WO2002074296A1 - Remedies for solid cancer containing hydroxamic acid derivatives as the active ingredient - Google Patents

Abstract

Preventives and/or remedies for solid cancer which contain as the active ingredient hydroxamic acid derivatives represented by the following general formula (I): wherein each symbol is as defined in the description; non-toxic salts thereof or prodrugs of the same. The compounds represented by the general formula (I), salts thereof and prodrugs of the same are useful as preventives and/or remedies for solid cancer.

Description

 Description Therapeutic agent for solid cancer containing hydroxamic acid derivative as active ingredient

 The present invention relates to a prophylactic and / or therapeutic agent for solid cancer containing a hydroxamic acid derivative, a nontoxic salt thereof and a prodrug thereof as an active ingredient, and a novel hydroxamic acid derivative, a nontoxic salt thereof and a prodode thereof. About rag.

 For details, see the general formula (I)

(Wherein all symbols have the same meanings as described below.), A prophylactic and / or therapeutic agent for solid cancer comprising a hydroxamic acid derivative, a non-toxic salt thereof or a prodrug thereof as an active ingredient; And a novel compound contained in the hydroxamic acid derivative of the general formula (I),

 1) (R) -N- (1-methoxy-1-methyl) ethoxy-6- (4- (4-diethylaminomethylphenyl) phenyl) -1-6-hydroxyhexaneamide,

 2) (R) -N- (1-methoxy-1-methyl) ethoxy-6- (4- (4- (2-methylethylethoxy) phenyl) phenyl) -1-6-hydroxyhexanamide,

3) (R) -N-hydroxy-6- (4- (4-phenyl) phenyl) -1-6-hydroxyhexaneamide, or 4) (R) —N-Hydroxy-6- (4- (4- (2-Gethylaminoethoxy) phenyl) phenyl) — 6-Hydroxyhexamide, a nontoxic salt thereof or a prodrug thereof. Landscape technology

 In the specification of PCT / JP00 / 06506, the compound represented by the general formula (I) inhibits the production of interleukin-16 to produce various inflammatory diseases, sepsis, multiple myeloma, Cellular leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, cystic sarcoma, rheumatoid arthritis, hypergammaglobulinemia, Castleman's disease, atrial myxoma, diabetes, autoimmune disease, hepatitis, colon It is described as being effective as a prophylactic and / or therapeutic agent for inflammation, graft-versus-host disease, infectious disease, endometriosis.

 However, it is hardly described that the compound represented by the general formula (I) is useful as a prophylactic and / or therapeutic agent for solid cancer. Disclosure of the invention

 The present inventors have conducted various experiments to confirm the effect on solid cancer. As a result, the hydroxamic acid derivative represented by the general formula (I), a non-toxic salt thereof, and a prodrug thereof have been shown to be used in solid cancer (for example, , Brain tumor, head and neck cancer, thyroid cancer, esophageal cancer, stomach cancer, large intestine (colon, rectum) cancer, liver cancer, gallbladder and bile duct cancer, kidney cancer, lung cancer, breast cancer, cervical cancer, uterine body cancer, ovarian cancer, Prostate cancer, testicular tumor, bladder cancer, renal pelvis and ureteral tumor, adrenal cancer, neuronal tumor, glioma, bone tumor, rhabdomyosarcoma, osteosarcoma, soft tissue sarcoma, eosinophilic granuloma, malignant melanoma, skin The present invention was found to be useful as a prophylactic and / or therapeutic agent for cancer, glioblastoma, Wilms tumor and the like, and achieved the present invention.

That is, the present invention (1) General formula (I)

Where R ¹ is

 (a) a C1-8 alkyl group,

 (b) a C2-8 alkenyl group,

 (c) a C2-8 alkynyl group,

 (d) a halogen atom,

 (e) a nitro group,

 (f) a nitril group,

 (g) trifluoromethyl group,

 (h) trifluoromethoxy group,

(i) —〇R ² groups,

(J) one SR ² groups,

(k) — ⁴ NR ³ R groups,

(1) ^Five CORs,

 (m) keto group,

 (n) one Cy c group,

(o) —OR ² groups, —SR ² groups, 1 NR ³ R ⁴ groups, 1 COR ⁵ groups or C 1-8 alkyl groups substituted by Cy c 1 groups,

(P) - S0 ₂ R ¹⁰ group,

(q) 101 (Cl-8 alkylene group) —OR ¹¹ group,

(r) nitrile group, one S0 ₂ R ¹⁰ group or one O— (C 1-8 alkylene group) C 1-8 alkyl group substituted by one OR ¹¹ group, (s) —〇 (C 1-8 alkylene group) NR ¹² R ¹³ groups,

(T) - S- (C l~8 alkylene group) one NR ¹² R ¹³ group,

(u) a C 1-8 alkyl group substituted by a C 1-8 alkylene group or a NR ¹² R ¹³ group or a S— (C 1-8 alkylene group) NR ¹² R ¹³ group; V) —OR ² groups, 1 SR ² groups, 1 NR ³ R ⁴ groups, 1 COR ⁵ groups, 1 Cyc group, 1 nitrile group, 1 S〇 ₂ R ^{1 ()} group, —O— (C l ~ 8 alkylene groups) 1 OR ¹¹ group, _〇— (C 1-8 alkylene group) —NR ¹² R ¹³ group or 1 S— (C 1-87 alkylene group) 1 C 2— substituted by NR ¹² R ¹³ group 8 Alkenyl group, or

(w) _〇R ² groups, 1 SR ² groups, — NR ³ R ⁴ groups, 1 COR ⁵ groups, 1 Cyc group, 1 nitrile group, 1 S〇 ₂ R ^{1 ()} group, —〇 1 (C L～8 alkylene group) one oR ¹¹ group, one O- (C l~8 alkylene) - substituted by NR ¹² R ¹³ group or -S- (〇 1-8 § alkylene group) one NR ¹² R ¹³ group Represents a C 2-8 alkynyl group,

R ² represents a hydrogen atom, a C1-8 alkyl group, a C2-9 acyl group or a Cy 1 group,

R ³ and R ⁴ each independently represent a hydrogen atom, a C 1-8 alkyl group, a C 2-9 acyl group or a Cyc 1 group,

R ⁵ is hydroxyl, C l~8 alkyl group, C l~8 alkoxy group, _NR ⁶ R ⁷ Motoma other represents 1 group Cyc,

R ⁶ and R ⁷ each independently represent a hydrogen atom, a C 1-8 alkyl group or a Cy 1 group,

R ^1D represents a C 1-8 alkyl group or a Cy c 1 group,

Cy c1 group is a C3-7 monocyclic carbocycle or a 5-7 membered monocyclic heterocycle containing 1-4 nitrogen atoms, 1 oxygen atom and Z or 1 sulfur atom. Represents a ring, R ¹¹ represents a hydrogen atom, a Cl-8 alkyl group, a C2-9 acyl group or a Cyc1 group,

R ¹² and R ¹³ are each independently a hydrogen atom, C L～8 alkyl group, a C2 to 9 Ashiru group or Cy c 1 group,

m represents 0 or an integer of 1 to 5,

Ring A contains C 3-15 monocyclic, bicyclic, tricyclic carbocyclic or 1-4 nitrogen atoms, 1-2 oxygen atoms and Z or 1-2 sulfur atoms 5-18 Member represents a monocyclic, bicyclic or tricyclic heterocycle,

Ring B contains C5-15 monocyclic, bicyclic, tricyclic carbocyclic aryl or 1-4 nitrogen atoms, 1-2 oxygen atoms and / or 1-2 sulfur atoms5 Represents an 18-membered monocyclic, bicyclic, or tricyclic heteroaryl ring;

E represents a single bond, one CH = CH— or —C≡C—

R ⁸ is

 (a) a C1-8 alkyl group,

 (b) C 1-8 alkoxy group,

 (c) a halogen atom,

 (d) a nitro group,

 (e) nitrile group,

 (f) trifluoremethyl group, or

 (g) represents a trifluoromethoxy group.

However, when E represents a single bond, R ¹ and R ⁸ may be taken together to represent a C 1-4 alkylene group.

n represents 0 or an integer of 1 to 5,

R ⁹ represents a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group. ]

Hydroxamic acid derivatives, their non-toxic salts or their prod A prophylactic and / or therapeutic agent for solid cancer containing a rug body as an active ingredient, and

 (2) 1) (R) -N- (1-methoxy-1-methyl) ethoxy-6- (4- (4-methylethylaminophenyl) phenyl) -6-hydroxyhexanamide, '

 2) (R) -N- (1-methoxy-1-methyl) ethoxy-6- (4- (4- (2-getylaminoethoxy) phenyl) phenyl) -1-6-hydroxyhexanamide,

 3) (R) -N-hydroxy-6- (4- (4-ethylethylaminophenyl) phenyl) -6-hydroxyhexanamide, or

 4) (R) mono-N-hydroxy-6- (4- (4- (2-getylaminoethoxy) phenyl) phenyl)-6-hydroxyhexanamide, a non-toxic salt thereof or a prodrug thereof. Detailed description of the invention

 In the compound represented by the general formula (I) according to the present invention, all isomers are included unless otherwise indicated. For example, alkyl, alkoxy, and alkylene groups include straight-chain and branched ones. In addition, isomers (E, Z, cis, trans) in double bonds, rings and condensed rings, and isomers due to the presence of asymmetric carbon (R, S, α, | 3 isomers, enantiomers, diastereomers) 1), optically active substance having optical activity (D, L, d, 1, (+), (1) form), polar form by chromatographic separation (high polar form, low polar form), equilibrated compound, And racemic mixtures are included in the present invention.

In the present specification, a C 1-8 alkyl group refers to a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof. It is.

 The C2-8 alkenyl group is a vinyl, probenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentagenenyl, hexenyl, heptagenyl, octagenyl, hexatrienyl, heptatrienyl, octatrienyl group and isomers thereof. It is.

 C2-8 alkynyl groups include ethynyl, propiel, butynyl, pentenyl, hexynyl, heptynyl, octynyl, butyudiinyl, pentadiynyl, hexaziynyl, heptadinyl, octadinyl, hexatriynyl, heptatriynyl, and octatriynyl; Is an isomer of

 Halogen atoms are fluorine, chlorine, bromine and iodine atoms.

 The C 1-4 alkylene group is a methylene, ethylene, trimethylene, tetramethylene group and isomers thereof.

 The C1-8 alkylene group is a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene group and isomers thereof.

 The C2-9 acetyl group is an acetyl, propionyl, butyryl, paleryl, hexanoyl, heptanyl, octanoyl, nonanoyl group and isomers thereof.

 The C1-8 alkoxy group is a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group and isomers thereof.

The C 3-7 monocyclic carbocycle means a C 3-7 monocyclic aromatic carbocycle, a partially saturated carbocycle and a fully saturated carbocycle. For example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, benzene ring, etc. You.

A 5- to 7-membered monocyclic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom is 1 to 4 nitrogen atoms, 1 oxygen Means a 5- to 7-membered monocyclic heteroaryl containing an atom and or one sulfur atom and saturated or partially or entirely thereof. For example, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiane (thiopyran), cepin, oxazole, isoxazole, isoxazole, isoxazole , Isothiazole, oxaziazole, oxazine, oxazineazine, oxazepine, oxazineazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, pyrroline, pyrrolidine, imidazoline, imidazoline, pyrazolidine, pyrazolidine , Dihydropyridine, dihydropyrimidine, dihydropyrida Gin, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydroazepine, dihydrodazepine, tetrahydroazepine, tetrahydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, Dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole , Dihydrothiazole, tetrathiazole thiazole, dihydroisothiazole, tetrahydroisothiazol, tetrahydrooxadiazole, tetrahydrooxaazine, tetrahydrooxa Ajin, tetrahydronaphthyl O hexa § Ze pin Tetorahi mud O hexa di § Ze pins, tetrahydropyran thiadiazolidin Ichiru, tetrahydrothienyl Ah Jin, tetrahydrothienyl Asia Jin, tetrahydrothienyl Ah Ze pin Tetorahido Rotiadiazepine, morpholine, thiomorpholine rings and the like.

 C3-15 monocyclic, bicyclic, and tricyclic carbocycles are C3-15 monocyclic, bitricyclic aromatic carbocycles, partially saturated carbocycles, and all saturated carbocycles Means a carbon ring. For example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, silicon, benzene, pentane, indene, naphthalene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphene Rene, perhydropentalene, perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroloacenaphthylene, perhydrobiphenylene ring, etc. Is mentioned.

A 5- to 18-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms is 1 to 5- to 18-membered mono-, bi-, and tricyclic heteroaryls containing 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms and some or all thereof Means that they are saturated. For example, pyrrol, imidazole, pyrazole, triazol, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiane (chopyran), chepin, oxazole. , Isoxazole, thiazole, isothiazole, oxazine diazole, oxazine, oxazine diazine, oxazepine, oxazine diazepine, thiadiazol, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, benzofuran, benzofuran, benzofuran, benzofuran, benzofuran, benzofuran, benzofuran. , Indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, Cinnoline, benzoxazole, Benzothiazole, benzimidazole, carbazole, acridine, dibenzofuran, dibenzothiophene, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidin, tetrazolin, tetrazolidine, dihydropyridine, dihydropyrimidine Dihydropyridazine, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydroazepine, dihydrodiazepine, tetrahydroazepine, tetrahydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran , Dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiophene) Rothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, thiazol dihydroxide, thiazole tetrahydroxide, dihydroisothiazole, tetrahydroisothiazol, tetrahydrooxazine Zol, tetrahydroxazine, tetrahydroxazine diazine, tetrahydroxoxazepine, tetrahydrooxazine diazepine, tetrahydrothiadiazazopine, tetrahydrothiadiazepine, morpholine, thiomorpholine, indoline, isoindoline , Dihydrobenzofuran, perhydrobenzov benzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazo Dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, tetrahydronaphthyridine Quinoxaline, par Hydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrodrosinenoline, dihydrobenzoxazole, parahydrobenzoxazole, dihydrobenzozothiazole, parahydrobenzozothiazole , Dihydrobenzimidazole, perhydrobenzimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzozepine, benzodiazepine, indoloxazepine, Indolote lahydroxazepine, indoloxazedazepine, indolotetrahydrooxazedazepine, indolothiazepine, indolotetrahydrothiazendroazepine, indolotetra Droazepine, indolozepine, indrotetrahydrodiazepine, benzofurazan, benzothiadiazole, benzotriazole, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, parahydrocarbazole, dihydroacridine , Tetrahydroacridine, parahydroacridine, dihydrodibenzothiofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, perhydrodibenzofuran, perhydrodibenzothiophene, 1,3-dioxindan, 1,4- And a dioxotetrahydronaphthalene ring.

 C5 to C15 monocyclic, bicyclic, and tricyclic carbocyclic aryls are cyclopentene, cyclohexadiene, cycloheptadiene, cycloheptoleline, benzene, indene, naphthalene, fluorene, and anthracene ring. And the like.

A 5- to 18-membered monocyclic, bicyclic or tricyclic heteroaryl ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms is , Imidazole, triazole, tetrazole, pyrazole, pyridine, pyra Gin, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiane (chopyran), chepin, oxazole, isoxazole, thiazole, isothiazole, franzane, oxazine, oxazine, oxazine, oxazine, oxazine, oxazine, oxazine , Thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, benzonolin Thiazole, benzimidazole, benzoxepin, benzoxa Pin, benzoxaziazepine, benzochepine, benzothiazepine, benzothiadiazepine, benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazolyl, acridine, dibenzofuran, dibenzothiophene ring, etc. Is received.

 In the present invention, unless otherwise specified, the symbol

.. * ,,,, indicate that they are connected to the other side of the paper (ie, α-configuration),

Ζ indicates that it is connected to the front side of the page (that is, ^

Ζ indicates Q! —, 3—, or a mixture thereof,

No means that it is a mixture of one- and -configurations. [salt] The present invention includes all non-toxic salts. For example, common salts, acid addition salts, hydrate salts and the like can be mentioned.

 The compounds according to the invention are converted into the corresponding salts by known methods. Non-toxic, water-soluble salts are preferred. Suitable salts include salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (such as tetramethylammonium, triethylamine, And salts of methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-dalcamine, and the like. The compounds according to the invention are converted into the corresponding acid addition salts by known methods. The acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, trifluoroacetate, lactate, tartrate, oxalate Such as, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, dalconate Organic acid salts.

 Further, the compound or a salt thereof according to the present invention can be converted to a hydrate by a known method.

Further, the prodrug of the present invention is a compound of the formula (I) wherein one CO NH OH group is

(In the formula, R ¹⁴ represents a C 1-8 alkyl group or a C 1-8 alkyl group substituted by a C 1-8 alkoxy group.) Or

に変換されたものを意味する。

Means converted to

 Among the compounds according to the present invention, ring A is a C3-10 monocyclic, bicyclic carbon ring or 1-4 nitrogen atoms, 1-2 oxygen atoms and / or 1-2 A 5- to 10-membered monocyclic or bicyclic heterocyclic ring containing a sulfur atom is preferred. In particular, a C 5-7 monocyclic carbocycle or a 5-10 membered monocyclic ring containing 1-2 nitrogen atoms, 1-2 oxygen atoms and / or 1-2 sulfur atoms, Cyclic heterocycles are preferred. More preferred are benzene, cyclohexane, benzoxazole, benzothiazole, benzimidazole, benzothiophene, and benzofuran rings.

The R ^{1, (1)} C l~8 alkyl group, (2) -OR ² group, (3) - SR ² group, (4) a halogen atom, (5) Cyc l, ( 6) _NR 3 R 4 Preference is given to groups or (7) a C 1-8 alkyl group substituted by an OR ² group, an SR ² group, a halogen atom, a Cycl, —NR ³ R ⁴ group. In particular, (1) a C1-8 alkyl group, (2) a C1-8 alkoxy group, (3) a C1-8 alkylthio group, (4) a halogen atom, (5) 1 to 4 nitrogen atoms, 5- to 7-membered monocyclic heterocycle containing one oxygen atom and Z or one sulfur atom, (6) di (C1-8 alkyl) amino group or (7) C1-8 alkoxy A 5- to 7-membered monocyclic heterocyclic ring containing a C1-8 alkylthio group, a halogen atom, 1-4 nitrogen atoms, 1 oxygen atom and or 1 sulfur atom, di (Cl 88 alkyl group) A C 1-8 alkyl group substituted by an amino group is preferred. More preferred are a methyl group, a methoxy group, a methylthio group, a chlorine atom, a dimethylamino group, Mouth pillamino group, morpholine ring, piperidine ring, piperazine ring, methoxymethyl group, methylthiomethyl group, dimethylaminomethyl group, dipropylaminomethyl group, morpholine-1-ylmethyl group, piperidine-1 _ Ylmethyl group and piperazine-11-ylmethyl group.

 As the stereoisomer of a hydroxyl group, an R-form, an S-form or a mixture thereof is preferable. In particular, an R-form or an S-form is preferable. More preferred is the S-form.

 E is preferably a single bond, —CH = CH— or —C≡C—, and more preferably a single bond or —C≡C_.

 Ring B includes C 5-10 monocyclic, bicyclic carbocyclic aryl or 1-4 nitrogen atoms, 1-2 oxygen atoms and Z or 1-2 sulfur atoms. A 15-membered monocyclic or bicyclic heteroaryl is preferred. Particularly preferred are benzene, naphthalene, pyridine, thiophene, benzofuran and benzoxazole rings.

R ⁸ is preferably a C 1-4 alkyl group. Particularly preferred is a methyl group.

R ⁹ is preferably a hydrogen atom, a C 1-4 alkyl group, a C 2-4 alkenyl group, or a C 2-4 alkynyl group. Particularly preferred are a hydrogen atom, a methyl group and an aryl group.

 m is preferably 0 or an integer of 1 to 5. Particularly preferred is 0 or 1.

 n is preferably 0 or an integer of 1 to 5. Particularly preferred is 0 or 1.

More preferred compounds for use in the present invention include the compounds described in Examples described later, the compounds shown in Tables 1 to 7 below, and salts thereof.

CZ0 / Z0df / X3d 96 mOOAV

Ζ Halla CZ0 / Z0df / X3d 96m mO OAV 81

ε 拏 £lO/iOdf/I3d 96ひん 0/ZO OAV 表 4

ε Halla £ lO / iOdf / I3d 96 Hin 0 / ZO OAV Table 4

表 5

Table 5

表 6

Table 6

表 7

Table 7

[本発明に係る化合物の製造方法]

[Method for producing compound according to the present invention]

 The hydroxamic acid derivatives represented by the general formula (I), their non-toxic salts or their prodrugs according to the present invention can be produced by the following methods or the methods described in Examples.

 [1] Of the compounds represented by the general formula (I), the prodrugs represented by the general formula (IA) can be produced by the following methods (a) to (c).

(a) Among the prodrugs represented by the general formula (IA), compounds in which R ¹ does not represent a group containing an amino group, a thiol group or a lipoxyl group, that is, a compound represented by the general formula (IA—a)

(Wherein, R ¹ — ^a has the same meaning as R ¹ , provided that it does not represent a group containing an amino group, a thiol group, or a carbonyl group, and other symbols have the same meanings as described above. The compound represented by the general formula (II)

(式中、 すべての記号は前記と同じ意味を表す。 ） で示される化合物と一般 式 （III)

(Wherein all symbols have the same meanings as described above.) And a compound represented by the general formula (III):

H ₂ N—OR 14 (III)

(Wherein, R ¹⁴ has the same meaning as described above.) The compound can be produced by subjecting the compound to an amidation reaction. This amidation reaction is known, for example,

 (1) a method using an acid halide,

 (2) a method using a mixed acid anhydride,

 (3) A method using a condensing agent, and the like.

 To illustrate these methods,

 (1) A method using an acid halide is, for example, a method in which a carboxylic acid is converted to an acid halide agent (oxalyl) in an organic solvent (chloroform, salted methylene, dimethyl ether, tetrahydrofuran, or the like) or without a solvent. Chloride and thionyl chloride) at −20 ° C. to reflux temperature, and the resulting acid halide is reacted with amine in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.). The reaction is carried out at 0 to 40 ° C in an inert organic solvent (eg, chloroform, methylene chloride, getyl ether, tetrahydrofuran). Alternatively, the reaction can be carried out by reacting with an acid halide in an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueous alkali solution (aqueous sodium bicarbonate or sodium hydroxide solution) at a temperature of 0 to 40 ° C.

 (2) A method using a mixed acid anhydride includes, for example, a method in which a carboxylic acid is mixed with an tertiary amine (pyridine, triethylamine, dimethylaniline, or the like) in an organic solvent (chloroform, methylene chloride, dimethyl ether, tetrahydrofuran, or the like) or without a solvent. Reaction with an acid halide (e.g., pivaloyl chloride) or an acid derivative (e.g., ethyl ethyl chloroformate, isobutyl chloroformate) in the presence of dimethylaminopyridine or the like at 0 to 40 ° C. to obtain a mixed acid. The reaction is carried out by reacting the anhydride with an amine in an organic solvent (e.g., chloroform, methylene chloride, getyl ether, tetrahydrofuran) at 0 to 40 ° C.

(3) The method using a condensing agent is, for example, a method in which a carboxylic acid and an amine are converted into a tertiary amine (pyridine) in an organic solvent (e.g., , bird Condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino)) in the presence or absence of ethylamine, dimethylaniline, dimethylaminopyridine, etc.) Propyl] carbodiimide (E DC), 1, 1'-Ipyldionymidazole (CD I), 2-chloro-1 -methylpyridinium iodine, 1-propanephosphonic acid cyclic anhydride The reaction is carried out at 0 to 40 ° C with or without 1-hydroxybenztriazole (HOBt).

 The reactions (1), (2) and (3) are desirably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

 (b) Among the prodrugs represented by the general formula (IA), the compound represented by the general formula (IA-a) is represented by the general formula (IV)

(Wherein, X represents a halogen atom, and other symbols have the same meanings as described above).

(式中、 すべての記号は前記と同じ意味を表す。 ） で示される化合物をカツ プリング反応に付すことにより製造することもできる。 (Wherein all symbols have the same meanings as described above.) Or a compound represented by the general formula (VI):

(Wherein all symbols have the same meanings as described above). The compound can also be produced by subjecting the compound to a coupling reaction.

This reaction is known. For example, in an organic solvent (benzene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, etc.), a base (sodium ethylate, sodium hydroxide, potassium hydroxide) is used. , Triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, triammonium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) and catalysts (tetrakis (triphenyl) Phosphine) palladium CPd (PPh ₃ ) ₄ ), bis (triphenylphosphine) dichloride palladium (PdCl ₂ (PPh ₃ ) ₂ ), palladium acetate (Pd (0Ac) ₂ ), palladium black, 1,1'-bis (Diphenylphosphine Inofue mouth) Dichloropa Indium (PdCl ₂ (dppf) _2), Nishioi匕Jiarirupara Jiumu (PdCl ₂ (allyl) _2), iodide Fuenirubisu (triphenyl phosphine) palladium (PhPdI (PPh _{3) 2),} etc.) the presence, at room temperature to 120 It is performed by reacting at ° C.

(c) Among the prodrugs represented by the general formula (IA), a compound in which R ¹ represents a group containing any one of an amino group, a thiol group, and a lipoxyl group, that is, a compound represented by the general formula ( IA—c)

(式中、 R^1-cは、 アミノ基、 チオール基、 力ルポキシル基のうちいずれかを 含有する基を表し、 他の記号は前記と同じ意味を表す。 ） で示される化合物 は、 前記一般式 （IA— a) のうちアミノ基、 チオール基、 カルボキシル基 が保護された化合物、 すなわち一般式 （ I A— a 1) (^,A"^a1)

(Wherein, R ^1-c represents a group containing any one of an amino group, a thiol group, and a propyloxyl group, and the other symbols have the same meanings as described above.). A compound in which the amino group, thiol group and carboxyl group of formula (IA-a) are protected, that is, a compound represented by general formula (IA-a1) ( ^{, A} " ^a1 )

(R ¹

(In the formula, R ¹ one ^al., Protected Amino group represents a group containing any of the protected thiol group or a protected force Rupokishiru group and the other symbols have the same meanings as described above. ) Can be produced by subjecting the compound of the formula to a deprotection reaction.

 Examples of the protecting group for an amino group include a benzyloxycarbonyl group, an aryloxycarbonyl group, a t-butoxycarbonyl group, a trifluoroacetyl group, and a 91-fluorenylmethoxycarbonyl group.

 Examples of the protecting group for the thiol group include a benzyl group, a methoxybenzyl group, an acetamidomethyl group, a triphenylmethyl group, and an acetyl group. Examples of the protective group for the carbonyl group include a methyl group, an ethyl group, a t-butyl group, a benzyl group, and an aryl group.

 The amino-, thiol- or carboxyl-protecting group is not particularly limited as long as it can be easily and selectively eliminated, in addition to the above. For example, those described in T. W. Greene et al., Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience, New York, 1999 are used.

 Deprotection reactions of amino, thiol or carboxyl groups are well known and include, for example,

 (1) Deprotection reaction under alkaline conditions,

 (2) Deprotection reaction under acidic conditions,

 (3) Deprotection reaction using hydrogenolysis,

 (4) Deprotection reaction using a metal complex.

To illustrate these methods, (1) The deprotection reaction under the a / potassium condition is performed, for example, by using an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.). Using alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at 0 to 40 ° C. Done at temperature.

 (2) The deprotection reaction under acidic conditions can be performed, for example, in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, anisol, etc.), an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.), or an inorganic acid. It is carried out in an acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide / acetic acid, etc.) at a temperature of 0 to 100 ° C.

 (3) Deprotection reactions using hydrogenolysis include, for example, solvents (ethers (tetrahydrofuran, dioxane, dimethoxyethane, getyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene, etc.). , Toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixture of two or more of them Etc.) Medium, in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere at normal pressure or under pressure, or in the presence of ammonium formate, temperature of 0 to 200 It is done in.

 (4) The deprotection reaction using a metal complex is performed, for example, in an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, etc.), a trapping reagent (hydrogenated triptyltin, dimedone, etc.) and z or an organic acid (acetic acid, etc.). The reaction is performed at a temperature of 0 to 40 ° C. using a metal complex (such as a tetrakistriphenylphosphine palladium (0) complex) in the presence of

As will be readily understood by those skilled in the art, using these deprotection reactions By dividing, the desired compound of the present invention can be easily produced.

 [2] The hydroxamic acid derivative represented by the general formula (I) according to the present invention can be produced by the following methods (d) and (e).

(d) Among the hydroxamic acid derivatives represented by the general formula (I), a compound in which R ¹ does not represent a group containing an amino group, a thiol group, or a hydroxyl group, that is, a compound represented by the general formula (D)

(Wherein all symbols have the same meanings as described above.) Are produced by subjecting the compound represented by the above general formula (II) and hydroxylamine (H ₂ N-OH) to an amidation reaction. be able to.

 This amidation reaction is performed by the same operation as the above-mentioned method.

 (e) The hydroxamic acid derivative represented by the general formula (I) can be produced by subjecting the compound represented by the general formula (IA) to a deprotection reaction. This deprotection reaction of hydroxamic acid is known, for example,

 (1) Deprotection reaction under alkaline conditions,

 (2) Deprotection reaction under acidic conditions,

 (3) Deprotection reaction using hydrogenolysis and the like.

These deprotection reactions are performed by the same operation as in the method described above. In the present invention, the deprotection reaction of hydroxamic acid refers to a general deprotection reaction that can be easily understood by those skilled in the art, such as a deprotection reaction under alkaline conditions, a deprotection reaction under acid conditions, and hydrogenolysis. This means the deprotection reaction used, and the desired compound of the present invention can be easily produced by using these reactions properly. be able to.

As will be readily understood by those skilled in the art, hydroxamic acid protecting groups include t-butyl, —C (CH ₃ ) ₂ —OCH ₃ and benzyl, but others are readily available. The group is not particularly limited as long as it is a group which can be selectively eliminated. For example, those described in TW Greene et al., Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience, New York, 1999 are used.

[3] The prodrug derivative represented by the general formula (IB) according to the present invention is a compound represented by the general formula (IA), wherein the R ¹⁴ group represents a 1-methoxy-11-methylethyl group, Formula (IA-3)

( ^-3 )

(Wherein all symbols have the same meanings as described above.). The compound can be produced by subjecting the compound to a methanol removal reaction.

This demethanol reaction is known, and is carried out in an organic solvent (benzene, toluene, dioxane, pyridine, etc.) at a temperature of 60 to 150 ° C. The compounds represented by the general formulas (II) and (IV) are known per se or can be easily produced by the following reaction schemes 1 and 2 or known methods. Reaction process formula 1

反応工程式 2

Reaction process formula 2

前記反応工程式中、 尺¹⁽⁾¹は( 1〜4ァルキル基または—（：^1₂ ：11₂0 H₂CH₂OCH₃基を表し、 R¹— ^a、 R⁸、 R⁹、 R¹⁴、 環 A、 環 B、 E、 m、 n、 Xは前記と同じ意味を表す。

The reaction scheme, scale ^{1 () 1} (1-4 Arukiru group or _{- (: ^ 1 2: 11} 2 0 H 2 CH 2 represent OCH ₃ ^{group, R 1 - a, R 8} , R 9, R ¹⁴ , ring A, ring B, E, m, n and X have the same meaning as described above.

 In the above reaction scheme, each reaction is carried out by a known method. In the above reaction scheme, the compound represented by the general formula (X), the general formula (XIV), the general formula (III), the general formula (V) or the general formula (VI) used as a starting material is It is known per se or can be easily produced by a known method.

 In each of the reactions herein, the reaction product is purified by conventional purification means, for example, distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium gayate, thin-layer chromatography, or column chromatography. It can be purified by a method such as chromatography, washing, or recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions.

 The other starting materials and reagents in the present invention are known per se or can be produced by known methods.

 [Toxic]

 The compounds of the general formula (I), their non-toxic salts and their prodrugs used in the present invention have very low toxicity and can be judged to be sufficiently safe for use as pharmaceuticals. Industrial applicability

 [Application to pharmaceutical products]

The compounds used in the present invention include solid cancers (for example, brain tumor, head and neck cancer, thyroid cancer, esophageal cancer, stomach cancer, large intestine (colon, rectum) cancer, liver cancer, gallbladder and bile duct cancer, kidney cancer, lung cancer, breast cancer, child cancer). Cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, testicular tumor, bladder cancer, renal pelvis Ureteral tumor, adrenal cancer, neuronal tumor, glioma, bone tumor, rhabdomyosarcoma, osteosarcoma, soft tissue sarcoma, eosinophilic granuloma, malignant melanoma, skin cancer, glioblastoma, Wilms tumor, etc.) It is useful as a prophylactic and / or therapeutic agent.

 In order to use the compound according to the present invention represented by the general formula (I), a non-toxic salt thereof or a prodrug thereof for the above-mentioned purpose, it is usually necessary to administer orally or parenterally, systemically or locally. It is administered in the form.

 Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, per adult, once per day, in the range of lmg to 100mg, once to several times a day Is administered orally or parenterally (preferably intravenously) once to several times a day, in a range of 0.1 mg to 100 mg per adult per day, or It is continuously administered intravenously for 1 hour to 24 hours a day.

 Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or may be required outside the range.

 When the compound of the present invention is administered, it is used as a solid preparation for oral administration, a liquid preparation for oral administration, and an injection, an external preparation, a suppository and the like for parenteral administration.

 Solid preparations for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules.

In such solid dosage forms for oral administration, the one or more active substances may be as such or excipients (such as lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (such as hydroxypropylcellulose, polyester). Vinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrant (calcium fiber monoglycolate, etc.), lubricant (magnesium stearate, etc.), It is mixed with stabilizers and solubilizers (glutamic acid, aspartic acid, etc.), etc., and used in the form of a formulation according to the usual method. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Also included are capsules of absorbable materials such as gelatin. Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such solutions, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (such as purified water, ethanol or a mixture thereof). Further, the liquid preparation may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffer and the like.

 Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections which are used by dissolving or suspending in a solvent before use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and combinations thereof are used. Further, this injection may contain a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. Good. They are prepared by sterilization or aseptic processing in the final step. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and dissolved in sterile distilled water for injection or other solvents before use.

 Other preparations for parenteral administration include topical solutions, ointments, salves, inhalants, sprays, suppositories and vaginal preparations containing one or more active substances and prescribed in a conventional manner. Pessaries etc. are included.

Sprays include sodium bisulfite in addition to commonly used diluents. Buffers that provide isotonicity with such stabilizers, for example, isotonic agents such as sodium chloride, sodium citrate, or citrate may be included. Methods for producing spray agents are described in detail, for example, in U.S. Pat. Nos. 2,868,691 and 3,095,355. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a graph showing changes in tumor volume of mice to which the compound according to the present invention was administered.

 FIG. 2 shows the tumor weight of a mouse to which the compound of the present invention was orally administered daily for 31 days. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail by reference examples and examples, but the present invention is not limited thereto.

 The solvent in kakkoko indicated at the point of separation by chromatography and in TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

 The solvent in the kakkou indicated at the NMR indicates the solvent used for the measurement. Reference example 1

アジピン酸モノェチルエステル （34.8g) に、 塩化チォニル （72m l) を加えた。 反応混合物を 100°Cで 1.5時間撹拌した。 反応混合物を濃縮し、 アジピン酸クロライドモノェチルエステルを得た。 塩化アルミニウム （53.3 g) のジクロロメタン （500m l) 懸濁液に、 5°Cで 4一クロロビフエ二 ル （37.7g) を加えた。 反応混合物を 1 5分間撹拌した後、 5 でアジピン 酸クロライドモノェチルエステルのジクロロメタン （200ml) 溶液を加 えた。 反応混合物を室温で 2時間撹拌した。 反応混合物に氷水を加え、 ジク ロロメタンで抽出した。 抽出物を水、 飽和炭酸水素ナトリウム水溶液、 飽和 塩化ナトリウム水溶液で洗浄し、 無水硫酸マグネシウムで乾燥し、 濃縮した。 得られた残渣をへキサン/酢酸ェチルで再結晶化し、 乾燥し、 下記の物性値 を有する標題化合物 （53.8g) を得た。 6- (4- (4-phenyl) phenyl) 1-oxohexanoate

To monoethyl adipate (34.8 g) was added thionyl chloride (72 ml). The reaction mixture was stirred at 100 ° C for 1.5 hours. The reaction mixture was concentrated to obtain adipic acid chloride monoethyl ester. To a suspension of aluminum chloride (53.3 g) in dichloromethane (500 ml) was added 4-chlorobiphenyl (37.7 g) at 5 ° C. After stirring the reaction mixture for 15 minutes, a solution of adipic acid chloride monoethyl ester in dichloromethane (200 ml) was added at 5. The reaction mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was recrystallized from hexane / ethyl acetate and dried to give the title compound (53.8 g) having the following physical data.

TLC: R f 0 · 60 (cloth holm),

参考例 2 _{NMR (CDC1 3): δ 8.04} (d, J = 8.8Hz, 2H), 7.64 (d, J = 8.8Hz, 2H), 7.56 (d, J = 8.4Hz, 2H), 7. 4 (d, J = 8.4 Hz, 2H), 4.14 (q, J = 7.2Hz, 2H), 3.03 (t, J = 6.6Hz, 2H), 2.38 (t, J = 7.0 Hz, 2H), 1.95-1.60 (m, 4H ), 1.26 (t,

Reference example 2

参考例 1で製造した化合物 （10.02g) のジクロロメタン （300m l) と メタノール（100m 1)の混合溶液に、 0°Cで水素化ホウ素ナトリウム（5.4 g) を加えた。 反応混合物を室温で 2時間撹拌した。 反応混合物を飽和塩化 アンモニゥム水溶液に注ぎ、 ジクロロメタンで抽出した。 抽出物を飽和塩化 ナトリウム水溶液で洗浄し、 無水硫酸ナトリウムで乾燥し、 濃縮し、 下記の 物性値を有する標題化合物 （10.03g) を得た。 6- (4 (4-chlorophenyl) phenyl) 1-hydroxyhexanoate

To a mixed solution of the compound (10.02 g) produced in Reference Example 1 in dichloromethane (300 ml) and methanol (100 ml), sodium borohydride (5.4 g) was added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with dichloromethane. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the title compound (10.03 g) having the following physical data.

TLC: Rf 0.25 (black mouth form),

_{NMR (CDC1 3): δ 7.65-7.34} (m, 8H), 4.73 (t, J = 6.2Hz, 1H), 4.11 (q, J = 7.0Hz, 2H), 2.03 (t, J = 7.0Hz, 2H ), 1.90-1.30 (m, 6H), 1.23 (t, J = 7.0Hz, 3H). Reference example 3

 6- (4- (4-cyclophenyl) phenyl) 1-hydroxyhexanoic acid

参考例 2で製造した化合物 （10.03g) のエタノール （10 Oml) 溶液に、 2 N水酸化ナトリゥム水溶液 (50ml) を加えた。 反応混合物を 60 で 1時間撹拌した。 反応混合物に IN塩酸水溶液を加え、 酢酸ェチルで抽出し た。 抽出物を飽和塩ィヒナトリウム水溶液で洗浄し、 無水硫酸ナトリウムで乾 燥し、 濃縮した。 得られた残渣をイソプロピルアルコールで再結晶化し、 乾 燥し、 下記の物性値を有する標題化合物 （9.12g) を得た。

To a solution of the compound (10.03 g) produced in Reference Example 2 in ethanol (10 Oml) was added a 2N aqueous sodium hydroxide solution (50 ml). Reaction mixture at 60 Stir for 1 hour. An aqueous solution of IN hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated. The obtained residue was recrystallized from isopropyl alcohol and dried to give the title compound (9.12 g) having the following physical data.

TLC: R f 0.52 (form: tetrahydrofuran: acetic acid = 10: 4: 1),

NMR (d ₆ -DMS0): δ 11.80 (brs, 1H), 7.68 (d, J = 8 Hz, 2H), 7.61 (d, J = 8 Hz, 2H), 7.9 (d, J = 8 Hz, 2H) , 7.40 (d, J = 8Hz, 2H), 5.16 (brs, 1H), 4.65-4.0 (m, 1H), 2.18 (t, J = 7Hz, 2H), 1.80-1.05 (m, 6H). Example 1

 N- (1-Methoxy-1-methyl) ethoxy-6- (4 (4-chlorophenyl) phenyl) -1-6-hydroxyhexanamide

参考例 3で製造した化合物 （7.74g) のジメチルホルムアミド （1 50m 1) 溶液に、 アルゴン雰囲気下、 1—ェチルー 3— [3— （ジメチルァミノ） プロピル] カルポジイミド （6.99g) 、 1ーヒドロキシベンゾトリアゾ一ル (5.58g) 、 （1—メトキシ一 1—メチルェチル） ヒドロキシァミン（8.0g) 、 トリェチルァミン （15.5ml) を加えた。 反応混合物を室温で一晩撹拌した。 反応混合物を氷水に注ぎ、 酢酸ェチルで抽出した。 抽出物を飽和炭酸水素ナ トリウム水溶液、 飽和塩ィヒナトリウム水溶液で洗浄し、 無水硫酸ナトリウム で乾燥し、 濃縮した。 得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸ェチル：へキサン： トリェチルァミン =80 : 20 : 1) によって精 製し、 下記の物性値を有する標題化合物 （8. lg) を得た。

To a solution of the compound (7.74 g) prepared in Reference Example 3 in dimethylformamide (150 ml) was added 1-ethyl-3- [3- (dimethylamino) propyl] carposimide (6.99 g) and 1-hydroxybenzotriene in an argon atmosphere. Azol (5.58 g), (1-methoxy-11-methylethyl) hydroxyamine (8.0 g) and triethylamine (15.5 ml) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium salt of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The obtained residue is subjected to silica gel column chromatography. The product was purified by (ethyl acetate: hexane: triethylamine = 80: 20: 1) to give the title compound (8.lg) having the following physical data.

TLC: R f 0.50 (ethyl acetate: methanol = 20: 1),

_{NMR (CDC1 3): 6 7.73} (brs, 1H), 7.60-7.35 (m, 8H), 4.74 (t, J = 6Hz, 1H), 3.31 (s, 3H), 2.50-1.15 (m, 8H), 1.41 (s, 6H). Example 2

 N-Hydroxy-6- (4- (4-chlorophenyl) phenyl) -6-Hydroxyhexaneamide

To a solution of the compound prepared in Example 1 (7.27 g) in methanol (100 ml), concentrated hydrochloric acid (2.0 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and azeotroped with ethanol. Ethyl acetate was added to the obtained residue, and the precipitated crystals were filtered and dried to give the title compound (5.55 g) having the following physical data.

TLC: R f 0.21 (form: methanol: acetic acid = 10: 1: 1), NMR (d ₆ -DMS0): δ 10.31 (s, 1H), 8.64 (s, 1H), 7.68 (d, J = 8, 8Hz, 2H), 7.65 (d, J = 8.8Hz, 2H), 7.50 (d, J = 8.4Hz, 2H), 7.40 (d, J = 8.4Hz, 2H), 5.15 (d, J = 4.4 Hz, 1H), 4.54 (m, 1H), 1.93 (t, J = 7.3Hz, 2H), 1.70-1.40 (m, 4H), 1.0-1.10 (m, 2H). Example 2 (1) to 2 (5)

 4 Using the corresponding benzene derivative in place of monochlorobiphenyl, the same operation as in Reference Example 1—Reference Example 2 → Reference Example 3—Example 1 → Example 2 was performed to obtain the title compound shown below. . Example 2 (1)

 N-hydroxy-6- (4-piphenyl) -1-6-hexanamide,

TLC： R f 0.42 (酢酸ェチル：メタノール =39 ： 1) 、

TLC: R f 0.42 (ethyl acetate: methanol = 39: 1),

NMR (d ₆ -DMS0): δ 10.29 (brs, 1H), 8.64 (brs, 1H), 7.66-7.58 (m, 4H), 7.47-7.30 (m, 5H), 5.18-5.09 (in, 1H), 4.57-4.55 (m, 1H), 1.91 (t, J = 7.5Hz, 2H), 1.64-1.4 (m, 4H), 1.0-1.20 (m, 2H). Example 2 (2)

 N-Hydroxy-6 (4-cyclohexylphenyl) -1-6-hexanamide

TLC : R f 0.32 (酢酸ェチル） 、

TLC: R f 0.32 (ethyl acetate),

NMR (d ₆ -DMSO): δ 10.29 (s, IH), 8.63 (s, IH), 7.19 (d, J = 7.8Hz, 2H), 7.12 (d, J-7.8Hz, 2H), 4.98 (d , J = 4.5Hz, IH), 4.40-4.38 (m, IH), 2.48-2.40 (m, IH), 1.89 (t, J = 7.5Hz, 2H), 1.81-1.12 (m, 16H). Example 2 (3)

 N-hydroxy-6- (4- (4-methylphenyl) phenyl) 6-hydroxyhexaneamide

TLC: R f 0.43 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.29 (brs, IH), 8.62 (d, J = 1.5 Hz, IH), 7.56 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 7.25 (d.J = 8.4Hz, 2H), 5.11 (d.J = 4.5Hz, IH), 4.54-4.48 (m, IH), 2.33 ( s, 3H), 1.91 (t, J = 7.5Hz, 2H), 1.63-1.16 (m, 6H). Example 2 (4)

N-Hydroxy-6- (4 (4-methoxyphenyl) phenyl) -1-Hydroxyhexanamide

TLC: R f 0.27 (form: methanol: acetic acid = 90: 10: 1) NMR (d ₆ -DMS0): <5 10.29 (brs, 1H), 8.63 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 8.1Hz, 2H), 7.53 (d, J = 8.1Hz, 2H), 7.34 (d, J = 8.1Hz, 2H), 7.00 (d, J = 8.1Hz, 2H), 5.10 ( d, J = 4.5Hz, 1H), 4.53-4.47 (m, 1H), 3.78 (s, 3H), 1.91 (t, J = 7.2Hz, 2H), 1.66-1.15 (m, 6H). Example 2 (5)

 N—Hydroxy 6— (4-

Phenyl) 1-hydroxyhexanamide

TLC: R f 0.16 (ethyl acetate),

NMR (d ₆ -DMS0): d 10.29 (s, 1H), 8.63 (s, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 4.98 (d , J = 4.4Hz, 1H), 4.43 (m, 1H), 2.41 (m, 1H), 2.00-0.90 (m, 21H), 0.88 (t, J = 7.0Hz, 3H). Reference example 4

Ethyl (R) — 6— (4- (4-chlorophenyl) phenyl) —6-— Droxyhexanoate

OH

参考例 1で製造した化合物 （17.2 g) のテトラヒドロフラン （1500m l ) 溶液に、 室温で 1. OM (S) 一 2—メチルーォキサザポロリジンのトルエン溶 液 （5m l ) を加えた。 反応混合物を— 1 5°Cに冷却し、 1.0Mポラン ·ジメ チルスルフィ ド錯体のテトラヒドロフラン溶液 (21.3m l ) を加えた。 反応 混合物を室温で 3時間撹拌した。 反応混合物にメタノールを加え、 一晩撹拌 した。 反応混合物を濃縮し、 酢酸ェチルで希釈し、 水、 飽和塩化ナトリウム 水溶液で洗浄し、 硫酸マグネシウムで乾燥し、 濃縮した。 得られた残渣をシ リカゲルカラムクロマトグラフィー （へキサン：酢酸ェチル = 1 ： 1) によ つて精製し、 下記の物性値を有する標題化合物 （1 7 g、 94.1% e. e.、 HP LC) を得た。

To a solution of the compound (17.2 g) produced in Reference Example 1 in tetrahydrofuran (1500 ml) was added a solution of 1.OM (S) -12-methyl-oxazaporolidine in toluene (5 ml) at room temperature. The reaction mixture was cooled to −15 ° C., and a 1.0 M solution of a polan dimethyl sulfide complex in tetrahydrofuran (21.3 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. Methanol was added to the reaction mixture, and the mixture was stirred overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (17 g, 94.1% ee, HP LC) having the following physical data. .

 TLC: R f 0.25 (black mouth form),

HPLC: 13.7 minutes (retention time)

 Column: Daicel Chiral Cell AD-RH (DAICEL CHIRAL CEL AD-RH), 4.6 x 150 mm;

 Eluent: acetonitrile: water = 75: 25;

 UV: 260 nm;

 Flow rate: 1. Om1 / min. Reference example 5

Ethyl (S) — 6— (4— (4-chlorophenyl) phenyl) Droxy Hexanoe Unit

1. Instead of the toluene solution of OM (S) -1-methyl-oxazaporolidine, 1. Using the toluene solution of OM (R) -2-methyl-oxazaporolidine, Reference Example 4 The title compound (91% ee, HPLC) having the following physical data was obtained.

 TLC: R f 0.25 (black mouth form),

HPLC: 9.8 minutes (retention time)

 Column: DAICEL CHIRAL CEL AD-RH, 4.6X 150 mm;

 Eluent: acetonitrile: water = 75: 25;

 UV: 260 nm;

 Flow rate: 1. Om1 / min. Example 3

 (R)-(+) — N-Hydroxy-6- (4- (4-chlorophene: phenyl)) — 6-Hydroxyhexaneamide

参考例 2で製造した化合物の代わりに、 参考例 4で製造した化合物を用い て、 参考例 3→実施例 1→実施例 2と同様の操作をし、 下記の物性値を有す る標題化合物 （98.7% e. e.、 HPLC) を得た。

Using the compound prepared in Reference Example 4 instead of the compound prepared in Reference Example 2, perform the same operation as in Reference Example 3 → Example 1 → Example 2 to give the title compound having the following physical property values (98.7% ee, HPLC).

TLC: R f 0.21 (cloth form: methanol: acetic acid = 10: 1: 1), [a] _D : +9.27 (c 0.280, methanol),

HPLC: 16.8 minutes (retention time),

 Column: DAICEL CHIRAL CEL AD-RH, 4.6X 15 Omm;

 Eluent: acetonitrile: water = 35:65;

 UV: 260 nm;

 Flow rate: 1.0 ml / min. Example 3 (1)

 (S)-(_) 1-N-hydroxy-6- (4- (4-chlorophenyl) phenyl) 6-hydroxyhexanamide

参考例 4で製造した化合物の代わりに、 参考例 5で製造した化合物を用い て、実施例 3と同様の操作をし、下記の物性値を有する標題化合物（> 98 % e. e.、 HPLC) を得た。

In the same manner as in Example 3 except that the compound prepared in Reference Example 4 was used instead of the compound prepared in Reference Example 4, the title compound (> 98% ee, HPLC) having the following physical properties was obtained. Was.

TLC: R f 0.21 (cloth form: methanol: acetic acid = 10: 1: 1), [«] _D : -9.60 (c 0.265, methanol),

HPLC: 11.6 minutes (retention time)

Column: DAICEL CHIRAL CEL AD-RH, 4.6X 15 Omm; Eluent: acetonitrile: water = 35:65;

 UV: 260 nm;

 Flow rate: 1. Om1 / min. Reference example 6

 N- (1-Methoxy-1-methyl) ethoxy-6- (4-iodophenyl) -6-hydroxyhexanamide

(4) Reference example 1 → Reference example 2 → Reference example 3—The same operation as in Example 1 was carried out using benzene instead of monochlorobiphenyl to obtain the title compound having the following physical data.

 TLC: Rf 0.40 (ethyl acetate),

_{NMR (CDC1 3): δ 7.69-7.63} (m, 3H), 7.08 (d, J-8.2Hz, 2H), 4.64 (t, J-6.2Hz, 1H), 3.31 (s, 3H), 2.42-1.21 (m, 8H), 1.1 (s, 6H). Example 4

 N- (1-Methoxy-1-methyl) ethoxy-6- (4- (benzofuran-2-yl) phenyl) -6-hydroxyhexanamide

参考例 6で製造した化合物 （440mg) のジメチルホルムアミド （10 ml) に、 リン酸三カリウム （333mg) 、 テトラキス （トリフエニルホ スフイン） パラジウム （120mg) 、 ベンゾフラン一 2—ボロン酸 （40 Omg) を加えた。 反応混合物を 60°Cで 2時間撹拌した。 反応混合物に水 を加え、 酢酸ェチルで抽出した。 抽出物を飽和塩化ナトリウム水溶液で洗浄 し、 硫酸ナトリウムで乾燥し、 濃縮した。 得られた残渣をシリカゲルカラム クロマトグラフィ一 （酢酸ェチル：へキサン = 1 ： 1→7 ： 3→1 ： 0) に よって精製し、 下記の物性値を有する標題化合物 （178mg) を得た。 TLC： R f 0.39 (酢酸ェチル） 。 実施例 5

Tripotassium phosphate (333 mg), tetrakis (triphenylphosphine) palladium (120 mg), and benzofuran-2-boronic acid (40 mg) were added to dimethylformamide (10 ml) of the compound (440 mg) produced in Reference Example 6. . The reaction mixture was stirred at 60 ° C for 2 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1 → 7: 3 → 1: 0) to give the title compound (178 mg) having the following physical data. TLC: R f 0.39 (ethyl acetate). Example 5

 N-Hydroxy _6 _ (4- (benzofuran-2-yl) phenyl) 6-hydroxyhexanamide

実施例 1で製造した化合物の代わりに、 実施例 4で製造した化合物を用い て、 実施例 2と同様の操作をし、 下記の物性値を有する標題化合物を得た。 TLC： R f 0.29 (酢酸ェチル） 、

The same operation as in Example 2 was carried out using the compound prepared in Example 4 instead of the compound prepared in Example 1, to obtain the title compound having the following physical data. TLC: R f 0.29 (ethyl acetate),

NMR (d ₆ — DMS0): δ 10.28 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.65-7.59 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.37 (s, 1H), 7.32-7.21 (m, 2H), 4.58-4.51 On, 1H), 1.90 (t, J = 7.2Hz, 2H), 1.62-1.14 (m, 6H). Example 5 (1) to 5 (18) -Using the corresponding boronic acid instead of 2-boronic acid, the same operation as in Example 4 → Example 5 was performed to obtain the title compound shown below. Example 5 (1)

 N-Hydroxy-6- (4- (pyridine-4-yl) phenyl) -6-hydroxyhexaneamide

TLC: R f 0.33 (cloth form: methanol: acetic acid = 90: 10: 1), NMR (d ₆ _DMS0): δ 10.30 (s, 1H), 8.63 (s, 1H), 8.61 (dd, J = 4.8Hz, 1.5 Hz, 2H), 7.74 (d, J = 8.1Hz, 2H), 7.68 (dd, J = 4.8Hz, 1.5Hz, 2H), 7.44 (d, J-8.1Hz, 2H), 5.21 (d, J-4.5Hz, 1H), 4.58-4.52 (m, 1H), 1.91 (t, J = 7.2Hz, 2H), 1.64-1.14 (m, 6H). Example 5 (2)

 N-Hydroxy-1- (4- (pyridine-3-yl) phenyl) -1-hydroxyhexanamide

TLC: R f 0.34 (Black form: methanol: acetic acid = 90: 10: 1) NMR (d ₆ — DMSO): δ 10.29 (s, 1H), 8.86 (d, J = l.8Hz, 1H), 8.62 (s, 1H), 8.54 (dd, J = 4.8Hz, 1.8Hz, 1H) , 8.06-8.02 (m, 1H), 7.65 (d, J = 8.1Hz, 2H), 7.48-7.43 (in, 1H), 7.42 (d, J = 8.1Hz, 2H), 5.17 (d, J = 4.5 Hz, 1H), 4.56-4.50 (m, 1H), 1.90 (t, J = 7.5Hz, 2H), 1.63-1.18 (m, 6H). Example 5 (3)

 N-Hydroxy-6- (4 (2-chlorophenyl) phenyl) 1-Hydroxyhexanamide

TLC： R f 0.25 (酢酸ェチル） 、

TLC: R f 0.25 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.55-7.52 (m, 1H),

7.40-7.33 (m, 7H), 5.16 (d, J = 4.5Hz, 1H), 4.54-4.51 (m, 1H), 1.91 (t, J = 6.9 Hz, 2H), 1.65-1.20 (m, 6H) . Example 5 (4)

 N-Hydroxy-1- (4- (3-chlorophenyl) phenyl) -1-Hydroxyhexanamide

T L C : R f 0.23 (酢酸ェチル） 、

TLC: R f 0.23 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.68 (t, J = 1.8 Hz. 1H), 7.63-7.60 (m, 3H), 7.46 (t, J = 8.1Hz, 1H), 7.40-7.37 (m, 3H), 5.16 (d, J = 4.2Hz, 1H), 4.54-4.50 (m, 1H), 1.90 (t, 1 = 1.2Hz, 2H), 1.63 -1.20 (m, 6H). Example 5 (5)

 N-Hydroxy-6- (4- (4-bromophenyl) phenyl) 6-Hydroxyhexanamide

TLC: Rf 0.35 (ethyl acetate: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.31 (s, 1H), 8.64 (s, 1H), 7.70-7.50 (m, 6H), 7.40 (d, J = 8.4Hz, 2H), 5.15 (d, J = 4.5Hz, 1H), 4.54 (m, 1H), 1.93 (t, J = 7.2Hz, 2H), 1.70-1.20 (m, 6H) ₀ Example 5 (6)

N-hydroxy-6- (4 (thiophen-2-yl) phenyl) -6-hydroxyhexanamide

TLC: R f 0.26 (ethyl acetate),

NMR (d ₆ -DMSO): δ 10.28 (s, 1H), 8.62 (brs, 1H), 7.57 (d, J = 8.7Hz, 2H), 7.49 (dd, J = 5.1Hz, 1.Hz, 1H) , 7.45 (dd, J = 3.6Hz, 1.2Hz, 1H), 7.32 (d, J = 8.7Hz, 2H), 7.10 (dd, J = 5.1Hz, 3.6Hz, 1H), 5.13 (d, J = 4.5 Hz, 1H), 4.51-4.45 (, 1H), 1.89 (t, J = 6.9Hz, 2H), 1.60-1.15 (m, 6H). Example 5 (7)

 N-hydroxy-6- (4- (furan_2-yl) phenyl) 1-hydroxyhexanamide

TLC: R f 0.27 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.28 (brs, 1H), 8.65 (brs, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.33 (d , J = 8.4Hz, 2H), 6.87 (d, J = 3.6Hz, 1H), 6.56 (dd, J = 3.6Hz, 2.1Hz, 1H), 5.13 (d, J = 4.5Hz, 1H), 4.50- 4.45 (m, 1H), 1.89 (t, J-7.2Hz, 2H), 1.60-1.12 (m, 6H) ₀ Example 5 (8)

N-hydroxy-1 6— (4— (1,3-dioxy 2,3-dihydroin Den 5-yl) phenyl)-6-

TLC: R f 0.22 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.28 (s, 1H), 8.62 (brs, 1H), 7.51 (d, J = 8.1Hz, 2H), 7.32 (d, J = 8.1Hz, 2H), 7.21 (d , J = l.8Hz, 1H), 7.10 (dd, J = 8.1Hz, 1.8Hz '1H), 6.96 (d, J-8.1Hz, 1H), 6.03 (s, 2H), 5.10 (d, J = 4.5Hz, 1H), 4.52-4.47 (m, 1H), 1.90 (t, J = 7.2Hz, 2H), 1.60-1.12 (m, 6H). Example 5 (9)

 N-Hydroxy-6- (4- (4-Methylthiophenyl) phenyl) _6-Hydroxyhexanamide

TLC: R f 0.27 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.28 (s, 1H), 8.62 (brs, 1H), 7.59 (d, J = 8.Hz, 2H), 7.57 (d, J = 8.4Hz, 2H), 7.36 ( d, J = 8.4Hz, 2H), 7.32 (d, J = 8.4Hz, 2H), 5.12 (d, J-4.2Hz, 1H), 4.53-4.48 (m, 1H), 3.30 (s, 3H), 1.90 (t, J = 7.2Hz, 2H), 1.62-1.16 (m, 6H). Example 5 (10)

 N-Hydroxy-1- (4 (naphthylene-1-yl) phenyl) -6-hydroxyhexanamide

TLC: Rf 0.30 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.31 (s, 1H), 8.64 (s, 1H), 7.99-7.91 (m, 2H), 7.80 (d, J = 8.1Hz, 1H), 7.58-7.39 (m, 8H), 5.19 (d, J = 4.5Hz, 1H), 4.61-4.55 Cm, 1H), 1.94 (t, J-7.5Hz, 2H), 1.68-1.23 (m, 6H) ₀ Example 5 (1 1 )

 N-Hydroxy-6- (4 (naphthyl-2-yl) phenyl) -6-hydroxyhexanamide

TLC ： R f 0.27 (酢酸ェチル） 、

TLC: R f 0.27 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 7.99-7.90 (m, 3H), 7.83 (dd, J = 8.1Hz, 1.5Hz , 1H), 7.75 (d, J = 8.1Hz, 2H), 7.55- 7.47 (m, 2H), 7.43 (d, J = 8.1Hz, 2H), 5.16 (d, J = 4.2Hz, 1H), 4.60-4.51 (m, 1H), 1.91 (t, J = 7.2Hz, 2H ), 1.66-1. 0 (m, 6H). Example 5 (12)

 N-Hydroxy-6- (4- (4-acetylphenylyl) phenyl)-6-hydroxyhexanamide

TLC: R f 0.19 (form: methanol: triethylamine = 8: 1: 1),

NMR (d ₆ -DMS0): δ 10.31 (s, 1H), 8.64 (s, 1H), 8.03 (d, J = 8.4Hz, 2H), 7.82 (d, J = 8.4Hz, 2H), 7.70 (d , J = 8.4Hz, 2H), 7.44 (d, J = 8.4HZ, 2H), 5.18 (d, J = 4.5Hz, 1H), 4.56 (m, 1H), 2.61 (s, 3H), 1.92 (t , J = 7.8Hz, 2H), 1.70-1.42 (m, 4H), 1.2-1.18 (m, 2H). Example 5 (13)

N-Hydroxy-6- (4- (4-hydroxyphenyl) phenyl) -1-6-Hexanehexamide

TLC: R f 0.23 (ethyl acetate),

NMR (d ₆ — DMSO): δ 10.28 (s, 1H), 9.47 (s, 1H), 8.62 (s, 1H), 7.48 (d, J = 8.4Hz, 2H), 7.44 (d, J = 8.7Hz) , 2H), 7.31 (d, J = 8.4Hz, 2H), 6.81 (d, J = 8.7Hz, 2H), 5.07 (d, J = 4.2Hz, 1H), 4.51-4.45 (m, 1H), 1.90 (t, J = 7.2Hz, 2H), 1.62-1.17 (m, 6H).

 Example 5 (14)

 N-Hydroxy-6- (4- (dibenzofuran-4-1yl) phenyl) -1-6-hydroxyhexanamide

TLC: R f 0.29 (ethyl acetate),

NMR (d ₆ -DMS0): <5 10.30 (s, 1H), 8.63 (s, 1H), 8.18 (d, J = 7.2Hz, 1H), 8.13 (dd, J = 7.5Hz, 1.2Hz, 1H) , 7.84 (d, J = 8.1Hz, 2H), 7.73 (d, J-7.2Hz, 1H), 7.67 (dd, J = 7.5Hz, 1.2Hz, 1H), 7.56-7.39 (m, 5H), 5.19 (d, J = 4.2Hz, 1H), 4.60-4.55 (m, 1H), 1.93 (t, J = 7.2Hz, 2H), 1.66-1.21 (m, 6H). Example 5 (1 5)

 N-Hydroxy-6- (4- (2-methoxyphenyl) phenyl) -6-hydroxyhexanamide

TLC: R f 0.20 (black mouth form: methanol: triethylamine = 8: 1: 1),

NMR (d ₆ -DMS0): δ 10.31 (s, 1H), 8.65 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.36-7.23 (in, 2H), 7.33 (d, J = 8.4Hz, 2H), 7.10 (d, J = 8.4Hz, 1H), 7.02 (t, J = 7.5Hz, 1H), 5.11 (d, J = 4.5Hz, 1H), 4.51 (m, 1H), 3.76 (s, 3H), 1.93 (t, J = 7.2Hz, 2H), 1.68-1.15 (m, 6H).

 Example 5 (16)

 N-Hydroxy-6- (4 (3-methoxyphenyl) phenyl) -6-hydroxyhexanamide

TLC: R f 0.20 (form of mouth: methanol: triethylamine = 8 1: 1), NM (d ₆ -DMS0): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.60 (d, J = 8.1Hz, 2H), 7, 38 (d, J = 8.1Hz, 2H), 7.36 (t, J = 8.1Hz, 1H), 7.23-7.13 (m, 2H), 6.95--6.87 (m, 1H), 5.14 (d, J = 4.2Hz, 1H), 4.53 (m, 1H), 3.80 ( s, 3H), 1.92 (t, J = 7.2Hz, 2H), 1.70-1.15 (m, 6H). Example 5 (17)

 N-Hydroxy 6 _ (4- (4_trifluoromethylphenyl) phenyl) — 6-Hydroxyhexaneamide

TLC： R f 0.20 (クロ口ホルム：メタノール： トリェチルァミン =8 ： 1 : 1) ,

TLC: R f 0.20 (form: methanol: triethylamine = 8: 1: 1),

NMR (d ₆ -DMS0): 6 10.31 (s, 1H), 8.65 (s, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.80 (d, J = 8.7 Hz, 2H), 7.69 (d , J = 8.7Hz, 2H), 7.44 (d, J = 8.7Hz, 2H), 5.20 (d, J = 4.2Hz, 1H), 4.56 (m, 1H), 1.93 (t, J = 7.5 Hz, 2H ), 1.70-1.15 (m, 6H). Example 5 (18)

N-hydroxy-6_ (4 (4-t-butylphenyl) phenyl) -6-hydroxyhexaneamide

TLC: R f 0.20 (form of form: methanol: triethylamine = 8: 1: 1)

NMR (d ₆ -DMS0): δ 10.31 (s, 1H), 8.64 (s, 1H), 7.57 (d, J = 8.4 Hz, 4H), 7.46 (d, J = 8.4 Hz, 2H), 7.38 (d , J = 8.4Hz, 2H), 5.13 (d, J = 4.2Hz, 1H), 4.52 (m, 1H), 1.92 (t, J-7.2Hz, 2H), 1.65-1.20 (m, 6H), 1.31 (s, 9H). Reference Example 7

 2- (2-methoxyethoxy) ethyl 6- (4-bromophenyl) -6-oxohexanoet

To a solution of 6- (4-bromophenyl) -16-oxohexanoic acid (52 g) in dichloromethane (200 ml) was added oxalyl chloride (32 ml). The reaction mixture was stirred at 40 ° C. for 3 hours. The reaction mixture was concentrated. A solution of the obtained residue in toluene (500 ml) was added dropwise to di (ethylene glycol) methyl ether (65 ml) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour, and trieduramine (25 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract is washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. did. Methanol was added to the obtained residue, and the insoluble matter was filtered. The filtrate was concentrated to give the title compound (88 g) having the following physical data.

 TLC: R f 0.43 (hexane: ethyl acetate = 2: 3),

_{NMR (CDC1 3): d 7.81} (d, J = 8.7Hz, 2H), 7.60 (d, J = 8.7Hz, 2H), 4.24

(t, J = 4.8Hz, 2H), 3.69 (t, J = 4.8Hz, 2H), 3.66-3.62 (m, 2H), 3.56-3.53

(m, 2H), 3.38 (s, 3H), 2.95 (t, J = 7.2Hz, 2H), 2.40 (t, J = 7.2Hz, 2H),

1.83-1.67 On, 4H). Reference Example 8

 2- (2-methoxyethoxy) ethyl 6- [4- (N- (2-hydroxy-1-5-methylphenyl) pothambamoyl) phenyl] -1-6-oxohexanoate

参考例 7で製造した化合物 （75 g) のジメチルァセトアミド （300ml) 溶液に、 アルゴン雰囲気下、 4ーメチルー 2—ァミノフエノール (17.9g) 、 ジクロロビス （トリフエニルホスフィン） パラジウム （Π) (2.78g) 、 ト リフエニルホスフィン (2.07g) 、 1, 8ージァザビシクロ [5. 4. 0] ゥンデセー 7—ェン (23.7m 1 ) を加えた。 反応混合物をアルゴン雰囲気下 から一酸化炭素雰囲気下へ置換した。 反応混合物を 150°Cで Ϊ.5時間撹拌 した。 反応混合物を水に注ぎ、 酢酸ェチルで抽出した。 抽出物を 1N塩酸水 溶液、 水、 飽和塩化ナトリウム水溶液で洗浄し、 無水硫酸マグネシウムで乾 燥し、 濃縮した。 得られた残渣をジェチルエーテルで洗浄し、 下記の物性値 を有する標題化合物 （51.3g) を得た。

Under a argon atmosphere, 4-methyl-2-aminophenol (17.9 g), dichlorobis (triphenylphosphine) palladium (Π) (2.78) were added to a solution of the compound (75 g) prepared in Reference Example 7 in dimethylacetamide (300 ml) under an argon atmosphere. g), triphenylphosphine (2.07 g) and 1,8 diazabicyclo [5.4.0] pendase 7-ene (23.7 m 1) were added. The reaction mixture was replaced from an argon atmosphere to a carbon monoxide atmosphere. The reaction mixture was stirred for 1.5 hours at 150 ° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract is washed with a 1N aqueous hydrochloric acid solution, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Dried and concentrated. The obtained residue was washed with getyl ether to give the title compound (51.3 g) having the following physical data.

 TLC: Rf 0.27 (hexane: ethyl acetate = 1: 2),

_{NMR (CDC1 3): δ 8.29} (brs, 1H), 8.04 (d, J = 8.7Hz, 2H), 8.00-7.98 (m,

1H), 7.97 (d, J = 8.7Hz, 2H), 7.19 (s, 1H), 6.98-6.93 (m, 2H), 4.24 (t,

J = 5.0Hz, 2H), 3.70 (t, J = 5.0Hz, 2H), 3.66-3.63 (m, 2H), 3.56-3.53 (m,

2H), 3.37 (s, 3H), 3.02 (t, J = 6.9Hz, 2H), 2.40 (t, J = 6.9Hz, 2H), 2.29

(s, 3H), 1.86-1.68 (m, 4H). Reference Example 9

 2- (2-Methoxyethoxy) ethyl 6_ [4- (5-Methylbenzoxoxazol-1-2-yl) phenyl] -1-6-oxohexanoate

参考例 8で製造した化合物 （49 g) のトルエン (500ml) 懸濁液に、 カンファースルホン酸 （24.9 g) を加えた。 反応混合物をディーンス夕一ク (Dean-Stark) を用いて水を除きながら、 150 °Cで 3.5時間撹拌した。 反 応混合物を氷水に注ぎ、 酢酸ェチルで抽出した。 抽出物を飽和炭酸水素ナト リウム水溶液、 水、 飽和塩化ナトリウム水溶液で洗浄し、 無水硫酸マグネシ ゥムで乾燥し、 濃縮した。 得られた残渣をシリカゲルカラムクロマトグラフ ィー （ジクロロメタン：酢酸ェチル =10 ： 1〜1 ： 1) で精製し、 下記の 物性値を有する標題化合物 （33. lg) を得た。

To a suspension of the compound (49 g) produced in Reference Example 8 in toluene (500 ml) was added camphorsulfonic acid (24.9 g). The reaction mixture was stirred at 150 ° C for 3.5 hours while removing water using Dean-Stark. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 10: 1 to 1: 1). The title compound (33.lg) having physical properties was obtained.

 TLC: R f 0.42 (hexane: ethyl acetate = 1: 2),

_{NMR (CDC1 3): (5} 8.33 (d, J = 8.7Hz, 2H), 8.08 (d, J = 8.7Hz, 2H), 7.58

(d, J = l.5Hz, 1H), 7.8 (d, J = 8.1Hz, 1H), 7.20 (dd, J = 8.1, 1.5Hz, 1H),

4.25 (t, J = 4.8Hz, 2H), 3.70 (t, J = 4.8Hz, 2H), 3.66-3.62 (m, 2H), 3.57-3.53

(m, 2H), 3.38 (s, 3H), 3.05 (t, J = 7.0Hz, 2H), 2.50 (s, 3H), 2.42 (t,

J = 7.0Hz, 2H), 1.87-1.70 (m, 4H). Reference example 9 (1)

 2- (2-Methoxyethoxy) ethyl 6- [4- (Benzoxazole-1-yl) phenyl] —6-oxohexanoate

The same operation as in Reference Example 8 → Reference Example 9 was carried out using 2-aminophenol instead of 4-methyl-1-aminophenol to obtain the title compound having the following physical property values.

 TLC: R f 0.45 (hexane: ethyl acetate = 2: 3),

_{NMR (CDC1 3): δ 8.35} (d, J = 8.8Hz, 2H), 8.09 (d, J = 8.8Hz, 2H), 7.85-7.77 (in, 1H), 7.67-7.58 (m, 1H), 7 5-7.37 (m, 2H), 4.24 (t, J = 4.8Hz, 2H), 3.72 (t, J = 4.8Hz, 2H), 3.67-3.62 (m, 2H), 3.58-3.53 (m, 2H ), 3.38 (s, 3H), 3.05 (t, J = 7.0Hz, 2H), 2.42 (t, J = 7.0Hz, 2H), 1.90-1.70 (m, 4H). Reference example 10

 2- (2-methoxyethoxy) ethyl 6- [4- (2- (4-methylthiophenyl) ethynyl) phenyl] -6-oxohexanoate

参考例 7で製造した化合物 （80 g) のジメチルホルムアミド （310ml) とトリエチルァミン （155m 1 ) 混合溶液に、 アルゴン雰囲気下、 1—ェチ二 ルー 4ーメチルチオベンゼン (27.5 g) 、 ジクロロビス （トリフエニルホス フィン） パラジウム （II) (10.9 g) を加えた。 反応混合物を 50°Cで 3時 間撹拌した。 反応混合物を氷冷した 2 N塩酸水溶液に注ぎ、 酢酸ェチルで抽 出した。 抽出物を 2 N塩酸水溶液、 飽和炭酸水素ナトリウム水溶液、 飽和塩 化ナトリウム水溶液で洗浄し、 無水硫酸マグネシウムで乾燥し、 濃縮した。 得られた残渣をシリカゲルカラムクロマトグラフィー （へキサン：酢酸ェチ ル= 2 ： 1→2 ： 3→クロ口ホルム：メタノール =20 ： 1) で精製し、 下 記の物性値を有する標題化合物 （41. lg) を得た。

To a mixed solution of the compound (80 g) prepared in Reference Example 7 in dimethylformamide (310 ml) and triethylamine (155 ml) was added 1-ethynyl 4-methylthiobenzene (27.5 g), dichlorobis ( Triphenylphosphine) palladium (II) (10.9 g) was added. The reaction mixture was stirred at 50 ° C for 3 hours. The reaction mixture was poured into an ice-cooled 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with a 2N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 2: 3 → chloroform: methanol = 20: 1) to give the title compound having the following physical property values ( 41. lg).

TLC: Rf 0.21 (hexane: ethyl acetate = 2: 1),

_{NMR (CDC1 3): δ 7.93} (d, J = 8.6Hz, 2H), 7.59 (d, J-8.6Hz, 2H), 7.46 (d, J = 8.6Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 4.28-4.20 On, 2H), 3.75-3.60 (m, 4H), 3.60-3.50 (m, 2H), 3.38 (s, 3H), 2.99 (t, J = 7.0Hz, 2H), 2.51 (s, 3H), 2.41 (t, J = 7.0Hz, 2H), 1.85-1.65 (m, 4H). Reference example 1 1 2- (2-methoxyethoxy) ethyl 6- [4- (4-methylthiophene) phenyl] _ 6-oxohexanoate

参考例 7で製造した化合物と 4—メチルチオフェ二ルポロン酸を用いて、 実施例 4と同様の操作をし、 下記の物性値を有する標題化合物を得た。

The same operation as in Example 4 was carried out using the compound produced in Reference Example 7 and 4-methylthiophenolpolonic acid to obtain the title compound having the following physical data.

TLC: f 0.24 (hexane: ethyl acetate = 1: 1),

_{NMR (CDC1 3): δ 8.01} (d, J = 8.7Hz, 2H), 7.65 (d, J = 8.7Hz, 2H), 7.56 (d, J = 8.4Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 4.25 (t, J = 4.8Hz, 2H), 3.70 (t, J = 4.8Hz, 2H), 3.66-3.63 (m, 2H), 3.56-3.53 (m, 2H), 3.38 (s , 3H), 3.01 (t, J = 6.9Hz, 2H), 2.53 (s, 3H), 2.41 (t, J = 6.9Hz, 2H), 1.86-1.70 (m, 4H) _C Reference example 1 2

 Methyl 6- [4- (4-methylthiophenenyl) phenyl] 1-oxohexanoate

アジピン酸モノメチルエステルと 4一 (N, N—ジメチルァミノ） メチル ビフエ二ルを用いて、 参考例 1と同様の操作をし、 下記の物性値を有する標 題化合物を得た。

The same operation as in Reference Example 1 was performed using adipic acid monomethyl ester and 4- (N, N-dimethylamino) methyl biphenyl to obtain a target having the following physical property values. The title compound was obtained.

 TLC: R f 0.51 (dichloromethane: methanol = 4: 1),

_{NMR (CDC1 3): δ 8.01} (d, J = 8.7Hz, 2H), 7.68 (d, J = 8.7Hz, 2H), 7.59 (d, J = 8.3Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 3.67 (s, 3H), 3.50 (s, 2H), 3.02 (t, J = 7.0Hz, 2H), 2.39 (t, J = 7.0Hz, 2H), 2.29 (s, 6H), 1.86-1.70 (m, 4H) _C Example 6

 (R)-(+)-N- (1-Methoxy-1-methyl) ethoxy-6- [4- (5-Methylbenzoxazol-2-yl) phenyl] -16-hydroxy

参考例 9で製造した化合物を用いて、 参考例 4—参考例 3—実施例 1と同 様の操作をし、 下記の物性値を有する標題化合物を得た。

The same operation as in Reference Example 4—Reference Example 3—Example 1 was performed using the compound produced in Reference Example 9 to obtain the title compound having the following physical data.

[a] _D : +22.46 (c 0.615, dimethylformamide),

TLC: R f 0.34 (ethyl acetate),

_{NMR (CDC1 3): δ 8.19} (d, J = 8.1 Hz, 2H), 7.84 (brs, 1H), 7.54-7.53 (m, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.44 (d , J = 8.1Hz, 1H), 7.16-7.13 (m, 1H), 4.80-4.75 (m, 1H), 3.30 (s, 3H), 2.48 (s, 3H), 2.42-2.08 (m, 2H ), 1.94-1.32 (m, 6H), 1.1 (s, 6H). Example 6 (1) to 6 (4)

 Instead of the compound produced in Reference Example 9, the same operation as in Example 6 was carried out using the compound produced in Reference Example 9 (1), Reference Example 10, Reference Example 11 or Reference Example 12, and The title compound shown below was obtained. Example 6 (1)

 (R) 1-N- (1-Methoxy-1-methyl) ethoxy 6- [4- (Benzoxazol-2-yl) phenyl] -1-6-hydroxyhexanamide

TLC: R f 0.50 (black port Holm: methanol: acetic acid = 90: 10: 1), NMR (CDC1 3): δ 8.22 (d, J = 8.2 Hz, 2H), 7.83 (br, 1H), 7.75 (m , 1H), 7.59 (m, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.35 (m, 2H), 4.76 (t, J = 6.5 Hz, 1H), 3.30 (s, 3H), 2.45 -2.12 (m, 2H), 1.85-1.62 On, 4H), 1.53-1.38 (m, 2H), 1.41 (s, 6H). Example 6 (2)

(R) -N- (1-Methoxy-1-methyl) ethoxy-6- [4- (2- (4-methyl ^^ thiophenenyl) ethynyl) phenyl] -16-hydroxyhexanamide

TLC: R f 0.41 (black port Holm: methanol: acetic acid = 90: 10: 1), NMR (CDC1 3): 6 7.86 (br, 1H), 7.48 (d, J - 8.4 Hz, 2H), 7.42 (d , J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 4.68 (t-like, J = 6.0 Hz, 1H), 3.31 (s , 3H), 2.49 (s, 3H), 2.40-2.10 (m, 2H), 1.82-1.65 (m, 4H), 1.50-1.35 (m, 2H), 1.41 (s, 6H). Example 6 (3)

 (R) — N— (1-Methoxy-1-methyl) ethoxy— 6— [4- (4 Methylthiophenyl) phenyl] -1-6-hydroxyhexanamide

TLC: R f 0.44 (ethyl acetate),

_{NMR (CDC1 3): <5} 7.79 (br, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.38 (d, 8.5 Hz, 2H), 7.31 (d, J-8.5 Hz, 2H), 4.71 (i, J = 6.0 Hz, 1H), 3.30 (s, 3H), 2.52 (s, 3H), 2.3-2.08 (m, 2H), 1.90- 1.65 (m, 5H), 1.57-1.36 (m, 1H), 1.1 (s, 6H). Example 6 (4)

 (R)-(+)-N (1-methoxy-1-methyl) ethoxy-6- [4- (4-phenyl) phenyl] _6-hydroxyhexanamide

[a] _D : +22.6 (c 1.04, dimethylformamide),

TLC: R f 0.17 (cloth form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 7.58 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.12 (d, J = 4.5 Hz, 1H), 4.52 (in, 1H), 3.39 (s, 2H), 3.18 (s, 3H), 2.14 (s, 6H), 1.98 (t , J = 7.2 Hz, 2H), 1.65-1.54 (m, 2H), 1.49 (m, 2H), 1.0-1.18 (m, 2H), 1.24 (s, 6H). Example 7

(R) — (+) —N-Hydroxy 6— [4- (5-Methylbenzoxazol—2-yl) phenyl] _ 6-Hydroxyhexanamide

実施例 6で製造した化合物を用いて、 実施例 2と同様の操作をし、 下記の 物性値を有する標題化合物を得た。

The same operation as in Example 2 was performed using the compound prepared in Example 6 to obtain the title compound having the following physical data.

 TLC: f 0.28 (form: methanol = 9: 1),

m.p .: 178-179. C,

[] _D : +31.0 (c 1.05, dimethylformamide),

NMR (d ₆ — DMS0): δ 10.30 (s, 1H), 8.63 (s, 1H), 8.12 (d, J-8.4Hz, 2H), 7.63 (d, J = 8.4Hz, 1H), 7.57 (m , 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.22 (m, 1H), 5.31 (d, J = 4.2 Hz, 1H), 4.59 (m, 1H), 2.43 (s, 3H), 1.91 (t, J = 7.2 Hz, 2H), 1.65-1.56 (m, 2H), 1.54-1.5 (m, 2H), 1.41-1.18 (m, 2H). Example 7 (1) to 7 (4)

 The same operation as in Example 7 was carried out using the compounds prepared in Examples 6 (1) to 6 (4) instead of the compound prepared in Example 6, and if desired, an acid addition was carried out by a usual method. The title compound shown below was obtained. Example 7 (1)

(R)-(+)-N-hydroxy-6_ [4- (benzoxazolyl-2-yl) phenyl] -1-hydroxyhexanamide

TLC: R f 0.20 (cloth form: methanol: acetic acid = 90: 10: 1), m.p .: 160-161 ° C,

[] _D · +10.10 (c 0.81, methanol),

NMR (d ₆ -DMS0): δ 10.31 (s, 1H), 8.64 (s, 1H), 8.14 (d, J = 8.2Hz, 2H), 7.82-7.72 (m, 2H), 7.54 (d, J = 8.2Hz, 2H), 7.47-7.34 (m, 2H), 5.32 (d, J = 4.4Hz, 1H), 4.64-4.57 (m, 1H), 1.92 (t, J = 7.0Hz, 2H), 1.70- 1.10 (m, 6H). Example 7 (2)

 (R)-(+)-N-hydroxy-6- [4- (2- (4-methylthiophenyl) ethynyl) phenyl] -1-6-hydroxyhexaneamide

TLC: Rf 0.43 (cloth form: methanol: acetic acid = 60: 10: 1) m.p .: 173-176,

 [a] D: +31.5 (c 1.02, dimethylformamide),

NMR (d ₆ — DMS0): δ 10.30 (s, 1H), 8.62 (s, 1H), 7.48 (d, J = 8.0Hz, 2H), 7.47 (d, J = 8.4Hz, 2H), 7.35 (d, J = 8.0Hz, 2H), 7.28 (d, J = 8.4Hz, 2H), 5.22 (d, J = 4.4Hz, 1H), 4.60- 4.45 (m, 1H), 2.51 (s, 3H), 1.92 (t, J = 7.2Hz, 2H), 1.70-1.10 (ra, 6H). Example 7 (3)

 (R) 1 (+) _N-hydroxy-1 6- [4 (4-methylthiophenenyl) phenyl] 1-hydroxyhexanamide

TLC: R f 0.23 (black form: methanol = 9: 1),

m. p .: 194 ~ 197Τ

la] _D : +6.86 (c 0 · 105, methanol),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.62 (s, 1H), 7.61-7.55 (m, 4H), 7.38-7.29 (m, 4H), 5.12 (d, J = 4.4 Hz, 1H), 4.58-4.42 (m, 1H), 2.49 (s, 3H), 1.90 (t, J = 7. Hz, 2H), 1.66-1.02 (m, 6H). Example 7 (4)

(R) mono (+)-N-hydroxy-1 6- [4- (4- (dimethylaminomethyl) phenyl) phenyl] — 6-hydroxyhexanamide hydrochloride

 • HCI

TLC: Rf 0.14 (form: methanol = 2: 1),

m.p .: 214-217. C,

[a] _D : +26.54 (c 0.11, methanol),

NMR (d ₆ — DMSO): d 10.79 (s, 1H), 10.33 (s, 1H), 8.63 (s, 1H), 7.73 (d, J = 8.2Hz, 2H), 7.64-7.62 (m, 4H) , 7.39 (d, J-8.2Hz, 2H), 5.17 (d, J = 3.9Hz, 1H), 4.58-4.49 (m, 1H), 4.27 (s, 2H), 2.68 (s, 6H), 1.91 ( t, J = 6.9Hz, 2H), 1.64-1.18 (m, 2H). Example 8 (1) to 8 (4)

 Using the corresponding compound in place of 4-bicloth biphenyl, Reference Example 1 → Reference Example 2 → Reference Example 3 → Example 1 → Example 2 was repeated, and the following title compound was obtained. Obtained. Example 8 (1)

 N-Hydroxy-6- (4- (trans-4-phenyl) _6-Hydroxyhexanamide

TLC : f 018 (酢酸ェチル） 、

TLC: f 018 (ethyl acetate),

NMR (d ₆ -DMS0): 6 10.30 (s, 1H), 8.63 (s, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 4.99 (d , J = 3.9 Hz, 1H), 4.42 (m, 1H), 2.40 (in, 1H), 1.91 (t, J = 7.2 Hz, 2H), 1.90-0.90 (m, 21H), 0.85 (t, J = 6.9 Hz, 3H). Example 8 (2)

 N—Hydroxy 6— (4—

Phenyl) — 6-hydroxyhexanamide

TLC: R f 0.12 (form: methanol: triethylamine = 8: 1: 1),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.64 (s, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 4.99 (d , J = 4.5 Hz, 1H), 4.54 (d, J = 4.5 Hz, 1H), 4.42 (q, J = 4.5 HZ, 1H), 3.52-3.36 (m, 1H), 2.60-2.30 (m, 1H) , 1.95-1.83 (m, 4H), 1.80-1.65 (m, 2H), 1.63-1.10 (m, 10H). Example 8 (3)

N-Hydroxy-6 (4-cyclopentylphenyl) 1-hydroxyhexanamide

TLC: R f 0.18 (Black-mouthed form: methanol: triethylamine = 8: 1: 1)

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.64 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8, 4 Hz, 2H), 5.00 (d, J = 3.9 Hz, 1H), 4.43 (q, J: 3.9 Hz, 1H), 3.00-2.85 (in, 1H), 2.06-1.84 (in, 4H), 1.83-1.38 (m, 10H), 1.38-1.10 (m. 2H). Example 8 (4)

 N-Hydroxy-1-61 [4- (morpholine-1-^^^) phenyl] -6-hydroxyhexanamide

TLC: R f 0.20 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.27 (s, 1H), 8.61 (s, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.80 (d , J = 4.2 Hz, 1H), 4.40-4.35 (m, 1H), 3.72-3.69 (m, 4H), 3.05-3.02 (m, 4H), 1.88 (t, J = 7.5 Hz, 2H), 1.62- 1 · 07 (m, 6H). Example 9

 N-Hydroxy 6- [3- (4-phenylphenyl) phenyl] -1-hydroxyhexanamide

参考例 6で製造した化合物の代わりに、 メチル 6— （3—ブロモフエ二 ル） 一 6—ォキソへキサノエートを用いて、 実施例 4→参考例 2→参考例 3 →実施例 1→実施例 2と同様の操作をし、 以下の物性値を有する標題化合物 を得た。

Example 4 → Reference Example 2 → Reference Example 3 → Example 1 → Example 2 using methyl 6- (3-bromophenyl) -16-oxohexanoate instead of the compound prepared in Reference Example 6. The title compound having the following physical data was obtained by the same procedure as in above.

 TLC: R f 0.27 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.28 (brs, 1H), 8.62 (brs, 1H), 7.75-7.64 z (m, 3H), 7.57 (s, 1H), 7.52-7.47 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H) 7.31 (d, J = 6.9 Hz, 1H), 5.16 (d, J = 4.5 Hz, 1H), 4.58-4.52 (m, 1H), 1.90 (t, J = 7 2 Hz, 2H), 1.64-1.20 (m, 6H). Example 9 (1)

 N-Hydroxy-6- [2- (4-chlorophenyl) phenyl] -1-hydroxyhexanamide

メチル 6— （3—ブロモフエニル） — 6—ォキソへキサノエートの代わ りに、 メチル 6一 (2 _ブロモフエニル) - 6一ォキソへキサノエ一卜を 用いて、 実施例 9と同様の操作をし、 以下の物性値を有する標題化合物を得 た。

The same operation as in Example 9 was carried out using methyl 6- (2-bromophenyl) -6-oxohexanoate instead of methyl 6- (3-bromophenyl) -6-oxohexanoate, and The title compound having the following physical data was obtained.

 TLC: R f 0.26 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.24 (s, 1H), 8.61 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.9-7.46 (m, 2H), 7.0- 7.24 (in, 4H), 7.11-7.09 (m, 1H), 5.03 (d, J = 4.2 Hz, 1H), 4.49-4.44 (m, 1H), 1.80 (t, J = 7.5 Hz, 2H), 1.56 —1.02 (m, 6H). Example 10

 N-Hydroxy-6- [4-((IE) —2-phenylvinyl) phenyl] -6-hydroxyhexanamide

参考例 6で製造した化合物とスチレンを用いて、 参考例 10→実施例 2と 同様の操作をし、 以下の物性値を有する標題化合物を得た。

Using the compound produced in Reference Example 6 and styrene, the same operation as in Reference Example 10 → Example 2 was performed to obtain the title compound having the following physical property values.

TLC: R f 0.34 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.28 (s, 1H), 7.59-7.51 (in, 4H), 7.38-7.21 (m, 5H), 7.21 (s, 2H), 4.49-4.45 (m, 1H), 1.89 (t, J = 7.5 Hz, 2H), 1.60-1.12 (m, 6H). Example 10 (1) and 10 (2) The same operation as in Example 10 was carried out using a corresponding compound instead of styrene to obtain the title compound shown below. Example 10 (1)

 N-Hydroxy _ 6— [4— ((1 E) —2— (pyridine-14%) bi: le) phenyl] — 6-hydroxyhexanamide

TLC: R f 0.22 (ethyl acetate: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.28 (s, 1H), 8.62 (s, 1H), 8.51 (d, J = 5.4 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.53 (d , J = 5.4 Hz, 2H), 7.51 (d, J = 16.2 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 16.2 Hz, 1H), 5.14 (d, J = 4.8 Hz, 1H), 4.52-4.46 (m, 1H), 1.89 (t, J = 7.5 Hz, 2H), 1.60-1.10 (m, 6H). Example 10 (2)

 N-Hydroxy-6- [4-((IE) —2- (Pyridine-1-yl) vinyl) phenyl] -1-6-Hexanehexamide

TLC : R f 0.22 (酢酸ェチル：メタノール = 9 : 1) 、 NMR (d₆ - DMS0) ： δ 10.29 (s, 1Η), 8.63 (s, 1H), 8.56-8.54 (m, 1H), 7.77 (dt, J = 7.5 Hz, 1.5 Hz, 1H), 7.64 (d, J = 16.2 Hz, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.27 (d, J - 16.2 Hz, 1H), 7.25-7.21 (m, 1H), 5.13 (d, J = 4.5 Hz, 1H), 4.52-4.80 (m, 1H), 1.90 (t, J = 7.5 Hz, 2H), 1.63-1.18 (m, 6H)。 参考例 1 3

TLC: R f 0.22 (ethyl acetate: methanol = 9: 1), NMR (d ₆ -DMS0): δ 10.29 (s, 1Η), 8.63 (s, 1H), 8.56-8.54 (m, 1H), 7.77 ( dt, J = 7.5 Hz, 1.5 Hz, 1H), 7.64 (d, J = 16.2 Hz, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.27 (d, J-16.2 Hz, 1H), 7.25-7.21 (m, 1H), 5.13 (d, J = 4.5 Hz, 1H), 4.52-4.80 (m, 1H), 1.90 (t, J = 7.5 Hz, 2H), 1.63-1.18 (m, 6H). Reference Example 1 3

 6-[4- (4_chlorophenyl) phenyl] — 6-oxohexanoic acid

参考例 1で製造した化合物を用いて、 参考例 3と同様の操作をし、 以下の 物性値を有する標題化合物を得た。

Using the compound produced in Reference Example 1, the same operation as in Reference Example 3 was performed to obtain the title compound having the following physical data.

TLC: R f 0.50 (ethyl acetate),

NMR (d ₆ -DMS0): δ 12.00 (s, 1H), 8.05 (d, J-8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H) ), 7.56 (d, J = 8.4 Hz, 2H), 3.07 (t, J = 6.6 Hz, 2H), 2.27 (t, J = 7.4 Hz, 2H), 1.80-1.50 (m, 4H). Reference Example 14

参考例 13で製造した化合物 （560mg) のテトラヒドロフラン （20 m 1 )溶液にアルゴン雰囲気下、 O で 0.82 mm o 1 /mlのメチルマグネ シゥムョーダイドジェチルエーテル溶液 （10.8m l) を加えた。 反応混合物 を室温で 1時間撹拌した。 反応混合物に 1 N塩酸水溶液を加え、 酢酸ェチル で抽出した。 抽出物を水、 飽和塩化ナトリウム水溶液で洗浄し、 無水硫酸マ グネシゥムで乾燥し、 濃縮した。 得られた残渣をシリカゲルカラムクロマト グラフィー （へキサン：酢酸ェチル = 1 ： 1) によって精製し、 以下の物性 値を有する標題化合物 （442mg) を得た。 6- [4- (4-monophenyl) phenyl] 6-hydroxyheptanoic acid

To a solution of the compound (560 mg) prepared in Reference Example 13 in tetrahydrofuran (20 ml) was added a 0.82 mmol / ml methylmagnesium dyde dimethyl ether solution (10.8 ml) with O under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 hour. A 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (442 mg) having the following physical data.

TLC: R f 0.30 (hexane: ethyl acetate = 1: 2),

_{NMR (CDC1 3): δ 7.54-7.46} (m, 6H), 7.39 (d, J = 8.4Hz, 2H), 2.30 (t, J = 7.2Hz, 2H), 1.84 (m, 2H), 1.66-1.56 (m, 2H), 1.58 (s, 3H), 1.5-1.32 On, 1H), 1.30-1.18 (m, 1H). Example 1 1

 N-Hydroxy-6- [4- (4-chlorophenyl) phenyl] —6-Hyd ヽ

参考例 1 4で製造した化合物を用いて、 実施例 1→実施例 2と同様の操作 をし、 以下の物性値を有する標題化合物を得た。

Using the compound produced in Reference Example 14, the same operation as in Example 1 → Example 2 was performed to obtain the title compound having the following physical properties.

TLC: R f 0.27 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.24 (s, 1H), 8.60 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.49 (d , J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 4.87 (s, 1H), 1.85 (t, J = 7.2 Hz, 2H), 1.74-1.60 On, 2H), 1. 4-1.34 (m, 2H), 1.30-1.20 (m, 1H), 1.05-0.93 (m, 1H). Example 1 1 (1)

 N-hydroxy-1-6- [4- (4-chlorophenyl) phenyl] -1-hydroxy-1-7-octenamide

メチルマグネシウムョーダイドジェチルエーテル溶液の代わりに、 ビニル マグネシウムブロミドを用いて、参考例 14→実施例 1 1と同様の操作をし、 以下の物性値を有する標題化合物を得た。

The same operation as in Reference Example 14 → Example 11 was performed using vinyl magnesium bromide instead of the methyl magnesium iodide getyl ether solution, to give the title compound having the following physical data.

TLC: R f 0.28 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.26 (s, 1H), 8.62 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.48 (d , J = 8.5 Hz, 4H), 6.12 (dd, J = 17.2, 10.6 Hz, 1H), 5.21 (dd, J = 17.2, 2.0 Hz, 1H), 5.15 (s, 1H), 5.00 (dd, J = 10.6, 2.0 Hz, 1H), 1.84 (m, 2H), 1.83-1.72 (m, 2H), 1.2 (m, 2H), 1.32-1.22 (m, 1H), 1.12-1.00 (m, 1H) . Example 1 1 (2)

 N-hydroxy-6- (4-biphenyl) -1-6-

参考例 1 3で製造した化合物の代わりに、 6— (4—ビフエニル） — 6— ォキソへキサン酸を用いて、 参考例 14→実施例 1 1と同様の操作をし、 以 下の物性値を有する標題化合物を得た。

Using 6- (4-biphenyl) -6-oxohexanoic acid instead of the compound produced in Reference Example 13, the same operation as in Reference Example 14 → Example 11 was carried out, and the following physical property values were obtained. The title compound was obtained.

TLC: R f 0.26 (ethyl acetate),

NMR (d ₆ -DMS0): δ 10.25 (s, 1H), 8.61 (s, 1H), 7.65-7.62 (m, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.43-7.41 (m, 2H), 7.35-7.29 (m, 1H), 4.86 (s, 1H), 1.85 (t, J = 7.2 Hz, 2H), 1.75-1.60 (m, 2H ), 1.40 (s, 3H), 1.42-1.18 (m, 3H), 1.04-0.91 On. 1H). Reference example 1 5

 6- [4- (4-Ethylphenyl) phenyl] -1-6-heptoheptane

参考例 13で製造した化合物の代わりに、 6— [4- (4—ェチルフエ二 ル） フエニル] 一 6—ォキソへキサン酸を用いて、 参考例 14と同様の操作 をし、 標題化合物のェナンチォマー混合物を得た。 このェナンチォマー混合 物を、 以下に示した方法によって光学分割することにより、 標題化合物の ( + ) 体と （一） 体をそれぞれ得た。

Using 6- [4- (4-ethylphenyl) phenyl] -16-oxohexanoic acid instead of the compound produced in Reference Example 13, the same operation as in Reference Example 14 was carried out to obtain the enantiomer of the title compound. A mixture was obtained. This enantiomer mixture was subjected to optical resolution by the method described below to obtain the (+)-form and the (-)-form of the title compound, respectively.

 A mixture of the enantiomer mixture (6.66 g), (1R, 2)-(+) — 1,2-diphenylethylenediamine (4.33 g), ethyl acetate (80 ml) and hexane (20 ml) were mixed. The mixture was refluxed and completely dissolved. The mixture was cooled to room temperature to precipitate crystals. The precipitated crystals were filtered and washed with a hexane: ethyl acetate = 1: 1 solution. The filtrate was concentrated. The obtained residue was used for production of (-)-isomer. The precipitated crystals are dissolved in ethyl acetate, washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous solution of sodium salt, dried over anhydrous magnesium sulfate, and concentrated. The (+) form of the title compound having the following physical property values ( 2.44 g, 92.4% ee, HPLC).

 The residue obtained by concentrating the filtrate was dissolved in ethyl acetate, washed with an aqueous solution of hydrochloric acid IN, water, and an aqueous solution of saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was mixed with (1 S, 2 S)-(1-)-1-1,2-diphenylethylenediamine (2.32 g), ethyl acetate (50 ml) and hexane (10 ml). The mixture was refluxed and completely dissolved. The mixture was cooled to room temperature to precipitate crystals. The precipitated crystals were filtered and washed with a hexane: ethyl acetate = 1: 1 solution. The precipitated crystals are dissolved in ethyl acetate, washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. (2.88 g) of the title compound having the following physical properties is obtained. , 89.9% ee, HPL C).

 (+) Body:

TLC: R f 0.46 (cloth form: methanol = 9: 1), Retention time: 6.99 minutes

 Column: DAICEL CHIRAL CEL AD-RH, 4.6X 150 mm;

 Eluent: acetonitrile: water = 65: 35;

 UV: 256 nm;

 Flow rate: 1. Om1 / min.

 (1) Body:

 TLC: Rf 0.46 (form: methanol = 9: 1)

 Retention time: 1.40 minutes

 Column: DAICEL CHIRAL CEL AD-RH, 4.6X15 Omm;

 Eluent: acetonitrile: water = 65: 35;

 UV: 256 nm;

 Flow rate: 1. Om 1 Z min. Example 12

 (+) -N-hydroxy-6- [4- (4-ethylphenyl) phenyl] -6-hydroxyheptaneamide

参考例 1 5で製造された化合物の （+ ) 体を用いて、 実施例 1→実施例 2 と同様の操作をし、 以下の物性値を有する標題化合物を得た。

Using the (+) form of the compound produced in Reference Example 15, the same operation as in Example 1 → Example 2 was performed to obtain the title compound having the following physical data.

[a] _D : +14.74 (c0 · 555, methanol),

 TLC: R f 0.35 (form: methanol = 9: 1),

NMR (d ₆ -DMSO): δ 10.26 (s, 1H), 8.62 (s, 1H), 7.55 (d, J = 8.4 Hz, 4H), 7.45 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 4.85 (s, 1H), 2.62 (q, J = 7.4 Hz, 2H), 1.86 (t, J = 7.4 Hz, 2H), 1.78-1.56 (m, 2H), 1.55-1.21 (m, 6H), 1.20 (t, J = 7.4 Hz, 3H), 1.12-0.85 (m, 1H). Example 1 2 (1)

 (_) 1-N-hydroxy-1 6- [4- (4-ethylphenyl) phenyl] 1-6-hydroxyheptaneamide

参考例 1 5で製造された化合物の （一） 体を用いて、 実施例 1 2と同様の 操作をし、 以下の物性値を有する標題化合物を得た。

The same operation as in Example 12 was carried out using the (one) form of the compound produced in Reference Example 15 to give the title compound having the following physical data.

[] _D : -12.18 (c 0.74, methanol),

TLC: R f 0.35 (form: methanol = 9: 1),

NMR (d ₆ -D S0): δ 10.26 (s, 1H), 8.62 (s, 1H), 7.55 (d, J = 8.4 Hz, 4H), 7.45 (d, J = 8.4 Hz, 2H), 7.27 ( d, J = 8.4 Hz, 2H), 4.85 (s, 1H), 2.62 (q, J = 7.4 Hz, 2H), 1.86 (t, J = 7.4 Hz, 2H), 1.78-1.56 (m, 2H), 1.55-1.21 (in, 6H), 1.20 (t, J = 7.4 Hz, 3H), 1.12-0.85 On, 1H). Example 13 (1 :) to 13 (44)

Using the corresponding ketone derivative in place of the compound produced in Reference Example 1, the same operation as in Reference Example 4—Reference Example 3 → Example 1 → Example 2 was carried out, and if desired, by a usual method. Conversion to the acid addition salt gave the title compound shown below. Example 13 (1)

 (R) — (+) — N-Hydroxy-6- (4-biphenyl) _6-hydroxyhexanamide

[a] _D : +15.1 (c 0.245, methanol),

TLC: R f 0.25 (form: methanol: acetic acid = 90: 10: 1) NMR (d ₆ -DMSO): δ 10.29 (s. 1H), 8.63 (s, 1H), 7.65-7.57 (m, 4H) ), 7.46-7.30 (m, 5H), 5.13 (d, J = 4.5 Hz, 1H), 4.54-4.49 (m, 1H), 1.91 (t, J = 7.2 Hz, 2H), 1.64-1.4 ( m, 4H), 1.40-1.22 (m, 2H) ₀ Example 13 (2)

 (R)-(+)-N-hydroxy-6- [4 (4-methylphenyl) phenyl] -6-hydroxyhexaneamide

[ひ] _D： +11.53 (c 0.215、 メタノール） 、

[H] _D : +11.53 (c 0.215, methanol),

TLC: R f 0.22 (form: methanol: acetic acid = 90: 10: 1) NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.62 (s, 1H), 7.56-7.51 (in, 4H) ), 7.34 (d, J = 8.1 Hz, 2H), 7.24 (d, j = 8.1 Hz, 2H), 5.11 (d, J = 4.5 Hz, 1H), 4.52-4.48 (m, 1H), 2.32 (s, 3H ), 1.90 (t, J = 7.5 Hz, 2H), 1.62-1.15 (m, 6H). Example 13 (3)

 (R) 1-(+) — N-hydroxy-6- [4- (3-methylphenyl) phenyl] 1-hydroxyhydroxyamide

ί ] _D： +8.43 (c 0.37、 メタノール） 、

ί] _D : +8.43 (c 0.37, methanol),

TLC: R f 0.22 (form: methanol: acetic acid = 90: 10: 1), NMR (d ₆ -DMS 0): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.44-7.29 (m, 5H), 7.14 (d, J = 7.5 Hz, 1H), 5.12 (d, J = 4.5 Hz, 1H), 4.59-4.48 (m, 1H), 2.35 (s, 3H), 1.90 (i, J = 7.2 Hz, 2H), 1.63-1.12 (m, 6H). Example 13 (4)

(R) 1-(+)-N-hydroxy-6- [4- (benzoxazolyl-21-yl) phenyl] -1-6-hydroxyhexanamide

[a] _D : +14.5 (c 0.195, methanol),

TLC: Rf 0.25 (cloth form: methanol: acetic acid = 90: 10: 1), NMR (d ₆ -DMS0): δ 10.28 (s, 1H), 8.62 (s, 1H), 7.84 (d , J = 8.4 Hz, 2H), 7.65-7.58 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.37 (s, 1H), 7.33-7.19 (m, 2H), 5.19 ( d, J = 4.4 Hz, 1H), 4.59-4.45 (m, 1H), 1.89 (t, J = 7.2 Hz, 2H), 1.62-1.05 (m, 6H).

 Example 13 (5)

 (R) — N-Hydroxy _ 6— [4- (2-Phenylethynyl) phenyl] -1-6-hydroxyhexanamide

TLC: R f 0.24 (form: methanol: = 9: 1),

NMR (d ₆ -DMS0): δ 10.28 (s, 1H), 8.62 (s, 1H), 7.55-7.32 (m, 9H), 5.20 (d, J = 4.4 Hz '1H), 4.56-4.44 (m, 1H), 1.89 (t, J = 7.0 Hz, 2H), 1.60-1.08 (in, 6H). Example 13 (6)

 (R) 1 (+) — N-Hydroxy 1 6 — [4- phen-1-phenyl) phenyl] 1 6-Hydroxyhexanamide

[ ] _D : +13.88 (c 0.085、 メタノール） 、

[] _D : +13.88 (c 0.085, methanol),

TLC: R f 0.25 (form: methanol: acetic acid = 90: 10: 1) NMR (d ₆ -DMS0): δ 10.28 (s, 1H), 8.62 (s, 1H), 7.96-7.92 (m, 1H ), 7.84-7.79 (m, 2H), 7.70 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 7.36-7.28 (m, 2H), 5.18 (d, J = 4.4 Hz, 1H), 4.59-4.48 (m, 1H), 1.89 (t, J = 6.8 Hz. 2H), 1.65-1.10 On, 6H). Example 13 (7)

 (R) —N-Hydroxy-6- [4- (4- (cyanomethyl) phenyl) phenyl] -1-6-Hexaneamide

TLC: R f 0.28 (ethyl acetate: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.38 (d, J =

8.1 Hz, 2H), 5 14 (d, J = 4.5 Hz, 1H), 4.52 (m, IH), 4.06 (s, 2H), 1.91 (t, J = 7.2 Hz, 2H), 1.64-1.54 (m , 2H), 1.54-1.4 (m, 2H), 1.39-1.16 (m, 2H).

 Example 13 (8)

 () 1 N-Hydroxy _ 6— [4 (4 _ethylphenyl) phenyl]-6-hydroxyhexanamide

TLC ： R f 0.29 (クロ口ホルム：メタノール = 9 ： 1) 、

TLC: R f 0.29 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.42-10.20 (br, IH), 8.75-8.55 (br, IH), 7.56 (d,

J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 5.12 (d, J- 4.4 Hz, IH), 4.58-4.45 (m, IH), 2.62

(q, J = 7.6 Hz, 2H), 1.91 (t, J = 7.4 Hz, 2H), 1.70-1.10 (m, 6H), 1.19 (t, J = 7.6 Hz, 3H).

 Example 13 (9)

(R) —N-Hydroxy-6- [4- (4-propylphenyl) phenyl] -1-6-hydroxyhexanamide

TLC: R f 0.29 (form: methanol = 9: 1),

NMR (d ₆ — DMS0): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.57 (d, J = 8.4 Hz,

2H), 7.54 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.25 (d, J =

8.4 Hz, 2H), 5.12 (d, J = 4.4 Hz, 1H), 4.58-4.44 On, 1H), 2.57 (t, J =

7.4 Hz, 2H), 1.92 (t, J = 7.4 Hz, 2H), 1.72-1.10 (m, 8H), 0.90 (t, J = 7.8 Hz, 3H). Example 13 (10)

 (R) —N-Hydroxy-6— [4- (4-biphenyl) phenyl] 1-hydroxyhexanamide

TLC: R f 0.26 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.78-7.60 (m, 8H), 7.54-7.30 (m, 5H), 5.15 (d, J = 4.4 Hz, 1H), 4.59-4.46 (m, 1H), 1.91 (t, J-6.8 Hz, 2H), 1.65-1.10 (m, 6H). Example 13 (1 1)

 (R) —N-Hydroxy-6- [4- (1-methylbiperidine-14-yl) phenyl] -1-6-hydroxyhexaneamide hydrochloride

TLC: R f 0.12 (methanol),

NMR (d ₆ -DMS0): δ 10.53 (br, 1H), 10.31 (s, 1H), 8.64 (br, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz) , 2H), 5.06 (br, 1H), 4.44 (t, 6.0 Hz, 1H), 3.46-3.28 (m, 3H), 3.09-2.96 (in, 2H), 2.73 (d-like, J = 4.2 Hz, 3H), 2.00-1.87 (m, 6H), 1.58-1.41 (m, 4H), 1.37-1.15 (m, 2H) _C Example 13 (12)

 (R) —N—Hydroxy— 6— [4- (Indone-2-yl) phenyl] —6-Hydroxyhexanamide

TLC ： R f 0.33 (クロ口ホルム：メタノール：酢酸 = 60 ： 10 ： 1 ) 、 NMR (d₆-DMS0) ： δ 11.42 (s, 1H), 10.25 (s, 1H), 8.62 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.47 (d， J = 7.5 Hz, 1H) 7.40-7.30 (m, 3H), 7.10-7.00 (m， 1H), 7.00-6.90 (m, 1H), 6.81 (d, J = 1.2 Hz, 1H)， 5.12 (d, J = 4.5 Hz, 1H), 4.55-4.42 (m, 1H), 1.88 (t, J = 7.4 Hz, 2H), 1.70-1.40 (m, 4H), 1. 0-1.10 (m, 2H)。

TLC: R f 0.33 (clonal form: methanol: acetic acid = 60: 10: 1), NMR (d ₆ -DMS0): δ 11.42 (s, 1H), 10.25 (s, 1H), 8.62 (s, 1H) , 7.76 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 7.5 Hz, 1H) 7.40-7.30 (m, 3H), 7.10-7.00 (m, 1H), 7.00-6.90 (m, 1H), 6.81 (d, J = 1.2 Hz, 1H), 5.12 (d, J = 4.5 Hz, 1H), 4.55-4.42 (m, 1H), 1.88 ( t, J = 7.4 Hz, 2H), 1.70-1.40 (m, 4H), 1.0-1.10 (m, 2H).

 Example 1 3 (1 3)

 (R) — (+) —N-hydroxy-6— [4- (4_cyanophenyl) phenyl] -1-6-hydroxyhexanamide

[]. : +4.60 (c 0.265, methanol),

TLC: R f 0.34 (ethyl acetate: methanol = 19: 1),

NM (d ₆ -DMS0): 510.28 (brs, 1H), 8.63 (s, 1H), 7.90 (d, J-9.0 Hz, 2H), 7.85 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.42 (d, J-8.1 Hz, 2H), 5.19 (d, J = 4.8 Hz, 1H), 4.58-4.51 (m, 1H), 1.90 (t, J = 7.2 Hz , 2H), 1.59-1.14 (m, 6H). Example 13 (14)

(R)-(+) _N-hydroxy-6 _ [4-phenyl-2-methylphenyl] — 6-hydroxyhexaneamide

[α] _D : +18.31 (c 0.225, methanol),

TLC: R f 0.37 (ethyl acetate: methanol = 19: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.63-7.60 (m, 2H), 7.46-7.39 (m, 5H), 7.34-7.28 (m, 1H), 5.02 (d, J = 4.5 Hz, 1H), 4.72-4.68 (m, 1H), 2.32 (s, 3H), 1.92 (i, J = 6.9 Hz, 2H), 1.60-1.22 (m, 6H). Example 13 (15)

 (R) _N-hydroxy-6- (4-cycloheptylphenyl) 16-hydroxyhexanamide

TLC: Rf 0.43 (ethyl acetate: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.28 (s, 1H), 8.63 (s, 1H), 7.17 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 4.98 (d , J = 4.5 Hz, 1H), 4.41 (m, 1H), 2.61 (m, 1H), 1.89 (t, J-7.2 Hz, 2H), 1.81-1.1 (m, 16H), 1.37-1.10 ( m, 2H). Example 13 (16) (R) —N-Hydroxy-6- (9,10-dihydrophen-2-yl) -1-6-Hexanehexamide

TLC: R f 0.37 (ethyl acetate: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1H), 8.63 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.31-7.17 (m, 5H), 5.10 (d, J = 4.5 Hz, 1H), 4.47 (m, 1H), 2.79 (s, 4H), 1.91 (t, J-7.2 Hz, 2H), 1.63-1.44 (m, 4H), 1. 1-1.17 On, 2H). Example 13 (17)

 (R) 1-N-hydroxy-6- [4- (1-ethoxycarbonylpiberidin-4-yl) phenyl] -1-6-hydroxyhexanamide

TLC: R f 0.42 (ethyl acetate: methanol = 9: 1),

NMR (d ₆ -DMS0): 510.29 (s, 1H), 8.63 (s, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 5.01 (d, J = 4.2 Hz, 1H), 4.42 (m, 1H), 4.11-4.01 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 2.83 On, 2H), 2.65 (m, 1H), 1.89 (t, J = 7.2 Hz, 2H), 1.75-1.71 ( m, 2H), 1.55-1.2 (m, 6H), 1.37-1.25 On '2H), 1.18 (t, J = 7.0 Hz, 3H) ₀ Example 1 3 (1 8)

 (R)-(+) — N-Hydroxy _ 6— [4- (4- (N-Methylcarbamoyl) phenyl) phenyl] -1-6-hydroxyhexaneamide

[] _D : +12.37 (c 0.08, methanol),

TLC: Rf 0.33 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.29 (s, 1Η), 8.63 (brs, 1H), 8.48-8.43 (m, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.73 (d, J- 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.18 (brs, 1H), 4.56-4.50 (m, 1H), 2.78 (d, J = 4.8 Hz, 3H), 1.90 (t, J = 7.5 Hz, 2H), 1.63-1.11 (m, 6H). Example 13 (1 9)

(R) mono (+)-N-hydroxy-6- (4-cyclohexylphenyl) -6-hydroxyhexanamide

[«] _D : +12.65 (c 0.16, methanol),

TLC: R f 0.31 (black form: methanol = 19: 1),

NMR (d ₆ — DMS0): 6 10.27 (s, 1H), 8.62 (s, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 4.98 (d , J-4.2 Hz, 1H), 4.42-4.36 (m, 1H), 2.5-2.39 (m, 1H), 1.89 (t, J = 7.2 Hz, 2H), 1.80-1.09 (m, 17H). Example 13 (20)

 (R) — N-Hydroxy-1 6_ [4- (5-Hy 2) phenyl] 1-Hydroxyhexanamide

TLC: R f 0.27 (form: methanol: acetic acid = 60: 10: 1), NMR (d ₆ -DMS0): δ 10.25 (s, 1H), 9.18 (s, 1H), 8.60 (s, 1H) , 7.77 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 6.89 (d, J = 2.6 Hz, 1H), 6.69 (dd, J = 8.8, 2.6 Hz, 1H), 5.17 (d, J = 4.4 Hz, 1H), 4.60-4.40 (m, 1H), 1.88 (t, J = 7.1 Hz, 2H), 1.70-1.10 (, 6H). Example 13 (21)

(R) 1 N-Hydroxy _6— [4- (2- (4-Methylphenyl) ethyl: le) phenyl] _ 6-Hydroxyhexaneamide

TLC: R f 0.41 (form: methanol: acetic acid = 60: 10: 1), NMR (d ₆ — DMS0): δ 10.27 (s, 1H), 8.65 (s, 1H), 7.50-7.35 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.18 (d, J = 4.4 Hz, 1H), 4.60-4.40 (m, 1H), 2.30 ( s, 3H), 1.87 (t, J-7.1 Hz, 2H), 1.65-1.00 (m, 6H). Example 13 (22)

 (R) —N-Hydroxy-6— [4-((1E) —2 -— (4-Methylphenyl) vinyl) phenyl] — 6-Hydroxyhexaneamide

TLC: R f 0.43 (form: methanol: acetic acid = 60: 10: 10) NMR (d ₆ -DMS0): d 10.28 (s, 1H), 7.53-7.38 (m, 4H), 7.26 (d, J = 8.0 Hz, 2H), 7.20-7.05 On, 4H), 4.45 (t, J = 6.4 Hz, 1H), 2.25 (s, 3H), 1.87 (t, J = 7.0 Hz, 2H), 1.70-1.00 (m, 6H) ₀ Example 1 3 (2 3)

 (R) — N-Hydroxy-6- [4- (4-l) phenyl] -1-Hydroxyhexanamide

TLC: R f 0.25 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.43-7.38 (m, 4H), 5.15 (d, 4.5 HZ, 1H), 4.55-4.95 (in, 1H), 1.90 (t, J-7.5 Hz, 2H), 1.63-1.12 (m, 6H). Example 13 (24)

 (R) —N-Hydroxy-6 _ [4- (4-ethylthiophenyl) phen :: L] -1-6-hydroxyhexanamide

T L C : f 0.40 (酢酸ェチル：メタノ一ル = 4 : 1) 、

TLC: f 0.40 (ethyl acetate: methanol = 4: 1),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.59 (d, J-8.4 Hz,

2H), 7.58 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 4H), 5.13 (br, 1H),

4.51 (t, J = 6.0 Hz, 1H), 3.00 (q, J = 7.2 Hz, 2H), 1.91 (t, J = 7.0 Hz,

2H), 1.58 (m, 2H), 1.8 (m, 2H), 1.39-1.16 (m, 2H), 1.24 (t, J = 7.2 Hz,

3H).

 Example 13 (25)

 (R) — N-Hydroxy-6- [4- (4-methoxyphenyl) phenyl] • 6-Hydroxyhexaneamide

TLC: R f 0.23 (ethyl acetate: methanol = 4: 1),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.64 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.34 (d , J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 5.11 (d, J = 4.2 Hz, 1H), 4.50 (m, 1H), 3.77 (s, 3H), 1,91 (t, J = 7.2 Hz, 2H), 1.57 (m, 2H), 1.48 (m, 2H), 1.39-1.16 (m, 2H). Example 13 (26)

(R) 1-N-hydroxy-6- [4- (4- (1-methylethyl) phenyl) phenyl] -6-hydroxyhexanamide

TLC: Rf 0.20 (cloth form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.29 (s, 1Η), 8.63 (brs, 1H), 7.55 (d, J = 8.4

Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Jz, 2H), 7.30 (d,

J = 8.4 Hz, 2H), 5.11 (brs, 1H), 4.50 (t, J = 6.0 Hz, 1H), 2.98-2.82 (m,

1H), 1.90 (t, J = 7.2 Hz, 2H), 1.62-1.0 (, 6H), 1.21 (d, J = 6.9 Hz,

6H). Example 13 (27)

 (R) 1-N-hydroxy-6- [4- (4- (N, N-dimethylcarbamoylmethyl) phenyl) phenyl] — 6-hydroxyhexanamide

TLC: R f 0.21 (black form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.57 (d, J = 8.0 Hz, 4H), 7.37 (d, J = 8.0 Hz, 2H), 7.28 (d , J = 8.0 Hz, 2H), 5.13 (d, J: 4.4 Hz, lH), 4.59-4.46 (m, 1H), 3.71 (s, 2H), 3.01 (s, 3H), 2.83 (s, 3H) , 1.91 (t, J = 7.0 Hz, 2H), 1.65-1.10 (m, 6H) Example 1 3 (28)

 (R) 1-N-Hydroxy-1-6- [4- (benzothiazo-l-l-r-phenyl) phenyl] _ 6-hydroxyhexanamide

TLC R f 0.24 (form: methanol = 91)

NMR (d ₆ -DMS0) δ 10.30 (s, 1H), 8.64 (s, 1H), 8.18-8.12 (m, 1H), 8.09-7.98 (m, 3H), 7.60-7.40 (m, 4H), 5.38 -5.22 (m, 1H), 4.65-4.55 (m, 1H), 1.92 (t, J = 7.4 Hz, 2H), 1.70-1.15 (m, 6H). Example 13 (29)

 (R) —N-Hydroxy-6- [4- (4- (methoxymethoxymethyl) phenyl) phenyl] — 6-Hydroxyhexaneamide

TLC R f 0.30 (Black mouth form: methanol = 9 1)

NMR (d ₆ -DMS0) 6 10.30 (s, 1H), 8.64 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 5.14 (d, J = 4.4 Hz, 1H, 4.66 (s, 2H), 4.60-4.45 (m, 3H), 3.31 (s, 3H), 1.92 (t, J = 7.0 Hz, 2H), 1.70-1.12 (m, 6H) Example 13 (30)

 (R)-(+)-N-hydroxy-6

Sazoru 2-yl) phenyl]-6-

[«] _D : +7.31 (c 0.19, methanol),

TLC: R f 0.15 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.29 (s, 1H), 8.63 (brs, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 1H), 7.52 (d , J = 8.7 Hz, 2H), 7.0 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 5.29 (brs, 1H), 4.60-4.56 (m , 1H), 3.83 (s, 3H), 1.90 (t, J = 7.5 Hz, 2H), 1.63-1.20 (m, 6H). Example 13 (31)

(R) —N-Hydroxy-6— [4- (6-Methylbenzoxazolyl-2-yl) phenyl] -1-6-hydroxyhexaneamide

TLC: R f 0.28 (cloth form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1Η), 8.90-8.30 (br, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 1.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.21 (dd, 8.2, 1.0 Hz, 1H), 5.60-4.90 (br, 1H), 4.60 (t, J = 6.2 Hz, 1H), 2.46 (s, 3H), 1.91 (t, J = 7.4 Hz, 2H), 1.68-1.12 (m, 6H). Example 13 (32)

 (R) —N-hydroxy-6- [4- (4-methoxymethylphenyl) phenyl] -1-6-hydroxyhexaneamide

TLC: R f 0.39 (Form: methanol = 9: 1),

NMR (d ₆ -DMS0): 510.31 (s, 1H), 9.10-8.10 (br, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.59 (d, J-8.4 Hz, 2H), 7.38 ( d, J = 8.4 Hz, 4H), 5.50-4.70 (br, 1H), 4.52 (t, J = 6.2 Hz, 1H), 4.43 (s, 2H), 3.30 (s, 3H), 1.91 (t, J = 7.4 Hz, 2H), 1.70-1.10 (m, 6H). Example 1 3 (3 3)

 (R) —N-hydroxy-6- [4- (5-methoxybenzoxazolyl-2-yl) phenyl] -1-6-hydroxyhexanamide

TLC: R f 0.13 (form: methanol: acetic acid = 90: 10: 1), NMR (d ₆ -DMS0): δ 10.25 (s, 1H), 8.62 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 9.0, 2.4 Hz, 1H), 5.29 (d, J = 4.5 Hz, 1H), 4.62-4.52 (m, 1H), 3.79 (s, 3H), 1.88 (t, J = 7.2 Hz, 2H), 1.65- 1.10 (m, 6H).

 Example 13 (34)

(R) —N-Hydroxy-6— [4- (4-Methoxybenzoxazol-1-yl) phenyl] — 6-Hydroxyhexaneamide

TLC: R f 0.28 (cloth form: methanol = 9: 1),

NMR (d ₆ — DMS0): δ 10.32 (s, 1Η), 8.64 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.53 (d, 8.4 Hz, 2H), 7.40-7.28 (ra , 2H), 7.02-6.90 (, 1H), 5.31 (d, J = 4.4 Hz, 1H), 4.66-4.54 On, 1H), 3.99 (s, 3H), 1.92 (t, J = 7.4 Hz, 2H) , 1.70-1.10 (m, 6H).

 Example 13 (35)

 (R) ― (+) —N-Hydroxy 6— [4- (4- (Piperidin-11-ylmethyl) phenyl) phenyl] —6-Hydroxyhexanamide 塩 酸 HCl

[a] _D : +6.17 (c 0.12, methanol),

TLC: R f 0.21 (form: methanol = 4: 1),

NMR (d ₆ -DMS0): δ 10.1-10.31 (m, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.65-7.61 (m, 4H), 7.39 (d, J = 8.1 Hz, 2H), 4.52 (t, 6.3 Hz, 1H), 4.26 (d, J = 5.1 Hz, 2H), 3.32-3.27 (m, 2H), 2.91-2.78 (m, 2H), 1.90 (t, J = 7.2 Hz, 2H) Example 1 3 (3 6)

 (R)-(+) — N-hydroxy-1-6- [4- (4-hydroxybenzoxazole-2-yl) phenyl] -1-hydroxyhexanamide

[] _D : +6.33 (c 0.12, methanol),

TLC: Rf 0.42 (form: methanol = 17: 3),

NMR (d ₆ -DMS0): δ 10.35 (s, 1H), 10.30 (s, 1H), 8.63 (s, 1H), 8.10 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz) , 2H), 7.21-7.14 (m, 2H), 6.78--6.75 On, 1H), 5.30 (d, J = 4.5 Hz, 1H), 4.62-4.54 (m, 1H), 1.91 (t, J = 7.2 H z, 2H), 1.62-1.16 (m, 6H). Example 13 (37)

 (R) —N—Hydroxy-1 6— [4— (6—Hydro

2-yl) phenyl] —6-hydroxyhexaneamide

TLC: R f 0.21 (form: methanol: acetic acid = 60: 10: 1),

NMR (d DMS0): 6 10.25 (s, 1H), 9.80 (s, 1H), 8.60 (s, 1H), 8.03

(d, J = 8.2 Hz, 2H), 7.56-7.42 (m, 3H), 7.05 (d, J = 2.2 Hz, 1H), 6.81 (dd, J = 8.4, 2.2 Hz, 1H), 5.25 (d, J = 4.4 Hz, 1H), 4.62-4.50 (m, 1H), 1.88 (t, J = 7.4 Hz, 2H), 1.70-1.10 (m, 6H). Example 13 (38)

 (R) 1 N-Hydroxy-6- [4-((IE) -2- (4-methylthiophenyl) vinyl) phenyl] — 6-Hydroxyhexanamide

TLC: R f 0.22 (form: methanol: acetic acid = 90: 10: 1) NMR (d DMS0): 6 10.25 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H), 7.30-7.05 (m, 6H), 4.45 (t, J = 6.1 Hz, 1H), 2.45 (s, 3H), 1.87 (t, J = 7.2 Hz, 2H), 1.65- 1.00 (m, 6H). Example 13 (39)

(R) —N—Hydroxy 6— [4 (5—Me 1 2— Phenyl) — 6-hydroxyhexanamide

TLC: R f 0.27 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.42 (d , J = 8.4 Hz, 2H), 7.30 (s, 1H), 7.14 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.8, 2.6 Hz, 1H), 5.21 (d, J-4.4 Hz, 1H), 4.60-4.48 (m, 1H), 3.79 (s, 3H), 1.91 (t, J = 7.0 Hz, 2H), 1.68-1.14 (m, 6H). Example 13 (40)

 (R) _N-Hydroxy-6- [4- (5-Methylthioben-2-yl) phenyl] -16-hydroxyhexanamide

TLC: R f 0.27 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1H), 8.82-8.42 (br, 1H), 7.84 (d, J 8.4 Hz, 2H), 7.60-7.52 (m, 2H), 7.43 (d, 8.4 Hz, 2H), 7.31 (s, 1H), 7.23 (dd, J = 8.8, 2.0 Hz. 1H), 5.42-4.96 (br, 1H), 4.54 (t, J = 6.4 Hz, 1H), 2.51 (s, 3H), 1.92 (t, J = 7.0 Hz, 2H), 1.70-1.12 (m, 6H).

 Example 13 (4 1)

 (R)-(+)-N-hydroxy-6- [4- (4- (2- (dimethylamino) ethyl) phenyl) phenyl] -1-6-hydroxyhexanamide salt

[a] _D： +22.11 (c 0.635, ジメチルホルムアミド） 、

[a] _D : +22.11 (c 0.635, dimethylformamide),

 TLC: Rf 0.12 (form: methanol = 7: 3),

NMR (d ₆ -DMS0): 510.60 (s, 1H), 10.32 (s, 1H), 8.62 (s, 1H), 7.62 (d, 1 = 8.4 Hz '2H), 7.57 (d, J = 8.4 Hz, 2H), 7.38-7.33 (m, 4H), 5.14 (d, J = 4.2 Hz, 1H), 4.54-4.48 (m, 1H), 3.30-3.25 (m, 2H), 3.06-3.00 (m, 2H) , 2.78 (s, 6H), 1.91 (t, J = 7.2 Hz, 2H), 1.62-1.15 (m, 6H).

 Example 13 (42)

(R)-(+) _N-hydroxy _ 6 [4- (4- (2- (dimethylamino) ethoxy) phenyl) phenyl] 6 _hydroxyhexanamide ·

 HCI

[a] _D : +20.47 (c 1.005, dimethylformamide),

TLC: R f 0.32 (Holhol: medium = 4: 1),

NMR (d ₆ -DMS0): δ 10.56 (br, 1H), 10.32 (s, 1H), 8.63 (s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz , 2H), 7.35 (d, 8.5 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 5.12 (d, J = 4.2 Hz, 1H), 4.05 (m, 1H), 4.39 (t, J = 5.0 Hz, 2H), 3.50 (t, J = 5.0 Hz, 2H), 2.83 (s, 6H), 1.91 (t, J = 7.2 Hz, 2H), 1.57 (m, 2H), 1.50 (m, 2H) ), 1.39-1.17 (m, 2H). Example 13 (43)

 (R) mono (+) — N-hydroxy-6— [4- (4- (2- (ethylamino) ethyl) phenyl) phenyl] —6-hydroxyhexaneamide salt

La] _D： +18.58 (c 0.93, ジメチルホルムアミド） 、

La] _D : +18.58 (c 0.93, dimethylformamide),

TLC: R f 0.25 (Form: methanol = 9: 1) NMR (d ₆ -DMSO): <510.47 (brs, 1H), 10.32 (s, 1H), 8.62 (brs, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz , 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 5.13 (brs, 1H), 4.53-4.49 (m, 1H), 3.31-3.01 (m, 8H), 1.90 (t, J = 6.9 Hz, 2H), 1.62-1.15 (m, 6H), 1.23 (t, J = 6.9 Hz, 6H). Example 13 (44)

 (R) -N-hydroxy-6- [4- (4- (2-hydroxyethyl) phenyl) phenyl] -1-6-hydroxyhexanamide

TLC: R f 0.28 (form: methanol = 9: 1),

NMR (d ₆ — DMS0): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.36 (d , J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 5.12 (d, J = 4.5 Hz, 1H), 4.64 (t, J = 5.3 Hz, 1H), 4.51 (m, 1H) ), 3.61 (m, 2H), 2.74 (t, J = 7.0 Hz, 2H), 1.91 (t, J-7.0 Hz, 2H), 1.63-1.3 (m, 4H), 1.40-1.15 (m, 2H). Example 14 (1) to 14 (5)

Using the corresponding ketone derivative in place of the compound produced in Reference Example 1, the same operation as in Reference Example 5 → Reference Example 3 → Example 1 → Example 2 was performed, and if desired, by a usual method. Conversion to the acid addition salt gave the title compound shown below. Example 14 (1)

 (S) 1 (1) 1 N-hydroxy-1 6- [4 (4-methylthiophenyl) phenyl] 1-6-hydroxyhexanamide

[a] _D : -26.3 (c 0.99, dimethylformamide),

TLC: R f 0.21 (Form: methanol = 9: 1)

NMR (d ₆ — DMS0): δ 10.29 (s, 1H), 8.63 (s 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 5.12 (d, J = 3.9 Hz, 1H), 4.51 (m, 1H), 2.50 (s, 3H), 1.91 (t, J = 7.5 Hz, 2H), 1.65-1.15 (m, 6H). Example 14 (2)

 (S) 1- (1-)-N-hydroxy-6- [4- (2- (4-methylthiophenyl) ethynyl) phenyl] -1-6-hydroxyhexaneamide

• 33.4 (c 0.99, dimethylformamide) TLC: R f 0.19 (cloth form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.28 (s, 1H), 8.62 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.33 (d , J = 8.4 Hz, 2H), 7.27 (d, J 8.4 Hz, 2H), 5.20 (d, J = 4.8 Hz, 1H), 4.51 (m, 1H), 2.49 (s, 3H), 1.90 (i , J = 7.2 Hz, 2H), 1.60-1.0 (m, 4H), 1.35-1.15 (m, 2H). Example 14 (3)

 (S) ― (I) —N-Hydroxy-6— [4- (benzoxazol-2-yl) phenyl] -1-Hydroxyhexanamide

[] _D : -11.5 (c 0.81, methanol),

TLC: Rf 0.21 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1H), 8.64 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.82-7.75 (m, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.45-7.30 (m, 2H), 5.32 (d, J = 4.8 Hz, 1H), 4.65-4.56 (m, 1H), 1.92 (t, J = 7.0 Hz, 2H), 1.70- 1.20 (in, 6H). Example 14 (4)

(S) ― (-) —N-Hydroxy-6- [4- (5-Methylbenzoxazol-2-yl) phenyl] — 6-Hydroxyhexaneamide

[] _D : -33.4 (c 0.99, dimethylformamide),

TLC: R f 0.23 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.29 (d, J = 1.5 Hz, 1H), 8.63 (d, J = 1.5 Hz, 1H), 8.12 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.23 (dd, J = 8.4, 1.2 Hz, 1H), 5.32 (d , J = 4.2, 1H), 4.60 (m, 1H), 2.43 (s, 3H), 1.91 (t, J = 6.9 Hz, 2H), 1.70-1.20 (m, 6H).

 Example 14 (5)

 (S) 1 (1) 1 N-Hydroxy _6— [4- (4- (dimethylaminomethyl) phenyl) phenyl] 1-6-Hydroxyhexaneamide 'hydrochloride

 HCI

[a] _D : -5.39 (c 0.495, water),

TLC: R f 0.25 (form: methanol = 2: 1),

NMR (d ₆ -DMS0): δ 10.31 (m, 2H), 8.64 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.16 (i, 1H), 4.53 (m, 1H), 4.29 (s, 2H), 2.71 (s, 6H), 1.91 (t, J = 7.0 Hz, 2H), 1.65-1.15 (m, 6H). Example 15

 (R) — N— (1-methoxy_1-methyl) ethoxy-6— [4- (4- (morpholine-1-41-methyl) phenyl) phenyl] -1-6-xanamide

参考例 1で製造した化合物の代わりに、 メチル 6— [4— （4一 （モル ホリン— 4一ィルメチル) フエニル) フエニル] 一 6一ォキソへキサノエ一 トを用いて、 参考例 4→参考例 3→実施例 1と同様の操作をし、 以下の物性 値を有する標題化合物を得た。

Reference Example 4 → Reference Example using methyl 6- [4-((4- (morpholine-41-methyl) phenyl) phenyl) -1] 6-oxohexanoate instead of the compound prepared in Reference Example 1. 3 → The same operation as in Example 1 was performed to obtain the title compound having the following physical data.

 TLC: Rf 0.46 (form: methanol = 6: 1),

_{NMR (CDC1 3): 6 7.74} (brs, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 4.74-4.70 On, 1H), 3.73-3.70 (m, 4H), 3.30 (s, 3H), 2.48-2.45 (ni, 4H), 2.19-2.08 (m , 2H), 1.91-1.34 (m, 6H), 1.1 (s, 6H). Example 15 (1)

(R) — N— (1-Methoxy-1-methyl) ethoxy-6— [4- (4-phenyl) phenyl] -1-6-hydroxyhexa Namide

メチル 6 - [4- (4- (モルホリンー 4一ィルメチル) フエニル) フ ェニル] 一 6一ォキソへキサノエ一トの代わりに、 メチル 6 - [4一 (4 一 (ジプロピルアミノメチル) フエニル） フエニル] —6—ォキソへキサノ エー卜を用いて、 実施例 1 5と同様の操作をし、 以下の物性値を有する標題 化合物を得た。

Methyl 6- [4- (4- (morpholine-4-1methyl) phenyl) phenyl] Instead of 1-oxohexanoate, methyl 6- [4- (4- (4- (dipropylaminomethyl) phenyl) phenyl) The same operation as in Example 15 was performed using —6-oxohexanoate to give the title compound having the following physical data.

 TLC: R f 0.31 (form: methanol = 9: 1),

_{NMR (CDC1 3): δ 7.76} (br, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 4H), 4.72 (dd, J = 7.0, 5.8 Hz, 1H), 3.59 (s, 2H), 3.30 (s, 3H), 2.40 (t-like, J = 7.5 Hz, 4H), 2.34 (in, 2H), 1.84 -1.67 (m, 4H), 1.56-1.36 (m, 2H), 1.50 (m, J = 7.5 Hz, 4H), 1.1 (s, 6H), 0.87 (t, J = 7.5 Hz, 6H). Example 16

(R)-(+) — N-hydroxy-1 6— [4 (4- (morpholine—4-methyl) phenyl) phenyl] —6—h: de · hydrochloride

 HCI In place of the compound prepared in Example 1, the same operation as in Example 2 was carried out using the compound prepared in Example 15, and further converted into an acid adduct salt by a conventional method. The title compound having physical properties was obtained.

[a] _D : +6.17 (c 0.12, methanol),

TLC: R f 0.21 (black form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 11.30 (brs, 1H), 10.32 (brs, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.63 (d , J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 4.52 (t, J = 6.3 Hz, 1H), 4.34 (d, J = 5.1 Hz, 2H), 3.94-3.75 (m, 4H), 3.20-2.95 On, 4H), 1.93 (t, J-7.2 Hz, 2H), 1.65-1.15 (m, 6H). Example 16 (1)

 (R) 1 (+) —N-hydroxy _ 6— [4- (4- (dipropylaminomethyl) phenyl) phenyl] — 6-hydroxyhexanamide

実施例 1 5 (1) で製造した化合物を用いて、 実施例 1 6と同様の操作を し、 または通常の方法によって、 酸付加物塩に変換し、 以下の物性値を有す る標題化合物をそれぞれ得た。

The same operation as in Example 16 was performed using the compound prepared in Example 15 (1). The compound was converted into an acid addition salt by a conventional method to give the title compound having the following physical data.

Furi:

[a] _D : +20.85 (c 1.01, dimethylformamide),

TLC: R f 0.37 (form: methanol = 6: 1),

NMR (d ₆ — DMS0): δ 10.26 (br, 1H), 8.65 (br, 1H), 7.58 (d, J = 8.4 Hz, 4H), 7.36 (d, J = 8.4 Hz, 2H), 7.35 (d , J = 8.4 Hz, 2H), 5.12 (br, 1H), 4.51 (t, J = 6.0 Hz, 1H), 3.52 (s, 2H), 2.33 (t, J = 7.2 Hz, 4H), 1.91 (t , J = 7.2 Hz, 2H), 1.64-1.55 (m, 2H), 1.51-1.37 (m, 6H), 1.36-1.17 (m, 2H), 0.82 (t, J = 7.2 Hz, 6H).

TLC: R f 0.37 (form: methanol = 6: 1),

NMR (d ₆ -DMS0): δ 10.58 (br, 1Η), 10.32 (s, 1H), 8.62 (br, 1H), 7.74

(d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H),

7.40 (d, J = 8.4 Hz, 2H), 5.17 (br, 1H), 4.53 (t, J = 6.3 Hz, 1H), 4.32

(s, 2H), 2.93 (m, 4H), 1.91 (t, J = 7.2 Hz, 2H), 1.82-1.66 (m, 4H),

1.65-1.55 (m, 2H), 1.48 (m, 2H), 1.40-1.20 (m, 2H), 0.86 (t, J = 7.2 Hz,

6H). Examples 17 (1) and 17 (2)

Instead of the compound prepared in Reference Example 1, methyl 6- (5-phenylthiophen-2-yl) _ 6-oxohexanoate or methyl 6- (5-phenylbenzofuran-2-yl) Using 6-oxohexanoate, the same operation as in Reference Example 4—Reference Example 3 → Example 1 → Example 2 was performed to obtain the title compound shown below. Example 17 (1)

 (R) 1-N-hydroxy-6 (5-phenylthiophene-2-yl) 6-hydroxyhexanamide

TLC: Rf 0.19 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.42-10.20 (br, IH), 8.80-8.55 (br, IH), 7.64-7.56 (m, 2H), 7.43-7.20 (m, 4H), 6.90 (d, J = 3.2 Hz, IH), 5.59 (d, J = 4.0 Hz, 1H), 4.80-4.65 (in, IH), 1.93 (t, J = 7.4 Hz, 2H), 1.76-1.15 (m, 6H) C exemplary Example 17 (2)

(R) -N-Hydroxy-6- (5-phenylphenylfuran-2-yl) -6-hydroxyhexanamide '

TLC: R f 0.28 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.31 (s, IH), 8.65 (s, IH), 7.83 (m, IH), 7.70-7.52 (m, 4H), 7.50-7.28 (m, 3H), 6.75 ( s, IH), 5.53 (d, J = 5.4 Hz, IH), 4.72-4.58 (m, 1H), 1.93 (t, J-7.4 Hz, 2H), 1.84-1.62 (m, 2H), 1.60-1.18 Reference Example 16

 (R) —benzyl 6- [4- (4- (methoxycarbo) phenyl) phenyl] —6-hydroxyhexanoate

参考例 1で製造した化合物の代わりに、 ベンジル 6— [4- (4— (メ トキシカルポニル) フエニル） フエニル] 一 6一ォキソへキサノエ一卜を用 いて、 参考例 4と同様の操作をし、 以下の物性値を有する標題化合物を得た。 T L C： R f 0.19 (クロ口ホルム：酢酸ェチル =19 ： 1) 。 参考例 1 7

The same operation as in Reference Example 4 was carried out using benzyl 6- [4- (4- (methoxycarbonyl) phenyl) phenyl] 16-oxohexanoate instead of the compound prepared in Reference Example 1. The title compound having the following physical data was obtained. TLC: R f 0.19 (black-mouthed form: ethyl acetate = 19: 1). Reference Example 1 7

 (R) -6- [4- (4- (Methoxycarbonyl) phenyl) phenyl] -6-hydroxyhexanoic acid

参考例 1 6で製造した化合物 （1.36g) のメタノール （20ml) とテト ラヒドロフラン （10ml) 溶液に、 10%パラジウムカーボン （136mg) を加えた。 反応混合物を水素雰囲気下、 室温で 1.5時間撹拌した。 反応混合 物をろ過し、 濃縮した。 得られた残渣をエーテルで洗浄し、 乾燥し、 以下の 物性値を有する標題化合物 （951m g) を得た。

To a solution of the compound (1.36 g) produced in Reference Example 16 in methanol (20 ml) and tetrahydrofuran (10 ml), 10% palladium carbon (136 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered and concentrated. The obtained residue was washed with ether and dried to give the title compound (951 mg) having the following physical data.

TLC: R f 0.32 (chloroform: methanol = 9: 1). Example 18

 (R) 1-N-hydroxy-6- [4- (4- (methoxycarbonyl) phenyl) phenyl] -1-6-hydroxyhexanamide

参考例 1 7で製造した化合物を用いて、 実施例 1→実施例 2と同様の操作 をし、 以下の物性値を有する標題化合物を得た。

The same operation as in Example 1 → Example 2 was performed using the compound produced in Reference Example 17 to give the title compound having the following physical data.

TLC: R f 0.28 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1H), 8.64 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.68 (d , J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 5.18 (d, J = 4.4 Hz, 2H), 4.61-4.48 (m, 1H), 3.86 (s, 3H), 1.91 (t, J = 7.4 Hz, 2H), 1.67-1.10 (m, 6H). Example 19

(R) —N—Hydroxy-6— [4 -— (4 lipoxyphenyl) ] — 6-hydroxyhexanamide

参考例 1 7で製造した化合物を用いて、 実施例 1—参考例 3—実施例 2と 同様の操作をし、 以下の物性値を有する標題化合物を得た。

Using the compound produced in Reference Example 17, the same operation as in Example 1-Reference Example 3-Example 2 was performed to obtain the title compound having the following physical data.

TLC: R f 0.16 (form: methanol: acetic acid = 90: 10: 1), NMR (d ₆ -DMS0): δ 10.31 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 5.40-4.90 (br.1H), 4.61-4.47 (m, 1H), 1.92 (t, J = 7.0 Hz, 2H), 1.70-1.10 (m, 6H) _C Reference Example 18

 (R) —Methyl 6- [4- (4-methylthiophenyl) phenyl] -6-hydroxyhexanoate

参考例 1で製造した化合物の代わりに、 メチル 6— [4— （4—メチル チォフエニル） フエニル] 一 6—ォキソへキサノエートを用いて、 参考例 4 と同様の操作をし、 以下の物性値を有する標題化合物を得た。 T L C : R f 0.25 (へキサン：酢酸ェチル =2 : 1) 、 NMR (CDC1₃) ： δ 7.57-7.49 (m, 4H), 7.39 (d, J=8.4Hz, 2H), 7.32 (d, J=8.4Hz, 2H), 4.72 (t, J=6.2Hz, 1H), 3.65 (s, 3H), 2.32 (t, J=7.4Hz, 2H), 1.88-1.25 (in, 6H)。 参考例 19

The same operation as in Reference Example 4 was carried out using methyl 6- [4- (4-methylthiophenyl) phenyl] -6-oxohexanoate instead of the compound prepared in Reference Example 1, and the following physical property values were obtained. The title compound was obtained. TLC: R f 0.25 (hexane: acetic acid Echiru = 2: 1), NMR ( CDC1 3): δ 7.57-7.49 (m, 4H), 7.39 (d, J = 8.4Hz, 2H), 7.32 (d, J = 8.4Hz, 2H), 4.72 (t, J = 6.2Hz, 1H), 3.65 (s, 3H), 2.32 (t, J = 7.4Hz, 2H), 1.88-1.25 (in, 6H). Reference Example 19

 (R) monomethyl 6- [4- (4-methylsulfonylphenyl) phenyl] -6-hydroxyhexanoate

参考例 18で製造した化合物 （335mg) のジクロロメタン （10m l) 溶液に、 0°Cで、 m—クロ口過安息香酸 （504mg) を加えた。 反応混合 物を 0°Cで、 1時間撹拌した。 反応混合物にチォ硫酸ナトリウム水溶液を加 え、 酢酸ェチルで抽出した。 抽出物を水、 飽和塩化ナトリウム水溶液で洗浄 し、 無水硫酸ナトリウムで乾燥し、 濃縮し、 以下の物性値を有する標題化合 物 （349mg) を得た。

To a solution of the compound (335 mg) produced in Reference Example 18 in dichloromethane (10 ml) at 0 ° C. was added m-chloroperbenzoic acid (504 mg). The reaction mixture was stirred at 0 ° C for 1 hour. An aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the title compound (349 mg) having the following physical data.

 TLC: Rf 0.51 (hexane: ethyl acetate = 1: 4),

_{NMR (CDC1 3): <5} 8.00 (. D, J = 8 Hz, 2H), 7.76 (d, J = 8.4Hz, 2H), 7.59 (d, J = 8.4Hz, 2H), 7.46 (d, J = 8.4Hz, 2H), 4.80-4.72 (m, 1H), 3.66 (s, 3H), 3.09 (s, 3H), 2.32 (t, 1 = 7.5Hz, 2H), 1.90-1.30 (m, 6H) . Example 20 (R) — (+) — N-hydroxy-6_ [4- (4-methylsulfonylphenyl) phenyl] -1-6-hydroxyhexaneamide

参考例 2で製造した化合物の代わりに、 参考例 19で製造した化合物を用 いて、 参考例 3—実施例 1→実施例 2と同様の操作をし、 以下の物性値を有 する標題化合物を得た。

Using the compound prepared in Reference Example 19 instead of the compound prepared in Reference Example 2, the same operation as in Reference Example 3—Example 1 → Example 2 was carried out to obtain the title compound having the following physical properties. Obtained.

[«] _D : +9.84 (c 0.125, methanol),

TLC: Rf 0.12 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): 6 10.29 (s, 1H), 8.63 (s, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.7 Hz, 2H), 7.69 (d , J-8.7 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 5.19 (d, J = 4.5 Hz, 1H), 4.59-4.51 (m, 1H), 3.23 (s, 1H), 1.90 (t, J = 7.5 Hz, 2H), 1.62-1.18 (m, 6H). Reference Example 20

 (R) monomethyl 6- [4- (4-hydroxymethylphenyl) phenyl]-6-hydroxyhexanoate

参考例 1で製造した化合物の代わりに、 メチル 6— [4一 （4ーホルミ ルフエニル） フエエル] 一 6—ォキソへキサノエートを用いて、 参考例 4と 同様の操作をし、 以下の物性値を有する標題化合物を得た。

The same operation as in Reference Example 4 was carried out using methyl 6- [4- (4-formylphenyl) phenyl] -16-oxohexanoate instead of the compound produced in Reference Example 1, and the following physical properties were obtained. The title compound was obtained.

TLC: R f 0.27 (hexane: ethyl acetate = 1: 1),

_{NMR (CDC1 3): δ 7.59} (. D, J = 8 Hz, 2H), 7.57 (d, J = 8.4Hz, 2H), 7.44 (d, J = 8.4Hz, 2H), 7.40 (d, J = 8.4Hz, 2H), 4.78-4.66 (m, 3H), 3.66 (s, 3H), 2.32 (t, J = 7.6Hz, 2H), 2.02-1.20 (m, 6H). Example 21

 (R) 1 N-hydroxy-6- [4- (4-hydroxymethylphenyl) phenyl] —6-hydroxyhexanamide

参考例 2で製造した化合物の代わりに、 参考例 20で製造した化合物を用 いて、 参考例 3→実施例 1→実施例 2と同様の操作をし、 以下の物性値を有 する標題化合物を得た。

Using the compound prepared in Reference Example 20 instead of the compound prepared in Reference Example 2, the same operation as in Reference Example 3 → Example 1 → Example 2 was carried out to give the title compound having the following physical properties. Obtained.

 TLC: R f 0.13 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 10.30 (s, 1H), 8.80-8.50 (br.1H), 7.60 (d, J = 8.0 Hz, 2H), 7.58 (d, 8.0 Hz, 2H), 7.37 (d , J = 8.0 Hz, 4H), 5.40-5.00 (br, 2H), 4.60-4.40 (m, 3H), 1.91 (t, J = 7.0 Hz, 2H), 1.70-1.10 (m, 6H). Example 22

N-methoxy-6- [4- (4-chlorophenyl) phenyl] -1-6-hydr Roxyhexaneamide

(1_Methoxy-1-methylethyl) The same operation as in Example 1 was performed using methoxylamine instead of hydroxyamine to give the title compound having the following physical data.

 TLC: R f 0.27 (ethyl acetate),

_{NMR (CDC1 3): δ 8.21} (br, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 4H), 4.74-4.70 (m, 1H), 3.72 (s, 3H), 2.44-2.04 (m, 3H), 1.90-1.62 (m, 4H), 1.58-1.34 (m, 2H) ₀ Example 23

 (R)-(+) 1 5— (5,5-Dimethyl-1,4,2-dioxazoline-3-yl) _ 1- [4- (5-Methylbenzoxazole—2_yl) Enyl] pentane-1-all

実施例 6で製造した化合物 （3 g) のトルエン （10 Om l) 溶液を 1 0 0°Cで 3時間撹拌した。 反応混合物を濃縮し、 得られた残渣を- エーテルで洗浄し、 乾燥し、 以下の物性値を有する標題化合物 （2.83g) を 得た。

A solution of the compound (3 g) prepared in Example 6 in toluene (10 Oml) was added to 10 The mixture was stirred at 0 ° C for 3 hours. The reaction mixture was concentrated, and the obtained residue was washed with -ether and dried to give the title compound (2.83 g) having the following physical data.

[a] _D : +24.59 (c 0.81, dimethylformamide),

TLC: R f 0.21 (hexane: ethyl acetate = 2: 1),

_{NMR (CDC1 3): δ 8.21} (d, J = 8.4 Hz, 2H), 7.54 (brs, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.17-7.14 (m, 1H), 4.79-4.75 (m, 1H), 2.48 (s, 3H), 2.30 (t, J = 7.2 Hz, 2H), 1.91-1.33 (m, 6H), 1.53 (s, 6H). Example 23 (1) and 23 (2)

 In place of the compound prepared in Example 6, the compound prepared in Example 6 (3) or 6 (4) was used, and if necessary, further converted into an acid additive salt by a usual method. The title compound shown in was obtained. Example 23 (1)

 (R) 5- (5,5-dimethyl-1,4,2-dioxazoline-3-yl) 1-1- [4- (4-methylthiophenyl) phenyl] pentane-1-ol

TLC: R f 0.57 (hexane: ethyl acetate = 1: 1),

_{NMR (CDC1 3): δ 7.54} (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H); 7.39 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 4.71 (m, 1H), 2.52 (s, 3H), 2.30 (t, J = 7.5 Hz, 2H), 1.94-1.72 (m, 2H), 1.66 On, 2H), 1.57-1.35 (m, 2H), 1.53 (s, 3H), 1.52 (s, 3H).

 Example 23 (2)

 (R) -5- (5,5-Dimethyl-1,4,2-dioxazoline-3-yl) 1-1- [4- (4- (dimethylaminomethyl) phenyl) phenyl] pentan-1-ol · 1.5 fumarate

[ ] _D： +15.9 (c 1.16、 ジメチルホルムアミド) 、

[] _D : +15.9 (c 1.16, dimethylformamide),

 TLC: R f 0.30 (form: methanol = 9: 1),

NMR (d ₆ -DMS0): δ 7.63 (d, J = 8.3 Hz, 2H), 7.60 (d, 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3) Hz, 2H), 6.57 (s, 3H), 4.54 (t, J = 6.0 Hz, 1H), 3.71 (s, 2H), 2.34 (s, 6H), 2.26 (t, J = 7.2 Hz, 2H), 1.67-1.23 (, 6H), 1.3 (s, 6H).

 Example 24

参考例 1で製造した化合物の代わりに、 メチル 6— [4- (4一 (2 - (モルホリン— 4 _ィル） エトキシ） フエニル） フエニル] — 6—ォキソへ キサノエートを用いて、 参考例 4→参考例 3→実施例 1と同様の操作をし、 以下の物性値を有する標題化合物を得た。 (R) — N— (1-methoxy-1-methyl) ethoxy 6— [4 (4- (2- (morpholine-4-yl) ethoxy) phenyl) phenyl] 6—hydroxyhexanamide

Reference example 4 was repeated using methyl 6- [4- (4- (2- (morpholine-4-yl) ethoxy) phenyl) phenyl] —6-oxohexanoate instead of the compound prepared in Reference example 1. → Reference Example 3 → The same operation as in Example 1 was performed to obtain the title compound having the following physical properties.

TLC: R f 0.50 (form: methanol = 9: 1),

_{NMR (CD 3 0D): δ} 7.52 (d, J = 8.7 Hz, 2H), 7.51 (d, J - 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 4.62 (t, J = 6.6 Hz, 1H), 4.17 (t, J = 5.4 Hz, 2H), 3.72 (t, J = 4.7 Hz, 4H), 3.28 (s, 3H), 2.82 (t, J = 5.4 Hz, 2H), 2.61 (t, J = 4.7 Hz, 4H), 2.13 (t, J = 7.2 Hz, 2H), 1.86-1.70 (m, 2H), 1.64 (m, 2H) , 1.50-1.23 (m, 2H), 1.33 (s, 6H) _C Example 24 (1)

 (R) 1 N_ (1-Methoxy-1-methyl) ethoxy 6- [4- (4- (2- (morpholine_4_yl) ethyl) phenyl) phenyl] _ 6-hydroxyhexanamide

OH

 ,

ゝ 0, 0CH ₃ Methyl 6— [4 -— (4- (2- (morpholine—4-yl) ethoxy) phenyl) phenyl] Instead of 1-6-oxohexanoate, methyl 6— [4- (4- (2 -(Morpholine-41-yl) ethyl) phenyl) phenyl] —The same operation as in Example 24 was carried out using 6-oxohexanoate to give the title compound having the following physical data.

 TLC: Rf 0.46 (form: methanol = 9: 1),

_{NMR (CDC1 3): δ 7.70} (brs, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 4.74-4.69 (m, 1H), 3.77-3.73 (m, 4H), 3.30 (s, 3H), 2.87-2.81 (m, 2H), 2.65-2.60 (m, 2H), 2.55-2.53 (m, 4H), 2.19-1.32 (m, 8H), 1.1 (s, 6H). Example 2 5

 (R)-(+) —N-hydroxy— 6— [4 (4— (2— (morpholine • 4 ^^^) ethoxy) phenyl) phenyl] 6—

 Dehydrochloride

 HCI In place of the compound prepared in Example 1, the same operation as in Example 2 was carried out using the compound prepared in Example 24, and further converted into an acid adduct salt by a conventional method. The title compound having physical properties was obtained.

[H] _D : +13.52 (c 0.84, dimethylformamide),

TLC: R f 0.31 (form: methanol = 9: 1), NMR (d ₆ -DMS0): d 10.92 (brs, 1H), 10.30 (s, 1H), 8.61 (brs, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz , 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 5.12 (brs, 1H), 4.53-4.41 (m, 3H), 4.01-3.93 (m, 2H), 3.84-3.74 (m, 2H), 3.60-3.12 (m, 6H), 1.90 (t, J = 7.2 Hz, 2H), 1.62-1.12 (m, 6H). Example 2 5 (1)

 (R) ― (+) —N-Hydroxy— 6— [4- (4- (2- (morpholine-1_4_yl) ethyl) phenyl) phenyl] -1-6-hydroxyhexaneamide hydrochloride

実施例 24 (1) で製造した化合物を用いて、 実施例 2 5と同様の操作を し、 または通常の方法によって、 酸付加物塩に変換し、 以下の物性値を有す る標題化合物を得た。

Using the compound prepared in Example 24 (1), the same procedure as in Example 25 was performed, or the compound was converted to an acid addition salt by a conventional method to give the title compound having the following physical data. Obtained.

[] _D : +16.80 (c 0.815, dimethylformamide),

TLC: R f 0.41 (form: methanol = 17: 3),

NMR (d ₆ — DMS0): δ 10.82 (brs, 1H), 10.30 (s, 1H), 8.62 (brs, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz , 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 5.13 (brs, 1H), 4.53-4.49 (m, 1H), 4.00-3.96 (m, 2H), 3.96-3.72 (m, 2H), 3.51-3.7 (m, 2H), 3.39-3.25 (m, 2H), 3.18-3.02 (m, 4H), 1.90 (t, J = 7.2 Hz, 2H), 1.64-1.16 (m, 6H). Examples 26 to 26 (1)

 The same operation as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Example 1 was performed using the corresponding benzene derivative instead of 4-chlorobiphenyl to obtain the present invention compound shown below. Example 26

 (R) 1 N— (1-methoxy-1 1-methyl) ethoxy 6— (4- (4-methylethylaminophenyl) phenyl) 1-6-hydroxyhexane

TLC: R f 0.30 (form: methanol = 9: 1),

_{NMR (CDC1 3): δ 7.95} (br, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 4.70 (t-like, 1H), 3.60 (s, 2H), 3.30 (s, 3H), 2.54 (q, J = 7.2 Hz, 4H), 2.40-2.08 (m, 2H), 1.90-1.66 (m, 4H), 1.58-1.36 (m, 2H), 1.0 (s, 6H), 1.06 (t, J = 7.2 Hz, 6H). Example 26 (1)

 (R) 1 N— (1-methoxy-1-methyl) ethoxy 6— (4- (4 (2-getylaminoethoxy) phenyl) phenyl)

Xanamide

TLC: R f 0.50 (black form: methanol = 4: 1). Examples 27 to 27 (1)

 The same operations as in Example 2 were carried out using the compounds prepared in Examples 26 to 26 (1) instead of the compound prepared in Example 1, to obtain the following compounds of the present invention. Example 27

 (R) —N-Hydroxy-6 _ (4- (4-Jethenyl) phenyl) 1-Hydroxyhexanamide hydrochloride

TLC: R f 0.20 (form: methanol = 4: 1),

NMR (DMS0-d ₆ ): δ 10.62 (br, 1H), 10.33 (s, 1H), 8.63 (s, 1H), 7.73

(d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H),

7.40 (d, J = 8.4 Hz, 2H), 5.17 (br, 1H), 4.53 (br, 1H), 4.29 (s, 2H),

3.04 (m, 4H), 1.91 (t, J = 7.2 Hz, 2H), 1.65-1.55 (m, 2H), 1.48 (m, 2H), 1.40-1.20 (m, 2H), 1.25 (t, J = 7.2 Hz, 6H). Example 27 (1)

 (R) 1 N-hydroxy-6- (4- (4- (2-

B) phenyl) phenyl) 1-hydroxyhexanamide 'hydrochloride

TLC: R f 0.33 (form: methanol: acetic acid = 50: 50: 1) NMR (DMS0-d ₆ ): δ 10.70-10.50 (br, 1H), 10.30 (s, 1H), 8.60 (s, 1H) ), 7.58 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 5.15-5.05 (br, 1H), 4.55-4.45 (br, 1H), 4.39 (t, J = 5.0 Hz, 2H), 3.52-3.40 (m, 2H), 3.25-3.10 (m, 4H), 1.88 ( t, J = 7.4 Hz, 2H), 1.65-1.10 (m, 12H) ₀

[Pharmacological effect]

Inhibitory effect on proliferation of various cancer cells (in vitro)

Various cancer cells were seeded on a 96-well plate at a cell density of 5,000 cells I well, and after about 20 hours, seven compounds according to the present invention shown in Table 8 were added. Twenty-four hours after addition, deoxybromouridine (BrDU) was taken up for about 3 hours, and the amount taken up was measured using an ELISA kit (catalog number 647-229, manufactured by Behringer Mannheim). The BrDU uptake inhibition rate of the compound of the present invention was calculated, and the 50% inhibitory concentration (IC ₅ ) was determined from the concentration inhibition curve. The results are shown in Table 8 below.

 The various cancer cells used in this experiment were obtained from the following facilities.

A549: Human lung cancer; American Type Culture Collection (ATCC), Colon26: Mouse rectal cancer; Center for Medical Cell Resources, Tohoku University,

A375: Human malignant melanoma; American Type Culture Collection (ATCC),

PANC-1: human kidney cancer; American Type Culture Collection (ATCC),

 KATOIII: human gastric cancer; American Type Culture Collection (ATCC),

 HepG2: Human liver cancer; American Type Culture Collection (ATCC),

 LU99: Human Lung Cancer; Human Science Research Resource Bank, Human Science Foundation

 LU65: Human Lung Cancer; Human Science Promotion Foundation Hyuns Research Resource Bank,

PC14: Human lung cancer; RIKEN

ヒト肺癌細胞 PC14皮下移植マウスに対する作用 （イン · ビポ）

Effects on human lung cancer cells PC14 subcutaneously transplanted mice (in vivo)

The human lung cancer cells PC14 cultured in-Vito port, ImM EDTA was treated with phosphate buffer containing saline (PBS), Hank's (GIBCO- BRL Co.) solution using 2 X 1 0 ⁷ cel ls / ml of cell suspension was prepared. Transfer the cell suspension to a 6-week-old female BALB / c nude mice (Nippon Charls River Co., Ltd.) were inoculated into two subcutaneous sites on the back at 4 × 10 ⁶ cells / 200 L / site. One day after inoculation, the tumor was divided into groups based on the tumor volume as an index, and from the next day, the compound of Example 7 (4) according to the present invention suspended in 0.5% methylcellulose (MC) was treated at a volume of 200 zL / mouse for 1 day. Oral administration every day until the day before the end of the experiment. Similarly, a control group (control) was orally administered with 0.5% MC. The tumor volume of each individual was determined by measuring the minor axis and major axis of the tumor using an electronic caliper, and calculating the tumor volume based on the following equation. On the day of the experiment (day 31), tumor tissues were excised and weighed. The experiment was performed with 9 cases in each group.

Tumor volume (mm ³ ) = minor axis (mm) ² X major axis (mm) / 2

 Fig. 1 shows the change in tumor volume, and Fig. 2 shows the tumor weight.

 From the results of the above experiments, it has been clarified that the compound according to the present invention is useful for various solid cancers.

 [Formulation example]

 Formulation Example 1

 The following components were mixed by a conventional method and then tableted to obtain 100 tablets each containing 5 Omg of the active ingredient.

 • (R) ― (+) —N-hydroxy-1 6— (4- (4-chlorophenyl) phenyl) 1-6-hydroxyhexanamide …… 5. Og

, Carboxymethylcellulose calcium (disintegrant) …… 0.2g

• Magnesium stearate (lubricant) ... 0.1 lg

'Microcrystalline cellulose …… 4.7g Formulation example 2

After mixing the following components in the usual manner, the solution is sterilized in the usual way, filled into ampoules in 5 ml portions, freeze-dried in the usual way, and used in an amount of 20 mg per ampoule. 100 ampoules containing a sex component were obtained.

 • (R)-(+)-N-hydroxy-6- (4- (4-chlorophenyl) phenyl) -6-hydroxyhexaneamide 2.0 g

'Mannitol 20 gdistilled water 500 ml

Claims

The scope of the claims 1. General formula (I)

Where R ¹ is  (a) a C1-8 alkyl group,  (b) a C2-8 alkenyl group,  (c) a C2-8 alkynyl group,  (d) an halogen atom,  (e) Motoki Nitoguchi,  (f) nitrile group,  (g) trifluoromethyl group,  (h) trifluoromethoxy group, (i) —OR ² (j) — ² SRs, (k) — ⁴ NR ³ Rs, (1) -COR ⁵ group,  (m) keto group,  (n) one Cy c group, (o) one OR ² group, -SR ² group, - NR ³ R ⁴ group, - COR ⁵ group or C 1 to 8 alkyl group substituted by a C yc 1 group, (p) —S0 ₂ R ¹⁰ groups, (q) one hundred and one (C l~8 alkylene group) one OR ¹¹ group, (r) nitrile group, one SC ^ R ¹ . Group or one O— (C 1-8 alkylene group) C 1-8 alkyl group substituted by one OR ¹¹ group, (s) —〇-1 (Cl-8 alkylene group) — NR ¹² R ¹³ group, (t) -S- (Cl-8 alkylene group) _NR ¹² R ¹³ groups, (u) —〇— (C 1-8 alkylene group) one NR ¹² R ¹³ group or one S— (C 1-8 alkylene group) —C 1-8 alkyl group substituted by NR ¹² R ¹³ group , (V) — OR ² groups, 1 SR ² groups, — NR ³ R ⁴ groups, — COR ⁵ groups, 1 Cyc group, 1 nitrile group, ¹⁰ S0 ₂ R ¹⁰ groups, 110 (C1-8 alkylene Group) —OR ¹¹ group, —〇 (C 1-8 alkylene group) _NR ¹² R ¹³ group or —S— (C 1-8 alkylene group) — C 2-8 substituted by NR ¹² R ¹³ group An alkenyl group, or (w) - OR ² group, - SR ² group, one NR ³ R ⁴ group, one COR ⁵ group, C yc 1 group, nitrile group, - SOSR ^1. Group, one hundred and one (C l~8 alkylene group) one OR ¹¹ group, - O- (C l~8 alkylene group) - NR ¹² R ¹³ group or - S- (from 01 to 8 § alkylene group) - NR ¹² the C2~8 alkynyl group substituted by R ¹³ groups and tables, R ² represents a hydrogen atom, a C1-8 alkyl group, a C2-9 acyl group or a Cy 1 group, R ³ and R ⁴ each independently represent a hydrogen atom, a C1-8 alkyl group, a C2-9 acyl group or a Cyc1 group, R ⁵ is hydroxyl, C L～8 alkyl group, C L～8 alkoxy group, one NR ⁶ R ⁷ Motoma other represents a Cyc l group, R ⁶ and R ⁷ each independently represent a hydrogen atom, a C 1-8 alkyl group or C yc 1 、, 1 ^{1 ()} represents (1-8 alkyl group or 01 group, Cy c 1 group is a C 3-7 monocyclic carbocycle or 1-4 nitrogen atoms, 1 acid Represents a 5- to 7-membered monocyclic heterocyclic ring containing an elemental atom and or one sulfur atom, R ¹¹ represents a hydrogen atom, a C 1-8 alkyl group, a C 2-9 acyl group or a Cy 1 group, R ¹² and R ¹³ each independently represent a hydrogen atom, a C1-8 alkyl group, a C2-9 acyl group or a Cy1 group, m represents 0 or an integer of 1 to 5, Ring A contains a C3-15 monocyclic, bicyclic, tricyclic carbocycle or 1-4 nitrogen atoms, 1-2 oxygen atoms and / or 1-2 sulfur atoms, 5-18 members Represents a monocyclic, bicyclic or tricyclic heterocycle, Ring B contains 5 to 15 monocyclic, bicyclic or tricyclic carbocyclic aryls or 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms 5 Represents an 18-membered monocyclic, bicyclic, or tricyclic heteroaryl ring; E represents a single bond, — CH = CH— or one C≡C—, R ⁸ is  (a) a C1-8 alkyl group,  (b) C 1-8 alkoxy group,  (c) a halogen atom,  (d) a nitro group,  (e) nitrile group,  (f) a trifluoromethyl group, or  (g) represents a trifluoromethoxy group. However, when E represents a single bond, R ¹ and R ⁸ may be taken together to represent a C 1-4 alkylene group. n represents 0 or an integer of 1 to 5, R ⁹ is a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group or a C2-8 Represents an alkynyl group. ] A prophylactic and / or therapeutic agent for solid cancer comprising a hydroxamic acid derivative represented by the formula (I), a nontoxic salt thereof or a prodrug thereof as an active ingredient. 2. Solid cancers include brain, head and neck, thyroid, esophagus, stomach, colon (rectum), liver, gallbladder, bile duct, kidney, lung, breast, cervix, uterine cancer , Ovarian cancer, prostate cancer, testicular tumor, bladder cancer, renal pelvis / ureteral tumor, adrenal cancer, neuronal tumor, glioma, bone tumor, rhabdomyosarcoma, osteosarcoma, soft tissue sarcoma, eosinophilic granuloma, malignant black 2. The preventive and / or therapeutic agent for solid cancer according to claim 1, which is a chromoma, skin cancer, glioblastoma, or Wilms tumor. 3.1) (R) 1-N- (1-methoxy-1-methyl) ethoxy-6- (4- (4-ethylethylaminophenyl) phenyl) 1-6-hydroxyhexanamide, 2) (R) — N— (1-methoxy-1-methyl) ethoxy-6 _ (4- (4- (2- getylaminoethoxy) phenyl) phenyl) 1-6-hydroxyhexanamide,  3) (R) 1-N-hydroxy-6- (4- (4-methylethylaminophenyl) phenyl) 1-hydroxyhexanamide, or 4) (R) 1 N-Hydroxy-6- (4-1 (4- (2-Gethylaminoethoxy) phenyl) phenyl) -6-Hydroxyhexamide, their non-toxic salts or their prodrugs.