメタン、クロロホルム等のハロゲン化炭素、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いはこれらの混液に溶かす。次に、この溶液に、ピリジン、トリエチルアミン、DMAP、DBU、DBN、等の塩基存在下、OHC-L³'-[D]-COORで表されるアルデヒド、例えばアリールアルデヒドまたはアリール基置換アルカナール及び酢酸、シュウ酸或いはトリフルオロ酢酸等の酸を加える。さらに、シアノトリヒドロホウ酸ナトリウム、或いは、水素化ホウ素ナトリウム等の還元剤を加え、室温或いは25〜100℃で1〜１０時間撹拌し、還元的アミノ化反応を行う。 [Step 1B]

An amine represented by [B] -L ² NH ₂ , for example, a hydrochloride of a substituted aniline or aryl group-substituted alkylamine, a halogenated carbon such as dichloromethane or chloroform, an ether such as tetrahydrofuran or dioxane, a nitrile such as acetonitrile, or methanol Dissolve in alcohol such as ethanol or a mixture of these. Next, an aldehyde represented by OHC-L ³ ′-[D] -COOR such as aryl aldehyde or aryl group-substituted alkanal is added to this solution in the presence of a base such as pyridine, triethylamine, DMAP, DBU, DBN, and the like. Add an acid such as acetic acid, oxalic acid or trifluoroacetic acid. Further, a reducing agent such as sodium cyanotrihydroborate or sodium borohydride is added and stirred at room temperature or 25 to 100 ° C. for 1 to 10 hours to perform a reductive amination reaction.

Alternatively, the reductive amination reaction may be performed as follows. That is, first, [B] amine free base represented by -L ² NH _2, dichloromethane, carbon halides, tetrahydrofuran, ethers such as dioxane, chloroform, etc., nitriles such as acetonitrile, methanol, alcohol such as ethanol, or dissolved in these mixture, OHC-L ³ '- Add [D] aldehydes represented by -COOR and acetic acid, an acid such as oxalic acid or trifluoroacetic acid. Further, a reducing agent such as sodium cyanotrihydroborate or sodium borohydride is added and stirred at room temperature or 25 to 100 ° C. for 1 to 10 hours to perform a reductive amination reaction.

  The reaction solution obtained by the reductive amination reaction is concentrated under reduced pressure, and the residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, and washed with acid, sodium bicarbonate, saturated saline, or the like. . After drying over anhydrous sodium sulfate or magnesium sulfate, the solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography as necessary to obtain a secondary amine compound represented by the general formula (1B).

まず、二級アミン体(1B)をテトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いは、これらの混液に溶かす。次に、この溶液に、炭酸カリウム、炭酸ナトリウム、或いは、炭酸水素ナトリウムの存在下、X-L¹OHで表されるハロゲン化アルコール、例えば2-ブロモアルカノールまたは2-ブロモエタノールを加え、室温または25〜100℃で1〜24時間撹拌する。反応液から沈殿物を濾過して除いた後、濾液を減圧濃縮する。残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(2B)で示される三級アミン体を得る。 [Step 2B]

First, the secondary amine compound (1B) is dissolved in an ether such as tetrahydrofuran or dioxane, a nitrile such as acetonitrile, an alcohol such as methanol or ethanol, or a mixture thereof. Next, a halogenated alcohol represented by XL ¹ OH, such as 2-bromoalkanol or 2-bromoethanol, is added to this solution in the presence of potassium carbonate, sodium carbonate, or sodium hydrogen carbonate, at room temperature or 25- Stir at 100 ° C. for 1-24 hours. After removing the precipitate from the reaction solution by filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography as necessary to obtain a tertiary amine compound represented by the general formula (2B).

一般式(2B)で示される三級アミン体および水酸化カリウム又は水酸化ナトリウムのメタノール又はエタノール溶液に、ヒドロキシルアミンのメタノール又はエタノール溶液を加え、0〜60℃で1〜24時間攪拌する。反応溶液にドライアイス（固体状二酸化炭素の商品名）を加え、生じた沈殿物を濾過して取り除いた後、濾液を減圧濃縮する。残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、目的の化合物[I-2]を得る。 [Step 3B]

A methanol or ethanol solution of hydroxylamine is added to a methanol or ethanol solution of the tertiary amine compound represented by the general formula (2B) and potassium hydroxide or sodium hydroxide, and the mixture is stirred at 0 to 60 ° C. for 1 to 24 hours. Dry ice (trade name of solid carbon dioxide) is added to the reaction solution, and the resulting precipitate is removed by filtration, and then the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography as necessary to obtain the desired compound [I-2].

まず、ClH₃N-L³-[D]-COORで表されるアミン塩酸塩、例えば置換アニリンまたはアリール基置換アルキルアミンの塩酸塩を、ジクロロメタン、クロロホルム等のハロゲン化炭素、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いは、これらの混液に溶かす。次に、この溶液に、ピリジン、トリエチルアミン、DMAP、DBU、DBN、等の塩基存在下、OHC-L¹'-OTBSで表される(tert- ブチルジメチルシリルオキシ)アルカナール及び酢酸、シュウ酸或いはトリフルオロ酢酸等の酸を加える。さらに、シアノトリヒドロホウ酸ナトリウム、或いは、水素化ホウ素ナトリウム等の還元剤を加え、還元的アミノ化反応を行う。室温或いは25〜100℃で1〜１０時間撹拌後、反応液を減圧濃縮する。残渣をトルエン、エーテル、酢酸エチル、クロロホルム、塩化メチレン、等に溶解し、酸、重曹、飽和食塩水等で洗浄後、無水硫酸ナトリウム或いは硫酸マグネシウムで乾燥する。この溶液を減圧濃縮し、残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(1B’)で示される二級アミン体を得る。 [Step 1B ']

First, an amine hydrochloride represented by ClH ₃ NL ^3- [D] -COOR, for example, a hydrochloride of a substituted aniline or an aryl group-substituted alkylamine, a halogenated carbon such as dichloromethane or chloroform, an ether such as tetrahydrofuran or dioxane, Dissolve in a nitrile such as acetonitrile, an alcohol such as methanol or ethanol, or a mixture thereof. Next, to this solution, pyridine, triethylamine, DMAP, DBU, DBN, the presence of a base like, represented by OHC-L ¹ '-OTBS (tert- butyldimethylsilyloxy) alkanal and acid, or oxalic acid An acid such as trifluoroacetic acid is added. Furthermore, a reductive amination reaction is performed by adding a reducing agent such as sodium cyanotrihydroborate or sodium borohydride. After stirring at room temperature or 25 to 100 ° C. for 1 to 10 hours, the reaction solution is concentrated under reduced pressure. The residue is dissolved in toluene, ether, ethyl acetate, chloroform, methylene chloride, etc., washed with acid, sodium bicarbonate, saturated saline, etc., and dried over anhydrous sodium sulfate or magnesium sulfate. This solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography as necessary to obtain a secondary amine compound represented by the general formula (1B ′).

まず、一般式(1B’)で示される二級アミン体を、ジクロロメタン、クロロホルム等のハロゲン化炭素、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いは、これらの混液に溶かす。次に、この溶液に、ピリジン、トリエチルアミン、DMAP、DBU、DBN、等の塩基存在下、[B]-L²'CHOで表されるアルデヒド、例えばアリールカルボキサアルデヒド及び酢酸、シュウ酸或いはトリフルオロ酢酸等の酸を加える。さらに、シアノトリヒドロホウ酸ナトリウム、或いは、水素化ホウ素ナトリウム等の還元剤を加え、還元的アミノ化反応を行う。室温或いは25〜100℃で1〜１０時間撹拌後、反応液を減圧濃縮し、残渣をトルエン、エーテル、酢酸エチル、クロロホルム、塩化メチレン等の適宜な溶媒に溶解し、酸、重曹、飽和食塩水等で洗浄する。無水硫酸ナトリウム或いは硫酸マグネシウムで乾燥後、この溶液を減圧濃縮し、残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(2B’)で示される三級アミン体を得る。 [Step 2B ']

First, the secondary amine compound represented by the general formula (1B ') is a halogenated carbon such as dichloromethane or chloroform, an ether such as tetrahydrofuran or dioxane, a nitrile such as acetonitrile, an alcohol such as methanol or ethanol, or a mixture thereof. Dissolve in. Next, in this solution, in the presence of a base such as pyridine, triethylamine, DMAP, DBU, DBN, etc., an aldehyde represented by [B] -L ² 'CHO, for example, arylcarboxaldehyde and acetic acid, oxalic acid or trifluoro Add an acid such as acetic acid. Furthermore, a reductive amination reaction is performed by adding a reducing agent such as sodium cyanotrihydroborate or sodium borohydride. After stirring at room temperature or 25-100 ° C. for 1-10 hours, the reaction solution is concentrated under reduced pressure, and the residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, and then acid, sodium bicarbonate, saturated brine Wash with etc. After drying over anhydrous sodium sulfate or magnesium sulfate, the solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography as necessary to obtain a tertiary amine compound represented by the general formula (2B ′).

三級アミン体(2B’)を、トリフルオロ酢酸、塩化水素酸、硫酸、臭化水素酸、ヨウ化水素酸等の酸の水溶液に溶かし、室温〜100℃で10分〜7時間撹拌する。反応液を減圧濃縮し、残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(3B’)で示される三級アミン体を得る。 [Step 3B ']

The tertiary amine compound (2B ′) is dissolved in an aqueous solution of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and the mixture is stirred at room temperature to 100 ° C. for 10 minutes to 7 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography as necessary to obtain a tertiary amine compound represented by the general formula (3B ′).

一般式(3B’)で示される三級アミン体および水酸化カリウム又は水酸化ナトリウムのメタノール又はエタノール溶液に、ヒドロキシルアミンのメタノール又はエタノール溶液を加え、0〜60℃で1〜24時間攪拌する。反応溶液にドライアイスを加え、生じた沈殿物を濾過して取り除いた後、濾液を減圧濃縮する。残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、目的の化合物[I-2]を得る。 [Step 4B ']

A methanol or ethanol solution of hydroxylamine is added to a methanol or ethanol solution of the tertiary amine compound represented by the general formula (3B ′) and potassium hydroxide or sodium hydroxide, and the mixture is stirred at 0 to 60 ° C. for 1 to 24 hours. Dry ice is added to the reaction solution, and the resulting precipitate is removed by filtration, and then the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography as necessary to obtain the desired compound [I-2].

ClH₃N-L³-[D]-COORで表されるアミン塩酸塩、例えば置換アニリンまたはアリール基置換アルキルアミンの塩酸塩を、ジクロロメタン、クロロホルム等のハロゲン化炭素、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いはこれらの混液に溶かす。次に、この溶液に、ピリジン、トリエチルアミン、DMAP、DBU、DBN、等の塩基存在下、[B]-L²’CHOで表されるアルデヒド、例えばアリールアルデヒドまたはアリール基置換アルカナール及び酢酸、シュウ酸或いはトリフルオロ酢酸等の酸を加える。さらに、シアノトリヒドロホウ酸ナトリウム、或いは、水素化ホウ素ナトリウム等の還元剤を加え、室温或いは25〜100℃で1〜１０時間撹拌し、還元的アミノ化反応を行う。 [Step 1B '']

Amine hydrochloride represented by ClH ₃ NL ^3- [D] -COOR, for example, hydrochloride of substituted aniline or aryl group-substituted alkylamine, halogenated carbon such as dichloromethane and chloroform, ether such as tetrahydrofuran and dioxane, acetonitrile, etc. In nitrile, methanol, ethanol and other alcohols, or a mixture thereof. Next, in this solution, in the presence of a base such as pyridine, triethylamine, DMAP, DBU, DBN, etc., an aldehyde represented by [B] -L ² 'CHO, for example, an aryl aldehyde or an aryl group-substituted alkanal and acetic acid, Add acid or acid such as trifluoroacetic acid. Further, a reducing agent such as sodium cyanotrihydroborate or sodium borohydride is added and stirred at room temperature or 25 to 100 ° C. for 1 to 10 hours to perform a reductive amination reaction.

Alternatively, the reductive amination reaction may be performed as follows. That is, first, a free base of amine hydrochloride represented by ClH ₃ NL ^3- [D] -COOR is used, a halogenated carbon such as dichloromethane and chloroform, an ether such as tetrahydrofuran and dioxane, a nitrile such as acetonitrile, methanol, and ethanol. In an alcohol or a mixture thereof, and an aldehyde represented by [B] -L ² 'CHO and an acid such as acetic acid, oxalic acid or trifluoroacetic acid are added. Further, a reducing agent such as sodium cyanotrihydroborate or sodium borohydride is added and stirred at room temperature or 25 to 100 ° C. for 1 to 10 hours to perform a reductive amination reaction.

  The reaction solution obtained by the reductive amination reaction is concentrated under reduced pressure, and the residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, and washed with acid, sodium bicarbonate, saturated saline, or the like. . After drying over anhydrous sodium sulfate or magnesium sulfate, the solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography as necessary to obtain a secondary amine compound represented by the general formula (1B).

まず、二級アミン体(1B)を、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル等のニトリル、メタノール、エタノール等のアルコール、或いは、これらの混液に溶かす。次に、この溶液に、L¹'CHOで表されるホルムアルデヒド或いはアルキルアルデヒド及び酢酸、シュウ酸或いはトリフルオロ酢酸等の酸を加える。さらに、シアノトリヒドロホウ酸ナトリウム、或いは、水素化ホウ素ナトリウム等の還元剤を加え、還元的アルキル化反応を行う。室温或いは25〜100℃で1〜１０時間撹拌後、反応液を減圧濃縮し、残渣をトルエン、エーテル、酢酸エチル、クロロホルム、塩化メチレン等の適宜な溶媒に溶解し、酸、重曹、水酸化カリウム、飽和食塩水等で洗浄する。残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、一般式(2B'')で示される三級アミン体を得る。 [Process 2B '']

First, the secondary amine (1B) is dissolved in an ether such as tetrahydrofuran or dioxane, a nitrile such as acetonitrile, an alcohol such as methanol or ethanol, or a mixture thereof. Next, formaldehyde or alkylaldehyde represented by L ¹ 'CHO and an acid such as acetic acid, oxalic acid or trifluoroacetic acid are added to this solution. Further, a reducing agent such as sodium cyanotrihydroborate or sodium borohydride is added to perform a reductive alkylation reaction. After stirring at room temperature or 25-100 ° C. for 1-10 hours, the reaction solution is concentrated under reduced pressure, and the residue is dissolved in an appropriate solvent such as toluene, ether, ethyl acetate, chloroform, methylene chloride, and then acid, sodium bicarbonate, potassium hydroxide. Wash with saturated saline. The residue is purified by silica gel column chromatography as necessary to obtain a tertiary amine compound represented by the general formula (2B ″).

一般式(2B'')で示される三級アミン体および水酸化カリウム又は水酸化ナトリウムのメタノール又はエタノール溶液に、ヒドロキシルアミンまたはその塩酸塩のメタノール又はエタノール溶液を加え、0〜60℃で1〜24時間攪拌する。反応溶液にドライアイスを加え、生じた沈殿物を濾過して取り除いた後、濾液を減圧濃縮する。残渣を、必要に応じてシリカゲルカラムクロマトグラフィーにより精製し、目的の化合物[I-3]を得る。 [Process 3B '']

A methanol or ethanol solution of hydroxylamine or a hydrochloride thereof is added to a methanol or ethanol solution of a tertiary amine compound represented by the general formula (2B '') and potassium hydroxide or sodium hydroxide, and 1 to Stir for 24 hours. Dry ice is added to the reaction solution, and the resulting precipitate is removed by filtration, and then the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography as necessary to obtain the target compound [I-3].

  The flowchart B has been described above.

  Next, examples of the present invention will be described. However, the present invention is not limited to the following examples.

[Measurement conditions]
In the following data, all melting points (mp) are uncorrected values. Nuclear magnetic resonance (NMR) spectrum was measured using JEOL trade name JNM-EX270 FT NMR SYSTEM (270 MHz at ¹ H measurement). Chemical shifts are expressed in parts per million (ppm). Tetramethylsilane (TMS) was used for the internal standard of 0 ppm. Coupling constants (J) are shown in hertz and the abbreviations s, d, t, q, m and br are singlet, doublet, triplet, quadruple, respectively. Represents a quartet, a multiplet, and a broad line. The infrared (IR) spectrum was measured by KBr method using Shimadzu Corporation trade name FTIR-8400. Mass spectrometry (MS) uses the JEOL brand name Tandem MStation JMS-700, electron impact ionization (EI-MS), electrospray ionization (ESI-MS), or fast atom collision ionization (FAB-MS). It went by. High resolution mass spectrometry (HR-MS, HR-EI-MS, and HR-FABMS) was also performed using the instrument described above. Thin layer chromatography (TLC) was performed using pre-coated silica gel plates (Merck trade name Merck Silica gel 60 F254 PLC Plate). For all column chromatography separations, silica gel (Merck trade name Merck Silica gel 60) was used. All chemicals were reagent grade and were purchased from Wako Pure Chemical Industries, Ltd., Sigma-Aldorich. Co., Kanto Chemical Co., Ltd., and Tokyo Chemical Industry Co., Ltd.

[Synthesis]
The compounds (carboxamide derivatives) of Examples 1 to 11 were synthesized as follows.

Example 1
N- (2-aminophenyl) -4-{[benzyl (2-hydroxyethyl) amino] methyl} benzamide

(Compound 1)

(Step 1A)
tert-Butyl 4- (chlorocarbonyl) benzylcarbamate (Compound 1a)
4-{[(tert-Butoxycarbonyl) amino] methyl} benzoic acid (14.2 g) in anhydrous toluene (240 mL) was added to anhydrous dimethylformamide (0.16 mL), pyridine (27 mL), oxalyl dichloride ( 9.7 mL) was added in order, and the mixture was stirred at room temperature for 6 hours. After the precipitate was filtered off from the reaction solution, the filtrate was concentrated under reduced pressure to obtain colorless oily compound 1a (15.1 g, yield 99%) as a crude product.

(Step 2A)
tert-Butyl 4-[(2-nitroanilino) carbonyl] benzylcarbamate (Compound 1b)
O-Nitroaniline (12.2 g) was added to a pyridine solution (240 mL) of compound 1a (21.6 g), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, dissolved in chloroform, washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (chloroform) to obtain yellow crystalline compound 1b (17.3 g, yield 58%). The instrumental analysis data of this compound is shown below.

[Compound 1b] mp 129.4-131.6 ° C; IR (KBr) cm ^-1 3356, 1678, 1607, 1583, 1433, 1366, 1171, 970, 899, 870; ¹ H NMR (CD ₃ OD) δ1.48 (9H , s, ^t Bu), 4.42 (2H, d, J = 5.6 Hz, PhC H ₂ ), 7.23 (1H, t, J = 7.6 Hz, arom.H ₁ ), 7.46 (2H, d, J = 8.0 Hz , arom.H ₂ ), 7.72 (1H, t, J = 7.2 Hz, arom.H ₁ ), 7.97 (2H, d, J = 8.4 Hz, arom.H ₂ ), 8.29 (1H, dd, J = 1.2 , 8.2 Hz, arom.H ₁ ), 9.00 (1H, dd, J = 1.6, 8.6 Hz, arom.H ₁ ); EI-MS m / z: 371 (M) ⁺ ; HR-EI-MS m / z : (M) ⁺ calculated value C ₁₉ H ₂₁ N ₃ O ₅ , 371.1481; measured value, 371.1487.

(Process 3A)
4- (Aminomethyl) -N- (2-nitrophenyl) benzamide hydrochloride (Compound 1c)
To a solution of compound 1b (17.1 g) in methanol (1700 mL) was added 12 N hydrochloric acid (60 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure and dried to obtain yellow crystalline compound 1c (14.0 g, yield 99%). The instrumental analysis data of this compound is shown below.

[Compound 1c] mp 223.3-226.7 ° C; IR (KBr) cm ^-1 3373, 2905, 1688, 1609, 1585, 1454, 1387, 1198, 959, 887; ¹ H NMR (CDCl ₃ ) δ4.23 (2H, s, PhC H ₂ ), 7.39 (1H, t, J = 7.2 Hz, arom.H ₁ ), 7.66 (2H, d, J = 8.4 Hz, arom.H ₂ ), 7.76 (1H, t, J = 6.8 Hz, arom.H ₁ ), 8.06 (2H, d, J = 8.0 Hz, arom.H ₂ ), 8.20 (1H, dd, J = 1.6, 8.2 Hz, arom.H ₁ ), 8.35 (1H, d, J = 8.4 Hz, arom.H ₁ ); EI-MS m / z: 271 (M) ⁺ ; HR-EI-MS m / z: (M) ⁺ calculated C ₁₄ H ₁₃ N ₃ O ₃ , 271.0957; Actual value, 271.0959.

(Process 4A)
4-[(Benzylamino) methyl] -N- (2-nitrophenyl) benzamide (Compound 1d)
To a solution of compound 1c (5.5 g) in methanol (440 mL), triethylamine (2.5 mL), benzaldehyde (1.8 mL), acetic acid (4.4 mL), and sodium cyanotrihydroborate (1.13 g) were added in this order, and Stir for hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 1) to obtain yellow crystalline compound 1d (3.34 g, yield 51.6%). The instrumental analysis data of this compound is shown below.

[Compound 1d] mp 91.0-92.8 ° C; IR (KBr) cm ^-1 3377, 3328, 2939, 2332, 1682, 1607, 1583, 1435, 1273; ¹ H NMR (CDCl ₃ ) δ3.81 (2H, s, PhC H ₂ NH), 3.90 (2H, s, C H ₂ PhCO), 7.19 -7.35 (6H, m, arom.H ₆ ), 7.53 (2H, d, J = 8.4 Hz, arom.H ₂ ), 7.73 (1H, t, J = 7.2 Hz, arom.H ₁ ), 7.96 (2H, d, J = 8.0 Hz, arom.H ₂ ), 8.28 (1H, dd, J = 1.6, 8.4 Hz, arom.H ₁ ), 9.00 (1H, dd, J = 1.2, 8.6 Hz, arom.H ₁ ), 11.3 (1H, s, CON H ); EI-MS m / z: 361 (M) ⁺ ; HR-EI-MS m / z: (M) ⁺ calculated C ₂₁ H ₁₉ N ₃ O ₃ , 361.1426; found, 361.1450.

(Process 5A)
4-{[Benzyl (2-hydroxyethyl) amino] methyl} -N- (2-nitrophenyl) benzamide (Compound 1e)
To a solution of compound 1d (3.2 g) in acetonitrile (85 mL) were added potassium carbonate (4.9 g) and 2-bromoethanol (12.5 mL) in this order, and the mixture was stirred at 60 ° C. for 8 hours. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 1) to obtain yellow oily compound 1e (1.47 g, yield 41%). The instrumental analysis data of this compound is shown below.

[Compound 1e] IR (KBr) cm ^-1 3362, 2806, 1688, 1607, 1502, 1454, 1433, 1275, 1146, 980, 862; ¹ H NMR (CD ₃ OD) δ2.54 (2H, t, J = 6.4 Hz, NC H ₂ CH ₂ OH), 3.52 (2H, s, PhC H ₂ NH), 3.55 (2H, s, C H ₂ PhCO), 3.58 (2H, t, J = 6.4 Hz, NCH ₂ C H ₂ OH), 7.08-7.75 (9H, m, arom.H ₉ ), 7.76 (2H, t, J = 8.8 Hz, arom.H ₂ ), 8.00 (1H, dd, J = 1.6, 8.4 Hz, arom .H ₁ ), 8.49 (1H, dd, J = 1.2, 8.4 Hz, arom.H ₁ ); FAB-MS m / z: 406 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₂₃ H ₂₄ N ₃ O ₄ , 406.1767; measured value, 407.1765.

(Step 6A)
N- (2-aminophenyl) -4-{[benzyl (2-hydroxyethyl) amino] methyl} benzamide

(Compound 1)
To a solution of compound 1e (1.4 g) in methanol (120 mL) were added tin (II) chloride dihydrate (4.87 g) and ammonium acetate (2.87 g), and the mixture was stirred at 60 ° C. for 1 hour. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. This was dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain yellow crystalline compound 1 (0.53 g, yield 40%). The instrumental analysis data of this compound is shown below.

[Compound 1] mp 119.2-121.9 ° C; IR (KBr) cm ^-1 3360, 2795, 2714, 1632, 1611, 1531, 1362, 1232, 1161, 885; ¹ H NMR (CD ₃ OD) δ2.64 (2H , t, J = 6.0 Hz, NC H ₂ CH ₂ OH), 3.62 (2H, t, J = 7.6 Hz, NCH ₂ C H ₂ OH), 3.68 (2H, s, PhC H ₂ NH), 3.74 (2H , s, C H ₂ PhCO), 6.73-7.37 (9H, m, arom.H ₉ ), 7.51 (2H, d, J = 8.4 Hz, arom.H ₂ ), 7.93 (2H, d, J = 8.0 Hz , arom.H ₂ ); EI-MS m / z: 375 (M) ⁺ ; HR-EI-MS m / z: (M) ⁺ calculated C ₂₃ H ₂₅ N ₃ O ₂ , 375.1947; measured value, 375.1973 .

Example 2
N- (2-aminophenyl) -4-({(2-hydroxyethyl) [(1-methyl-1H-indol-3-yl) methyl] amino} methyl) benzamide (Compound 2)

(Process 4A)
4-({[(1-Methyl-1H-indol-3-yl) methyl] amino} methyl) -N- (2-nitrophenyl) benzamide (Compound 2a)
To a solution of compound 1c (3.0 g) in methanol (330 mL) was added triethylamine (1.5 mL), 1-methylindole-3-carboxaldehyde (1.56 g), acetic acid (3.3 mL), sodium cyanotrihydroborate (0.61 g). ) In order and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the obtained residue was recrystallized with a chloroform: hexane mixed solvent to obtain yellow crystalline compound 2a (1.65 g, yield 40.6%). The instrumental analysis data of this compound is shown below.

[Compound 2a] mp 178.5-181.3 ° C; IR (KBr) cm ^-1 2878, 2773, 2704, 1674, 1585, 1506, 1339, 1251, 1150, 972, 739; ¹ H NMR (DMSO-d ₆ ) δ3. 83 (3H, s, NMe), 4.27 (2H, s, 1-methyl-1H-indole-C H ₂ ), 4.34 (2H, s, C H ₂ Phe), 7.12-8.03 (13H, m, arom. H ₁₃ ), 9.52 (1H, brs, CH ₂ N H ), 10.88 (1H, s, CON H ); FAB-MS m / z: 415 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₂₄ H ₂₃ N ₄ O ₃ , 415.1770; measured value, 415.1786.

(Process 5A)
4-({(2-hydroxyethyl) [(1-methyl-1H-indol-3-yl) methyl] amino} methyl) -N- (2-nitrophenyl) benzamide (Compound 2b)
To a suspension of compound 2a (0.7 g) in acetonitrile (17 mL) were added potassium carbonate (0.93 g) and 2-bromoethanol (2.4 mL) in this order, and the mixture was stirred at 60 ° C. for 7 hours. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 8: 5) to obtain yellow oily compound 2b (0.48 g, yield 62.7%). The instrumental analysis data of this compound is shown below.

[Compound 2b] IR (KBr) cm ⁻¹ 3356, 2930, 2822, 1805, 1774, 1688, 1607, 1454, 1271, 1146, 1072, 899; ¹ H NMR (CDCl ₃ ) δ2.68 (2H, t, J = 5.6Hz, NC H ₂ CH ₂ OH), 3.61 (2H, t, J = 5.6Hz, NCH ₂ C H ₂ OH), 3.68 (2H, s, 1-methyl-1H-indole-C H ₂ ) , 3.70 (3H, s, NMe), 3.80 (2H, s, C H ₂ Phe), 6.97-8.92 (13H, m, arom.H ₁₃ ), 11.23 (1H, s, CONH); FAB-MS m / z: 459 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₆ H ₂₇ N ₄ O ₄ , 459.2032; measured value, 459.2017.

(Step 6A)
N- (2-aminophenyl) -4-({(2-hydroxyethyl) [(1-methyl-1H-indol-3-yl) methyl] amino} methyl) benzamide (Compound 2)
To a solution of compound 2b (0.22 g) in methanol (18 mL) were added tin (II) chloride dihydrate (0.66 g) and ammonium acetate (0.39 g), and the mixture was stirred at 60 ° C. for 10 minutes. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. This was dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After concentrating this solution under reduced pressure, the obtained residue was purified with a PLC plate (chloroform: hexane = 9: 1) to obtain Compound 2 (26.4 mg, yield 12.6%) as brown crystals. The instrumental analysis data of this compound is shown below.

[Compound 2] mp 154.1-156.7 ° C; IR (KBr) cm ^-1 3725, 2924, 2820, 1651, 1612, 1506, 1454, 1327, 1051, 976, 856; ¹ H NMR (CDCl ₃ ) δ2.68 ( 2H, t, J = 5.6Hz, NC H ₂ CH ₂ OH), 3.58 (2H, t, J = 5.6Hz, NCH ₂ C H ₂ OH), 3.63 (2H, s, 1-methyl-1H-indole- C H ₂ ), 3.75 (3H, s, NMe), 3.82 (2H, s, C H ₂ Phe), 6.79-8.02 (13H, m, arom.H ₁₃ ); FAB-MS m / z: 429 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₆ H ₂₉ N ₄ O ₂ , 429.2291; measured value, 429.2263.

Example 3
N- (2-aminophenyl) -4-{[(1,3-benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} benzamide (Compound 3)

(Process 4A)
4-{[(1,3-Benzodioxol-5-ylmethyl) amino] methyl} -N- (2-nitrophenyl) benzamide (Compound 3a)
To a solution of compound 1c (1.0 g) in methanol (88 mL), triethylamine (0.45 mL), 1,3-benzodioxol-5-carboxaldehyde (0.49 g), acetic acid (0.88 mL), cyanotrihydroboric acid Sodium (0.20 g) was added in order and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 2: 1) to obtain yellow crystalline compound 3a (0.33 g, yield 24.8%). The instrumental analysis data of this compound is shown below.

[Compound 3a] mp 74.6-76.8 ° C; IR (KBr) cm ^-1 ; 3371, 2885, 2800, 2340, 1684, 1604, 1450, 1377, 1192, 988, 899; ¹ H NMR (CD ₃ OD) δ ₃ . 68 (2H, s, 1,3-benzodioxole-C H ₂ ), 3.82 (2H, s, PhC H ₂ ), 5.92 (2H, s, OCH ₂ ), 6.75 -6.81 (2H, m, arom .H ₂ ), 6.88 (1H, d, J = 1.2 Hz, arom.H ₁ ), 7.36-8.43 (8H, m, arom.H ₈ ); FAB-MS m / z: 406 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₂ H ₂₀ N ₃ O ₅ , 406.1403; found, 406.1388.

(Process 5A)
4-{[(1,3-Benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} -N- (2-nitrophenyl) benzamide (Compound 3b)
To a suspension of compound 3a (0.19 g) in acetonitrile (4.7 mL) were added potassium carbonate (0.13 g) and 2-bromoethanol (0.67 mL) in this order, and the mixture was stirred at 60 ° C. overnight. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 2) to obtain yellow oily compound 3b (0.2 g, yield 94.1%). The instrumental analysis data of this compound is shown below.

[Compound 3b] IR (KBr) cm ⁻¹ 3362, 2887, 2316, 1805, 1774, 1688, 1587, 1248, 1148, 1074, 972, 773; ¹ H NMR (CDCl ₃ ) δ2.68 (2H, t, J = 5.6Hz, NC H ₂ CH ₂ OH), 3.55 (2H, s, 1,3-benzodioxole-C H ₂ ), 3.62 (2H, t, J = 5.6Hz, NCH ₂ C H ₂ OH ), 3.69 (2H, s, PhC H ₂ ), 5.95 (2H, s, OCH ₂ ), 6.73-6.82 (3H, m, arom.H ₃ ), 7.22 (1H, t, J = 6.0 Hz, arom. H ₁ ), 7.49 (2H, d, J = 8.4 Hz, arom.H ₂ ), 7.72 (1H, t, J = 8.4 Hz, arom.H ₁ ), 7.97 (2H, d, J = 8.0 Hz, arom .H ₂ ), 8.28 (1H, dd, J = 1.6, 8.6 Hz, arom.H ₁ ), 9.00 (1H, dd, J = 1.2 Hz, 8.6 Hz, arom.H ₁ ), 11.34 (1H, s, PhCON H ); FAB-MS m / z: 450 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₄ H ₂₄ N ₃ O ₆ , 450.1665; measured value, 450.1692.

(Step 6A)
N- (2-aminophenyl) -4-{[(1,3-benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} benzamide (Compound 3)
To a solution of compound 3b (0.22 g) in methanol (7.9 mL) was added tin (II) chloride dihydrate (0.36 g) and ammonium acetate (0.22 g), and the mixture was stirred at 60 ° C. for 5 minutes. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. This was dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After concentrating this solution under reduced pressure, the obtained residue was purified by PLC plate (ethyl acetate: hexane = 4: 1) to obtain Compound 3 (23.0 mg, yield 20.1%) as yellow crystals. The instrumental analysis data of this compound is shown below.

[Compound 3] mp 135.2-137.3 ° C; IR (KBr) cm ^-1 3389, 3310, 2939, 2833, 1638, 1524, 1439, 1325, 1248, 1057, 860; ¹ H NMR (CD ₃ OD) δ2.52 (2H, t, J = 6.0 Hz, NC H ₂ CH ₂ OH), 3.45 (2H, s, 1,3-benzodioxole-C H ₂ ), 3.53 (2H, t, J = 6.0 Hz, NCH ₂ C H ₂ OH), 3.59 (2H, s, PhC H ₂ ), 5.80 (2H, s, OCH ₂ ), 6.63-7.21 (7H, m, arom.H ₇ ), 7.43 (2H, d, J = 8.0 Hz, arom.H ₂ ), 7.84 (2H, d, J = 8.0 Hz, arom.H ₂ ); FAB-MS m / z: 420 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₂₄ H ₂₆ N ₃ O ₄ , 420.1923; measured value, 420.1919.

Example 4
N- (2-aminophenyl) -4-{[(3,4-difluorobenzyl) (2-hydroxyethyl) amino] methyl} benzamide (Compound 4)

(Process 4A)
4-{[(3,4-Difluorobenzyl) amino] methyl} -N- (2-nitrophenyl) benzamide (Compound 4a)
To a solution of compound 1c (3.6 g) in methanol (317 mL), triethylamine (1.62 mL), 3,4-difluorobenzaldehyde (1.27 ml), acetic acid (3.17 mL), and sodium cyanotrihydroborate (0.73 g) were sequentially added. The mixture was further stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 3) to obtain yellow crystalline compound 4a (1.49 g, yield 32.0%). The instrumental analysis data of this compound is shown below.

[Compound 4a] mp 65.6-67.8 ° C; IR (KBr) cm ^-1 3346, 3261, 2835, 1923, 1678, 1607, 1433, 1344, 1271, 899; ¹ H NMR (CDCl ₃ ) δ 3.77 (2H, s, 3,4-difluorophenyl-C H ₂ ), 3.89 (2H, s, PhC H ₂ ), 7.06-7.26 (5H, m, arom.H ₄ ), 7.52 (2H, d, J = 8.0 Hz , arom.H ₂ ), 7.74 (1H, t, J = 7.2 Hz, arom.H ₁ ), 7.97 (2H, dd, J = 2.0, 8.4 Hz, arom.H ₂ ), 8.29 (1H, dd, J = 1.6, 8.4 Hz, arom.H ₁ ); FAB-MS m / z 398 (M + H) ⁺ ; EI-MS m / z: 397 (M) ⁺ ; HR-EI-MS m / z: (M ) ⁺ Calculated value C ₂₁ H ₁₇ F ₂ N ₃ O ₃ , 397.1238; Actual value, 397.1259.

(Process 5A)
4-{[(3,4-Difluorobenzyl) (2-hydroxyethyl) amino] methyl} -N- (2-nitrophenyl) benzamide (Compound 4b)
To a suspension of compound 4a (0.92 g) in acetonitrile (23 mL) were added potassium carbonate (0.64 g) and 2-bromoethanol (0.82 mL) in this order, and the mixture was stirred at 60 ° C. overnight. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 2) to obtain yellow oily compound 4b (0.94 g, yield 92.3%). The instrumental analysis data of this compound is shown below.

[Compound 4b] IR (KBr) cm ⁻¹ 3481, 3352, 2922, 1684, 1607, 1499, 1456, 1340, 1205, 955; ¹ H NMR (CDCl ₃ ) δ2.68 (2H, t, J = 5.6 Hz , NC H ₂ CH ₂ OH), 3.57-3.65 (4H, m, 3,4-difluorophenyl-C H ₂ , NCH ₂ C H ₂ OH), 3.66 (2H, s, PhC H ₂ ), 3.69 (2H , s, PhC H ₂ ), 7.02-7.50 (6H, m, arom.H ₆ ), 7.72 (1H, t, J = 7.2 Hz, arom.H ₁ ), 7.96-8.29 (2H, m, arom.H ₂ ), 8.99 (1H, d, J = 1.3, arom.H ₁ ), 9.01 (1H, d, J = 1.2 Hz, arom.H ₁ ); FAB-MS m / z: 442 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₂₃ H ₂₂ F ₂ N ₃ O ₄ , 442.1578; found value, 442.1558.

N- (2-aminophenyl) -4-{[(3,4-difluorobenzyl) (2-hydroxyethyl) amino] methyl} benzamide (Compound 4)
To a solution of compound 4b (0.46 g) in methanol (30 mL) were added tin (II) chloride dihydrate (1.38 g) and ammonium acetate (0.83 g), and the mixture was stirred at 60 ° C. for 30 minutes. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. This was dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After concentrating this solution under reduced pressure, the obtained residue was purified by PLC plate (ethyl acetate: hexane = 4: 1) to obtain Compound 4 (0.13 g, yield 29.2%) as yellow crystals. The instrumental analysis data of this compound is shown below.

[Compound 4] mp 137.6-140.1 ° C; IR (KBr) cm ^-1 3356, 2959, 2357, 1611, 1516, 1458, 1325, 1203, 970, 940; ¹ H NMR (CD ₃ OD) δ 2.68 (2H , t, J = 5.2 Hz, NC H ₂ CH ₂ OH), 3.48 (2H, s, 3,4-Difluorophenyl-C H ₂ ), 3.60-3.69 (4H, m, NCH ₂ C H ₂ OH, PhC H ₂ ), 3.59 (2H, s, PhC H ₂ ), 6.85-7.45 (9H, m, arom.H ₉ ), 7.89 (2H, d, J = 7.6 Hz, arom.H ₂ ); FAB-MS m / z: 412 (M + H) ⁺ ; EI-MS m / z: 411 (M) ⁺ ; HR-EI-MS m / z: (M) ⁺ calculated C ₂₃ H ₂₃ F ₂ N ₃ O ₂ , 411.1758; found, 411.1787.

Example 5
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (4-methoxybenzyl) amino] methyl} benzamide (Compound 5)

(Process 4A)
4-{[(4-Methoxybenzyl) amino] methyl} -N- (2-nitrophenyl) benzamide (Compound 5a)
To a solution of compound 1c (1.0 g) in methanol (100 mL), triethylamine (0.45 mL), 4-methoxybenzaldehyde (0.4 ml), acetic acid (1.0 mL), sodium cyanotrihydroborate (0.20 g) were added in this order. Stir at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 3: 2) to obtain green crystalline compound 5a (0.25 g, yield 20.0%). The instrumental analysis data of this compound is shown below.

[Compound 5a] mp 58.0-60.3 ° C; IR (KBr) cm ^-1 3369, 2822, 1682, 1607, 1551, 1508, 1437, 1339, 986, 935; ¹ H NMR (CDCl ₃ ) δ3.71 (2H, s, 4-methoxyphenyl-C H ₂ ), 3.78 (3H, s, OMe), 3.88 (2H, s, PhC H ₂ ), 6.86 (2H, d, J = 6.4 Hz, arom.H ₂ ), 7.17 (1H, t, J = 7.2 Hz, arom.H ₁ ), 7.25 (2H, d, J = 8.4 Hz, arom.H ₂ ), 7.49 (2H, d, J = 8.0 Hz, arom.H ₂ ) , 7.66 (1H, t, J = 6.0 Hz, arom.H ₁ ), 7.93 (2H, d, J = 8.4 Hz, arom.H ₂ ), 8.23 (1H, dd, J = 1.6, 8.6 Hz, arom. H ₁ ), 8.97 (1H, dd, J = 1.2, 8.4 Hz, arom.H ₁ ), 11.30 (1H, s, CONH); EI-MS m / z: 391 (M) ⁺ ; HR-EI-MS m / z: (M) ⁺ calculated value C ₂₂ H ₂₁ N ₃ O ₄ , 391.1532; measured value, 391.1534.

(Process 5A)
4-{[(2-hydroxyethyl) (4-methoxybenzyl) amino] methyl} -N- (2-nitrophenyl) benzamide (Compound 5b)
To a solution of compound 5a (0.21 g) in acetonitrile (10 mL) were added potassium carbonate (0.29 g) and 2-bromoethanol (0.75 mL) in this order, and the mixture was stirred at 60 ° C. overnight. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 3: 2) to obtain a green oily compound 5b (0.16 g, yield 75.3%). The instrumental analysis data of this compound is shown below.

[Compound 5b] IR (KBr) cm ^-1 3360, 2930, 1805, 1774, 1688, 1607, 1454, 1340, 1074, 899; ¹ H NMR (CDCl ₃ ) δ2.67 (2H, t, J = 5.6 Hz , NC H ₂ CH ₂ OH), 3.56-3.62 (4H, m, 4-methoxyphenyl-C H ₂ , NCH ₂ C H ₂ OH), 3.69 (2H, s, PhC H ₂ ), 3.79 (3H, s , OMe), 6.87 (2H, d, J = 6.8 Hz, arom.H ₂ ), 7.22-7.24 (3H, m, arom.H ₃ ), 7.50 (2H, d, J = 8.4 Hz, arom.H ₂ ), 7.71 (1H, t, J = 5.6 Hz, arom.H ₁ ), 7.93 (2H, d, J = 1.6 Hz, arom.H ₂ ), 8.25 (1H, dd J = 1.2, 8.4 Hz, arom. H ₁ ), 8.94 (1H, d, J = 7.6Hz, arom.H ₁ ), 11.27 (1H, s, CONH); FAB-MS m / z: 436 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₂₄ H ₂₆ N ₃ O ₅ , 436.1872; measured value, 436.1855.

(Step 6A)
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (4-methoxybenzyl) amino] methyl} benzamide (Compound 5)
To a solution of compound 5b (0.15 g) in methanol (13 mL) were added tin (II) chloride dihydrate (0.47 g) and ammonium acetate (0.28 g), and the mixture was stirred at 60 ° C. for 30 minutes. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. This was dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by PLC plate (ethyl acetate) to obtain Compound 5 (17 mg, yield 12.0%) as yellow crystals. The instrumental analysis data of this compound is shown below.

[Compound 5] mp 127.0-129.1 ° C; IR (KBr) cm ^-1 3360, 2924, 2359, 1611, 1506, 1454, 1321, 1240, 939; ¹ H NMR (CDCl ₃ ) δ 2.68 (2H, t, J = 5.6 Hz, NC H ₂ CH ₂ OH), 3.59-3.62 (4H, m, 4-methoxyphenyl-C H ₂ , NCH ₂ C H ₂ OH), 3.68 (2H, s, PhC H ₂ ), 3.81 (3H, s, OMe), 6.85-6.88 (4H, m, arom.H ₄ ), 7.10 (1H, t, J = 6.0 Hz, arom.H ₁ ), 7.22 (2H, d, J = 8.8 Hz, arom.H ₂ ), 7.34 (1H, d, J = 8.0 Hz, arom.H ₁ ), 7.44 (2H, d, J = 8.4 Hz, arom.H ₂ ), 7.81 (1H, s, CONH), 7.87 (2H, d, J = 8.4 Hz, arom.H ₂ ); EI-MS m / z: 405 (M) ⁺ ; HR-EI-MS m / z: (M) ⁺ calculated value C ₂₄ H ₂₇ N ₃ O ₃ , 405.2052; found, 405.2057.

Example 6
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (3-pyridinylmethyl) amino] methyl} benzamide (Compound 6)

(Process 4A ')
4-{[(2-{[tert-Butyl (dimethyl) silyl] oxy} ethyl) amino] methyl} -N- (2-nitrophenyl) benzamide (Compound 6a)
To a methanol solution (650 ml) of compound 1c (8.0 g), triethylamine (3.6 mL), (tert-butyldimethyloxy) acetaldehyde (5.0 ml), acetic acid (0.65 mL) and sodium cyanotrihydroborate (1.63 g) were added. It added in order and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentrating this solution under reduced pressure, the obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 3: 2) to obtain a green oily compound 6a (3.75 g, yield 33.5%). The instrumental analysis data of this compound is shown below.

[Compound 6a] IR (KBr) cm ^-1 3360, 2928, 2855, 1692, 1607, 1502, 1454, 1339, 1256, 1074, 899; ¹ H NMR (CD ₃ OD) δ0.02 (6H, s, Si (CH ₃ ) ₂ ), 0.86 (9H, s, Si ^t Bu), 2.64 (2H, t, J = 5.2 Hz, NC H ₂ CH ₂ OSi), 3.70 (2H, t, J = 5.2 Hz, NCH ₂ C H ₂ OSi), 3.80 (2H, s, PhC H ₂ ), 7.24 (1H, t, J = 6.4 Hz, arom.H ₁ ), 7.43 (2H, d, J = 8.4 Hz, arom.H ₂ ) , 7.63 (1H, t, J = 6.0 Hz, arom.H ₁ ), 7.85 (1H, t, J = 8.4 Hz, arom.H ₁ ), 8.09 (1H, dd, J = 1.6, 8.2 Hz), 8.38 (1H, dd, J = 1.2, 8.8 Hz); FAB-MS m / z: 430 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₂ H ₃₂ N ₃ O ₄ Si, 430.2162; measured value, 430.2176.

(Process 5A ')
4-{[(2-{[tert-Butyl (dimethyl) silyl] oxy} ethyl) (3-pyridinylmethyl) amino] methyl} -N- (2-nitrophenyl) benzamide (Compound 6b)
To a solution of compound 6a (1.5 g) in methanol (20 mL), 3-pyridinecarboxaldehyde (0.33 mL), acetic acid (0.2 mL), and sodium cyanotrihydroborate (0.22 g) were added in this order, and the mixture was stirred at room temperature for 5 hours. Stir. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentrating this solution under reduced pressure, the obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 3: 2) to obtain a green oily compound 6b (0.67 g, yield 36.6%). The instrumental analysis data of this compound is shown below.

[Compound 6b] IR (KBr) cm ^-1 3360, 2928, 2855, 1692, 1607, 1501, 1433, 1339, 1146, 1016, 937; ¹ H NMR (CD ₃ OD) δ0.02 (6H, s, Si (CH ₃ ) ₂ ), 0.87 (9H, s, Si ^t Bu), 2.59 (2H, t, J = 6.0 Hz, NC H ₂ CH ₂ OSi), 3.68 (2H, t, J = 4.0 Hz, NCH ₂ C H ₂ OSi), 3.72 (2H, s, C H ₂ PhCO), 3.75 (2H, s, pyridine-C H ₂ ), 7.18-8.53 (12H, m, arom.H ₁₂ ); FAB-MS m / z: 521 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₂₈ H ₃₇ N ₄ O ₄ Si, 521.2584; measured value, 521.2580.

(Step 6A ')
N- (2-aminophenyl) -4-{[(2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) (3-pyridinylmethyl) amino] methyl} benzamide (Compound 6c)
To a solution of compound 6b (0.61 g) in methanol (14 mL) was added tin (II) chloride dihydrate (1.76 g) and ammonium acetate (1.04 g), and the mixture was stirred at 60 ° C. for 1 hour. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. This was dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain brown oily compound 6c (0.38 g, yield 59%). The instrumental analysis data of this compound is shown below.

[Compound 6c] IR (KBr) cm ^-1 2928, 2855, 2822, 1649, 1502, 1452, 1315, 1099, 937, 835; ¹ H NMR (CD ₃ OD) δ0.03 (6H, s, Si (CH ₃ ) ₂ ), 0.87 (9H, s, Si ^t Bu), 2.62 (2H, t, J = 5.6 Hz, NC H ₂ CH ₂ OSi), 3.71 (2H, t, J = 4.4 Hz, NCH ₂ C H ₂ OSi), 3.73 (2H, s, C H ₂ PhCO), 3.74 (2H, s, pyridine-C H ₂ ), 6.74-8.51 (12H, m, arom.H ₁₂ ); FAB-MS m / z: 491 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₈ H ₃₉ N ₄ O ₂ Si, 491.2842; found, 491.2827.

(Step 7A ')
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (3-pyridinylmethyl) amino] methyl} benzamide (Compound 6)
A 95% trifluoroacetic acid solution (3.4 mL) of compound 6c (0.32 g) was stirred at 50 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain brown oily compound 6 (0.24 g, yield 98%). The instrumental analysis data of this compound is shown below.

[Compound 6] IR (KBr) cm ^-1 3624, 2851, 2611, 1730, 1680, 1632, 1454, 1315, 1198, 1134, 837; ¹ H NMR (CD ₃ OD) δ 3.89 (2H, t, J = 5.2 Hz, NC H ₂ CH ₂ OH), 3.92 (2H, s, pyridine-C H ₂ ), 4.62 (2H, t, J = 7.8 Hz, NCH ₂ C H ₂ OH), 4.79 (2H, s, C H ₂ PhCO), 7.34-9.06 (12H, m, arom.H ₁₂ ); FAB-MS m / z: 377 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ Calculated C ₂₂ H ₂₅ N ₄ O ₂ , 377.1978; found, 377.1987.

Example 7
N-hydroxy-4-{[(2-hydroxyethyl) (2-naphthylmethyl) amino] methyl} benzamide (Compound 7)

(Step 1B '')
Methyl 4-{[(2-naphthylmethyl) amino] methyl} benzoate (compound 7a)
To a solution of methyl 4- (aminomethyl) benzoate hydrochloride (5.0 g) in dichloromethane (50 mL), triethylamine (0.41 mL), 2-naphthaldehyde (3.88 g), and sodium borohydride (0.94 g) were sequentially added. In addition, the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, washed with 10% aqueous potassium carbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. After concentration of this solution under reduced pressure, the resulting residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 4) to obtain colorless crystal compound 7a (2.2 g, yield 29.6%). The instrumental analysis data of this compound is shown below.

[Compound 7a] mp 56.3-59.2 ° C; IR (KBr) cm ^-1 2951, 2824, 1715, 1508, 1437, 1308, 1275, 1196, 1016, 860, 756; ¹ H NMR (CDCl ₃ ) δ3.90 ( 2H, s, NaphC H ₂ ), 3.91 (3H, s, CO ₂ Me), 3.97 (2H, s, PhC H ₂ ), 7.42-7.49 (5H, m, arom.H ₅ ), 7.75-7.83 (4H , m, arom.H ₄ ), 7.99 (1H, m, J = 2.2 Hz, arom.H ₁ ), 8.01 (1H, m, arom.H ₁ ); EI-MS m / z: 305 (M) ⁺ ; HR-EI-MS m / z: (M) ⁺ calculated C ₂₀ H ₁₉ NO ₂ , 305.1416; measured value, 305.1415.

(Step 2B)
Methyl 4-{[(2-hydroxyethyl) (2-naphthylmethyl) amino] methyl} benzoate (compound 7b)
To a solution of compound 7a (0.5 g) in acetonitrile (16 mL) were added potassium carbonate (0.45 g) and 2-bromoethanol (.2.3 mL) in this order, and the mixture was stirred at 60 ° C. overnight. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 2) to obtain colorless crystalline compound 7b (0.23 g, yield 39.7%). The instrumental analysis data of this compound is shown below.

[Compound 7b] mp 93.5-96.1 ° C; IR (KBr) cm ^-1 3528, 2827, 2708, 1715, 1609, 1508, 1360, 1173, 986, 854; ¹ H NMR (CDCl ₃ ) δ 2.71 (2H, t, J = 5.2 Hz, NC H ₂ CH ₂ OH), 3.61 (2H, t, J = 6.4 Hz, NCH ₂ C H ₂ OH), 3.71 (2H, s, NaphC H ₂ ), 3.77 (2H, s , PhC H ₂ ), 3.90 (3H, s, CO ₂ Me), 7.37-7.50 (5H, m, arom.H ₅ ), 7.71 (1H, s, arom.H ₁ ), 7.77-7.83 (3H, m , arom.H ₃ ), 8.00 (1H, d, J = 1.6 Hz, arom.H ₁ ), 8.01 (1H, d, J = 1.6 Hz, arom.H ₁ ); EI-MS m / z: 349 ( M) ⁺ ; HR-EI-MS m / z: (M) ⁺ calculated C ₂₂ H ₂₃ NO ₃ , 349.1678; found, 349.1691.

(Step 3B)
N-hydroxy-4-{[(2-hydroxyethyl) (2-naphthylmethyl) amino] methyl} benzamide (compound 7)
A 2M hydroxylamine methanol solution (1.4 mL) was added to a 1M potassium hydroxide methanol solution (0.25 mL) of compound 7b (0.1 g), and the mixture was stirred at room temperature for 5 hours. Dry ice was added to the reaction solution, and the resulting precipitate was removed by filtration, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified with a PLC plate (chloroform: methanol = 17: 3) to obtain a brown crystalline compound 7 (27.9 mg, yield 27.6%). The instrumental analysis data of this compound is shown below.

[Compound 7] mp 61.1-63.5 ° C; IR (KBr) cm ^-1 3647, 3529, 2826, 2360, 2340, 1616, 1124, 1016, 897, 856; ¹ H NMR (CD ₃ OD) δ2.62 (2H , t, J = 6.0 Hz, NC H ₂ CH ₂ OH), 3.56 (2H, t, J = 6.4 Hz, NCH ₂ C H ₂ OH), 3.70 (2H, s, NaphC H ₂ ), 3.77 (2H, s, PhC H ₂ ), 7.30-7.44 (5H, m, arom.H ₅ ), 7.70 (4H, d, J = 8.4 Hz, arom.H ₄ ), 7.87 (2H, d, J = 8.0 Hz, arom .H ₂ ); FAB-MS m / z: 351 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₁ H ₂₃ N ₂ O ₃ , 351.1709; , 351.1692.

Example 8
N-hydroxy-4-({(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] amino} methyl) benzamide (Compound 8)

(Step 1B)
Methyl 4-({[2- (1H-indol-3-yl) ethyl] amino} methyl) benzoate (Compound 8a)
To a solution of 3- (2-aminoethyl) indole (1.0 g) in methanol (11 mL), add methyl 4-formylbenzoate (1.0 g), acetic acid (0.11 ml), and sodium cyanotrihydroborate (0.39 g) in this order. In addition, the mixture was stirred overnight at room temperature. After removing the precipitate from the reaction solution, the filtrate was concentrated under reduced pressure. This was dissolved in chloroform, washed successively with 10% aqueous potassium carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (chloroform: methanol = 49: 1) to obtain a brown oily compound 8a (1.2 g, yield 63.0%). The instrumental analysis data of this compound is shown below.

[Compound 8a] IR (KBr) cm ^-1 3408, 2843, 2361, 1715, 1612, 1435, 1416, 1109, 966, 743; ¹ H NMR (CDCl ₃ ) δ2.95-3.02 (4H, m, indole- C ₂ H ₄ ), 3.84 (2H, s, PhC H ₂ ), 3.89 (3H, s, CO ₂ Me), 6.98 (1H, s, indole-N H ), 7.08-7.33 (6H, m, arom. H ₆ ), 7.60 (1H, d, J = 8.0 Hz, arom.H ₁ ), 7.95 (2H, d, J = 8.0 Hz, arom.H ₂ ), 8.24 (1H, s, N H CH ₂ Ph) EI-MS m / z: 308 (M) ⁺ ; HR-EI-MS m / z: (M) ⁺ calculated C ₁₉ H ₂₀ N ₂ O ₂ , 308.1525; measured, 308.1495.

(Step 2B)
Methyl 4-({(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] amino} methyl) benzoate (compound 8b)
To a solution of compound 8a (0.62 g) in acetonitrile (20 mL) were added potassium carbonate (1.1 g) and 2-bromoethanol (.0.71 mL) in this order, and the mixture was stirred at 60 ° C. for 10 hours. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (chloroform: methanol = 49: 1) to obtain a brown oily compound 8b (0.47 g, yield 66.2%). The instrumental analysis data of this compound is shown below.

[Compound 8b] IR (KBr) cm ^-1 3410, 2949, 1715, 1611, 1574, 1456, 1283, 1113, 1018, 964; ¹ H NMR (CDCl ₃ ) δ 2.74 (2H, t, J = 6.0 Hz , NC H ₂ CH ₂ OH), 2.84-2.95 (4H, m, indole-C ₂ H ₄ ), 3.56 (2H, t, J = 6.0 Hz, NCH ₂ C H ₂ OH), 3.75 (2H, s, PhC H ₂ ), 3.91 (3H, s, CO ₂ Me), 6.93 (1H, s, indole-N H ), 7.02-7.43 (7H, m, J = 8.0 Hz, arom.H ₇ ), 7.92 (2H , d, J = 8.4 Hz, arom.H ₂ ), 8.06 (1H, s, N H CH ₂ Ph); EI-MS m / z: 352 (M) ⁺ ; HR-EI-MS m / z: ( M) ⁺ calculated value C ₂₁ H ₂₄ N ₂ O ₃ , 352.1787; measured value, 352.1780.

(Step 3B)
N-hydroxy-4-({(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] amino} methyl) benzamide (Compound 8)
To a solution of compound 8b (0.46 g) in 1M potassium hydroxide in methanol (1.4 mL) was added 2M hydroxylamine methanol solution (8.3 mL), and the mixture was stirred at room temperature for 4 hours. Dry ice was added to the reaction solution, and the resulting precipitate was removed by filtration, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (chloroform: methanol = 9: 1) to obtain brown crystalline compound 8 (0.1 g, yield 22.1%). The instrumental analysis data of this compound is shown below.

[Compound 8] mp 93.4-95.8 ° C; IR (KBr) cm ^-1 3532, 2851, 1715, 1611, 1574, 1456, 1283, 1113, 1018, 964; ¹ H NMR (CD ₃ OD) δ2.73-2.95 (6H, m, NC H ₂ CH ₂ OH, Indole-C ₂ H ₄ ), 3.63 (2H, t, J = 5.6 Hz, NCH ₂ C H ₂ OH), 3.80 (2H, s, PhC H ₂ ), 6.92 (1H, t, J = 7.6 Hz, arom.H ₁ ), 6.98 (1H, s, arom.H ₁ ), 7.04 (1H, t, J = 7.6 Hz, arom.H ₁ ), 7.29 (1H, d, J = 8.0 Hz, arom.H ₁ ), 7.37 (1H, d, J = 7.6 Hz, arom.H ₁ ), 7.44 (2H, d, J = 7.6 Hz, arom.H ₂ ), 7.67 (2H , d, J = 7.2 Hz, arom.H ₂ ); FAB-MS m / z: 354 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₂₀ H ₂₄ N ₃ O ₃ , 354.1818; found, 354.1832.

Example 9
4-{[(1,3-Benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} -N-hydroxybenzamide (Compound 9)

(Step 1B '')
Methyl 4-{[(1,3-benzodioxol-5-ylmethyl) amino] methyl} benzoate (Compound 9a)
Methyl 4- (aminomethyl) benzoate hydrochloride (1.3 g) in methanol (67 mL) was added to triethylamine (0.92 mL), 1,3-benzodioxol-5-carboxaldehyde (1.0 g), cyanotri Sodium hydroboron (0.94 g) was added in order, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. After concentration of this solution under reduced pressure, the resulting residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 2) to obtain colorless amorphous crystal compound 9a (0.65 g, yield 32.6%). . The instrumental analysis data of this compound is shown below.

[Compound 9a] mp 41.2-43.9 ° C; IR (KBr) cm ^-1 3308, 2839, 1947, 1703, 1240, 1092, 928, 802; ¹ H NMR (CDCl ₃ ) δ1.66 (1H, s, N H CH ₂ Phe), 3.69 (2H, s, 1,3-benzodioxole-C H ₂ ), 3.82 (2H, s, C H ₂ Phe), 3.90 (3H, s, CO ₂ Me), 5.95 ( 2H, s, OCH ₂ ), 6.75 (2H, d, J = 0.8 Hz, arom.H ₂ ), 6.85 (1H, s, arom.H ₁ ), 7.40 (2H, d, J = 8.8 Hz, arom. H ₂ ), 8.00 (2H, dd, J = 1.6, 6.6Hz, arom.H ₂ ); FAB-MS m / z: 300 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₁₇ H ₁₈ NO ₄ , 300.1236; measured value, 300.1238.

(Step 2B)
Methyl 4-{[(1,3-benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} benzoate (Compound 9b)
To a solution of compound 9a (0.38 g) in acetonitrile (16 mL) were added potassium carbonate (0.70 g) and 2-bromoethanol (.0.98 mL) in this order, and the mixture was stirred at 60 ° C. for 8 hours. After removing the precipitate from the reaction solution by filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 2: 3) to obtain a colorless oily compound 9b (0.13 g, yield 31.0%). The instrumental analysis data of this compound is shown below.

[Compound 9b] IR (KBr) cm ^-1 3433, 2951, 1720, 1489, 1281, 1040, 930, 756; ¹ H NMR (CDCl ₃ ) δ2.65 (2H, t, J = 5.6 Hz, NC H ₂ CH ₂ OH), 3.52 (2H, s, 1,3-benzodioxole-C H ₂ ), 3.59 (2H, t, J = 5.6Hz, NCH ₂ C H ₂ OH), 5.94 (2H, s, OCH ₂ ), 6.70-6.80 (3H, m, arom.H ₃ ), 7.39 (2H, d, J = 8.4Hz, arom.H ₂ ), 8.00 (2H, dd, J = 1.6, 7.2Hz, arom. H ₂ ); FAB-MS m / z: 344 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₁₉ H ₂₂ NO ₅ , 344.1498; measured, 344.1511.

(Step 3B)
4-{[(1,3-Benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} -N-hydroxybenzamide (Compound 9)
To a solution of compound 9b (0.1 g) in 1M potassium hydroxide methanol (1.2 mL) was added 2M hydroxylamine methanol solution (7.4 mL), and the mixture was stirred at room temperature for 4 hours. Dry ice was added to the reaction solution, and the resulting precipitate was removed by filtration, and then the filtrate was concentrated under reduced pressure. This was dissolved in chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure to obtain brown amorphous crystal compound 9 (74.1 mg, yield 72.9%). The instrumental analysis data of this compound is shown below.

[Compound 9] mp 90.0-92.3 ° C; IR (KBr) cm ^-1 2822, 2359, 1489, 1246, 1038, 930, 812, 754; ¹ H NMR (CDCl ₃ ) δ2.66 (2H, t, J = 5.6Hz, NC H ₂ CH ₂ OH), 3.48 (2H, s, 1,3-benzodioxole-C H ₂ ), 3.52-3.58 (4H, m, C H ₂ Phe, NCH ₂ C H ₂ OH ), 5.95 (2H, s, OCH ₂ ), 6.70-6.79 (3H, m, arom.H ₃ ), 7.39 (2H, d, J = 8.4Hz, arom.H ₂ ), 7.65 (2H, brs, arom .H ₂ ); FAB-MS m / z: 345 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₁₈ H ₂₁ N ₂ O ₅ , 345.1450; measured , 345.1440.

Example 10
N-hydroxy-4-{[methyl (2-naphthylmethyl) amino] methyl} benzamide (Compound 10)

(Process 2B '')
Methyl 4-{[methyl (2-naphthylmethyl) amino] methyl} benzoate (Compound 10a)
Compound 7a (0.5 g) and sodium cyanotrihydroboron (0.31 g) were sequentially added to a solution of formaldehyde (1.4 ml) in acetonitrile (6.6 mL). After 10 minutes, acetic acid (0.17 mL) was added, and the mixture was stirred at room temperature for 2 hours. Acetic acid (0.17 mL) was added to this solution and stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, dissolved in diethyl ether, washed with 2M aqueous potassium hydroxide solution and saturated brine in that order, and dried over anhydrous sodium sulfate. After concentration of this solution under reduced pressure, the resulting residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 4) to obtain colorless crystalline compound 10a (0.46 g, yield 88.3%). The instrumental analysis data of this compound is shown below.

[Compound 10a] mp 55.3-56.6 ° C; IR (KBr) cm ^-1 2951, 2797, 1719, 1690, 1576, 1414, 1277, 991, 824; ¹ H NMR (CDCl ₃ ) δ2.22 (3H, s, NCH ₃ ), 3.60 (2H, s, NaphCH ₂ ), 3.68 (2H, s, PhCH ₂ ), 3.90 (3H, s, CO ₂ Me), 7.42-7.55 (5H, m, arom.H ₅ ), 7.76 (1H, s, arom.H ₁ ), 7.82 (3H, d, J = 8.4 Hz, arom.H ₃ ), 8.01 (2H, d, J = 8.4 Hz, arom.H ₂ ); FAB-MS m / z: 320 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₁ H ₂₂ NO ₂ , 320.1651; measured value, 320.1671.

(Process 3B '')
N-hydroxy-4-{[methyl (2-naphthylmethyl) amino] methyl} benzamide (Compound 10)
To a solution of compound 10a (0.2 g) in 1M potassium hydroxide in methanol (5 mL) was added 2M hydroxylamine methanol solution (7.8 mL), and the mixture was stirred at room temperature for 7 hours. Dry ice was added to the reaction solution, and the resulting precipitate was removed by filtration, and then the filtrate was concentrated under reduced pressure. The obtained residue was suspended in distilled water, and after suction filtration, colorless crystalline compound 10 (66.4 mg, yield 33.1%) was obtained. The instrumental analysis data of this compound is shown below.

[Compound 10] mp 149.2-151.7 ° C .; IR (KBr) cm ⁻¹ 2990, 2800, 2378, 1923, 1719, 1653, 1558, 1327, 897; ¹ H NMR (CDCl ₃ ) δ2.11 (3H, s, NCH ₃ ), 3.54 (2H, s, NaphCH ₂ ), 3.65 (2H, s, PhCH ₂ ), 7.35 (2H, d, J = 8.0 Hz, arom.H ₂ ), 7.49 (2H, t, J = 3.6 Hz, arom.H ₂ ), 7.55 (1H, d, J = 8.4 Hz, arom.H ₁ ), 7.74 (2H, d, J = 7.6 Hz, arom.H ₂ ), 7.83 (1H, s, arom. H ₁ ), 7.88 (3H, d, J = 8.4 Hz, arom.H ₃ ); FAB-MS m / z: 321 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ Calculated C ₂₀ H ₂₁ N ₂ O ₂ , 321.1603; found, 321.1579.

Example 11
N-hydroxy-4-{[(2-hydroxyethyl) (3-quinolinylmethyl) amino] methyl} benzamide (Compound 11)

(Step 1B ')
Methyl 4-{[(2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) amino] methyl} benzoate (Compound 11a)
4- (Aminomethyl) benzoate hydrochloride (9.26 g) in dichloromethane (92 mL) was added to triethylamine (7.4 mL), (tert-butyldimethylsilyloxy) acetaldehyde (8.7 mL), sodium borohydride (1.7 g). ) Were added in order, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed successively with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane: chloroform: triethylamine = 100: 200: 700: 9) to give yellow oily compound 11a (5.0 g, yield). 33.6%). The instrumental analysis data of this compound is shown below.

[Compound 11a] IR (KBr) cm ^-1 3325, 1726, 1612, 1435, 1360, 1258, 1107, 1020, 939, 756; ¹ H NMR (CDCl ₃ ) δ0.02 (6H, s, Si (CH ₃ ) ₂ ), 0.76 (9H, s, Si ^t Bu), 2.67 (2H, t, J = 5.2 Hz, NC H ₂ CH ₂ OSi), 3.68 (2H, t, J = 5.2 Hz, NCH ₂ C H ₂ OSi), 3.81 (2H, s, C H ₂ PhCO), 3.85 (3H, s, CO ₂ Me), 7.34 (2H, d, J = 8.0 Hz, arom.H ₂ ), 7.94 (2H, d, J = 8.4 Hz, arom.H ₂ ); FAB-MS m / z: 324 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₁₇ H ₃₀ NO ₃ Si, 324.1995; measured value, 324.2025.

(Step 2B ')
Methyl 4-{[(2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) (3-quinolinylmethyl) amino] methyl} benzoate (Compound 11b)
To a methanol solution (1.2 ml) of compound 11a (0.2 g), 3-quinolinecarboxaldehyde (5.0 ml), acetic acid (11.7 μL) and sodium cyanotrihydroborate (40.2 mg) were added in this order, and the mixture was stirred at room temperature for 4 hours. Stir. The reaction mixture was concentrated under reduced pressure, dissolved in chloroform, washed successively with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (chloroform: methanol = 19: 1) to obtain brown oily compound 11b (0.11 g, yield 38.4%). The instrumental analysis data of this compound is shown below.

[Compound 11b] IR (KBr) cm ^-1 2951, 2955, 2330, 1722, 1611, 1497, 1387, 1279, 1192, 958, 812; ¹ H NMR (CDCl ₃ ) δ0.02 (6H, s, Si ( CH ₃ ) ₂ ), 0.85 (9H, s, Si ^t Bu), 2.67 (2H, t, J = 6.0 Hz, NC H ₂ CH ₂ OSi), 3.73 (2H, t, J = 6.0 Hz, NCH ₂ C H ₂ OSi), 3.75 (2H, s, quinoline-C H ₂ ), 3.86 (2H, s, C H ₂ PhCO), 3.89 (3H, s, CO ₂ Me), 7.34 (2H, d, J = 8.0 Hz, arom.H ₂ ), 7.94 (2H, d, J = 8.4 Hz, arom.H ₂ ), 7.25-8.09 (9H, m, arom.H ₉ ), 8.93 (1H, m, arom.H ₁ ) ; FAB-MS m / z: 465 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₇ H ₃₇ N ₂ O ₃ Si, 465.2573; found, 465.2563.

(Step 3B ')
Methyl 4-{[(2-hydroxyethyl) (3-quinolinylmethyl) amino] methyl} benzoate (Compound 11c)
A 95% trifluoroacetic acid solution (0.67 mL) of compound 11b (70 mg) was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by PLC plate (chloroform: methanol = 9: 1) to obtain brown oily compound 11c (40.8 mg, yield 77.4%). The instrumental analysis data of this compound is shown below.

[Compound 11c] IR (KBr) cm ^-1 3300, 2800, 1717, 1609, 1499, 1277, 1252, 1105, 982, 835; ¹ H NMR (CDCl ₃ ) δ 2.75 (2H, t, J = 5.2 Hz, NC H ₂ CH ₂ OH), 3.68 (2H, t, J = 5.2 Hz, NCH ₂ C H ₂ OH), 3.71 (2H, s, quinoline-C H ₂ ), 3.84 (2H, s, C H ₂ PhCO ), 3.88 (3H, s, CO ₂ Me), 7.23-8.12 (9H, m, arom.H ₉ ), 8.89 (1H, s, arom.H ₁ ); FAB-MS m / z: 351 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₁ H ₂₃ N ₂ O ₃ , 351.1706; found, 351.1716.

(Step 4B ')
N-hydroxy-4-{[(2-hydroxyethyl) (3-quinolinylmethyl) amino] methyl} benzamide (Compound 11)
To a solution of compound 11c (40 mg) in 1M potassium hydroxide in methanol (0.2 mL) was added 2M hydroxylamine methanol solution (1.1 mL), and the mixture was stirred at room temperature for 5 hours. Dry ice was added to the reaction solution, and the resulting precipitate was removed by filtration, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified with a PLC plate (chloroform: methanol = 9: 1) to obtain a brown crystalline compound 11 (40.8 mg, yield 51.9%). The instrumental analysis data of this compound is shown below.

[Compound 11] mp 62.9-65.2 ° C; IR (KBr) cm ^-1 2924, 2851, 1715, 1697, 1557, 1499, 1362, 1202, 1016, 897; ¹ H NMR (CD ₃ OD) δ 2.61 (2H, t, J = 6.0 Hz, NC H ₂ CH ₂ OH), 3.59 (2H, t, J = 6.0 Hz, NCH ₂ C H ₂ OH), 3.69 (2H, s, quinoline-C H ₂ ), 3.79 (2H , s, C H ₂ PhCO), 7.40-7.91 (8H, m, arom.H ₈ ), 8.19 (1H, s, arom.H ₁ ), 8.77 (1H, s, arom.H ₁ ); FAB-MS m / z: 352 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₂₀ H ₂₂ N ₃ O ₃ , 352.1661; measured value, 352.1644.

Example 12
N-hydroxy-4-{[(2-hydroxyethyl) (3-pyridinylmethyl) amino] methyl} benzamide (Compound 12)

(Step 2B ')
Methyl 4-{[(2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) (3-pyridinylmethyl) amino] methyl} benzoate (Compound 12a)
To a solution of compound 11a (1.3 g) in methanol (41 mL), 3-pyridinecarboxaldehyde (0.39 mL) and sodium cyanotrihydroborate (0.26 g) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved in chloroform, washed successively with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 2) to obtain yellow oily compound 12a (0.82 g, yield 48.6%). The instrumental analysis data of this compound is shown below.

[Compound 12a] IR (KBr) cm ^-1 3186, 2829, 2361, 1638, 1458, 1431, 1136, 1032, 1016, 895; ¹ H NMR (CDCl ₃ ) δ0.02 (6H, s, Si (CH ₃ ) ₂ ), 0.86 (9H, s, Si ^t Bu), 2.64 (2H, t, J = 6.0 Hz, NC H ₂ CH ₂ OSi), 3.68 (2H, s, pyridine-C H ₂ ), 3.71 (2H , s, C H ₂ PhCO), 3.73 (2H, t, J = 4.4 Hz, NCH ₂ C H ₂ OSi), 3.89 (3H, s, CO ₂ Me), 7.22-7.25 (1H, m, arom.H ₁ ), 7.47 (2H, d, J = 8.4 Hz, arom.H ₂ ), 7.72 (1H, m, arom.H ₁ ), 8.00 (2H, d, J = 8.4 Hz, arom.H ₂ ), 8.49 (1H, dd, J = 1.6, 4.6 Hz, arom.H ₁ ), 8.59 (1H, d, J = 1.2 Hz, arom.H ₁ ); FAB-MS m / z: 415 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₂₃ H ₃₅ N ₂ O ₃ Si, 415.2417; measured value, 415.2443.

(Step 3B ')
Methyl 4-{[(2-hydroxyethyl) (3-pyridinylmethyl) amino] methyl} benzoate (Compound 12b)
A 95% trifluoroacetic acid solution (8.8 mL) of compound 12a (0.82 g) was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (chloroform: methanol = 19: 1) to give yellow oily compound 12b (0.33 g, yield 54.2%). The instrumental analysis data of this compound is shown below.

[Compound 12b] IR (KBr) cm ^-1 3252, 2824, 1717, 1611, 1435, 1281, 1175, 1111, 1020, 964, 756; ¹ H NMR (CDCl ₃ ) δ 2.68 (2H, t, J = 5.6 Hz, NC H ₂ CH ₂ OH), 3.64-3.69 (6H, m, NCH ₂ C H ₂ OH, pyridine-C H ₂ , C H ₂ PhCO), 3.91 (3H, s, CO ₂ Me), 3.89 ( 3H, s, CO ₂ Me), 7.27 (1H, t, J = 4.8 Hz, arom.H ₁ ), 7.40 (2H, d, J = 8.0 Hz, arom.H ₂ ), 7.66 (1H, d, J = 7.6 Hz, arom.H ₁ ), 8.00 (2H, d, J = 8.0 Hz, arom.H ₂ ), 8.50 (1H, d, J = 4.8 Hz, arom.H ₁ ), 8.53 (1H, s, arom.H ₁ ); FAB-MS m / z: 301 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated C ₁₇ H ₂₁ N ₂ O ₃ , 301.1552; Value, 301.1563.

(Step 4B ')
N-hydroxy-4-{[(2-hydroxyethyl) (3-pyridinylmethyl) amino] methyl} benzamide (Compound 12)
To a solution of compound 12b (140 mg) in 1M potassium hydroxide in methanol (0.54 mL) was added 2M hydroxylamine methanol solution (3.4 mL), and the mixture was stirred at room temperature for 5 hours. Dry ice was added to the reaction solution, and the resulting precipitate was removed by filtration, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by PLC plate (chloroform: methanol = 9: 1) to obtain brown oily compound 12 (16.8 mg, yield 16.4%). The instrumental analysis data of this compound is shown below.

[Compound 12] IR (KBr) cm ⁻¹ 3186, 2829, 2361, 1638, 1458, 1431, 1313, 1136, 1032, 850; ¹ H NMR (CDCl ₃ ) δ 2.69 (2H, t, J = 5.6 Hz, NC H ₂ CH ₂ OH), 3.64-3.72 (6H, m, NCH ₂ C H ₂ OH, pyridine-C H ₂ , C H ₂ PhCO), 3.91 (3H, s, CO ₂ Me), 7.27 (1H, t, J = 4.8 Hz, arom.H ₁ ), 7.40 (2H, d, J = 8.0 Hz, arom.H ₂ ), 7.66 (1H, d, J = 7.6 Hz, arom.H ₁ ), 8.00 (2H , d, J = 8.0 Hz, arom.H ₂ ), 8.50 (1H, d, J = 4.8 Hz, arom.H ₁ ), 8.53 (1H, s, arom.H ₁ ); FAB-MS m / z: 302 (M + H) ⁺ ; HR-FAB-MS m / z: (M + H) ⁺ calculated value C ₁₆ H ₂₀ N ₃ O ₃ , 302.1505; measured value, 302.1511.

[Pharmacological test]
The pharmacological test of the compound of Examples 1-12 was conducted as follows.

Pharmacological test example 1 (histone deacetylase inhibitory action)
(1) Measurement of histone deacetylase inhibitory activity HDAC (histone deacetylase) inhibitory activity was measured and calculated for the compounds of Examples and the control compounds. As control compounds, MS-275 and SAHA synthesized by the present inventors were used.

  The measurement and calculation of the inhibitory activity was performed according to the method described in WO 01/040506 (PCT / JP00 / 08417) using an HDAC (histone deacetylase) fluorescence assay kit manufactured by Cyclex Corporation. First, for each assay procedure, 1 μl of the substrate peptide Boc-Val-Leu- (Ac) Lys-MCA in 10 mM DMSO was added to 64 μl of HDAC reaction buffer (25 mM Tris HCl, pH 7.5). And dispensed to a microplate for fluorescence measurement and kept at 30 ° C. Next, 10 μl of a histone deacetylase solution was added to each well, and a deacetylation reaction was performed at 30 ° C. for 60 minutes in the presence or absence of a sample (Example compound solution or control compound solution). After the reaction, add 5 μl of peptidase solution diluted to the optimal concentration using 25 mM Tris HCl, pH 7.5 and 20 μl of 5X protease reaction buffer, and measure the fluorescence intensity every 150 seconds with a microplate fluorescence reader. did. The composition of the 5X protease reaction buffer is 500 mM Tris HCl, pH 9.650 mM β-mercaptoethanol. The fluorescence intensity was measured with a Wallac 1420 ARVOsx multilabel counter (trade name, manufactured by amershampharmacia biotech).

Only SAHA uses partially purified enzyme HDACs, [ ³ H] acetylated histone as a substrate, WO 00/021979 (PCT / JP99 / 05597) and WO 03/070691 (PCT / JP03 / 01681) Inhibitory activity was measured according to the method described.

Table 1 shows the concentration (IC ₅₀ : nM) of the test substance (Example compound or control compound) that causes 50% enzyme inhibition.

  As can be seen from Table 1, the compound of this example showed HDAC (histone deacetylase) inhibitory activity equivalent to or better than MS-275 and SAHA. In particular, the compound of Example 9 exhibits more than 2 times the activity of SAHA and 20 times or more of MS-275, and the compounds of Examples 7, 10 and 11 are about 10 times or more of SAHA and MS- It was about 100 times more active than 275 or more.

Pharmacological Test Example 2 (Human colorectal cancer cell HCT116 growth inhibitory activity)
With respect to the compounds of Examples and control compounds, cytostatic activity was measured and IC ₅₀ was determined according to the method described in the paper (Bioorganic & Medicinal Chemistry. 2004, 12, 4351-4360). As control compounds, MS-275 and SAHA synthesized by the present inventors were used as in Pharmacological Test Example 1.

  The cell growth inhibitory activity was measured as follows. That is, first, human colon cancer cells HCT116 were seeded into a 96-well plate, followed by a sample solution (solvent: RPMI 1640 medium containing 10% fetal calf serum (Australia Moregatc Bio Tech, lot No. 49300604), 6 doses) or Blank solution was added. After culturing for 2 days, the cells were stained with 0.05% methylene blue dissolved in 10 mM Tris buffer (pH 8.5) and washed successively with distilled water. The staining dye was extracted with 3% hydrochloric acid, and OD660 (fluorescence intensity at a wavelength of 660 nm) was measured using a Benchmark Plus (trade name of Bio-Rad, USA) microplate reader, thereby inhibiting cell proliferation. Was measured.

Table 2 shows the concentration (IC ₅₀ : nM) that causes 50% enzyme inhibition of the test substance (Example compound or control compound).

  As can be seen from Table 2, all of the compounds of this example showed the human colon cancer cell HCT116 growth inhibitory activity equal to or higher than that of MS-275 and SAHA. In particular, the compounds of Examples 7 and 10 were much more excellent in HCT116 growth inhibitory activity than MS-275 and SAHA.

Pharmacological Test Example 3 (Solubility in 10% HCO60)
Histone deacetylase inhibitors (compounds of this example, MS-275 and SAHA) were added to 25 μl of HCO60, respectively, and shaken for 10 minutes with a vortex centrifuge (trade name of Iida Trading Co., Ltd.). Subsequently, 225 μl of water was added, and the mixture was further shaken with a vortex centrifuge for 10 minutes, and the solubility was examined visually. Table 3 shows the solubility of each compound. The upper limit of measurable solubility in this measurement was 20 mg / ml.

  As can be seen from Table 3, all of the compounds of this example showed a solubility equal to or higher than that of MS-275 and SAHA. In particular, the compounds of Examples 7, 9 and 11 showed excellent solubility of several times that of MS-275 and SAHA.

  The synthesis method and pharmacological test results of the compound of this example have been described above. However, the compounds of the present invention include a wide range of compounds as described above, and are not limited to the compounds of Examples 1-12. For example, as described above, a carboxamide derivative represented by the following chemical formula and compound name is also included in the compound of the present invention.

  As described above, the compound of the present invention has strong cancer cell growth inhibitory activity and the like, and is excellent in metabolic stability, solubility and the like. Furthermore, the compound of the present invention has an excellent HDAC inhibitory activity, so that, for example, a therapeutic and / or ameliorating agent for diseases related to cell proliferation, an effect enhancing agent for gene therapy, a cardiac hypertrophy improving agent, an immunosuppressive agent Also, it can be expected to be applied to various uses such as drugs that delay or prevent neurodegenerative diseases such as Huntington's disease caused by expansion of polyglutamine repeats.

Claims (7)

A carboxamide derivative represented by the following general formula [I] or a salt thereof.

In the formula [I],
L ¹ , L ² and L ³ are the same or different and each is a methylene group, an ethylene group (dimethylene group) or a trimethylene group;
[A] is a hydroxy group or a phenyl group or a naphthyl group substituted with one amino group;
[B] is a group represented by any of the following formulas (154), (155), (157), (159) and (161),

[C] is a hydroxy group,
[D] is an o-phenylene group, an m-phenylene group or a p-phenylene group,
In the formulas (154), (155), (157), (159) and (161),
R ¹ and R ² are each independently hydrogen, fluorine, chlorine, bromine, iodine, methoxy group, ethoxy group, propoxy group, isopropoxy group, t-butoxycarbonyloxy group, or R ¹ and R ² Together form a methylenedioxy group,
R ³ and R ⁴ are hydrogen,
X is NH or NCH ₃ . When [B] is a group represented by the formula (154), in the formula (154), R ¹ and R ² are each independently hydrogen, fluorine, chlorine, bromine, iodine, methoxy group, ethoxy A group, a propoxy group, an isopropoxy group, a t-butoxycarbonyloxy group, or R ¹ and R ² together form a methylenedioxy group,
When [B] is a group represented by the formula (155), in the formula (155), R ¹ is hydrogen;
When [B] is a group represented by the formula (157), in the formula (157), R ¹ is hydrogen;
When [B] is a group represented by the above (159), in the formula (159), R ¹ is hydrogen;
When [B] is a group represented by the above (161), in the formula (161), R ¹ is hydrogen.
The carboxamide derivative or a salt thereof according to claim 1. The carboxamide derivative is
N- (2-aminophenyl) -4-{[benzyl (2-hydroxyethyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-({(2-hydroxyethyl) [(1-methyl-1H-indol-3-yl) methyl] amino} methyl) benzamide;
N- (2-aminophenyl) -4-{[(1,3-benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} benzamide;
N- (2-aminophenyl) -4-{[(3,4-difluorobenzyl) (2-hydroxyethyl) amino] methyl} benzamide;
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (4-methoxybenzyl) amino] methyl} benzamide,
N- (2-aminophenyl) -4-{[(2-hydroxyethyl) (3-pyridinylmethyl) amino] methyl} benzamide,
N-hydroxy-4-{[(2-hydroxyethyl) (2-naphthylmethyl) amino] methyl} benzamide;
N-hydroxy-4-({(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] amino} methyl) benzamide;
4-{[(1,3-benzodioxol-5-ylmethyl) (2-hydroxyethyl) amino] methyl} -N-hydroxybenzamide,
N-hydroxy-4-{[(2-hydroxyethyl) (3-quinolinylmethyl) amino] methyl} benzamide;
The carboxamide derivative or a salt thereof according to claim 1 or 2, selected from the group consisting of N-hydroxy-4-{[(2-hydroxyethyl) (3-pyridinylmethyl) amino] methyl} benzamide.   The pharmaceutical composition for histone deacetylase (HDAC) inhibition containing the carboxamide derivative in any one of Claims 1-3, or its salt.   A pharmaceutical composition for treatment, alleviation and prevention of colorectal cancer, comprising the carboxamide derivative or a salt thereof according to any one of claims 1 to 3.   N-hydroxy-4-{[methyl (2-naphthylmethyl) amino] methyl} benzamide or a salt thereof.   A pharmaceutical composition for inhibiting histone deacetylase (HDAC), comprising N-hydroxy-4-{[methyl (2-naphthylmethyl) amino] methyl} benzamide or a salt thereof according to claim 6.